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Synacthen Ampoules 250mcg


1. Name Of The Medicinal Product

Synacthen® Ampoules 250mcg

2. Qualitative And Quantitative Composition

Tetracosactide acetate PhEur 250micrograms per ampoule.

3. Pharmaceutical Form

A clear colourless sterile solution in a clear glass ampoule.

4. Clinical Particulars 4.1 Therapeutic Indications

Diagnostic test for the investigation of adrenocortical insufficiency.

4.2 Posology And Method Of Administration

Adults: This preparation of Synacthen is intended for administration for diagnostic purposes only as a single intramuscular or intravenous dose; it is not to be used for repeated therapeutic administration.

The 30-minute Synacthen diagnostic test: This test is based on measurement of the plasma cortisol concentration immediately before and exactly 30 minutes after an intramuscular or intravenous injection of 250micrograms (1ml) Synacthen. Adrenocortical function can be regarded as normal if the post-injection rise in plasma cortisol concentration amounts to at least 200nmol/litre (70micrograms/litre).

Where the 30-minute test has yielded inconclusive results, or where it is desired to determine the functional reserve of the adrenal cortex, a 5-hour test can be performed with Synacthen Depot (see separate Summary of Product Characteristics). Furthermore, a 3-day test with Synacthen Depot may be used to differentiate between primary and secondary adrenocortical insufficiency.

Children: An intravenous dose of 250micrograms/1.73m? body surface area has been suggested. Thus for children aged 5 to 7 years, approximately half the adult dose will be adequate. For more accurate dosing of other ages, standard body surface area tables should be consulted.

Elderly: There is no evidence to suggest that dosage should be different in the elderly.

4.3 Contraindications

History of hypersensitivity to ACTH, Synacthen or Synacthen Depot. Synacthen is contra-indicated in patients with allergic disorders (e.g. asthma).

4.4 Special Warnings And Precautions For Use

Before using Synacthen, the doctor should make every effort to find out whether the patient is suffering from, or has a history of, allergic disorders (see Section 4.3 “Contra-indications”). In particular, he should enquire whether the patient has previously experienced adverse reactions to ACTH, Synacthen or other drugs.

Synacthen should only be administered under the supervision of appropriate senior hospital medical staff (e.g. consultants).

If local or systemic hypersensitivity reactions occur after the injection (for example, marked redness and pain at the injection site, urticaria, pruritus, flushing, faintness or dyspnoea), Synacthen or other ACTH preparations should be avoided in the future. Hypersensitivity reactions tend to occur within 30 minutes of an injection. The patient should therefore be kept under observation during this time.

Preparation should be made in advance to combat any anaphylactic reaction that may occur after an injection of Synacthen. In the event of a serious anaphylactic reaction occurring, the following measures must be taken immediately: administer adrenaline (0.4 to 1ml of a 0.1% solution intramuscularly or 0.1 to 0.2ml of a 0.1% solution in 10ml physiological saline slowly intravenously) as well as a large intravenous dose of a corticosteroid (for example 100mg to 500mg hydrocortisone, three or four times in 24 hours), repeating the dose if necessary.

The hydrocortisone product information prepared by the manufacturer should also be consulted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

The Synacthen test should not be utilised during pregnancy and lactation unless there are compelling reasons for doing so.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness.

4.8 Undesirable Effects

Hypersensitivity reactions:

Synacthen may provoke hypersensitivity reactions. In patients suffering from, or susceptible to, allergic disorders (especially asthma) this may take the form of anaphylactic shock (see Section 4.3 “Contra-indications”).

Hypersensitivity may be manifested as skin reactions at the injection site, dizziness, nausea, vomiting, urticaria, pruritus, flushing, malaise, dyspnoea, angioneurotic oedema and Quinke's oedema.

Other side effects are unlikely to be observed with short-term use of Synacthen as a diagnostic tool. Should information be required on the side effects reported with therapeutic use of tetracosactide acetate, see Synacthen Depot Summary of Product Characteristics.

4.9 Overdose

Overdosage is unlikely to be a problem when the product is used as a single dose for diagnostic purposes.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Tetracosactide acetate consists of the first 24 amino acids occurring in the natural corticotropic hormone (ACTH) sequence and displays the same physiological properties as ACTH. In the adrenal cortex, it stimulates the biosynthesis of glucocorticoids, mineralocorticoids, and, to a lesser extent androgens.

The site of action of ACTH is the plasma membrane of the adrenocortical cells, where it binds to a specific receptor. The hormone-receptor complex activates adenylate cyclase, stimulating the production of cyclic AMP (adenosine monophosphate) and so promoting the synthesis of pregnenolone from cholesterol. From pregnenolone the various corticosteroids are produced via different enzymatic pathways.

5.2 Pharmacokinetic Properties

Following an intravenous injection, elimination of tetracosactide acetate from the plasma consists of 3 phases. The half-lives of these phases are approximately 7 minutes (0 to 1 hour), 37 minutes (1 to 2 hours) and 3 hours thereafter.

Tetracosactide acetate has an apparent volume of distribution of approximately 0.4L/kg.

In the serum, tetracosactide acetate is broken down by serum endopeptidases into inactive oligopeptides and then by aminopeptidases into free amino acids. The rapid elimination from plasma is probably not attributable to this relatively slow cleavage process, but rather to the rapid concentration of the active substance in the adrenal glands and kidneys.

Following an iv dose of 131I-labelled tetracosactide acetate, 95 to 100% of the radioactivity is excreted in the urine within 24 hours.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber, which are additional to those already included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Acetic acid, sodium acetate, sodium chloride and water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Synacthen should be protected from light and stored in a refrigerator (2 - 8°C).

6.5 Nature And Contents Of Container

The ampoules are colourless glass PhEur type I. Five ampoules are packed in a cardboard box.

6.6 Special Precautions For Disposal And Other Handling

Shake well before use.

Administrative Data 7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL 16853/0017

9. Date Of First Authorisation/Renewal Of The Authorisation

25 June 1998

10. Date Of Revision Of The Text

February 2005

11. Legal Status

POM

Alliance, Alliance Pharmaceuticals and associated devices are registered Trademarks of Alliance Pharmaceuticals Ltd.


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Fatty acid derivative anticonvulsants


A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Fatty acid derivative anticonvulsants appear to increase the availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. They have several mechanisms of action. They have inhibitory action against GABA transaminase, which breaksdown GABA. This leads to increased concentration of GABA in the synapses. Other proposed mechanisms of action that account for their anticonvulsant properties is they either enhance the action of GABA or mimic its action at postsynaptic receptor sites. They also block voltage gated sodium channels and T-type calcium channels, and cause inhibitory activity in the brain.

Fatty acid derivatives are broad-spectrum anticonvulsant drugs, which are effective against most types of seizures. They can be used to treat absence seizures, tonic-clonic seizures, juvenile myoclonic epilepsy and complex partial seizures.

See also

Medical conditions associated with fatty acid derivative anticonvulsants:

Bipolar Disorder Epilepsy Hyperekplexia Mania Migraine Prevention Schizoaffective Disorder Seizure Prevention Seizures Drug List: Stavzor Depakote-Er-Extended-Release-Tablets Depakote Depakote-Sprinkles Depakene Depacon
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Boots Wind Relief Tablets


1. Name Of The Medicinal Product

Indigestion Relief Tablets, Double Action Indigestion Tablets, Antacid Plus Tablets, Gastricalm Tablets, Boots Wind Relief Tablets

2. Qualitative And Quantitative Composition

Active ingredient

Quantity/Unit dose

Dried Aluminium Hydroxide Gel EP

351 mg

(equivalent to 170mg aluminium oxide)

 

 

Magnesium hydroxide EP

164 mg

Simethicone HSE or Silicone Antifoam M HSE

25 mg

(activated methylpolysiloxane)

 

 

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars 4.1 Therapeutic Indications

For relief from discomfort of painful wind, indigestion, heartburn and excess acidity.

4.2 Posology And Method Of Administration

For oral administration.

Adults and children over 12 years: One or two tablets to be sucked or chewed after meals, at bedtime or whenever discomfort is felt.

Children 5 to 12 years: One tablet to be sucked or chewed after meals, at bedtime or whenever discomfort is felt.

Children under 5 years: Not recommended.

Elderly: There is no need for dosage reduction in the elderly.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

Hypophosphataemia.

4.4 Special Warnings And Precautions For Use

This product should be used with caution in patients with impaired renal function.

If symptoms persist for more than 5 days, consult your doctor.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

This product may interfere with the absorption of tetracyclines, chloroquine, penicillamine, phenothiazines and quinolone antibacterials, when these are given concomitantly.

4.6 Pregnancy And Lactation

There are no adequate human data from the use of aluminium hydroxide and magnesium hydroxide in pregnant women. Studies in animals have not been done. No data are available to suggest any harmful effects in pregnant women, associated with simethicone. Caution should therefore be exercised when taken by pregnant women.

Although some aluminium and magnesium may be secreted in breast mild, the concentration is too small to be harmful. Secretion of simethicone in the breast milk of nursing mothers has not been established but would be most unlikely

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

May occasionally cause diarrhoea or constipation, although the combination of magnesium and aluminium salts minimises these gastrointestinal effects.

4.9 Overdose

Symptoms of overdosage include nausea, vomiting, gastrointestinal irritation, diarrhoea/constipation. Treatment should be symptomatic and supportive.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Aluminium hydroxide and magnesium hydroxide have antacid properties and are used to neutralise gastric acid. Activated methylpolysiloxane (simethicone) has anti-foaming/deflatulent activity by virtue of its ability to change the surface tension of gas bubbles, thereby causing them to coalesce.

5.2 Pharmacokinetic Properties

Magnesium hydroxide reacts with hydrochloric acid in the stomach to produce magnesium chloride. Small amounts of magnesium salts may be absorbed and excreted in the urine, otherwise excretion if via the faeces.

Aluminium hydroxide reacts with hydrochloric acid in the stomach to form aluminium chloride, some of which is absorbed. Absorbed aluminium is eliminated in the urine. The majority of aluminium remains in the gastrointestinal tract and forms insoluble poorly absorbed aluminium salts including hydroxide, phosphate, carbonate and fatty acid derivatives, which are excreted in the faeces.

There is no date availability on the pharmacokinetics of activated methylpolysiloxane.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sorbitol pdr

Maize starch pdr

Povidone

Isopropyl alcohol

Icing sugar

Magnesium stearate

Peppermint oil Black leaf

Microcrystalline cellulose

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

PVC/PVDC blister heat sealed to aluminium foil.

Pack sizes: 12, 24, 36, 48

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 00014/0287

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 15 October 1982

Date of last renewal: 15 December 1992

10. Date Of Revision Of The Text

February 2004


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Carnitor 1 g Solution for Injection


1. Name Of The Medicinal Product

Carnitor 1 g Solution for Injection

2. Qualitative And Quantitative Composition

L-carnitine inner salt 1 g

3. Pharmaceutical Form

A clear, colourless or light straw- coloured solution

4. Clinical Particulars 4.1 Therapeutic Indications

Indicated for the treatment of primary and secondary carnitine deficiency in adults, children, infants and neonates.

Secondary carnitine deficiency in haemodialysis patients.

Secondary carnitine deficiency should be suspected in long-term haemodialysis patients who have the following conditions:

1. Severe and persistent muscle cramps and/or hypotensive episodes during dialysis.

2. Lack of energy causing a significant negative effect on the quality of life.

3. Skeletal muscle weakness and/or myopathy.

4. Cardiomyopathy.

5. Anaemia of uraemia unresponsive to or requiring large doses of erythropoietin.

6. Muscle mass loss caused by malnutrition.

4.2 Posology And Method Of Administration

For slow intravenous administration over 2-3 minutes

Adults, Children, infants and neonates

It is advisable to monitor therapy by measuring free and acyl carnitine levels in both plasma and urine.

The management of inborn errors of metabolism:

The dosage required depends upon the specific inborn error of metabolism concerned and the severity of presentation at the time of treatment. However, the following can be considered as a general guide.

In acute decompensation, dosages of up to 100 mg/kg/day in 3-4 divided doses are recommended. Higher doses have been used although an increase in adverse events, primarily diarrhoea, may occur.

Secondary carnitine deficiency in haemodialysis patients:

It is strongly recommended that, before initiating therapy with Carnitor, plasma carnitine is measured. Secondary carnitine deficiency is suggested by a plasma ratio of acyl to free carnitine of greater than 0.4 and/or when free carnitine concentrations are lower than 20 ?mol/litre.

A dose of 20mg per kg should be administered as an intravenous bolus at the end of each dialysis session (assuming three sessions per week). The duration of intravenous treatment should be at least three months, which is the time usually required to restore normal muscle levels of free carnitine. The overall response should be assessed by monitoring plasma acyl to free carnitine levels and by evaluating the patient's symptoms. When carnitine supplementation has been stopped there will be a progressive decline in carnitine levels. The need for a repeat course of therapy can be assessed by plasma carnitine assays at regular intervals and by monitoring the patient's symptoms.

Haemodialysis - maintenance therapy:

If significant clinical benefit has been gained by the first course of intravenous Carnitor then maintenance therapy can be considered using 1 g per day of Carnitor orally. On the day of the dialysis, oral Carnitor has to be administered at the end of the session.

4.3 Contraindications

Hypersensitivity to any of the constituents of the product.

4.4 Special Warnings And Precautions For Use

While improving glucose utilisation, the administration of L-carnitine to diabetic patients receiving either insulin or hypoglycaemic oral treatment may result in hypoglycaemia. Plasma glucose levels in these subjects must be monitored regularly in order to adjust the hypoglycaemic treatment immediately, if required.

The safety and efficacy of oral L-carnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral L-carnitine in patients with severely compromised renal function or in end stage renal disease (ESRD) patients on dialysis may result in an accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are usually excreted in the urine. This situation has not been observed following intravenous administration of L-carnitine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no known interactions.

4.6 Pregnancy And Lactation

Reproductive studies were performed in rats and rabbits. There was no evidence of a teratogenic effect in either species. In the rabbit but not in the rat, there was a statistically insignificant greater number of post implantation losses at the highest dose tested (600 mg/kg daily) as compared with control animals. The significance of these findings for man is unknown. There is no experience of use in pregnant patients with primary systemic carnitine deficiency.

Taking into account the serious consequences to a pregnant woman who has primary systemic carnitine deficiency stopping treatment, the risk to the mother of discontinuing treatment seems greater than the theoretical risk to the foetus if treatment is continued.

Levocarnitine is a normal component of human milk. Use of levocarnitine supplementation in nursing mothers has not been studied.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Various mild gastro-intestinal complaints have been reported during the long-term administration of oral levocarnitine, these include transient nausea and vomiting, abdominal cramps and diarrhoea.

Decreasing the dosage often diminishes or eliminates drug-related patient body odour or gastro-intestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration and after any dosage increase.

4.9 Overdose

There have been no reports of toxicity from levocarnitine overdosage. Overdosage should be treated with supportive care.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: A16AA01 (Amino acids and derivatives)

L-Carnitine is present as a natural constituent in animal tissues, micro-organisms and plants. In man the physiological metabolic requirements are met both by the consumption of food containing carnitine and the endogenous synthesis in the liver and kidneys from lysine with methionine serving as the methyl donor. Only the L-isomer is biologically active, playing an essential role in lipid metabolism as well as in the metabolism of ketone bodies as branched chain-amino-acids. L-Carnitine as a factor is necessary in the transport of long-chain fatty acids into the mitochondria – facilitating the oxidation of fatty acids rather than their incorporation into triglycerides. By releasing CoA from its thioesters, through the action of CoA; carnitine acetyl transferase, L-carnitine also enhances the metabolic flux in the Kreb's cycle; with the same mechanism it stimulates the activity of pyruvate dehydrogenase and in skeletal muscle, the oxidation of branched chain-amino acids. L-Carnitine is thus involved, directly or indirectly in several pathways so that its availability should be an important factor controlling not only the oxidative utilisation of fatty acids and ketone bodies but also that of glucose and some amino acids.

5.2 Pharmacokinetic Properties

The absorbed L-carnitine is transported to various organ systems via the blood. The presence of membrane-bound proteins in several tissues including red blood cells that bind carnitine, suggest that a transport system in the blood and a cellular system for the collective uptake is present in several tissues. Tissue and serum carnitine concentration depends on several metabolic processes, carnitine biosynthesis and dietary contributions, transport into and out of tissues, degradation and excretion may all affect tissue carnitine concentrations.

Absorption

L-Carnitine is absorbed by the mucosal cells of the small intestine and enters the blood stream relatively slowly; the absorption is probably associated with an active transluminal mechanism.

The apparent systemic availability after oral administration is limited (<10%) and variable.

Distribution

Absorbed L-carnitine is transported to various organ systems via the blood; it is thought that a transport system in the blood and a cellular system for selective uptake is involved.

Excretion

L-Carnitine is excreted mainly in the urine and is variable. The excretion is directly proportional to the blood levels.

Metabolism

L-Carnitine is metabolised to a very limited extent.

5.3 Preclinical Safety Data

L-Carnitine is a naturally occurring body substance in human beings, plants and animals. Carnitor products are used to bring the level of L-carnitine in the body up to those found naturally. Appropriate pre-clinical studies have been undertaken and show no signs of toxicity at normal therapeutic doses.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Hydrochloric acid 10%

Water for injection

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Store below 25oC.

Store in the original carton in order to protect from light.

6.5 Nature And Contents Of Container

Ph.Eur. Type 1 clear glass ampoules of 5 ml capacity.

The ampoules are packed in cardboard outer cartons containing 5 ampoules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sigma-Tau Industrie Farmaceutiche Riunite SpA,

Viale Shakespeare 47-00144,

Rome, Italy.

8. Marketing Authorisation Number(S)

PL 08381/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

30 November 1999

10. Date Of Revision Of The Text

November 2008


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Salactol Collodion


1. Name Of The Medicinal Product

SALACTOL™ COLLODION

2. Qualitative And Quantitative Composition

Salicylic Acid 16.7% w/w; Lactic Acid 16.7% w/w.

3. Pharmaceutical Form

Colourless or pale yellow/brown evaporative collodion paint.

4. Clinical Particulars 4.1 Therapeutic Indications

For the topical treatment of warts, verrucas, corns and calluses.

4.2 Posology And Method Of Administration

For adults, children and the elderly. Salactol should be applied once daily usually at night. It can take up to twelve (12) weeks for resistant lesions to disappear, and it is necessary to persevere with the treatment. Soak the affected site in warm water and pat dry. Gently rub the surface of the wart, verruca, corn or callus with a pumice stone or manicure emery board to remove any hard skin. Using the applicator provided, carefully apply a few drops of Salactol to the lesion, allowing each drop to dry before applying the next one. Take care to localise the application to the affected area. Plantar warts should be covered with an adhesive plaster. Leave for 24 hours. Repeat the procedure daily, after first removing any plaster.

4.3 Contraindications

Not to be used on or near the face, intertriginous or anogenital regions or by diabetics or individuals with impaired peripheral blood circulation. Not to be used on moles, birthmarks, hairy warts or on any other skin lesions for which Salactol is not indicated. Not to be used in cases of sensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Keep away from the eyes and mucous membranes. The gel should be applied carefully to the wart, verruca, corn or callus only, to avoid possible irritation of surrounding normal skin. Some mild, transient irritation may be expected, but in cases of more severe or persistent pain/irritation, the treatment should be suspended and/or discontinued. See also Section 4.8. Extremely flammable. Avoid spillage. Avoid inhaling vapour. Replace cap tightly after use.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No special precautions.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Salactol may be irritant in certain patients, which in rare instances may appear as a temporary blemish on the skin. See also Section 4.4.

4.9 Overdose

Any excessive use of Salactol could cause irritation of the skin. If this occurs, Salactol should be used more sparingly or applied less frequently. Accidental oral ingestion should be treated immediately by gastric lavage with a 2 to 5% aqueous sodium bicarbonate solution. Fluid and electrolyte balance should be monitored and appropriate supportive measures should be provided. Symptoms include headache, nausea, vomiting, diarrhoea and respiratory depression.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

The combination of salicylic acid and lactic acid in flexible collodion has been shown to be particularly efficacious in treating warts, verrucas, corns and calluses.

Salicylic acid has bacteriostatic and fungicidal actions as well as keratolytic properties. Its effectiveness for topical treatment of hyperkeratotic skin lesions is based on mild keratolytic action which produces slow and painless destruction of the epithelium. In the treatment of warts, a mild irritant reaction, which may render the virus more prone to immunologic stimulation or response, may add to the mechanical removal of infected cells. Apart from its antiseptic and caustic properties, lactic acid enhances the availability of salicylic acid from the dried collodion.

5.2 Pharmacokinetic Properties

Salactol contains 16.7% salicylic acid and 16.7% lactic acid in flexible collodion. The bioavailability of salicylic acid is reduced as the collodion film dries on the skin due to entrapment of the drug which inhibits release. The addition of lactic acid to salicylic acid collodion provides more efficient release of the salicylic acid, since the non-volatile lactic acid remains in the film, thus permitting continued release of the keratolytic which may otherwise be entrapped within the dried collodion film. Systemic absorption of salicylic acid or lactic acid after application to small circumscribed areas is exceedingly unlikely.

5.3 Preclinical Safety Data

No special information.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Pyroxylin; Colophony; Castor Oil; IMS; Ether.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

10 ml amber glass bottle with plastic cap, incorporating a specially designed spatula for ease of application. This is supplied as an original pack (OP).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dermal Laboratories

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

00173/5006R.

9. Date Of First Authorisation/Renewal Of The Authorisation

2 May 2006.

10. Date Of Revision Of The Text

June 2011.


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ZAMADOL 24hr 150 (200 / 300 / 400)mg TABLETS


1. Name Of The Medicinal Product

ZAMADOL 24hr 150 (200/300/400) mg prolonged release tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 150 (200/300/400) mg of tramadol hydrochloride

Excipient: Each prolonged-release tablet contains 0.60 (1.00/1.40/1.80) mg lactose monohydrate (see section 4.4).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release tablet

White film coated tablets marked T 150 (200/300/400)

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of moderate to severe pain.

4.2 Posology And Method Of Administration

ZAMADOL 24hr tablets should be taken at 24-hourly intervals and must be swallowed whole and not chewed.

As with all analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the clinical response of the individual patient. The correct dosage for any individual patient is that which controls the pain with no or tolerable side effects for a full 24 hours. Patients transferring from immediate release tramadol preparations should have their total daily dose calculated, and start on the nearest dose in the ZAMADOL 24hr range. It is recommended that patients are slowly titrated to higher doses to minimise transient side effects. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported. (See Section 4.4 Special Warnings and Precautions for Use).A total daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Adults and children over 12 years: The usual initial dose is one 150 mg tablet daily. If pain relief is not achieved, the dosage should be titrated upwards until pain relief is achieved.

Elderly patients: Dosing as for adults. The elimination half-life of tramadol may be prolonged in patients over 75 years . A starting dose of 150 mg daily is recommended. Dose titration upwards should be carefully monitored.

Patients with renal or hepatic insufficiency: The elimination half-life of tramadol may be prolonged in these patient populations. A starting dose of 150 mg daily is recommended. Dose titration upwards should be carefully monitored. Tramadol is not recommended for patients with severe renal impairment and/or severe hepatic impairment.

As tramadol is only removed very slowly by haemodialysis or by haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

Children under 12 years: ZAMADOL 24hr has not been studied in children. Safety and efficacy of ZAMADOL 24hr have not been established and the product should not be used in children.

4.3 Contraindications

Hypersensitivity to tramadol or to any of the excipients; acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.

Tramadol must not be used for narcotic withdrawal treatment.

4.4 Special Warnings And Precautions For Use

Warnings

At therapeutic doses withdrawal symptoms have been reported at a frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential the clinical need for continued analgesic treatment should be reviewed regularly.

In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.

Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Precautions

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold. (See Section 4.5 Interactions with other Medicaments and other forms of Interaction).

Tramadol should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses respiratory depression has infrequently been reported.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of tramadol with other centrally acting drugs, including alcohol, may potentiate CNS depressant effects.

Simultaneous treatment with carbamazepine may shorten the analgesic effect as a result of a reduction in serum levels of tramadol and its active metabolite.

Co-administration with cimetidine is associated with a small prolongation of the half-life of tramadol, but this is not clinically relevant.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors (SSRIs), tricyclic anti-depressants (TCAs), anti-psychotics and other seizure threshold lowering drugs to cause convulsions (see Section 4.4 Special Warnings and Special Precautions for Use and 5.2 Pharmacokinetic Properties). Co-administration with SSRIs may lead to an increase of 5HT associated effects.

Co-administered ritonavir may increase serum concentration of tramadol resulting in tramadol toxicity.

Digoxin toxicity has occurred rarely during co-administration of digoxin and tramadol.

MAO inhibitors: A serotoninergic syndrome is likely to occur: diarrhoea, tachycardia, sweating, tremor, confusion, coma. In case of recent treatment with MAOIs, treatment with tramadol should not be started until 15 days after cessation of treatment with MAOIs.

Other morphine derivatives (including anti-tussives, substitution treatments), benzodiazepines, barbiturates: Increased risk of respiratory depression, that may be fatal in overdosage.

Mixed agonists/antagonists (eg buprenorphine, nalbuphine, pentazocine): The analgesic effect of tramadol which is a pure agonist may be reduced, and a withdrawal syndrome may occur.

There have been isolated reports of interaction with coumarin anticoagulants resulting in an increased INR and so care should be taken when commencing treatment with tramadol in patients on anticoagulants.

The analgesic effect of tramadol is in part mediated by inhibition of the re-uptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirements of tramadol in patients with postoperative pain.

4.6 Pregnancy And Lactation

There are no adequate data from the use of tramadol in pregnant women. Animal studies have shown reproductive toxicity, but not teratogenic effects (see section 5.3). Tramadol crosses the placental barrier and chronic use during pregnancy can cause withdrawal symptoms in the new-born baby. Therefore, it should not be used during pregnancy.

Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in respiratory rate which are not usually clinically relevant.

During lactation very small amounts of tramadol and its metabolites (approximately 0.1% of an intravenous dose) are found in human breast milk. Therefore tramadol should not be administered during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Tramadol may cause drowsiness, blurred vision and dizziness which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.

4.8 Undesirable Effects

The following frequency categories form the basis for classification of the undesirable effects:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000) not known (cannot be estimated from the available data)

 

Very Common

Common

Uncommon

Rare

Very Rare

Immune system disorders

 

 

 

 

 

 

Hypersensitivity

Anaphylactic reaction

 

 

Psychiatric disorders

 

 

 

 

 

 

Hallucinations

Nightmare

Mood altered

Elevated mood

Dysphoria

Decreased activity

Illusion

Agitation

Anxiety

Nervousness

Insomnia

Nervous system disorders

Dizziness

 

 

Headache

Paraesthesia

Increased activity

Cognitive disorder

Sensory disturbance

Judgement impaired

Convulsion

Hyperkinesia

Tremor

Eye disorders

 

 

 

 

 

 

Blurred vision

 

 

Cardiac disorders

 

 

 

 

Palpitations

Tachycardia

Bradycardia

 

 

Vascular disorders

 

 

 

 

Orthostatic hypotension

Circulatory collapse

Hypertension

Flushing

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Dyspnoea

Asthma

Respiratory depression

Bronchospasm

Wheezing

 

 

Gastro-intestinal disorders

Nausea

Vomiting

Dry mouth

Retching

Constipat-ion

Abdominal discomfort

Anorexia

Diarrhoea

Gastro-intestinal disorder

Hepatobiliary disorders

 

 

 

 

 

 

 

 

Hepatic enzyme increased

Skin and subcutaneous tissue disorders

 

 

Hyperhidrosis

Pruritus

Rash

Urticaria

Angioedema

 

 

Renal and urinary disorders

 

 

 

 

 

 

Micturition disorder

Dysuria

Urinary retention

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

 

 

Muscular weakness

 

 

General disorders and administration site conditions Investigations

 

 

 

 

 

 

 

 

Drug withdrawal syndrome

4.9 Overdose

Symptoms of overdosage are typical of other opioid analgesics, and include miosis, vomiting, cardiovascular collapse, sedation and coma, seizures and respiratory depression. In severe cases tramadol overdose may result in a fatal outcome.

Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.

Emptying the gastric contents is useful to remove any unabsorbed drug, particularly when a modified release formulation has been taken.

5. Pharmacological Properties

Pharmacotherapeutic group: N02A X02

5.1 Pharmacodynamic Properties

Tramadol is a centrally acting analgesic (N02A X02). It is a non selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms that may contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and 5HT.

5.2 Pharmacokinetic Properties

Following oral administration of a single dose, tramadol is almost completely absorbed and the absolute bioavailability is approximately 70%. Tramadol is metabolised to O

Following administration of one ZAMADOL 24hr tablet 200 mg in the fasting state, a mean peak plasma concentration (Cmax) of 192 ng.ml-1 was attained. This was associated with a median tmax of 6 hours (range 4-8 hours). The availability of tramadol from the ZAMADOL 24hr tablet 200 mg was complete when compared with an immediate release tramadol solution 100 mg, after dose adjustment. In the presence of food, the availability and controlled release properties of ZAMADOL 24hr tablets were maintained, with no evidence of dose-dumping.

A single dose-proportionality study has confirmed a linear pharmacokinetic response (in relation to tramadol and O-desmethyltramadol) following administration of the 200 mg, 300 mg and 400 mg tablets. A steady state study has confirmed the dose adjusted bioequivalence of the 150 mg and 200 mg tablets administered once-daily. This study also confirmed that the ZAMADOL 24hr tablet 150 mg provided an equivalent peak concentration and extent of availability of tramadol to an immediate release capsule 50 mg administered 8-hourly. On this basis it is recommended that patients receiving immediate release tramadol should be transferred initially to the nearest daily dose of ZAMADOL 24hr tablets. It may be necessary to titrate the dose thereafter.

A further steady state study has demonstrated that immediate release tramadol tablets 50 mg, administered 6-hourly, provided plasma concentrations that were greater than would have been anticipated following administration of a single dose. This observation is consistent with a non-linear elimination of the drug substance. In contrast, the plasma concentrations from ZAMADOL 24hr tablet 200 mg administered once-daily were in line with single dose data, confirming that the controlled delivery of tramadol from ZAMADOL 24hr minimises the non-linearity associated with faster-releasing preparations. The more predictable plasma concentrations may lead to a more manageable dose titration process.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Studies in rats and rabbits have revealed no teratogenic effects. However, embryotoxicity was shown in the form of delayed ossification. Fertility, reproductive performance and development of offspring were unaffected.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core

Hydrogenated vegetable oil

Talc

Magnesium stearate

Film coat

Lactose Monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 4000

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30oC.

6.5 Nature And Contents Of Container

1) PVC blisters with aluminium backing foil (containing 2, 7, 10, 14, 15, 20, 28, 30, 50,56, 60 or 100 tablets).

2) Polypropylene containers with polyethylene lids (containing 2, 7, 10, 14, 15, 20, 28, 30, 50,56, 60 or 100 tablets).

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

UK

8. Marketing Authorisation Number(S)

PL 16950/0084 (85/86/87)

9. Date Of First Authorisation/Renewal Of The Authorisation

7 November 2001/19 June 2006

10. Date Of Revision Of The Text

August 2009


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Daktarin Aktiv Cream (McNeil Products Ltd)


1. Name Of The Medicinal Product

Daktarin Aktiv Cream

2. Qualitative And Quantitative Composition

Miconazole nitrate 2.0% w/w

(Each gram of cream contains 20mg of miconazole nitrate)

For excipients, see Section 6.1

3. Pharmaceutical Form

Cream

White homogeneous cream

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of athlete's foot.

4.2 Posology And Method Of Administration

For all ages.

Apply the cream twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

Method of administration: Cutaneous application.

4.3 Contraindications

Daktarin Aktiv Cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient in this product.

4.4 Special Warnings And Precautions For Use

Daktarin Aktiv Cream must not come into contact with the eyes.

If a reaction suggesting sensitivity or irritation should occur, the treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

4.6 Pregnancy And Lactation

Pregnancy

In animals, miconazole nitrate has shown no teratogenic effects but is foetotoxic at high oral doses. Only small amounts of miconazole nitrate are absorbed following topical administration. However, as with other imidazoles, miconazole nitrate should be used with caution during pregnancy.

Lactation

Topically applied miconazole is minimally absorbed into the systemic circulation, and it is not known whether miconazole is excreted in human breast milk. Caution should be exercised when using topically applied miconazole products during lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with Daktarin that meet threshold criteria are included. The adverse drug reactions are ranked by frequency, using the following convention:

Very common > 1/10

Common > 1/100 and < 1/10

Uncommon > 1/1,000 and < 1/100

Rare > 1/10,000, < 1/1,000

Very rare < 1/10,000, including isolated reports

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Immune system disorders

Very rare: anaphylactic reaction, hypersensitivity, angioneurotic edema.

Skin and subcutaneous tissue disorders

Very rare: urticaria, contact dermatitis, rash, erythema, pruritus, skin burning sensation.

General disorders and administration site conditions

Rare: application site reactions, including application site irritation.

4.9 Overdose

Symptoms

Cutaneous use: Excessive use can result in skin irritation, which usually disappears after discontinuation of therapy.

Treatment

Daktarin Aktiv Cream is intended for cutaneous use, not for oral use. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antifungals for dermatological/topical use; imidazole derivative) ATC code: D01A C02.

Miconazole is an imidazole antifungal agent and may act by interfering with the permeability of the fungal cell membrane. It possesses a wide antifungal spectrum and has some antibacterial activity.

5.2 Pharmacokinetic Properties

Absorption: There is little absorption through skin or mucous membranes when miconazole nitrate is applied topically.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of local irritation, single and repeated dose toxicity, genotoxicity, and toxicity to reproduction.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG 32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube lined with epoxyphenol resin. Cap made of white polypropylene for the 15, 30 and 70g sizes. Cap for 5g size made of high density polyethylene.

Daktarin Aktiv Cream may be supplied in packs of 5, 15, 30 and 70g.

*Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0304

9. Date Of First Authorisation/Renewal Of The Authorisation

01 July 2008

10. Date Of Revision Of The Text

10 July 2008


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Daktarin Cream (Janssen-Cilag Ltd)


1. Name Of The Medicinal Product

Daktarin Cream.

2. Qualitative And Quantitative Composition

Miconazole nitrate 2% w/w.

(Each gram of cream contains 20mg of miconazole nitrate)

For excipients, see Section 6.1

3. Pharmaceutical Form

Cream

White homogeneous cream.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of mycotic infections of the skin and nails and superinfections due to Gram-positive bacteria.

4.2 Posology And Method Of Administration

Route of administration:

Cutaneous use.

Recommended dosage:

For all ages:

Skin infections: Apply the cream twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

Nail infections: Apply the cream once or twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

4.3 Contraindications

Daktarin Cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient in this product.

4.4 Special Warnings And Precautions For Use

Daktarin Cream must not come into contact with the eyes.

If a reaction suggesting sensitivity or irritation should occur, the treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

4.6 Pregnancy And Lactation

Pregnancy

In animals miconazole nitrate has shown no teratogenic effects but is foetotoxic at high oral doses. Only small amounts of miconazole nitrate are absorbed following topical administration. However, as with other imidazoles, miconazole nitrate should be used with caution during pregnancy.

Lactation

Topically applied miconazole is minimally absorbed into the systemic circulation, and it is not known whether miconazole is excreted in human breast milk. Caution should be exercised when using topically applied miconazole products during lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with Daktarin that meet threshold criteria are included. The adverse drug reactions are ranked by frequency, using the following convention:

Very common

Common

Uncommon

Rare

Very rare <1/10,000, including isolated reports

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Immune system disorders

Very rare: anaphylactic reaction, hypersensitivity, angioneurotic edema

Skin and subcutaneous tissue disorders

Very rare: urticaria, contact dermatitis, rash, erythema, pruritus, skin burning sensation

General disorders and administration site conditions

Rare: application site reactions, including application site irritation

4.9 Overdose

Symptoms

Cutaneous use: Excessive use can result in skin irritation, which usually disappears after discontinuation of therapy.

Treatment

Daktarin Cream is intended for cutaneous use, not for oral use. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antifungals for dermatological/topical use; imidazole derivative) ATC code: D01A C02.

Miconazole nitrate is an imidazole antifungal agent and may act by interfering with the permeability of the fungal cell membrane. It possesses a wide antifungal spectrum and has some antibacterial activity.

5.2 Pharmacokinetic Properties

Absorption: There is little absorption through skin or mucous membranes when miconazole nitrate is applied topically.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of local irritation, single and repeated dose toxicity, genotoxicity, and toxicity to reproduction.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG-32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube inner lined with heat polymerised epoxy-phenol resin with a white polypropylene cap containing 15 g, 30 g or 70 g* of cream, or aluminium tube inner lined with heat polymerised epoxy-phenol resin with a high density polyethylene cap containing 5 g of cream.

*Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd,

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0016

9. Date Of First Authorisation/Renewal Of The Authorisation

13 May 1974 / 08 December 2008

10. Date Of Revision Of The Text

08 December 2008


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Quinidine Gluconate


Class: Class Ia Antiarrhythmics
Note: This monograph also contains information on Quinidine Sulfate
VA Class: CV300
CAS Number: 7054-25-3

Mortality

In many antiarrhythmic drug trials for non-life-threatening arrhythmias, active antiarrhythmic drug therapy was associated with increased mortality.163 167 168 169 170

Risk associated with antiarrhythmic drug therapy probably is greatest in patients with structural heart disease.163 167 168 169 170

A meta-analysis of data from several randomized, controlled studies in patients with atrial flutter and fibrillation indicates that quinidine therapy may be associated with a mortality rate >3 times higher than that associated with placebo.163 167 168 169 170

A meta-analysis in patients with various non-life-threatening ventricular arrhythmias showed mortality associated with quinidine was consistently greater than that associated with various other antiarrhythmic agents (i.e., flecainide, mexiletine, propafenone, tocainide).163 167 168 169 170

Introduction

Antiarrhythmic agent (class IA); antimalarial.119 161 163 167 168 169 170

Uses for Quinidine Gluconate

Comparably effective to procainamide for atrial or ventricular arrhythmias; choice based on pharmacokinetics and adverse effect profile.b

Supraventricular Tachyarrhythmias

Used principally for prophylactic therapy to maintain normal sinus rhythm after conversion of atrial fibrillation and/or flutter by other means.b

Abnormal ventricular rate and CHF should first be controlled by administration of digoxin.b Electrical cardioversion usually is considered the treatment of choice for conversion of atrial fibrillation or flutter.b

Prevention of recurrence of atrial fibrillation or flutter is controversial because mortality may increase despite recurrence suppression.b

May maintain normal sinus rhythm for long periods in recent onset of atrial fibrillation or flutter without CHF, atrial enlargement, or left ventricular hypertrophy, but long-standing atrial fibrillation is likely to recur even with quinidine maintenance therapy.b

Generally, quinidine should not be used prophylactically for atrial fibrillation if the ventricular rate is adequately controlled by digoxin and the patient is asymptomatic.b

Treatment of paroxysmal atrial tachycardia or paroxysmal AV junctional rhythm.b

Atrial Premature Complexes

Treatment of atrial premature complexes; however, these arrhythmias usually are treated with digoxin.b

Ventricular Premature Complexes (VPCs)

Treatment of VPCs; however, parenteral lidocaine is considered the drug of choice because quinidine can decrease myocardial contractility.b

Like other antiarrhythmic drugs, not shown to decrease mortality rate in VPCs associated with AMI.b

Avoid in treatment of asymptomatic VPCs.b

Not for treatment of cardiac glycoside-induced ventricular arrhythmias.b

VT

Treatment of paroxysmal VT that is not associated with complete heart block; however, treatment with cardioversion or lidocaine usually is preferred.b

Suppression and prevention of recurrent ventricular arrhythmias (e.g., sustained VT) that in the judgment of the clinician are life-threatening.b

Because of arrhythmogenic potential and the lack of evidence for improved survival for class I antiarrhythmic agents,146 147 not recommended for less severe VTs; avoid treatment in asymptomatic VPCs.b

Malaria

Treatment of severe, life-threatening malaria caused by Plasmodium falciparum.101 102 104 105 119 122 124 126 142 153 158 162 Drug of choice for initial treatment of severe malaria.101 126 142 153 154 158 162

Severe malaria usually is caused by P. falciparum and requires initial aggressive treatment with a parenteral antimalarial regimen initiated as soon as possible after diagnosis.158 162 Exchange transfusions can be considered if parasitemia is >10% or patient has cerebral malaria, altered mental status, non-volume-overload pulmonary edema, or renal complications.158 162

For initial treatment of severe malaria in adults or children, CDC recommends a regimen of IV quinidine gluconate in conjunction with doxycycline, tetracycline, or clindamycin (oral or IV as tolerated).158 162 After at least 24 hours and when parasitemia is reduced to <1% and an oral regimen can be tolerated, IV quinidine gluconate can be discontinued and oral quinine sulfate initiated to complete 3 or 7 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (3 days if malaria acquired in Africa or South America or 7 days if acquired in Southeast Asia).158 162

Because of potentially fatal consequences of delays in initiating treatment of severe malaria, institutional pharmacy services should be aware of the essential role of ready availability of IV quinidine gluconate.142 143 153 158 (See Availability for Use in Treatment of Severe Malaria under Cautions.)

When IV quinidine gluconate is unavailable or cannot be used because of intolerance or contraindications, parasitemia is high or has not responded to quinidine gluconate therapy, and a parenteral regimen is indicated, IV artesunate is available from CDC under an investigational new drug (IND) protocol for the treatment of severe malaria.158 162 171 172 WHO and other clinicians recommend artesunate as a drug of choice for the treatment of severe malaria.101 173

Although oral quinidine sulfate has been used for the treatment of malaria,167 170 including uncomplicated malaria† caused by multidrug-resistant P. falciparum,102 104 108 109 110 112 oral quinine sulfate is not included in CDC recommendations for treatment of uncomplicated or severe P. falciparum malaria.158 162

Assistance with diagnosis or treatment of malaria and assistance obtaining IV quinidine gluconate or IV artesunate for treatment of severe malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.158 162 171 172

Quinidine Gluconate Dosage and Administration General Arrhythmias

Initiate quinidine or adjust quinidine dosage in a setting where facilities and personnel for patient monitoring and resuscitation are continuously available, especially if used in patients with known structural heart disease or other risk factors for toxicity.163 167 168 169 170

ECG monitoring of cardiac function and determination of plasma concentrations are recommended, especially when given IV or when >2 g is administered orally daily, and in patients with an increased risk of adverse reactions to quinidine (e.g., severe heart disease, hypotension, hepatic or renal disease).b

Use for conversion of atrial fibrillation/flutter only after alternative measures (e.g., use of other drugs to control ventricular rate) have been inadequate.163 167 168 169 170 Discontinue quinidine if sinus rhythm is not restored within a reasonable amount of time.119 163 167 168 169 170

Discontinue quinidine and consider other means of conversion if QRS complex widens to 130% of its pretreatment duration, QTc interval widens to 130% of its pretreatment duration and is >500 milliseconds, P waves disappear, or patient develops clinically important tachycardia, symptomatic bradycardia, or hypotension.119 163 167 168 169 170

Malaria

Initiate IV quinidine gluconate regimen as soon as possible after severe P. falciparum malaria is diagnosed.158 162 CDC recommends the regimen be initiated in patients with strong clinical evidence of severe malaria, even if initial blood smears do not demonstrate parasitemia or indicate P. vivax, P. ovale, or P. malariae infection.158

CDC and others recommend the IV quinidine gluconate regimen be administered in an intensive care facility with close monitoring.101 111 122 123 124 125 126 141 153 158

Monitor BP, plasma quinidine concentrations, and ECG closely and monitor blood glucose periodically in patients receiving quinidine for treatment of malaria; adjust dosage accordingly.101 102 104 111 141 158 162

Because most deaths from severe malaria occur within the first 24–48 hours of illness, an initial loading dose is used to attain therapeutic plasma concentrations rapidly during this critical period of elevated parasitemia.158 A loading dose should not be used if patient received >40 mg/kg of quinine in the previous 48 hours or received mefloquine in the previous 12 hours.158

Calculate loading dose and infusion rate carefully to prevent acute cardiac events.153 Consider that the risk of serious ventricular arrhythmias associated with quinidine is increased by bradycardia, hypokalemia, hypomagnesemia, and concomitant use of drugs that can prolong QT interval (e.g., halofantrine [an antimalarial drug not commercially available in the US], mefloquine, quinine).101 153 158

CDC recommends consultation with a cardiologist and a clinician with experience in treating malaria.153 158 162 A cardiologist may be helpful if attempting to resume IV infusion of quinidine gluconate in patients who develop prolongation of QT interval or hypotension during treatment.153

Administration

Administer quinidine sulfate orally.163 167 Administer quinidine gluconate orally168 169 or by IV infusion.119

IM administration of quinidine gluconate is not recommended because absorption may vary depending on the patient’s peripheral perfusion.119

Oral Administration

Administer quinidine sulfate orally as conventional167 170 or extended-release tablets.163

Administer quinidine gluconate orally as extended-release tablets.168 169

May be administered with food or antacids to decrease adverse GI effects.b Avoid grapefruit juice.156 163 168 169 (See Specific Drugs and Foods under Interactions.)

To determine possible idiosyncrasy to quinidine, administer a test dose of 200 mg of quinidine sulfate orally several hours before initiating full dosage.b For children, the test dose for idiosyncrasy is 2 mg/kg (up to 200 mg) of quinidine sulfate orally.164 b

Extended-release Tablets

Used principally for maintenance therapy in the management of arrhythmias.b

Quinidine gluconate extended-release tablets may be broken in half in order to titrate dosage; however, do not chew or crush.168 169

IV Administration

Arrhythmias: Administer by IV infusion.119

Malaria: Administer by continuous or intermittent IV infusion.101 102 104 111 119 122 123 124 125 158 162

Dilution

Arrhythmias: Dilute contents of multiple-dose vial containing 800 mg of quinidine gluconate (10 mL of 80-mg/mL injection) in 40 mL of 5% dextrose injection to provide solution containing 16 mg/mL.119

Malaria (continuous IV infusion regimen): Dilute loading dose of 6.25 mg/kg of quinidine (10 mg/kg of quinidine gluconate)101 119 141 153 158 in approximately 5 mL/kg of 0.9% sodium chloride injection.119

Malaria (intermittent IV infusion regimen): Dilute loading dose of 15 mg/kg of quinidine (24 mg/kg of quinidine gluconate)119 153 158 in 250 mL of 0.9% sodium chloride injection.119

Rate of Administration

Minimize length of IV tubing because of quinidine adsorption to PVC tubing.119 (See Compatibility under Stability.)

Overly rapid IV administration can cause potentially severe cardiovascular effects.119 (See IV Administration under Cautions.)

Arrhythmias: Up to 0.25 mg/kg per minute (i.e., about 1 mL/kg per hour of 16-mg/mL dilution).119

Malaria (continuous IV infusion regimen): Give loading dose of 6.25 mg/kg of quinidine (10 mg/kg of quinidine gluconate) by IV infusion over 1–2 hours, followed by continuous IV infusions given at a rate of 12.5 mcg/kg of quinidine per minute (20 mcg/kg of quinidine gluconate per minute) for at least 24 hours.101 119 153 158 Administer infusion at a rate that maintains a plasma quinidine concentration of 3–8 mcg/mL.158 Decrease infusion rate or interrupt flow if corrected QT interval is >0.6 seconds, corrected QT interval exceeds baseline by >25%, QRS widening is >50% of baseline, or clinically important hypotension unresponsive to fluid expansion develops.111 124 128 158

Malaria (intermittent IV infusion regimen): Give loading dose of 15 mg/kg of quinidine (24 mg/kg of quinidine gluconate) by IV infusion over 4 hours, followed 4 hours later (i.e., 8 hours after the beginning of the loading-dose infusion) by maintenance doses of 7.5 mg/kg of quinidine (12 mg/kg of quinidine gluconate) given by IV infusion over 4 hours at 8-hour intervals.119 153 158 Administer infusion at a rate that maintains a plasma quinidine concentration of 3–8 mcg/mL.158 Decrease infusion rate or interrupt flow if corrected QT interval is >0.6 seconds, corrected QT interval exceeds baseline by >25%, QRS widening exceeds baseline by >50%, or clinically important hypotension unresponsive to fluid expansion develops.158

Dosage

Available as quinidine sulfate163 167 170 and quinidine gluconate.119 168 169 Dosage for treatment of arrhythmias usually expressed in terms of the salt;119 163 167 168 169 170 dosage for treatment of malaria expressed in terms of the base or salt.119 158 162

On a molar basis, approximately 267 mg of quinidine gluconate is equivalent to 200 mg of quinidine sulfate.b

Each 100 mg of quinidine gluconate contains 62.5 mg of quinidine.119

Pediatric Patients Quinidine Sulfate Arrhythmias† Oral

15–60 mg/kg of quinidine sulfate daily given in divided doses every 6 hours has been recommended by some clinicians.164 165 Others recommend 30 mg/kg daily or 900 mg/m2 daily, given in 5 divided doses.b

Quinidine Gluconate Arrhythmias† Oral

20–60 mg/kg of quinidine gluconate daily given in divided doses every 8 hours has been recommended by some clinicians.165

IV

30 mg/kg daily or 900 mg/m2 daily of quinidine gluconate, given in 5 divided doses, is recommended by some clinicians.b

Severe Malaria IV

Continuous IV infusion regimen: Initial loading dose of 6.25 mg/kg of quinidine (10 mg/kg of quinidine gluconate) given by IV infusion over 1–2 hours,101 119 158 162 followed by a maintenance infusion of 12.5 mcg/kg of quinidine per minute (20 mcg/kg of quinidine gluconate per minute) continued for ?24 hours and until parasitemia is reduced to <1% and oral quinine sulfate can be substituted.101 111 119 122 123 124 125 141 158 162 Some clinicians state initial loading dose should not exceed 375 mg of quinidine (600 mg of quinidine gluconate).101

Intermittent IV infusion regimen: Initial loading dose of 15 mg/kg of quinidine (24 mg/kg of quinidine gluconate) given by IV infusion over 4 hours, followed 4 hours later (i.e., 8 hours after the beginning of the loading-dose infusion) by maintenance doses of 7.5 mg/kg of quinidine (12 mg/kg of quinidine gluconate) given by IV infusion over 4 hours at 8-hour intervals until 3 maintenance doses have been administered and parasitemia is reduced to <1% and oral quinine sulfate can be substituted.119 153 158 162

After ?24 hours of quinidine gluconate and when clinically indicated, switch to oral quinine sulfate therapy to complete a total of 3 or 7 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (3 days if malaria was acquired in Africa or South America or 7 days if acquired in Southeast Asia).122 123 141 158 162

The IV quinidine gluconate regimen followed by oral quinine sulfate is used in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin (given IV or orally as tolerated).158

Adults Quinidine Sulfate Arrhythmias Oral

Conversion of atrial fibrillation/flutter (conventional tablets): Manufacturers recommend 400 mg of quinidine sulfate (332 mg of quinidine) every 6 hours initially; dose may be cautiously increased if conversion is not attained after 4 or 5 doses.167 170

Conversion of atrial fibrillation/flutter (extended-release tablets): Manufacturer recommends 300 mg of quinidine sulfate (249 mg of quinidine) every 8–12 hours initially; dose may be cautiously increased if conversion not attained, quinidine serum concentrations are within the therapeutic range, and the drug is well tolerated.163

If successful conversion of atrial fibrillation does not occur when quinidine serum concentrations are in the therapeutic range, further dosage increases generally are unsuccessful and increase the possibility of toxicity.b

Reduction in frequency of relapse into atrial fibrillation/flutter (conventional tablets): Manufacturers recommend 200 mg of quinidine sulfate (166 mg of quinidine) every 6 hours initially.167 170 Dose may be cautiously increased if well tolerated, serum quinidine concentrations are within therapeutic range, and average time between arrhythmic episodes has not been satisfactorily increased.167 170 Use such prophylaxis only if alternative measures have been inadequate and if potential benefits outweigh risks;167 170 consider mortality risk.167 170

Reduction in frequency of relapse into atrial fibrillation/flutter (extended-release tablets): Manufacturer recommends 300 mg of quinidine sulfate (249 mg of quinidine) every 8–12 hours initially.163 Dose may be cautiously increased if well tolerated, serum quinidine concentrations are within therapeutic range, and average time between arrhythmic episodes has not been satisfactorily increased.163 Use such prophylaxis only if alternative measures have been inadequate and if potential benefits outweigh risks;163 consider mortality risk.163

Manufacturers state that dosage regimens for suppression of life-threatening ventricular arrhythmias have not been adequately studied, but regimens similar to those used in the management of atrial fibrillation/flutter have been described.163 167 170 Whenever possible, such therapy should be guided by results of programmed electrical stimulation and/or Holter monitoring with exercise.163 167 170

Malaria Oral

300–600 mg or 10 mg/kg of quinidine sulfate every 8 hours for 5–7 days has been used for the treatment of uncomplicated P. falciparum malaria.102 103 108 109 110

Not included in CDC recommendations for treatment of uncomplicated or severe malaria.158 162 (See Malaria under Uses.)

Quinidine Gluconate Arrhythmias Oral

Conversion of atrial fibrillation/flutter (extended-release tablets): Manufacturers recommend 648 mg of quinidine gluconate (403 mg of quinidine) every 8 hours initially; dose may be cautiously increased if conversion is not attained after 3 or 4 doses.168 169 Alternatively, manufacturers state that a regimen of 324 mg of quinidine gluconate (202 mg of quinidine) may be given every 8 hours for 2 days, then 648 mg of quinidine gluconate (403 mg of quinidine) every 12 hours for 2 days, and then 648 mg of quinidine gluconate (403 mg of quinidine) every 8 hours for up to 4 days.168 169 If the 648-mg dose is not tolerated, the lower dosage can be continued for the last 4 days.168 169

Reduction in frequency of relapse into atrial fibrillation/flutter (extended-release tablets): Manufacturers recommend 324 mg of quinidine gluconate (202 mg of quinidine) every 8 or 12 hours initially.168 169 Dose may be cautiously increased if well tolerated, serum quinidine concentrations are within therapeutic range, and average time between arrhythmic episodes has not been satisfactorily increased.168 169 Use such prophylaxis only if alternative measures have been inadequate and if potential benefits outweigh risks;168 169 consider mortality risk.168 169

Manufacturers state that dosage regimens for suppression of life-threatening ventricular arrhythmias have not been adequately studied, but regimens similar to those used in the management of atrial fibrillation/flutter have been described.168 169 Whenever possible, such therapy should be guided by results of programmed electrical stimulation and/or Holter monitoring with exercise.168 169

IV

Treatment of symptomatic atrial fibrillation/flutter: Initially, up to 0.25 mg/kg of quinidine gluconate per minute (i.e., up to 1 mL/kg per hour) of 16-mg/mL dilution.119 Discontinue IV infusion as soon as sinus rhythm is restored.119

Most arrhythmias responsive to IV quinidine respond to a total IV dosage <5 mg/kg, although 10 mg/kg may be required in some patients.119 If conversion to sinus rhythm has not occurred after infusion of quinidine gluconate 10 mg/kg, discontinue the infusion and consider other means of cardioversion.119

Although dosing regimens for the management of life-threatening ventricular arrhythmias have not been systematically evaluated, regimens similar to that used in the management of atrial fibrillation/flutter have been described.119

Severe Malaria IV

Continuous IV infusion regimen: Initial loading dose of 6.25 mg/kg of quinidine (10 mg/kg of quinidine gluconate) given by IV infusion over 1–2 hours,101 119 141 158 162 followed by a maintenance infusion of 12.5 mcg/kg of quinidine per minute (20 mcg/kg of quinidine gluconate per minute) continued for ?24 hours and until parasitemia is reduced to <1% and oral quinine sulfate can be substituted.101 111 119 122 123 124 125 141 158 162 Some clinicians state initial loading dose should not exceed 375 mg of quinidine (600 mg of quinidine gluconate).101

Intermittent IV infusion regimen: Initial loading dose of 15 mg/kg of quinidine (24 mg/kg of quinidine gluconate) given by IV infusion over 4 hours, followed 4 hours later (i.e., 8 hours after the beginning of the loading-dose infusion) by maintenance doses of 7.5 mg/kg of quinidine (12 mg/kg of quinidine gluconate) given by IV infusion over 4 hours at 8-hour intervals until 3 maintenance doses have been administered and parasitemia is reduced to <1% and oral quinine sulfate can be substituted.119 153 158 162

After ?24 hours of quinidine gluconate and when clinically indicated, switch to oral quinine sulfate therapy to complete a total of 3 or 7 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (3 days if malaria was acquired in Africa or South America or 7 days if acquired in Southeast Asia).122 123 141 158

The IV quinidine gluconate regimen followed by oral quinine sulfate is used in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin (given IV or orally as tolerated).158 162

Prescribing Limits Pediatric Patients Arrhythmias† Quinidine Gluconate or Quinidine Sulfate Oral

2.4 g of quinidine sulfate or quinidine gluconate daily.165

Severe Malaria Quinidine Gluconate IV

Continuous IV infusion regimen: Maximum initial loading dose of 375 mg of quinidine (600 mg of quinidine gluconate).101

Adults Severe Malaria Quinidine Gluconate IV

Continuous IV infusion regimen: Maximum initial loading dose of 375 mg of quinidine (600 mg of quinidine gluconate).101

Special Populations Hepatic Impairment

Dosage reduction may be necessary to avoid toxicity.119 163 167 168 169 170

Renal Impairment

Dosage reduction may be necessary to avoid toxicity.119 163 167 168 169 170

In patients with severe malaria receiving IV quinidine gluconate, CDC states that initial (including loading) doses do not need to be reduced in those with renal failure.158 If renal failure persists or clinical improvement does not occur in such patients, CDC recommends reducing maintenance IV infusion rate by one-third to one-half on the third day of treatment.158

CHF

Dosage reduction may be necessary to avoid toxicity.119 163 167 168 169 170

Geriatric Patients

Select dosage with caution, usually starting at the low end of the dosage range, and consider age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.119

Cautions for Quinidine Gluconate Contraindications

Patients with AV junctional or idioventricular pacemaker, including those in complete AV block.119 163 167 168 169 170

History of quinidine- or quinine-associated thrombocytopenic purpura.119 163 167 168 169 170

Myasthenia gravis or other conditions that might be adversely affected by anticholinergic effects.119 163 167 168 169 170

Known hypersensitivity to quinidine.119 163 167 168 169 170

Warnings/Precautions Warnings Mortality

Pooled analysis of data from several randomized, controlled studies in patients with ventricular arrhythmias indicates that mortality rate associated with quinidine therapy is at least as high as that associated with other antiarrhythmic agents (e.g., flecainide, mexiletine, propafenone, tocainide).b

Use quinidine only for life-threatening arrhythmias.145 Avoid use for less severe ventricular arrhythmias and treatment of asymptomatic VPCs.145

Additionally, pooled analysis of data from several randomized, controlled studies in patients with atrial flutter and fibrillation indicates that quinidine therapy may be associated with a mortality rate more than 3 times higher than that associated with placebo;163 167 168 169 170 consider the increased risk of death when initiating quinidine therapy.144

Use with extreme caution, if at all, in patients with incomplete AV nodal block, since complete heart block and asystole may result.b Parenteral administration is especially hazardous in the presence of AV block, in the absence of atrial activity, and in patients with extensive myocardial injury.b

Proarrhythmic Effects

The possibility that potentially serious cardiac arrhythmias, including torsades de pointes, could occur if used concomitantly with other drugs that prolong the QTc interval should be considered and such combined use should be avoided.151

Hypokalemia, hypoxia, and disorders of acid-base balance must be eliminated as potentiating factors in patients who require large doses of antiarrhythmic agents to control ventricular arrhythmias.b

Paradoxical Increase in Ventricular Rate in Atrial Flutter/Fibrillation

Paradoxically, an extremely rapid ventricular rate may occur when used in the treatment of atrial flutter or fibrillation, due to a reduction in the degree of AV nodal block to a 1:1 ratio.b The anticholinergic action on the AV node also may increase the heart rate.b

This tachycardia may be prevented by prior digitalization.b

If cessation of atrial fibrillation or flutter is accompanied by depression of the normal pacemaker, an idioventricular rhythm (including ventricular tachycardia and fibrillation) may result.b

Exacerbated Bradycardia in Sick Sinus Syndrome

Possible marked sinus node depression and bradycardia.b

IV Administration

Overly rapid IV administration may cause peripheral vascular collapse and hypotension.119

Sensitivity Reactions Hypersensitivity Reactions

Idiosyncratic and hypersensitivity reactions to quinidine may occur, and the reaction to a test dose or the first dose of the drug should be observed carefully.b (See Oral Administration under Dosage and Administration.)

Observe for hypersensitivity for the first weeks of therapy.b

Symptoms of cinchonism such as tinnitus, headache, vertigo, fever, dizziness, lightheadedness, tremor, nausea, and disturbed vision may occur in sensitive patients after a single dose.b

Decrease dosage if signs of cinchonism appear.b

General Precautions Cardiovascular Effects

Possible syncope, probably due to ventricular tachycardia or fibrillation in usual doses.b May subside spontaneously, but occasionally are fatal.b If quinidine-induced syncope occurs, discontinue the drug.b Also may cause bradycardia.b

Severe hypotension may occur following IV administration or oral overdosage.b Vascular collapse, respiratory distress, and respiratory arrest may occur.b Reportedly related to the dose and rate of administration of the drug.102 107 119 Rapid IV injection of as little as 200 mg reportedly may cause a decrease in blood pressure of 40–50 mm Hg.119 Norepinephrine or metaraminol may be used if necessary to treat vascular collapse; artificial respiration and other supportive measures may be required.b

While substantial cardiovascular toxicity generally has not occurred, ECG changes, including prolonged QT interval, widened QRS complex, and flattened T waves (without dysrhythmia), have occurred frequently and hypotension and ventricular tachycardia have occurred occasionally in patients receiving IV quinidine gluconate for the treatment of Plasmodium falciparum malaria.102 104 108 124

Use with caution in patients without implanted pacemakers at high risk of complete atrioventricular block (e.g., digitalis intoxication, second-degree atrioventricular block, severe intraventricular conduction defects).163 167 168 169 170

Availability for Use in Treatment of Severe Malaria

Because of potentially fatal consequences of delays in initiating treatment of severe malaria, institutional pharmacy services should be aware of the essential role of ready availability of IV quinidine gluconate.b 142 143 153 158

If IV quinidine gluconate is not readily available for a patient with severe P. falciparum malaria (e.g., in hospitals where the drug is not maintained on formulary or otherwise available), health-care professionals should contact a nearby healthcare facility that stocks the drug.158 If a local source cannot be found, contact the local or regional distributor of the drug.158

If IV quinidine gluconate is unavailable, cannot be used because of intolerance or contraindications, or parasitemia is high or has not responded to quinidine gluconate therapy, IV artesunate is available from the CDC under an IND protocol for treatment of severe malaria.158 162 171 (See Malaria under Uses.)

Specific Populations Pregnancy

Category C.119 163 166 167 168 169 170

Generally considered relatively safe at usual dosages, but may exhibit oxytocic effect (possible abortion) at high dosages.166

Lactation

Distributed into milk.119 163 166 167 168 169 170 Avoid, if possible, in nursing women.119 163 167 168 169 170

Pediatric Use

Safety and efficacy as an antiarrhythmic agent in children not established.119 163 167 168 169 170 Has been used in children with arrhythmias†.165 b

Study and experience in children with malaria suggest that safety and efficacy of IV quinidine gluconate are similar to those in adults.119

Geriatric Use

Safety and efficacy not systematically studied in geriatric patients.119 167 168 169 170 Clinical studies did not include sufficient numbers of patients ?65 years of age to determine whether they respond differently than younger adults;119 other reported clinical experience has not identified differences in responses between geriatric adults and younger patients.119

When used in geriatric patients, select dosage with caution, usually initiating therapy at the low end of dosage range, and consider the greater frequency of decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy in this age group.119

Hepatic Impairment

Decreased clearance;119 163 167 168


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Adcal 1500mg chewable tablets


1. Name Of The Medicinal Product

Adcal 1500mg Chewable Tablets

2. Qualitative And Quantitative Composition

Per tablet:

Calcium carbonate: 1500mg

equivalent to 600mg of elemental calcium

3. Pharmaceutical Form

Chewable Tablet

4. Clinical Particulars 4.1 Therapeutic Indications

Adcal is a chewable tablet recommended as a supplementary source of calcium when normal requirements are high and in the correction of calcium deficiency in the diet. They can be used in osteoporosis therapy as an adjunct to more specific conventional treatments. Adcal chewable tablets can be used as a phosphate binding agent in the management of renal failure.

4.2 Posology And Method Of Administration

Oral.

Adults, elderly and children

Dietary deficiency and as an adjunct in osteoporosis therapy; 2 chewable tablets per day, preferably one tablet each morning and evening.

For use in binding phosphate in the management of renal failure in patients on renal dialysis, the dose should be adjusted for the individual patient and is dependent on the serum phosphate level.

The tablets should be chewed, not swallowed whole and taken just prior to, during or immediately following a meal.

4.3 Contraindications

Absolute contra-indications are hypercalcaemia resulting for example from myeloma, bone metastases or other malignant bone disease, sarcoidosis; primary hyperparathyroidism and vitamin D overdosage. Severe renal failure untreated by renal dialysis. Hypersensitivity to any of the tablet ingredients.

Relative contra-indications are osteoporosis due to prolonged immobilisation, renal stones, severe hypercalciuria.

4.4 Special Warnings And Precautions For Use

Patients with mild to moderate renal failure or mild hypercalciuria should be supervised carefully. Periodic checks of plasma calcium levels and urinary calcium excretion should be made in patients with mild to moderate renal failure or mild hypercalciuria.

Urinary calcium excretion should also be measured. In patients with a history of renal stones urinary calcium excretion should be measured to exclude hypercalciuria.

With long-term treatment it is advisable to monitor serum and urinary calcium levels and kidney function, and reduce or stop treatment temporarily if urinary calcium exceeds 7.5mmol/24 hours.

Allowances should be made for calcium and vitamin D supplements from other sources.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The risk of hypercalcaemia should be considered in patients taking thiazide diuretics since these drugs can reduce urinary calcium excretion. Hypercalcaemia must be avoided in digitalised patients.

The effects of digitalis and other cardiac glycosides may be accentuated with the oral administration of calcium combined with Vitamin D. Strict medical supervision is needed and, if necessary monitoring of ECG and calcium.

Certain foods (e.g. those containing oxalic acid, phosphate or phytinic acid) may reduce the absorption of calcium

Calcium salts may reduce the absorption of thyroxine, bisphosphonates, sodium fluoride, quinolone and tetracycline antibiotics or iron. It is advisable to allow a minimum period of four hours before taking the calcium.

Calcium absorption is reduced in patients receiving systemic corticosteroid therapy. This should be taken in to account when patients are receiving concomitant therapy.

4.6 Pregnancy And Lactation

During pregnancy and lactation treatment with Adcal should be under the direction of a physician. During pregnancy and lactation, requirements for calcium are increased but in deciding on the required supplementation allowances should be made for availability of these agents from other sources. If Adcal and iron supplements are both required to be administered to the patient, they should be taken at different times (see Section 4.5).

4.7 Effects On Ability To Drive And Use Machines

None known

4.8 Undesirable Effects

The use of calcium supplements has, rarely, given rise to mild gastro-intestinal disturbances, such as constipation, flatulence, nausea, gastric pain, diarrhoea.

4.9 Overdose

Overdosage may cause gastro-intestinal disturbances but would not be expected to cause hypercalcaemia except in patients treated with excessive doses of vitamin D. Treatment should be aimed at lowering serum calcium levels through a high fluid intake and low calcium diet. In severe cases treatments with corticosteroid and other specialist treatment may be necessary. Alkalosis is a potential but rare risk.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Calcium carbonate is a well established medicinal material and is used extensively for supplementation in deficiency states. Calcium carbonate is also widely used as an antacid.

5.2 Pharmacokinetic Properties

The pharmacokinetic profiles of calcium and its salts are well known. Calcium carbonate is converted to calcium chloride by gastric acid. Calcium is absorbed to the extent of about 15-25% from the gastro-intestinal tract while the remainder reverts to insoluble calcium carbonate and calcium stearate, and is excreted in the faeces.

5.3 Preclinical Safety Data

Calcium carbonate is a well known and widely used material and has been used in clinical practice for many years. As such toxicity is only likely to occur in chronic overdosage where hypercalcaemia could result.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Xylitol, polydextrose, pre-gelatinised starch, sodium saccharin, magnesium stearate, fruit flavour (contains propylene glycol and maltodextrin).

6.2 Incompatibilities

Not applicable, oral preparation.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package. Keep container in the outer carton.

6.5 Nature And Contents Of Container

PVC/PVdC aluminium foil blister packs of 10 (Physicians sample), or 100 tablets in a cardboard carton.

6.6 Special Precautions For Disposal And Other Handling

No special conditions

7. Marketing Authorisation Holder

ProStrakan Ltd.

Galabank Business Park

Galashiels

Scotland

TD1 1QH

8. Marketing Authorisation Number(S)

PL16508/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

04/10/2005

10. Date Of Revision Of The Text

November 2008

11 LEGAL CATEGORY

P


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Bazuka Extra Strength Gel


1. Name Of The Medicinal Product

BAZUKA™ EXTRA STRENGTH GEL

2. Qualitative And Quantitative Composition

Salicylic Acid 26.0% w/w.

3. Pharmaceutical Form

Collodion-like gel application.

4. Clinical Particulars 4.1 Therapeutic Indications

For the topical treatment of warts, verrucas, corns and calluses.

4.2 Posology And Method Of Administration

For adults, children and the elderly: Bazuka Extra Strength Gel should be applied once daily. The gel should be applied once every night. Treatment can take several weeks for resistant lesions to disappear and it is necessary to persevere with the treatment.

1. Every night, soak the affected site in warm water for 2 to 3 minutes.

2. Dry thoroughly with the patient's own towel.

3. Carefully apply one or two drops of the gel to the lesion and allow to dry over its surface. Take care to avoid surrounding normal skin. No adhesive plaster is necessary.

4. The following evening, carefully remove and discard the elastic film formed from the previous application, and re-apply the gel. Occasionally, if removal of the elastic film proves difficult, carefully re-apply the gel over it and allow to dry. This should help thicken the film to assist removal. If necessary, such re-application may be made on two or three successive days.

5. Once a week, gently rub away the treated surface using an emery board, as provided, or pumice stone used only for this purpose, before re-applying the gel.

6. The wart, verruca, corn or callus may take several weeks to disappear and it is important to persevere with the treatment.

7. At the end of treatment, if the elastic film is difficult to remove, it may be allowed to remain on the skin until it sheds.

4.3 Contraindications

Not to be used on or near the face, neck, intertriginous or anogenital regions, or by diabetics or individuals with impaired peripheral blood circulation.

Not to be used on moles, birthmarks, hairy warts or on any other skin lesions for which the gel is not indicated.

Not to be used in cases of sensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Keep away from the eyes, mucous membranes and from cuts and grazes.

The gel should be applied carefully to the wart, verruca, corn or callus only, to avoid possible irritation of surrounding normal skin.

Do not use excessively.

Some mild, transient irritation may be expected, but in cases of more severe or persistent pain/irritation, the treatment should be suspended and/or discontinued. See also section “Undesirable Effects”.

Avoid inhaling vapour, and keep cap firmly closed when not in use.

Contact with clothing, fabrics, plastics and other materials may cause damage, and should be avoided.

For external use only.

Keep all medicines out of reach and sight of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No special precautions necessary.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Bazuka Extra Strength Gel may be irritant in certain patients, which in rare instances may appear as a temporary blemish on the skin. See also section “Special Warnings and Precautions for Use”.

4.9 Overdose

Any excessive use of Bazuka Extra Strength Gel could cause irritation of the skin. If this occurs, Bazuka Extra Strength Gel should be used more sparingly or applied less frequently.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

The active ingredient, salicylic acid, is a well-established pharmacopoeial substance, which has been used extensively in dermatological therapy for its keratolytic properties.

When applied topically, and in high enough concentrations, salicylic acid acts by achieving a slow, painless destruction of the thickened stratum corneum. It softens and destroys the thickened stratum corneum of the affected tissue by reducing the adhesiveness of the corneocytes while causing the cornified epithelium to swell, soften, macerate and finally desquamate. In the treatment of warts and verrucas, a mild inflammatory reaction, which may render the virus more prone to immunologic attack, may assist resolution of the condition.

The use of topical salicylic acid formulated in simple dosage forms at high concentrations and in evaporative vehicles designed to concentrate in use, thereby localising the keratolytic precisely over circumscribed small areas of skin, is commonplace. It has become exceedingly popular with doctors and patients alike, where its safety and efficacy have been very well established through widespread use over many decades.

5.2 Pharmacokinetic Properties

Bazuka Extra Strength Gel presents 26% salicylic acid in an evaporative collodion-like gel application which dries to form a cohesive and adhesive film on the skin.

The formulation offers the highest concentration of salicylic acid commensurate with presenting it in a convenient collapsible aluminium tube fitted with a special applicator nozzle, allowing it to be dispensed precisely to the affected area(s). This minimises the spread of the preparation onto the surrounding healthy skin, which could otherwise lead to inflammation, irritation and poor patient compliance.

The film-forming characteristics of the collodion-like gel vehicle also offer distinct advantages in clinical usage. The gel quickly forms a surface film, well before it dries completely, thereby prolonging the period during which the keratolytic solution can properly infiltrate and achieve intimate contact with the surface layers of the thickened stratum corneum.

Furthermore, even when the film appears to dry completely, a proportion of the salicylic acid remains in solution within the vehicle, thus permitting continued release of the keratolytic, which may otherwise be entrapped within the dried collodion-like film. The gel yields a robust flexible film which is firmly anchored to the skin, and can therefore be used, even on the sole of the foot, without the added protection of a plaster.

The availability of salicylic acid has been demonstrated by applying the gel to the normal skin of human volunteers, whereupon the salicylic acid produced a marked irritant effect similar to that of existing preparations. In clinical use, its application will, of course, be restricted to the hyperkeratotic lesions.

5.3 Preclinical Safety Data

No special information.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Camphor; Povidone; Pyroxylin; Ethanol; Acetone.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Highly flammable - keep away from flames.

Do not store above 25°C.

6.5 Nature And Contents Of Container

Collapsible tube containing 5g, complete with special applicator, emery board and instructions.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Diomed Developments Limited

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK

8. Marketing Authorisation Number(S)

00173/0154.

9. Date Of First Authorisation/Renewal Of The Authorisation

19 July 2009.

10. Date Of Revision Of The Text

March 2004.


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Daktacort Ointment


1. Name Of The Medicinal Product

Daktacort™ Ointment.

2. Qualitative And Quantitative Composition

Miconazole nitrate 2% w/w and hydrocortisone 1% w/w.

3. Pharmaceutical Form

White, odourless, fatty ointment.

4. Clinical Particulars 4.1 Therapeutic Indications

For the topical treatment of inflamed dermatoses where infection by susceptible organisms and inflammation co-exist, eg intertrigo and infected eczema.

Moist or dry eczema or dermatitis including atopic eczema, primary irritant or contact allergic eczema or seborrhoeic eczema including that associated with acne.

Intertriginous eczema including inframammary intertrigo, perianal and genital dermatitis.

Organisms which are susceptible to miconazole are dermatophytes and pathogenic yeasts (eg Candida spp.). Also many Gram-positive bacteria including most strains of Streptococcus and Staphylococcus.

The properties of Daktacort indicate it particularly for the initial stages of treatment. Once the inflammatory symptoms have disappeared (after about 7 days), treatment can be continued where necessary with Daktarin™ Cream or Daktarin™ Powder.

4.2 Posology And Method Of Administration

For topical administration.

Daktacort Ointment should be applied topically two or three times daily.

The same dosage applies to both adults and children.

Use in elderly:

Natural thinning of the skin occurs in the elderly, hence corticosteroids should be used sparingly and for short periods of time.

In infants, long term continuous topical corticosteroid therapy should be avoided.

If after about 7 days' application, no improvement has occurred, cultural isolation of the offending organism should be followed by appropriate local or systemic antimicrobial therapy.

4.3 Contraindications

True hypersensitivity to any of the ingredients. Tubercular or viral infections of the skin or those caused by Gram-negative bacteria.

4.4 Special Warnings And Precautions For Use

When Daktacort is used by patients taking oral anticoagulants, the anticoagulant effect should be carefully monitored.

As with any topical corticosteroid, care is advised with infants and children when Daktacort is to be applied to extensive surface areas or under occlusive dressings including baby napkins; similarly, application to the face should be avoided.

In infants, long term continuous topical corticosteroid therapy should be avoided. Adrenal suppression can occur even without occlusion.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application (see Section 5.2 Pharmacokinetic properties), clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

Miconazole is a CYP3A4 inhibitor that can decrease the rate of metabolism of hydrocortisone. Serum concentrations of hydrocortisone may be higher with the use of Daktacort compared with topical preparations containing hydrocortisone alone.

4.6 Pregnancy And Lactation

In animals, miconazole nitrate has shown no teratogenic effects but is foetotoxic at high oral doses and administration of corticosteroids to pregnant animals can cause abnormalities of foetal development. The relevance of these findings to humans has not been established. However, combinations of topical steroids with imidazoles should be used in pregnant women only if the practitioner considers it to be necessary.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Rarely, local sensitivity may occur requiring discontinuation of treatment.

Additional adverse drug reactions reported in postmarketing reports with DAKTACORT CREAM but not with DAKTACORT OINTMENT are included in Table 1. The frequencies are based on spontaneous reporting rates, according to the following convention:

Very common Common Uncommon Rare Very rare <1/10,000, including isolated reports

Table 1. Adverse Drug Reactions Identified During Postmarketing Experience with Daktacort Cream by Frequency Category Estimated from Spontaneous Reporting Rates

     

Immune system disorders

 

Very rare

Anaphylactic reaction

   

Skin and Subcutaneous Tissue Disorders

 

Very rare

Contact dermatitis, Erythema, Rash

Review of adverse events reported with Daktacort Ointment did not find sufficient evidence to assess any of the events as adverse drug reactions associated with the use of Daktacort Ointment.

4.9 Overdose

Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Miconazole nitrate is a potent broad-spectrum antifungal and antibacterial agent with marked activity against dermatophytes, pathogenic yeasts (eg Candida spp) and many Gram-positive bacteria including most strains of Streptococcus and Staphylococcus.

Hydrocortisone is a widely used topical anti-inflammatory of value in the treatment of inflammatory skin conditions including atrophic and infantile eczema, contact sensitivity reactions and intertrigo.

5.2 Pharmacokinetic Properties

Absorption

Miconazole remains in the skin after topical application for up to 4 days. Systemic absorption of miconazole is limited, with a bioavailability of less than 1% following topical application of miconazole. Plasma concentrations of miconazole and/or its metabolites were measurable 24 and 48 hours after application. Approximately 3% of the dose of hydrocortisone is absorbed after application on the skin.

Distribution

Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%). More than 90% of hydrocortisone is bound to plasma proteins.

Metabolism and elimination

The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites over a four-day post-administration period. Smaller amounts of unchanged drug and metabolites also appear in urine.

The half-life of hydrocortisone is about 100 minutes. Metabolism takes place in the liver and tissues and the metabolites are excreted with the urine, mostly as glucuronides, together with a very small fraction of unchanged hydrocortisone.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Polyethylene 5.5% liquid paraffin gel.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store at or below 25°C.

6.5 Nature And Contents Of Container

Aluminium tube with polypropylene cap.

Each tube contains 5 g, 30 g or 75 g ointment.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0130

9. Date Of First Authorisation/Renewal Of The Authorisation Date of First Authorisation: 05/03/87 Renewal of Authorisation: 28/03/03 10. Date Of Revision Of The Text

2nd March 2009

LEGAL CATEGORY

POM.


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Dithrocream


1. Name Of The Medicinal Product

DITHROCREAM™

2. Qualitative And Quantitative Composition

Dithranol 0.1%, 0.25%, 0.5%, 1.0% or 2.0% w/w.

3. Pharmaceutical Form

Yellow aqueous cream.

4. Clinical Particulars 4.1 Therapeutic Indications

For the topical treatment of subacute and chronic psoriasis including psoriasis of the scalp.

4.2 Posology And Method Of Administration

Dithranol therapy customarily involves titrating the concentration applied to skin to suit individual patient's circumstances. Dithrocream is, therefore, available in five strengths. The different packs are colour coded as follows:

0.1%

pale blue

0.25%

red

0.5%

purple

1.0%

brown

2.0%

yellow

For adults and the elderly: It is important to determine each patient's optimal treatment strength, as too high a strength may induce a burning sensation. Where the response to Dithrocream has not previously been established, always commence with Dithrocream 0.1%, continuing for at least one week and then, if necessary, increase to the 0.25% followed by the 0.5%, the 1.0% and finally the 2.0% strength. The aim should be to build up gradually over approximately 4 weeks to the highest tolerated strength to produce the optimum therapeutic effect. This optimum concentration will depend upon such factors as the thickness and location of the psoriatic plaques, as well as the variation between individual patients in their reaction to dithranol.

Dithrocream should be applied sparingly, and only to the affected areas, once every 24 hours, at any convenient time of the day or evening. Rub the cream gently and carefully into the skin until completely absorbed. For use on the scalp, first comb the hair to remove scalar debris and, after suitably parting, rub the cream well into the affected areas. Remove by washing off the skin or scalp, usually no more than one hour after application (Short Contact Therapy). Alternatively, it may be applied at night before retiring and washed off in the morning.

Treatment should be continued until the skin is entirely clear, i.e. when there is nothing to feel with the fingers and the texture is normal. By gradually increasing the strength of cream applied, it should be possible to clear psoriasis patches within 4 to 6 weeks.

For children No additional special precautions necessary. However, use cautiously as described above for adults and the elderly, with regular supervision.

4.3 Contraindications

Not to be used on the face, or for acute or pustular psoriasis.

Not to be used in cases of sensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Dithrocream 0.5%, Dithrocream 1.0% and Dithrocream 2.0% should only be used for those patients who have failed to respond to lower strengths of dithranol. Dithrocream 1.0% and 2.0% should normally only be applied for 'short contact' periods.

Dithrocream 0.5%, Dithrocream 1.0% and Dithrocream 2.0% should always be used under medical supervision.

It is most important to avoid applying an excessive amount of the cream, which may cause unnecessary soiling and staining of the clothing and/or bed linen. After each period of treatment, a bath/shower should be taken to remove any residual cream. To prevent the possibility of discolouration, particularly where Dithrocream 1.0% or 2.0% has been used, always rinse the bath/shower with hot water immediately after washing/showering and then use a suitable cleanser to remove any deposit on the surface of the bath/shower.

After use on the scalp, a shampoo may be used to remove the Dithrocream residue. Great care must be taken when washing out the shampoo (which may contain some Dithrocream residue), to ensure that it does not get into the eyes or on the face. This is particularly important when the higher strengths of Dithrocream have been used.

Although a feeling of warmth at the application site is normal, if this amounts to a burning sensation, or if the lesions spread, treatment should be stopped at once, and the dosage re-evaluated by a doctor.

Dithrocream is not normally recommended for use on areas of folded skin such as the groin and beneath the breasts. Do not use high strengths on these sites.

Keep away from the eyes and mucous membranes.

Always wash the hands after use.

As long term use of topical corticosteroids is known to destabilise psoriasis, and withdrawal may give rise to a rebound phenomenon, an interval of at least one week should be allowed between the discontinuance of such steroids and the commencement of Dithrocream therapy. A suitably bland emollient may usefully be applied in the intervening period.

The excipients, chlorocresol and cetostearyl alcohol may on rare occasions give rise to allergic or local skin reactions (eg. contact dermatitis) in sensitive people.

Contact with fabrics, plastics and other materials may cause permanent staining and should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Although there is no experimental evidence to support the safety of the drug in pregnancy or during lactation, no adverse effects have been reported.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Some skin irritation and/or a feeling of warmth at the site of application is normally associated with dithranol therapy. Dithrocream applied at too high a strength or left in contact with the skin for too long may induce a burning sensation.

Dithrocream may cause temporary staining of the skin and/or hair.

4.9 Overdose

Dithranol is a cathartic (laxative) and if accidentally swallowed, it should be removed by gastric lavage.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Dithranol has been used in the treatment of sub-acute and chronic psoriasis for over 70 years and, during that time, it has become established as a safe and effective form of therapy. Its precise mode of action is still to be confirmed, although it has been shown to inhibit DNA replication, cellular respiration and key cellular enzymes eg glucose-6-phosphate dehydrogenase.

Because dithranol causes staining and irritation, it is now widely used in short contact therapy where the preparation is washed off the skin after periods of one hour or less. For this purpose, Dithrocream is particularly suitable, as it is convenient to apply and washes off easily in a bath or shower.

5.2 Pharmacokinetic Properties

The traditional formulations of dithranol are based on soft paraffin from which it is effectively released into the skin. In Dithrocream, during manufacture, the oily paraffin phase of the cream is heated until the dithranol entirely dissolves so that, on cooling, it is retained solely within the paraffin phase and does not spread into the aqueous phase. After application of Dithrocream to the skin, the water is lost through absorption and evaporation, leaving the oily phase which then acts in the same way as a dithranol ointment. However, since the cream may be rubbed into the skin more effectively than the ointment, it is convenient to apply and, owing to the presence of the emulsifying components, is easier to wash off.

The availability of the dithranol has now been confirmed in numerous publications detailing the results of clinical trials.

5.3 Preclinical Safety Data

No special information.

6. Pharmaceutical Particulars 6.1 List Of Excipients

White Soft Paraffin; Cetostearyl Alcohol; Salicylic Acid; Ascorbic Acid; Sodium Laurilsulfate; Chlorocresol; Purified Water.

Dithrocream 2.0% also contains Liquid Paraffin.

6.2 Incompatibilities

None known.

6.3 Shelf Life

48 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Replace cap tightly after use.

6.5 Nature And Contents Of Container

All strengths of Dithrocream are supplied in collapsible tubes containing 50 g. These are supplied as original packs (OP).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dermal Laboratories

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

Dithrocream 0.1%

00173/0029

Dithrocream 0.25%

00173/0028

Dithrocream 0.5%

00173/0027

Dithrocream 1.0%

00173/0039

Dithrocream 2.0%

00173/0045

9. Date Of First Authorisation/Renewal Of The Authorisation

31 July 2008.

10. Date Of Revision Of The Text

October 2006.


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Carnitor 330 mg Tablets


1. Name Of The Medicinal Product

Carnitor 330 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains L-Carnitine inner salt 330 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

White, round, standard biconvex tablets, approximately 13 mm diameter.

4. Clinical Particulars 4.1 Therapeutic Indications

Indicated for the treatment of primary and secondary carnitine deficiency in adults and children over 12 years of age.

4.2 Posology And Method Of Administration

For oral administration only.

Adults and children over 12 years of age

The tablets should be given in divided doses.

It is advisable to monitor therapy by measuring free and acyl carnitine levels in both plasma and urine.

The management of inborn errors of metabolism

The dosage required depends upon the specific inborn error of metabolism concerned and the severity of presentation at the time of treatment. However, the following can be considered as a general guide.

An oral dosage of up to 200mg/kg/day in divided doses (2 to 4) is recommended for chronic use in some disorders, with lower doses sufficing in other conditions. If clinical and biochemical symptoms do not improve, the dose may be increased on a short-term basis. Higher doses of up to 400mg/kg/day may be necessary in acute metabolic decompensation or the i.v. route may be required.

Haemodialysis - maintenance therapy

If significant clinical benefit has been gained by a first course of intravenous Carnitor then maintenance therapy can be considered using 1 g per day of Carnitor orally. On the day of the dialysis oral Carnitor has to be administered at the end of the session.

4.3 Contraindications

Hypersensitivity to any constituent of the product.

4.4 Special Warnings And Precautions For Use

While improving glucose utilisation, the administration of L-carnitine to diabetic patients receiving either insulin or hypoglycaemic oral treatment may result in hypoglycaemia. Plasma glucose levels must be monitored regularly in order to adjust the hypoglycaemic treatment immediately, if required.

The safety and efficacy of oral L-carnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral L-carnitine in patients with severely compromised renal function or in end stage renal disease (ESRD) patients on dialysis may result in an accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are usually excreted in the urine. This situation has not been observed following intravenous administration of L-carnitine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no known interactions.

4.6 Pregnancy And Lactation

Reproductive studies were performed in rats and rabbits. There was no evidence of a teratogenic effect in either species. In the rabbit but not in the rat there was a statistically insignificant greater number of post implantation losses at the highest dose tested (600mg/kg daily) as compared with control animals. The significance of these findings in man is unknown. There is no experience of use in pregnant patients with primary systemic carnitine deficiency. Taking into account the serious consequences in a pregnant woman who has primary systemic carnitine deficiency stopping treatment, the risk to the mother of discontinuing treatment seems greater than the theoretical risk to the foetus if treatment is continued.

Levocarnitine is a normal component of human milk. Use of levocarnitine supplementation in nursing mothers has not been studied.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Various mild gastro-intestinal complaints have been reported during the long term administration of oral levocarnitine, these include transient nausea and vomiting, abdominal cramps and diarrhoea.

Decreasing the dosage often diminishes or eliminates drug related patient body odour or gastro-intestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration and after any dosage increase.

4.9 Overdose

There have been no reports of toxicity from levocarnitine overdosage. Overdosage should be treated with supportive care.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: A16AA01 (Amino acids and derivatives)

L-Carnitine is present as a natural constituent in animal tissues, micro-organisms and plants. In man the physiological metabolic requirements are met both by the consumption of food containing carnitine and the endogenous synthesis in the liver and kidneys from lysine with methionine serving as the methyl donor. Only the L-isomer is biologically active, playing an essential role in lipid metabolism as well as in the metabolism of ketone bodies as branched chain-amino-acids. L-Carnitine as a factor is necessary in the transport of long-chain fatty acids into the mitochondria - facilitating the oxidation of fatty acids rather than their incorporation into triglycerides. By releasing CoA from its thioesters, through the action of CoA; carnitine acetyl transferase, L-carnitine also enhances the metabolic flux in the Kreb's cycle; with the same mechanism it stimulates the activity of pyruvate dehydrogenase and in skeletal muscle, the oxidation of branched-chain amino acids. L-Carnitine is thus involved, directly or indirectly in several pathways so that its availability should be an important factor controlling not only the oxidative utilisation of fatty acids and ketone bodies but also that of glucose and some amino acids.

5.2 Pharmacokinetic Properties

The absorbed L-carnitine is transported to various organ systems via the blood. The presence of membrane-bound proteins in several tissues including red blood cells that bind carnitine, suggest that a transport system in the blood and a cellular system for the collective uptake is present in several tissues. Tissue and serum carnitine concentration depend on several metabolic processes, carnitine bio-synthesis and dietary contributions, transport into and out of tissues, degradation and excretion may all affect tissue carnitine concentrations. Following administration, studies have demonstrated that a peak concentration of 71.89±5.13 ?M was achieved 6 hours after dosing. The pharmacokinetic parameters showed an absorption phase half life of 1.45 hours and an elimination phase with a half-life of 3.34 hours. The apparent bioavailability was 14%.

The urinary recovery in 14 hours was 6.02% of the administered dose.

5.3 Preclinical Safety Data

L-Carnitine is a naturally occurring body substance in human beings, plants and animals. Carnitor products are used to bring the level of L-carnitine in the body up to those found naturally. Appropriate pre-clinical studies have been undertaken and show no signs of toxicity at normal therapeutic levels.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Magnesium stearate (E572)

Polyvinylpyrrolidone

Microcrystalline cellulose (E460).

6.2 Incompatibilities

None known.

6.3 Shelf Life

Unopened shelf life of 60 months (5 years).

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Blister packed in quantities of 30, 90, 100 and 180.

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Sigma-Tau Industrie Farmaceutiche Riunite SpA,

Viale Shakespeare 47-00144,

Rome, Italy.

8. Marketing Authorisation Number(S)

PL 08381/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

15 August 1990

15 October 2000

10. Date Of Revision Of The Text

February 2009


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Gyno-Daktarin 20mg / g Cream


1. Name Of The Medicinal Product

Gyno-Daktarin 20mg/g cream

2. Qualitative And Quantitative Composition

Miconazole nitrate 2% w/w.

(Each gram of cream contains 20mg miconazole nitrate)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Vaginal cream.

The cream is white and homogeneous.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of mycotic vulvovaginitis and superinfections due to gram-positive bacteria.

4.2 Posology And Method Of Administration

Gyno-Daktarin cream is for vaginal administration.

Recommended dosage

Administer the contents of one applicator (about 5g of cream) once daily deeply into vagina for 10 – 14 days or twice daily for 7 days. For vulvitis the cream should be applied topically twice daily. Continue the course of treatment even after pruritus and leukorrhoea have disappeared or menstruation begins.

4.3 Contraindications

Gyno-Daktarin cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient of the cream.

4.4 Special Warnings And Precautions For Use

Should local sensitisation or an allergic reaction occur, treatment should be discontinued.

Appropriate therapy is indicated when the sexual partner is also infected.

Gyno-Daktarin cream does not stain skin or clothes.

The concurrent use of latex condoms or diaphragms with vaginal anti-infective preparations may decrease the effectiveness of latex contraceptive agents. Therefore Gyno-Daktarin cream should not be used concurrently with a latex condom or latex diaphragm.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after vaginal application, clinically relevant interactions occur very rarely. In patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored. The effects and side effects of other drugs metabolized by CYP2C9 (e.g.,oral hypoglycemics and phenytoin) and also CYP3A4 (e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin and calcium channel blockers such as dihydropyridines and verapamil), when co-administered with miconazole, can be increased and caution should be exercised.

Contact should be avoided between certain latex products such as contraceptive diaphragms or condoms and Gyno-Daktarin cream since the constituents of the cream may damage the latex. (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

Although intravaginal absorption is limited, Gyno-Daktarin cream should only be used in the first trimester of pregnancy only if, in the judgement of the physician, the potential benefits outweigh the possible risks.

Lactation

It is not known whether miconazole nitrate is excreted in human milk. Caution should be exercised when using Gyno-Daktarin cream during lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The safety of GYNO-DAKTARIN was evaluated in a total of 537 women with microbiologically confirmed candidiasis and symptoms (e.g., vulvovaginal itching, burning/irritation), or signs of vulvar erythema, edema, excoriation, or vaginal erythema or edema who participated in 2 single-blind clinical trials. Subjects were treated with miconazole intravaginally, randomly assigned to either a single 1,200 mg capsule, or a 7-day application of 2% vaginal cream. Adverse Drug Reactions (ADRs) reported by

In the table, the frequencies are provided according to the following convention:

Very common

Common

Uncommon

Rare

Very rare <1/10,000, including isolated reports

Table 1. Adverse Drug Reactions Reported by Gyno-Daktarin-treated Subjects in 2 Single Blind Clinical Trials

 

Body System/Organ Class

Frequency Category

Undesirable effects

 

Skin and subcutaneous tissue disorders

 

 

Common

Rash

Uncommon

Rash pruritic, urticaria

Reproductive System and Breast Disorders

 

 

Very common

Genital pruritus female, vaginal burning sensation, vulvovaginal discomfort

 

Common

Dysmenorrhoea

 

A range of additional reactions were reported during the clinical trials, such as: vaginal discharge, vaginal haemorrhage, vaginal pain, headache, dysuria, urinary tract infection, abdominal pain, rosacea, swelling face and nausea. However due to the design of these studies, a definitive causal relationship could not be established.

Table 2.Adverse Drug Reactions Identified During Postmarketing Experience with Gyno-Daktarin by Frequency Category Estimated from Spontaneous Reporting Rates

 

Immune System Disorders

 

Not known

Hypersensitivity including Anaphylactic and Anaphylactoid reactions, Angioedema

Skin and Subcutaneous Tissue Disorders

 

Not known

Pruritis

Reproductive System and Breast Disorders

 

Not known

Vaginal irritation, pelvic cramps

4.9 Overdose

Symptoms

In case of accidental ingestion, no problems are expected.

Treatment

In the event of accidental ingestion of large quantities, an appropriate method of gastric emptying may be used if considered appropriate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification:

(Anti-infectives and antiseptics, excl. combinations with corticosteroids, imidazole derivatives)

ATC code: G01A F04

Miconazole combines a potent antifungal activity against common dermatophytes and yeasts with an antibacterial activity against certain gram-positive bacilli and cocci.

Miconazole inhibits the biosynsthesis of ergosterol in fungi and changes the composition of other lipid components in the membrane, resulting in fungal cell necrosis.

In general, miconazole exerts a very rapid effect on pruritus, a symptom that frequently accompanies dermatophyte and yeast infections.

5.2 Pharmacokinetic Properties

Absorption: Miconazole persists in the vagina for up to 72 hours after a single dose. Systemic absorption of miconazole after intravaginal administration is limited, with a bioavailability of 1 to 2% following intravaginal administration of a 1200 mg dose. Plasma concentrations of miconazole are measurable within 2 hours of administration in some subjects, with maximal levels seen 12 to 24 hours after administration. Plasma concentrations decline slowly thereafter and were still measurable in most subjects 96 hours post-dose. A second dose administered 48 hours later resulted in a plasma profile similar to that of the first dose.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites over a four-day post-administration period. Smaller amounts of unchanged drug and metabolites also appear in urine. The mean apparent elimination half-life is 57 hours.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG-32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25?C.

6.5 Nature And Contents Of Container

Tube containing 15 g, 40 g or 78 g of cream.

The aluminium tube inner is lined with heat polymerised epoxy-phenol resin with a white polypropylene cap.

The cream is supplied with disposable cardboard vaginal applicators.

*Not all pack sizes are marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 0242/0015

9. Date Of First Authorisation/Renewal Of The Authorisation

12 December 2008

10. Date Of Revision Of The Text

23rd July 09


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Pentasa Suppositories 1g


1. Name Of The Medicinal Product

PENTASA® Suppositories 1g

2. Qualitative And Quantitative Composition

Each suppository contains mesalazine 1g

3. Pharmaceutical Form

Suppositories

Oblong, compressed white to light tan, speckled suppositories

4. Clinical Particulars 4.1 Therapeutic Indications

PENTASA Suppositories are indicated for the treatment of ulcerative proctitis.

4.2 Posology And Method Of Administration

Ulcerative Proctitis:

Usual adult dose: Acute treatment: 1 suppository daily for 2 to 4 weeks.

Maintenance treatment: 1 suppository daily.

Children: Not recommended.

Elderly Patients: The usual adult dose applies.

4.3 Contraindications

PENTASA is contraindicated in:

- patients with known sensitivity to salicylates

- children under the age of 15 years

- patients with severe liver and/or renal impairment

- patients allergic to any of the ingredients

4.4 Special Warnings And Precautions For Use

Serious blood dyscrasias have been reported rarely with mesalazine. Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.

Most patients who are intolerant or hypersensitive to sulphasalazine are able to use PENTASA without risk of similar reactions. However, caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). Caution is recommended in patients with impaired liver function.

It is recommended that mesalazine is used with extreme caution in patients with mild to moderate renal impairment (see section 4.3).

If a patient develops dehydration while on treatment with mesalazine, normal electrolyte levels and fluid balance should be restored as soon as possible.

Mesalazine induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concurrent use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions (see section 4.4).

Concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine or 6-mercaptopurine.

4.6 Pregnancy And Lactation

PENTASA should be used with caution during pregnancy and lactation and only if the potential benefit outweighs the possible hazards in the opinion of the physician.

Mesalazine is known to cross the placental barrier, but the limited data available on its use in pregnant women do not allow assessment of possible adverse effects. No teratogenic effects have been observed in animal studies.

Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

Mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite, acetyl mesalazine appears in similar or increased concentrations. There is limited experience of the use of oral mesalazine in lactating women. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhoea in the infant cannot be excluded.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects.

4.8 Undesirable Effects

Mesalazine may be associated with an exacerbation of the symptoms of colitis in those patients who have previously had such problems with sulphasalazine.

Undesirable effects are as follows:

Common

Gastrointestinal disorders:

(

Nausea, vomiting, diarrhoea, abdominal pain

 

Skin disorders:

 

Rash (including urticaria and erythematous rash)

 

General:

 

Headache

Rare

Blood disorders:

(

Leucopenia (including granulocytopenia), neutropenia, agranulocytosis, aplastic anaemia, thrombocytopenia

 

Nervous system disorders:

 

Peripheral neuropathy

 

Cardiac disorders:

 

Myocarditis, pericarditis

 

Respiratory disorders:

 

Allergic lung reactions (including dyspnoea, coughing, allergic alveolitis, pulmonary eosinophilia, pulmonary infiltration, pneumonitis)

 

Gastrointestinal disorders:

 

Pancreatitis, increased amylase

 

Liver:

 

Abnormalities of hepatic function and hepatotoxicity (including hepatitis, cirrhosis, hepatic failure)

 

Urogenital:

 

Abnormal renal function (including interstitial nephritis, nephrotic syndrome), urine discolouration (*see additional text)

 

Collagen disorders:

 

Lupus erythematosus-like reactions

Very rare

Blood disorders:

(<0.01% )

Anaemia, eosinophilia (as part of an allergic reaction) and pancytopenia

 

Liver:

 

Increased liver enzymes and bilirubin

 

Skin disorders:

 

Reversible alopecia, bullous skin reactions including erythema multiforme and Stevens-Johnson syndrome

 

Musculo-skeletal disorders:

 

Myalgia, arthralgia

 

Allergic reactions:

 

Hypersensitivity reactions, drug fever

*Renal failure has been reported. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

The mechanism of mesalazine induced myocarditis, pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.

Following rectal administration local reactions such as pruritus, rectal discomfort and urge may occur.

4.9 Overdose

Acute experience in animals:

Single oral doses of mesalazine of up to 5g/kg in pigs or a single intravenous dose of mesalazine at 920mg/kg in rats were not lethal.

Human experience:

No cases of overdose have been reported.

Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

Mechanism of action and pharmacodynamic effects:

Mesalazine is recognised as the active moiety of sulphasalazine in the treatment of ulcerative colitis. It is thought to act locally on the gut wall in inflammatory bowel disease, although its precise mechanism of action has not been fully elucidated.

Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4 and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. It is currently unknown which, if any of these mechanisms play a predominant role in the clinical efficacy of mesalazine.

5.2 Pharmacokinetic Properties

General characteristics of the active substance:

Disposition and local availability:

PENTASA suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. They are used to treat the rectum.

Biotransformation:

Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption:

The absorption following rectal administration is low, but depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2g (1g x 2), approximately 10% of the dose is absorbed after administration of suppositories.

Distribution:

Mesalazine and acetyl mesalazine do not cross the blood brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl mesalazine about 80%.

Elimination:

The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Povidone Ph. Eur.

Macrogol 6000 Ph. Eur.

Magnesium stearate Ph. Eur.

Talc Ph. Eur.

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25?C. Store in the original package.

6.5 Nature And Contents Of Container

Double aluminium foil blister strips of 7 suppositories each.

Pack size: 28

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Ferring Pharmaceuticals Ltd.

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ

8. Marketing Authorisation Number(S)

PL 3194/0045

9. Date Of First Authorisation/Renewal Of The Authorisation

5th December 2002

10. Date Of Revision Of The Text

February 2005

11. LEGAL CATEGORY

POM


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Refolinon Injection 2 ml / 10 ml


1. Name Of The Medicinal Product

Refolinon Injection

2. Qualitative And Quantitative Composition

Clear pale yellow liquid for injection containing leucovorin 3 mg/ml in ampoules of 2 ml and 10 ml, as the calcium salt

3. Pharmaceutical Form

Solution for injection

4. Clinical Particulars 4.1 Therapeutic Indications

Leucovorin (folinic acid) is the formyl derivative of tetrahydrofolic acid and is an intermediate product of the metabolism of folic acid. Leucovorin is used in cytotoxic therapy as an antidote to folic acid antagonists such as methotrexate. Leucovorin is effective in the treatment of megaloblastic anaemia due to folate deficiency.

Warning: Leucovorin should not be given simultaneously with a folic acid antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified.

4.2 Posology And Method Of Administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

1) Treatment of adverse drug reactions and intoxication induced by folic acid antagonists (injection only)

Trimetrexate toxicity: Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m? for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m?, or by oral route with four doses of 20 mg/m2 administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

Overdosage (possibly occurring with trimetrexate doses above 90 mg/m2 without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m2 IV every 6 hours for 3 days.

Trimethoprime toxicity:

After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

2) Therapy after high-dose methotrexate

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children: Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate. Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m2 body surface and should be considered with doses of 100 mg – 500 mg/m2 body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m?) to be given 12-24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is >0.5µmol/l, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of the methotrexate administration:

Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:

15 mg/m2

100 mg/m2

200 mg/m2

4.3 Contraindications

Leucovorin calcium should not be used in patients who have a known hypersensitivity to any of the constituents of the product.

Calcium folinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemia where vitamin B12 is deficient.

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported.

4.4 Special Warnings And Precautions For Use

Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Leucovorin should not be given simultaneously with a folic acid antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified.

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, as well as primidone and increase the frequency of seizures.

Concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the haematopoietic response to folic acid.

Calcium folinate may enhance the toxicity of fluorouracil.

4.6 Pregnancy And Lactation

Pregnancy:

There are no adequate and well-controlled clinical studies conducted in pregnant or breast feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.

Please refer to the SPC for methotrexate, other folate antagonists (and 5-fluorouracil) containing medicinal products.

Lactation

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Adverse reactions to leucovorin calcium are rare, but following intravenous and intramuscular administration occasional pyrexial reactions have been reported.

The most common dose-limiting adverse reaction occurring in patients receiving combination of calcium folinate and 5-fluorouracil are stomatitis and diarrhoea. In addition, haematological adverse reactions, such as leucocytopenia and thrombocytopenia, may occur. These adverse reactions are dose-dependent and their occurrence can usually be decreased by reducing the dosage of cytotoxic drugs. These adverse reactions can be controlled by close monitoring of haematological values, e.g. blood leucocyte and thrombocyte levels, and serum electrolyte (e.g. Na, K, Ca) and creatinine levels.

Anaphylactoid and urticaria allergic reactions have also been reported with the use of leucovorin.

4.9 Overdose

There have been no reported sequelae in patients who have received significantly more calcium folinate then the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-FU should be followed.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC Code: V03AF03

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. .) It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxics therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduce folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzymes forms of folic acid.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

5.2 Pharmacokinetic Properties

Absorption

Calcium folinate is rapidly absorbed in the gastrointestinal tract after oral administration. The oral absorption of calcium folinate is saturable at doses above 25mg. The bioavailability of calcium folinate is 97% for 25mg, 75% for 50mg, and 37% for 100mg. Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer. The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known. Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration. AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyltetrahydrofolate. Folate is concentrated in the cerebrospinal fluid, although distribution occurs to all body tissues.

Elimination

The elimination half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes for the inactive D-form, respectively. The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Hydrochloric Acid

Water for injections

6.2 Incompatibilities

None stated.

6.3 Shelf Life

24 Months

6.4 Special Precautions For Storage

Store at 2oC – 8oC and protect from light.

6.5 Nature And Contents Of Container

Type 1 colourless glass ampoules containing 2 or 10 ml. Packs of 5 or 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Prior to administration, calcium folinate should be inspected visually. The solution for injection or infusion should be clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded. Calcium folinate solution for injection or infusion is intended only for single use. Any unused potion of the solution should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00032/0346

9. Date Of First Authorisation/Renewal Of The Authorisation

17th July 2002

10. Date Of Revision Of The Text

November 2009

Ref: REA6.0


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Chirocaine 5mg / ml solution for injection / concentrate for solution for infusion


1. Name Of The Medicinal Product

Chirocaine 5 mg/ml solution for injection/concentrate for solution for infusion

2. Qualitative And Quantitative Composition

One ml contains 5 mg levobupivacaine as levobupivacaine hydrochloride.

Each ampoule contains 50 mg in 10 ml.

Excipients: 3.6mg/ml of sodium per ampoule.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection/concentrate for solution for infusion.

Clear colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Adults

Surgical anaesthesia

- Major, e.g. epidural (including for caesarean section), intrathecal, peripheral nerve block.

- Minor, e.g. local infiltration, peribulbar block in ophthalmic surgery.

Pain management

- Continuous epidural infusion, single or multiple bolus epidural administration for the management of pain especially post - operative pain or labour analgesia.

Children

Analgesia (ilioinguinal/iliohypogastric blocks).

4.2 Posology And Method Of Administration

Levobupivacaine should be administered only by, or under the supervision of, a clinician having the necessary training and experience.

The table below is a guide to dosage for the more commonly used blocks. For analgesia (e.g. epidural administration for pain management), the lower concentrations and doses are recommended. Where profound or prolonged anaesthesia is required with dense motor block (e.g. epidural or peribulbar block), the higher concentrations may be used. Careful aspiration before and during injection is recommended to prevent intravascular injection.

Aspiration should be repeated before and during administration of a bolus dose, which should be injected slowly and in incremental doses, at a rate of 7.5–30 mg/min, while closely observing the patient's vital functions and maintaining verbal contact.

If toxic symptoms occur, the injection should be stopped immediately.

Maximum dose

The maximum dosage must be determined by evaluating the size and physical status of the patient, together with the concentration of the agent and the area and route of administration. Individual variation in onset and duration of block does occur. Experience from clinical studies shows onset of sensory block adequate for surgery in 10-15 minutes following epidural administration, with a time to regression in the range of 6-9 hours.

The recommended maximum single dose is 150 mg.Where sustained motor and sensory block are required for a prolonged procedure, additional doses may be required. The maximum recommended dose during a 24 hour period is 400 mg. For post-operative pain management, the dose should not exceed 18.75 mg/hour.

Obstetrics

For caesarean section, higher concentrations than the 5.0 mg/ml solution should not be used (See 4.3). The maximum recommended dose is 150 mg.

For labour analgesia by epidural infusion, the dose should not exceed 12.5 mg/hour.

Children

In children, the maximum recommended dose for analgesia (ilioinguinal/iliohypogastric blocks) is 1.25 mg/kg/side.

The safety and efficacy of levobupivacaine in children for other indications have not been established.

Special populations

Debilitated, elderly or acutely ill patients should be given reduced doses of levobupivacaine commensurate with their physical status.

In the management of post-operative pain, the dose given during surgery must be taken into account.

There are no relevant data in patients with hepatic impairment (see sections 4.4 and 5.2).

Table of Doses

 

Concentration (mg/ml)1

Dose

Motor Block

Surgical Anaesthesia

     

Epidural (slow) bolus2 for surgery

- Adults

 

5.0-7.5

 

10-20 ml (50-150 mg)

 

Moderate to complete

Epidural slow injection3 for Caesarean Section

5.0

15-30 ml (75-150 mg)

Moderate to complete

Intrathecal

5.0

3 ml (15 mg)

Moderate to complete

Peripheral Nerve

 

Ilioinguinal/ Iliohypogastric blocks in children <12 years

2.5-5.0

 

2.5-5.0

1-40 ml (2.5-150 mg max

 

0.25-0.5 ml/kg (0.625-2.5 mg/kg)

Moderate to complete

 

Not applicable

Ophthalmic (peribulbar block)

7.5

5–15 ml (37.5-112.5 mg)

Moderate to complete

Local Infiltration

- Adults

 

2.5

 

1-60 ml (2.5-150 mg max )

 

Not applicable

Pain Management4

Labour Analgesia (epidural bolus5)

 

2.5

 

6-10 ml (15-25 mg)

 

Minimal to moderate

Labour Analgesia (epidural infusion)

1.256

4-10 ml/h (5-12.5 mg/h)

Minimal to moderate

Post-operative pain

1.256

2.5

10-15ml/h (12.5-18.75mg/h)

5-7.5ml/h (12.5–18.75mg/h)

Minimal to moderate

1 Levobupivacaine solution for injection/concentration for solution for infusion is available in 2.5, 5.0 and 7.5 mg/ml solutions.

2 Spread over 5 minutes (see also text).

3 Given over 15-20 minutes.

4 In cases where levobupivacaine is combined with other agents e.g. opioids in pain management, the levobupivacaine dose should be reduced and use of a lower concentration (e.g. 1.25 mg/ml) is preferable.

5 The minimum recommended interval between intermittent injections is 15 minutes.

6 For information on dilution, see section 6.6.

4.3 Contraindications

General contra-indications related to regional anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Levobupivacaine solutions are contra-indicated in patients with a known hypersensitivity to levobupivacaine, local anaesthetics of the amide type or any of the excipients (see section 4.8).

Levobupivacaine solutions are contra-indicated for intravenous regional anaesthesia (Bier's block).

Levobupivacaine solutions are contra-indicated in patients with severe hypotension such as cardiogenic or hypovolaemic shock.

Levobupivacaine solutions are contra-indicated for use in paracervical block in obstetrics (see section 4.6).

4.4 Special Warnings And Precautions For Use

All forms of local and regional anaesthesia with levobupivacaine should be performed in well-equipped facilities and administered by staff trained and experienced in the required anaesthetic techniques and able to diagnose and treat any unwanted adverse effects that may occur.

Levobupivacaine can cause acute allergic reactions, cardiovascular effects and neurological damage, see section 4.8.

Levobupivacaine should be used with caution for regional anaesthesia in patients with impaired cardiovascular function e.g. serious cardiac arrhythmias.

The introduction of local anesthetics via either intrathecal or epidural administration into the central nervous system in patients with preexisting CNS diseases may potentially exacerbate some of these disease states. Therefore, clinical judgment should be exercised when contemplating epidural or intrathecal anesthesia in such patients.

This medicinal product contains 3.6 mg/ml sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.

Epidural Anesthesia

During epidural administration of levobupivacaine, concentrated solutions (0.5-0.75%) should be administered in incremental doses of 3 to 5 ml with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. When a large dose is to be injected, e.g. in epidural block, a test dose of 3-5 ml lidocaine with adrenaline is recommended. An inadvertent intravascular injection may then be recognised by a temporary increase in heart rate and accidental intrathecal injection by signs of a spinal block. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given.

Epidural anaesthesia with any local anaesthetic may cause hypotension and bradycardia. All patients must have intravenous access established. The availability of appropriate fluids, vasopressors, anaesthetics with anticonvulsant properties, myorelaxants, and atropine, resuscitation equipment and expertise must be ensured (see section 4.9).

Major regional nerve blocks

The patient should have I.V. fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Use in Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Reactions may be due to intraarterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available.

Use in Ophthalmic Surgery

Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anaesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured. As with other anaesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions.

Special populations

Debilitated, elderly or acutely ill patients: levobupivacaine should be used with caution in debilitated, elderly or acutely ill patients (see section 4.2).

Hepatic impairment: since levobupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow e.g. alcoholics or cirrhotics (see section 5.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro studies indicate that the CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine. Although no clinical studies have been conducted, metabolism of levobupivacaine may be affected by CYP3A4 inhibitors eg: ketoconazole, and CYP1A2 inhibitors eg: methylxanthines.

Levobupivacaine should be used with caution in patients receiving anti-arrhythmic agents with local anaesthetic activity, e.g., mexiletine, or class III anti-arrhythmic agents since their toxic effects may be additive.

No clinical studies have been completed to assess levobupivacaine in combination with adrenaline.

4.6 Pregnancy And Lactation

Pregnancy

Levobupivacaine solutions are contraindicated for use in paracervical block in obstetrics. Based on experience with bupivacaine foetal bradycardia may occur following paracervical block (see section 4.3).

For levobupivacaine, there are no clinical data on first trimester-exposed pregnancies. Animal studies do not indicate teratogenic effects but have shown embryo-foetal toxicity at systemic exposure levels in the same range as those obtained in clinical use (see section 5.3). The potential risk for human is unknown. Levobupivacaine should therefore not be given during early pregnancy unless clearly necessary.

Nevertheless, to date, the clinical experience of bupivacaine for obstetrical surgery (at the term of pregnancy or for delivery) is extensive and has not shown a foetotoxic effect.

Lactation

Levobupivacaine excretion in breast milk is unknown. However, levobupivacaine is likely to be poorly transmitted in the breast milk, as for bupivacaine. Thus breast feeding is possible after local anaesthesia.

4.7 Effects On Ability To Drive And Use Machines

Levobupivacaine can have a major influence on the ability to drive or use machines. Patients should be warned not to drive or operate machinery until all the effects of the anaesthesia and the immediate effects of surgery are passed.

4.8 Undesirable Effects

The adverse drug reactions for Chirocaine are consistent with those known for its respective class of medicinal products. The most commonly reported adverse drug reactions are hypotension, nausea, anaemia, vomiting, dizziness, headache, pyrexia, procedural pain, back pain and foetal distress syndrome in obstetric use (see table below).

Adverse reactions reported either spontaneously or observed in clinical trials are depicted in the following table Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: very common (

System Organ Class

Frequency

Adverse Reaction

Blood and lymphatic system disorders

Very Common

Anaemia

Immune system disorders

Not known

Not known

Allergic reactions (in serious cases anaphylactic shock)

Hypersensitivity

Nervous system disorders

Common

Common

Not known

Not known

Not known

Not known

Not known

Not known

Dizziness

Headache

Convulsion

Loss of consciousness

Somnolence

Syncope

Paraesthesia

Paraplegia

Eye disorders

Not known

Vision blurred

Cardiac disorders

Not known

Not known

Not known

Not known

Not known

Atrioventricular block

Cardiac arrest

Ventricular tachyarrhythmia

Tachycardia

Bradycardia

Vascular disorders

Very common

Hypotension

Respiratory, thoracic and mediastinal disorders

Not known

Not known

Not known

Not known

Respiratory arrest

Laryngeal oedema

Apnoea

Sneezing

Gastrointestinal disorders

Very Common

Common

Not known

Nausea

Vomiting

Hypoasthesia oral

Loss of sphincter control

Skin and subcutaneous tissue disorders

Not known

Not known

Not known

Not known

Not known

Angioedema

Urticaria

Pruritus

Hyperhidrosis

Erythema

Musculoskeletal and connective tissue disorders

Common

Not known

Not known

Back pain

Muscle twitching

Muscular weakness

Renal and urinary disorders

Not known

Bladder dysfunction

Pregnancy, puerperium and perinatal conditions

Common

Foetal distress syndrome

General disorders and administration site conditions

Common

Pyrexia

Investigations

Not known

Not known

Cardiac output decreased

Electrocardiogram change

Injury, poisoning and procedural complications

Common

Procedural pain

Adverse reactions with local anaesthetics of the amide type are rare, but they may occur as a result of overdosage or unintentional intravascular injection and may be serious.

Cross-sensitivity among members of the amide-type local anesthetic group have been reported (see section 4.3).

Accidental intrathecal injection of local anaesthetics can lead to very high spinal anaesthesia.

Cardiovascular effects are related to depression of the conduction system of the heart and a reduction in myocardial excitability and contractility. Usually these will be preceded by major CNS toxicity, i.e. convulsions, but in rare cases, cardiac arrest may occur without prodromal CNS effects.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance or an injection of a non-sterile solution. Rarely, these may be permanent.

4.9 Overdose

Accidental intravascular injection of local anaesthetics may cause immediate toxic reactions. In the event of overdose, peak plasma concentrations may not be reached until 2 hours after administration depending upon the injection site and, therefore, signs of toxicity may be delayed. The effects of the drug may be prolonged.

Systemic adverse reactions following overdose or accidental intravascular injection reported with long acting local anaesthetic agents involve both CNS and cardiovascular effects.

CNS Effects

Convulsions should be treated immediately with intravenous thiopentone or diazepam titrated as necessary. Thiopentone and diazepam also depress central nervous system, respiratory and cardiac function. Therefore their use may result in apnoea. Neuro-muscular blockers may be used only if the clinician is confident of maintaining a patent airway and managing a fully paralysed patient.

If not treated promptly, convulsions with subsequent hypoxia and hypercarbia plus myocardial depression from the effects of the local anaesthetic on the heart, may result in cardiac arrhythmias, ventricular fibrillation or cardiac arrest.

Cardiovascular Effects

Hypotension may be prevented or attenuated by pre-treatment with a fluid load and/or the use of vasopressors. If hypotension occurs it should be treated with intravenous crystalloids or colloids and/or incremental doses of a vasopressor such as ephedrine 5-10 mg. Any coexisting causes of hypotension should be rapidly treated.

If severe bradycardia occurs, treatment with atropine 0.3 - 1.0 mg will normally restore the heart rate to an acceptable level.

Cardiac arrhythmia should be treated as required and ventricular fibrillation should be treated by cardioversion.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Local anaesthetics, amide

ATC Code N01B B10

Levobupivacaine is a long acting local anaesthetic and analgesic. It blocks nerve conduction in sensory and motor nerves largely by interacting with voltage sensitive sodium channels on the cell membrane, but also potassium and calcium channels are blocked. In addition, levobupivacaine interferes with impulse transmission and conduction in other tissues where effects on the cardiovascular and central nervous systems are most important for the occurrence of clinical adverse reactions.

The dose of levobupivacaine is expressed as base, whereas, in the racemate bupivacaine the dose is expressed as hydrochloride salt. This gives rise to approximately 13% more active substance in levobupivacaine solutions compared to bupivacaine. In clinical studies at the same nominal concentrations levobupivacaine showed similar clinical effect to bupivacaine.

In a clinical pharmacology study using the ulnar nerve block model, levobupivacaine was equipotent with bupivacaine.

5.2 Pharmacokinetic Properties

In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine. The plasma concentration of levobupivacaine following therapeutic administration depends on dose and, as absorption from the site of administration is affected by the vascularity of the tissue, on route of administration.

There are no relevant data in patients with hepatic impairment (see section 4.4).

There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.

Plasma protein binding of levobupivacaine in man was evaluated in vitro and was found to be> 97% at concentrations between 0.1 and 1.0 ?g/ml.

In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 + 22 minutes, Cmax 1.4 + 0.2 ?g/ml and AUC 70 + 27 ?g•min/ml.

The mean Cmax and AUC(0-24h) of levobupivacaine were approximately dose-proportional following epidural administration of 75 mg (0.5%) and 112.5 mg (0.75%) and following doses of 1 mg/kg (0.25%) and 2 mg/kg (0.5%) used for brachial plexus block. Following epidural administration of 112.5 mg (0.75%) the mean Cmax and AUC values were 0.58 µg/ml and 3.56?µg•h/ml respectively.

The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. The volume of distribution after intravenous administration was 67 litres.

Levobupivacaine is extensively metabolised with no unchanged levobupivacaine detected in urine or faeces. 3-hydroxylevobupivacaine, a major metabolite of levobupivacaine, is excreted in the urine as glucuronic acid and sulphate ester conjugates. In vitro studies showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl-levobupivacaine and 3-hydroxylevobupivacaine respectively. These studies indicate that the metabolism of levobupivacaine and bupivacaine are similar.

Following intravenous administration, recovery of levobupivacaine was quantitative with a mean total of about 95% being recovered in urine (71%) and faeces (24%) in 48 hours.

There is no evidence of in vivo racemisation of levobupivacaine.

5.3 Preclinical Safety Data

In an embryo-foetal toxicity study in rats, an increased incidence of dilated renal pelvis, dilated ureters, olfactory ventricle dilatation and extra thoraco-lumbar ribs was observed at systemic exposure levels in the same range as those obtained at clinical use. There were no treatment-related malformations.

Levobupivacaine was not genotoxic in a standard battery of assays for mutagenicity and clastogenicity. No carcinogenicity testing has been conducted.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Hydrochloric acid

Water for Injections

6.2 Incompatibilities

Levobupivacaine may precipitate if diluted with alkaline solutions and should not be diluted or co-administered with sodium bicarbonate injections. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Shelf life as packaged for sale: 3 years

Shelf life after first opening: The product should be used immediately

Shelf life after dilution in sodium chloride solution 0.9%: Chemical and physical in-use stability has been demonstrated for 7 days at 20-22°C. Chemical and physical in-use stability with clonidine, morphine or fentanyl has been demonstrated for 40 hours at 20-22°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special Precautions For Storage

Polypropylene ampoules: polypropylene ampoules do not require any special storage conditions.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Chirocaine is available in two presentations;

10 ml polypropylene ampoule in packs of 5, 10 & 20

10 ml polypropylene ampoule, in sterile blister packs of 5, 10 & 20

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only. Discard any unused solution.

The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used.

A sterile blister container should be chosen when a sterile ampoule surface is required. Ampoule surface is not sterile if sterile blister is pierced.

Dilutions of levobupivacaine standard solutions should be made with sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic techniques.

Clonidine 8.4 ?g/ml, morphine 0.05 mg/ml and fentanyl 4 ?g/ml have been shown to be compatible with levobupivacaine in sodium chloride 9 mg/ml (0.9%) solution for injection.

7. Marketing Authorisation Holder

Abbott Laboratories Ltd

Abbott House

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00037/0301

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 06th January 2000

Date of last renewal: 18th December 2008

10. Date Of Revision Of The Text

2nd July 2010


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Chirocaine 2.5mg / ml solution for injection / concentrate for solution for infusion


1. Name Of The Medicinal Product

Chirocaine 2.5 mg/ml solution for injection/concentrate for solution for infusion.

2. Qualitative And Quantitative Composition

One ml contains 2.5 mg levobupivacaine as levobupivacaine hydrochloride.

Each ampoule contains 25 mg in 10 ml.

Excipients: 3.6mg/ml of sodium per ampoule.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection/concentrate for solution for infusion.

Clear colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Adults

Surgical anaesthesia

- Major, e.g. epidural (including for caesarean section), intrathecal, peripheral nerve block.

- Minor, e.g. local infiltration, peribulbar block in ophthalmic surgery.

Pain management

- Continuous epidural infusion, single or multiple bolus epidural administration for the management of pain especially post-operative pain or labour analgesia.

Children

Analgesia (ilioinguinal/iliohypogastric blocks).

4.2 Posology And Method Of Administration

Levobupivacaine should be administered only by, or under the supervision of, a clinician having the necessary training and experience.

The table below is a guide to dosage for the more commonly used blocks. For analgesia (e.g. epidural administration for pain management), the lower concentrations and doses are recommended. Where profound or prolonged anaesthesia is required with dense motor block (e.g. epidural or peribulbar block), the higher concentrations may be used. Careful aspiration before and during injection is recommended to prevent intravascular injection.

Aspiration should be repeated before and during administration of a bolus dose, which should be injected slowly and in incremental doses, at a rate of 7.5–30 mg/min, while closely observing the patient's vital functions and maintaining verbal contact.

If toxic symptoms occur, the injection should be stopped immediately.

Maximum dose

The maximum dosage must be determined by evaluating the size and physical status of the patient, together with the concentration of the agent and the area and route of administration. Individual variation in onset and duration of block does occur. Experience from clinical studies shows onset of sensory block adequate for surgery in 10-15 minutes following epidural administration, with a time to regression in the range of 6-9 hours.

The recommended maximum single dose is 150 mg.Where sustained motor and sensory block are required for a prolonged procedure, additional doses may be required. The maximum recommended dose during a 24 hour period is 400 mg. For post-operative pain management, the dose should not exceed 18.75 mg/hour.

Obstetrics

For caesarean section, higher concentrations than the 5.0 mg/ml solution should not be used (See section 4.3). The maximum recommended dose is 150 mg.

For labour analgesia by epidural infusion, the dose should not exceed 12.5 mg/hour.

Children

In children, the maximum recommended dose for analgesia (ilioinguinal/iliohypogastric blocks) is 1.25 mg/kg/side.

The safety and efficacy of levobupivacaine in children for other indications have not been established.

Special populations

Debilitated, elderly or acutely ill patients should be given reduced doses of levobupivacaine commensurate with their physical status.

In the management of post-operative pain, the dose given during surgery must be taken into account.

There are no relevant data in patients with hepatic impairment (see sections 4.4 and 5.2).

Table of Doses

 

Concentration (mg/ml)1

Dose

Motor Block

Surgical Anaesthesia

     

Epidural (slow) bolus2 for surgery

- Adults

 

5.0-7.5

 

10-20 ml (50-150 mg)

 

Moderate to complete

Epidural slow injection3 for Caesarean Section

5.0

15-30 ml (75-150 mg)

Moderate to complete

Intrathecal

5.0

3 ml (15 mg)

Moderate to complete

Peripheral Nerve

Ilioinguinal/Iliohypogastric blocks in children <12 years

2.5-5.0

2.5-5.0

1-40 ml (2.5-150 mg max.)

0.25-0.5 ml/kg (0.625-2.5 mg/kg)

Moderate to complete

Not applicable

Ophthalmic (peribulbar block)

7.5

5–15 ml (37.5-112.5 mg)

Moderate to complete

Local Infiltration

- Adults

 

2.5

 

1-60 ml (2.5-150 mg max.)

 

Not applicable

Pain Management4

Labour Analgesia (epidural bolus5)

 

2.5

 

6-10 ml (15-25 mg)

 

Minimal to moderate

Labour Analgesia (epidural infusion)

1.256

4-10 ml/h (5-12.5 mg/h)

Minimal to moderate

Post-operative pain

1.256

2.5

10-15ml/h (12.5-18.75mg/h)

5-7.5ml/h (12.5 –18.75mg/h)

Minimal to moderate

1 Levobupivacaine solution for injection/concentration for solution for infusion is available in 2.5, 5.0 and 7.5 mg/ml solutions.

2 Spread over 5 minutes (see also text).

3 Given over 15-20 minutes.

4 In cases where levobupivacaine is combined with other agents e.g. opioids in pain management, the levobupivacaine dose should be reduced and use of a lower concentration (e.g. 1.25 mg/ml) is preferable.

5 The minimum recommended interval between intermittent injections is 15 minutes.

6 For information on dilution, see section 6.6.

4.3 Contraindications

General contra-indications related to regional anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Levobupivacaine solutions are contra-indicated in patients with a known hypersensitivity to levobupivacaine, local anaesthetics of the amide type or any of the excipients (see section 4.8).

Levobupivacaine solutions are contra-indicated for intravenous regional anaesthesia (Bier's block).

Levobupivacaine solutions are contra-indicated in patients with severe hypotension such as cardiogenic or hypovolaemic shock.

Levobupivacaine solutions are contra-indicated for use in paracervical block in obstetrics (see section 4.6).

4.4 Special Warnings And Precautions For Use

All forms of local and regional anaesthesia with levobupivacaine should be performed in well-equipped facilities and administered by staff trained and experienced in the required anaesthetic techniques and able to diagnose and treat any unwanted adverse effects that may occur.

Levobupivacaine can cause acute allergic reactions, cardiovascular effects and neurological damage, see section 4.8.

Levobupivacaine should be used with caution for regional anaesthesia in patients with impaired cardiovascular function e.g. serious cardiac arrhythmias.

The introduction of local anesthetics via either intrathecal or epidural administration into the central nervous system in patients with preexisting CNS diseases may potentially exacerbate some of these disease states. Therefore, clinical judgment should be exercised when contemplating epidural or intrathecal anesthesia in such patients.

This medicinal product contains 3.6 mg/ml sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.

Epidural Anesthesia

During epidural administration of levobupivacaine, concentrated solutions (0.5-0.75%) should be administered in incremental doses of 3 to 5 ml with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. When a large dose is to be injected, e.g. in epidural block, a test dose of 3-5 ml lidocaine with adrenaline is recommended. An inadvertent intravascular injection may then be recognised by a temporary increase in heart rate and accidental intrathecal injection by signs of a spinal block.

Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given.

Epidural anaesthesia with any local anaesthetic may cause hypotension and bradycardia. All patients must have intravenous access established. The availability of appropriate fluids, vasopressors, anaesthetics with anticonvulsant properties, myorelaxants, and atropine, resuscitation equipment and expertise must be ensured (see section 4.9).

Major regional nerve blocks

The patient should have I.V. fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Use in Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Reactions may be due to intraarterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available.

Use in Ophthalmic Surgery

Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anaesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions.

Special populations

Debilitated, elderly or acutely ill patients: levobupivacaine should be used with caution in debilitated, elderly or acutely ill patients (see section 4.2).

Hepatic impairment: since levobupivacaine is metabolised in the liver, it should be used cautiously in patients with liver disease or with reduced liver blood flow e.g. alcoholics or cirrhotics (see section 5.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro studies indicate that the CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine. Although no clinical studies have been conducted, metabolism of levobupivacaine may be affected by CYP3A4 inhibitors eg: ketoconazole, and CYP1A2 inhibitors eg: methylxanthines.

Levobupivacaine should be used with caution in patients receiving anti-arrhythmic agents with local anaesthetic activity, e.g., mexiletine, or class III anti-arrhythmic agents since their toxic effects may be additive.

No clinical studies have been completed to assess levobupivacaine in combination with adrenaline.

4.6 Pregnancy And Lactation

Pregnancy

Levobupivacaine solutions are contraindicated for use in paracervical block in obstetrics. Based on experience with bupivacaine foetal bradycardia may occur following paracervical block (see section 4.3).

For levobupivacaine, there are no clinical data on first trimester-exposed pregnancies. Animal studies do not indicate teratogenic effects but have shown embryo-foetal toxicity at systemic exposure levels in the same range as those obtained in clinical use (see section 5.3). The potential risk for human is unknown. Levobupivacaine should therefore not be given during early pregnancy unless clearly necessary.

Nevertheless, to date, the clinical experience of bupivacaine for obstetrical surgery (at the term of pregnancy or for delivery) is extensive and has not shown a foetotoxic effect.

Lactation

Levobupivacaine excretion in breast milk is unknown. However, levobupivacaine is likely to be poorly transmitted in the breast milk, as for bupivacaine. Thus breast feeding is possible after local anaesthesia.

4.7 Effects On Ability To Drive And Use Machines

Levobupivacaine can have a major influence on the ability to drive or use machines. Patients should be warned not to drive or operate machinery until all the effects of the anaesthesia and the immediate effects of surgery are passed.

4.8 Undesirable Effects

The adverse drug reactions for Chirocaine are consistent with those known for its respective class of medicinal products. The most commonly reported adverse drug reactions are hypotension, nausea, anaemia, vomiting, dizziness, headache, pyrexia, procedural pain, back pain and foetal distress syndrome in obstetric use (see table below).

Adverse reactions reported either spontaneously or observed in clinical trials are depicted in the following table. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, using the following convention: very common (

System Organ Class

Frequency

Adverse Reaction

Blood and lymphatic system disorders

Very Common

Anaemia

Immune system disorders

Not known

Not known

Allergic reactions (in serious cases anaphylactic shock)

Hypersensitivity

Nervous system disorders

Common

Common

Not known

Not known

Not known

Not known

Not known

Not known

Dizziness

Headache

Convulsion

Loss of consciousness

Somnolence

Syncope

Paraesthesia

Paraplegia

Eye disorder

Not known

Vision blurred

Cardiac disorders

Not known

Not known

Not known

Not known

Not known

Atrioventricular block

Cardiac arrest

Ventricular tachyarrhythmia

Tachycardia

Bradycardia

Vascular disorders

Very common

Hypotension

Respiratory, thoracic and mediastinal disorders

Not known

Not known

Not known

Not known

Respiratory arrest

Laryngeal oedema

Apnoea

Sneezing

Gastrointestinal disorders

Very Common

Common

Not known

Nausea

Vomiting

Hypoaesthesia oral

Loss of sphincter control

Skin and subcutaneous tissue disorders

Not known

Not known

Not known

Not known

Not known

Angioedema

Urticaria

Pruritus

Hyperhidrosis

Erythema

Musculoskeletal and connective tissue disorders

Common

Not known

Not known

Back pain

Muscle twitching

Muscular weakness

Renal and urinary disorders

Not known

Bladder dysfunction

Pregnancy, puerperium and perinatal conditions

Common

Foetal distress syndrome

General disorders and administration site conditions

Common

Pyrexia

Investigations

Not known

Not known

Cardiac output decreased

Electrocardiogram change

Injury, poisoning and procedural complications

Common

Procedural pain

Adverse reactions with local anaesthetics of the amide type are rare, but they may occur as a result of overdosage or unintentional intravascular injection and may be serious.

Cross-sensitivity among members of the amide-type local anesthetic group have been reported (see section 4.3).

Accidental intrathecal injection of local anaesthetics can lead to very high spinal anaesthesia.

Cardiovascular effects are related to depression of the conduction system of the heart and a reduction in myocardial excitability and contractility. Usually these will be preceded by major CNS toxicity, i.e. convulsions, but in rare cases, cardiac arrest may occur without prodromal CNS effects.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance or an injection of a non-sterile solution. These may result in localised areas of paraesthesia or anaesthesia, motor weakness, loss of sphincter control and paraplegia. Rarely, these may be permanent.

4.9 Overdose

Accidental intravascular injection of local anaesthetics may cause immediate toxic reactions. In the event of overdose, peak plasma concentrations may not be reached until 2 hours after administration depending upon the injection site and, therefore, signs of toxicity may be delayed. The effects of the drug may be prolonged.

Systemic adverse reactions following overdose or accidental intravascular injection reported with long acting local anaesthetic agents involve both CNS and cardiovascular effects.

CNS Effects

Convulsions should be treated immediately with intravenous thiopentone or diazepam titrated as necessary. Thiopentone and diazepam also depress central nervous system, respiratory and cardiac function. Therefore their use may result in apnoea. Neuro-muscular blockers may be used only if the clinician is confident of maintaining a patent airway and managing a fully paralysed patient.

If not treated promptly, convulsions with subsequent hypoxia and hypercarbia plus myocardial depression from the effects of the local anaesthetic on the heart, may result in cardiac arrhythmias, ventricular fibrillation or cardiac arrest.

Cardiovascular Effects

Hypotension may be prevented or attenuated by pre-treatment with a fluid load and/or the use of vasopressors. If hypotension occurs it should be treated with intravenous crystalloids or colloids and/or incremental doses of a vasopressor such as ephedrine 5-10 mg. Any coexisting causes of hypotension should be rapidly treated.

If severe bradycardia occurs, treatment with atropine 0.3-1.0 mg will normally restore the heart rate to an acceptable level.

Cardiac arrhythmia should be treated as required and ventricular fibrillation should be treated by cardioversion.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Local anaesthetics, amide

ATC Code N01B B10

Levobupivacaine is a long acting local anaesthetic and analgesic. It blocks nerve conduction in sensory and motor nerves largely by interacting with voltage sensitive sodium channels on the cell membrane, but also potassium and calcium channels are blocked. In addition, levobupivacaine interferes with impulse transmission and conduction in other tissues where effects on the cardiovascular and central nervous systems are most important for the occurrence of clinical adverse reactions.

The dose of levobupivacaine is expressed as base, whereas, in the racemate bupivacaine the dose is expressed as hydrochloride salt. This gives rise to approximately 13% more active substance in levobupivacaine solutions compared to bupivacaine. In clinical studies at the same nominal concentrations levobupivacaine showed similar clinical effect to bupivacaine.

In a clinical pharmacology study using the ulnar nerve block model, levobupivacaine was equipotent with bupivacaine.

5.2 Pharmacokinetic Properties

In human studies, the distribution kinetics of levobupivacaine following i.v. administration are essentially the same as bupivacaine. The plasma concentration of levobupivacaine following therapeutic administration depends on dose and, as absorption from the site of administration is affected by the vascularity of the tissue, on route of administration.

There are no relevant data in patients with hepatic impairment (see section 4.4).

There are no data in patients with renal impairment. Levobupivacaine is extensively metabolised and unchanged levobupivacaine is not excreted in urine.

Plasma protein binding of levobupivacaine in man was evaluated in vitro and was found to be> 97% at concentrations between 0.1 and 1.0 ?g/ml.

In a clinical pharmacology study where 40 mg levobupivacaine was given by intravenous administration, the mean half-life was approximately 80 + 22 minutes, Cmax 1.4 + 0.2 ?g/ml and AUC 70 + 27 ?g•min/ml.

The mean Cmax and AUC(0-24h) of levobupivacaine were approximately dose-proportional following epidural administration of 75 mg (0.5%) and 112.5 mg (0.75%) and following doses of 1 mg/kg (0.25%) and 2 mg/kg (0.5%) used for brachial plexus block. Following epidural administration of 112.5 mg (0.75%) the mean Cmax and AUC values were 0.58 µg/ml and 3.56?µg•h/ml respectively.

The mean total plasma clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 litres/hour and 1.3 hours, respectively. The volume of distribution after intravenous administration was 67 litres.

Levobupivacaine is extensively metabolised with no unchanged levobupivacaine detected in urine or faeces. 3-hydroxylevobupivacaine, a major metabolite of levobupivacaine, is excreted in the urine as glucuronic acid and sulphate ester conjugates. In vitro studies showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl-levobupivacaine and 3-hydroxylevobupivacaine respectively.These studies indicate that the metabolism of levobupivacaine and bupivacaine are similar.

Following intravenous administration, recovery of levobupivacaine was quantitative with a mean total of about 95% being recovered in urine (71%) and faeces (24%) in 48 hours.

There is no evidence of in vivo racemisation of levobupivacaine.

5.3 Preclinical Safety Data

In an embryo-foetal toxicity study in rats, an increased incidence of dilated renal pelvis, dilated ureters, olfactory ventricle dilatation and extra thoraco-lumbar ribs was observed at systemic exposure levels in the same range as those obtained at clinical use. There were no treatment-related malformations.

Levobupivacaine was not genotoxic in a standard battery of assays for mutagenicity and clastogenicity. No carcinogenicity testing has been conducted.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Hydrochloric acid

Water for Injections

6.2 Incompatibilities

Levobupivacaine may precipitate if diluted with alkaline solutions and should not be diluted or co-administered with sodium bicarbonate injections. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Shelf life as packaged for sale: 3 years

Shelf life after first opening: The product should be used immediately

Shelf life after dilution in sodium chloride solution 0.9%: Chemical and physical in-use stability has been demonstrated for 7 days at 20-22°C. Chemical and physical in-use stability with clonidine, morphine or fentanyl has been demonstrated for 40 hours at 20-22°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special Precautions For Storage

Polypropylene ampoules: polypropylene ampoules do not require any special storage conditions.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Chirocaine is available in two presentations;

10 ml polypropylene ampoule in packs of 5, 10 & 20

10 ml polypropylene ampoule, in sterile blister packs of 5, 10 & 20

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only. Discard any unused solution.

The solution/dilution should be inspected visually prior to use. Only clear solutions without visible particles should be used.

A sterile blister container should be chosen when a sterile ampoule surface is required. Ampoule surface is not sterile if sterile blister is pierced.

Dilutions of levobupivacaine standard solutions should be made with sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic techniques.

Clonidine 8.4 ?g/ml, morphine 0.05 mg/ml and fentanyl 4 ?g/ml have been shown to be compatible with levobupivacaine in sodium chloride 9 mg/ml (0.9%) solution for injection.

7. Marketing Authorisation Holder

Abbott Laboratories Ltd

Abbott House

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00037/0300

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 06 January 2000

Date of last renewal: 18th December 2008

10. Date Of Revision Of The Text

02nd July 2010


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Lemsip Max All in One Lemon (Reckitt Benckiser Healthcare (UK) Ltd)


1. Name Of The Medicinal Product

Lemsip Max All in One Lemon.

2. Qualitative And Quantitative Composition    

Active Ingredients

mg/sachet

Paracetamol

1000.00

Phenylephrine hydrochloride

12.2

Guaifenesin

200.00

3. Pharmaceutical Form

Powder for oral solution. Pale yellow powder.

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of symptoms of colds and influenza, including the relief of aches and pains, sore throat, headache, nasal congestion, lowering of temperature and chesty coughs.

4.2 Posology And Method Of Administration

Oral administration after dissolution in water. Adults and adolescents 12 years and over: One sachet dissolved by stirring in hot water and sweetened to taste. Dose may be repeated in 4-6 hours. No more than four doses should be taken in 24 hours. Not to be given to children under 12 without medical advice.

4.3 Contraindications

Hypersensitivity to any of the ingredients. Severe coronary heart disease. Hypertension.

4.4 Special Warnings And Precautions For Use

Use with caution in patients with Raynaud's phenomenon or diabetes mellitus. This product also contains 1973.3mg sucrose per sachet dose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Contains a source of phenylalanine. May be harmful for people with phenylketonuria. Phenylephrine should be used with care in patients with hyperthyroidism, cardiovascular disease, diabetes mellitus, closed angle glaucoma, prostatic enlargement and hypertension. Leaflet: Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage. Do not exceed the stated dose. Patients should be advised not to take other paracetamol – containing products or other cold and decongestant medicines concurrently. If symptoms persist, consult your doctor. Keep out of the reach and sight of children. If you are pregnant or are being prescribed medicine by your doctor, seek his advice before taking this product. Contains paracetamol (panel). Total sugars 2g. Immediate medical advice should be sought in the event of an overdose, even if you feel well.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect. Phenylephrine may adversely interact with other sympathomimetics, vasodilators and beta-blockers. Drugs, which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdosage. Not recommended for patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors.

Guaifenesin may increase the rate of absorption of paracetamol. Guaifenesin may interfere with diagnostic measurements of urinary 5-hydroxyindoleactic acid or vanillylmandelic acid.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast-feeding. Phenylephrine hydrochloride: Due to the vasoconstrictive properties of phenylephrine, the product should be used with caution in patients with a history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh this risk. There is no information on use in lactation. Guaifenesin: Has been linked with an increased risk of neural tube defects in a small number of women with febrile illness in the first trimester of pregnancy. The product should be used in pregnancy only if the benefits outweigh this risk. There is no information on use in lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. Phenylephrine hydrochloride: High blood pressure with headache, vomiting and rarely, palpitations. Also, rare reports of allergic reactions. Guaifenesin has occasionally been reported to cause gastro-intestinal discomfort, nausea and vomiting, particularly in very high doses.

4.9 Overdose

Paracetamol: Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of five or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors If the patient: (a) Is on long-term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes, or (b) Regularly consumes ethanol in excess of recommended amounts, or (c) Is likely to be glutathione deplete, e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia. Symptoms: Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Management: Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit.

Phenylephrine hydrochloride: Features of severe overdosage of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression. Treatment includes early gastric lavage and symptomatic and supportive measures. Hypertensive effects may be treated with an i.v. alpha-receptor-blocking agent. Guaifenesin: Very large doses may cause nausea and vomiting. The drug is, however, rapidly metabolised and excreted in the urine. Patients should be kept under observation and treated symptomatically.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: N02B E51.

Paracetamol: Paracetamol has both analgesic and antipyretic activity, which is believed to be mediated principally through its inhibition of prostaglandin synthesis within the central nervous system.

Phenylephrine hydrochloride: Phenylephrine is a post-synaptic alpha-receptor agonist with low cardioselective beta-receptor affinity and minimal central stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

Guaifenesin: Guaifenesin is an expectorant which reduces the viscosity of tenacious sputum.

5.2 Pharmacokinetic Properties

Paracetamol: Paracetamol is absorbed rapidly and completely from the small intestine, producing peak plasma levels after 15-20 minutes following oral dosing. The systemic availability is subject to first-pass metabolism and varies with dose between 70% and 90%. The drug is rapidly and widely distributed throughout the body and is eliminated from plasma with a T? of approximately 2 hours. The major metabolites are glucuronide and sulphate conjugates (>80%) which are excreted in urine.

Phenylephrine hydrochloride: Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of the nasal mucosa. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours.

Guaifenesin: Guaifenesin is absorbed from the gastrointestinal tract. It is rapidly metabolised by oxidation to ?-(2 methoxy-phenoxy) lactic acid; which is excreted in the urine.

5.3 Preclinical Safety Data

None available specific to the product.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Ascorbic acid

Sucrose

Citric acid

Sodium citrate

Lemon flavour no. 1

Aspartame (E951)

Saccharin sodium

Curcumin WD

6.2 Incompatibilities

None Known

6.3 Shelf Life

Two years.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

Heat-sealed sachet of paper/polyethylene/aluminium foil/ polyethylene laminate in an outer cardboard carton. Packs: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 sachets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS, East Yorkshire, United Kingdom.

8. Marketing Authorisation Number(S)

PL 00063/0168.

9. Date Of First Authorisation/Renewal Of The Authorisation

18/12/2006

10. Date Of Revision Of The Text

18/12/2006


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