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Boots Paracetamol 500 mg Capsules (P -32)


Boots Paracetamol 500 mg Capsules

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription to treat minor conditions. However, you still need to take it carefully to get the best results from it.

Keep this leaflet, you may need to read it again Ask your pharmacist if you need more information or advice What this medicine is for

This medicine contains a painkiller to relieve mild to moderate pain and fever.

It can be used to relieve headaches, migraine, rheumatic aches and pains, muscular pain and back pain, neuralgia, toothache, sore throat, period pain, fever and the symptoms of colds and flu.

Before you take this medicine

This medicine can be taken by adults and children aged 12 years and over. However, some people should not take this medicine or should seek the advice of their pharmacist or doctor first.

Do not take: If you are allergic to any of the ingredients Talk to your pharmacist or doctor: If you have severe kidney problems or severe liver problems (including a disease caused by drinking alcohol) If you are pregnant

You can take this medicine if you are breastfeeding.

Other important information

Information about some of the ingredients: Propyl parahydroxybenzoate (E216) and methyl parahydroxybenzoate (E218) in this medicine may cause allergic reactions (possibly delayed).

If you take other medicines

This medicine contains paracetamol.

Do not take with any other paracetamol-containing products.

Before you take these capsules, make sure that you tell your pharmacist about ANY other medicines you might be using at the same time, particularly the following:

Metoclopramide or domperidone (for feeling sick or being sick) Colestyramine (to reduce blood fat levels) Warfarin or other blood thinners - If you take warfarin you can take occasional amounts of this medicine, but talk to your doctor first before you take it on a regular basis

If you are unsure about interactions with any other medicines, talk to your pharmacist. This includes medicines prescribed by your doctor and medicine you have bought for yourself, including herbal and homeopathic remedies.

How to take this medicine

Check the foil is not broken before use. If it is, do not take that capsule.

Adults and children of 12 years and over: Take one or two capsules three or four times a day, if you need to.
Don’t take more than 8 capsules in any 24 hours. Don’t take more often than every 4 hours.

Swallow each capsule with water.

Do not give to children under 12 years.

Do not take more than the amount recommended above.

If symptoms do not go away talk to your doctor.

If you take too many capsules: 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. Go to your nearest hospital casualty department. Take your medicine and this leaflet with you.

Possible side effects

Most people will not have problems, but some may get some.

If you get any of these serious side effects, stop taking the capsules. See a doctor at once: Difficulty in breathing, swelling of the face, neck, tongue or throat (severe allergic reactions) These other effects are less serious. If they bother you talk to a pharmacist: Skin rash Unusual bruising, or infections such as sore throats - this may be a sign of very rare changes in the blood

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Store in the original package.

Keep this medicine in a safe place out of the sight and reach of children, preferably in a locked cupboard.

Use by the date on the end flap of the carton.

What is in this medicine

Each hard gelatin capsule contains Paracetamol 500 mg, which is the active ingredient.

As well as the active ingredient, the capsules also contain pregelatinised maize starch, magnesium stearate, sodium laurilsulfate. The capsule shell contains titanium dioxide (E171), erythrosine (E127), quinoline yellow (E104), Patent Blue V (E131), gelatin, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216).

The pack contains 32 hard gelatin capsules with a red cap and white body.

Who makes this medicine

Manufactured for

The Boots Company PLC Nottingham NG2 3AA

by the Marketing Authorisation holder

Bristol Laboratories Ltd Unit 3 Canalside Northbridge Road Berkhamsted Hertfordshire HP4 1EG

Leaflet prepared July 2007

If you would like any further information about this medicine, please contact

The Boots Company PLC Nottingham NG2 3AA

3448-32eMC-Xpil


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Prevident 5000 Sensitive


sodium fluoride and potassium nitrate gel
Dosage Form: gel, dentifrice
Colgate®
PreviDent®5000 ppm

SENSITIVE

Rx ONLY

1.1% Sodium Fluoride, 5% Potassium Nitrate

Prescription Strength Toothpaste for Sensitive Teeth

Prevident 5000 Sensitive Description

Self-topical neutral fluoride toothpaste containing 1.1% (w/w) sodium fluoride and 5% potassium nitrate.

Active Ingredients

Sodium fluoride 1.1% (w/w), Potassium nitrate 5%

Inactive Ingredients

water, hydrated silica, sorbitol, PEG-12, carrageenan, sodium lauryl sulfate, flavor, poloxamer 407, cocamidopropyl betaine, sodium saccharin, mica, sodium hydroxide, titanium dioxide, D&C yellow no. 10, FD&C blue no. 1

Prevident 5000 Sensitive - Clinical Pharmacology

Frequent topical applications to the teeth with preparations having a relatively high fluoride content increase tooth resistance to acid dissolution and enhance penetration of the fluoride ion into tooth enamel.

Indications and Usage for Prevident 5000 Sensitive

A dental caries preventive and sensitive teeth toothpaste; for twice daily self-applied topical use, followed by rinsing. Helps reduce the painful sensitivity of the teeth to cold, heat, acids, sweets or contact in adult patients and children 12 years of age and older. It is well established that 1.1% sodium fluoride is safe and extraordinarily effective as a caries preventive when applied frequently with mouthpiece applicators. 1-4 PreviDent® 5000 Sensitive brand of 1.1% sodium fluoride toothpaste with 5% potassium nitrate in a squeeze bottle is easily applied onto a toothbrush. This prescription toothpaste should be used twice daily in place of your regular toothpaste unless otherwise instructed by your dental professional. May be used in areas where drinking water is fluoridated since topical fluoride cannot produce fluorosis. (See WARNINGS for exception.)

Contraindications

Do not use in pediatric patients under age 12 years unless recommended by a dentist or physician.

Warnings

Not for systemic treatment - DO NOT SWALLOW. Keep out of reach of infants and children. Children under 12 years of age, consult a dentist or physician.

Note: Sensitive teeth may indicate a serious problem that may need prompt care by a dentist. See your dentist if the problem persists or worsens. Do not use this product longer than 4 weeks unless recommended by a dentist or physician.

Precautions General

Not for systemic treatment. DO NOT SWALLOW.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a study conducted in rodents, no carcinogenesis was found in male and female mice and female rats treated with fluoride at dose levels ranging from 4.1 to 9.1 mg/kg of body weight. Equivocal evidence of carcinogenesis was reported in male rats treated with 2.5 and 4.1 mg/kg of body weight. In a second study, no carcinogenesis was observed in rats, males or females, treated with fluoride up to 11.3 mg/kg of body weight. Epidemiological data provide no credible evidence for an association between fluoride, either naturally occurring or added to drinking water, and risk of human cancer.

Fluoride ion is not mutagenic in standard bacterial systems. It has been shown that fluoride ion has potential to induce chromosome aberrations in cultured human and rodent cells at doses much higher than those to which humans are exposed. In vivo data are conflicting. Some studies report chromosome damage in rodents, while other studies using similar protocols report negative results.

Potential adverse reproductive effects of fluoride exposure in humans has not been adequately evaluated. Adverse effects on reproduction were reported for rats, mice, fox, and cattle exposed to 100 ppm or greater concentrations of fluoride in their diet or drinking water. Other studies conducted in rats demonstrated that lower concentrations of fluoride (5 mg/kg of body weight) did not result in impaired fertility and reproductive capabilities.

Pregnancy Teratogenic Effects Pregnancy Category B

It has been shown that fluoride crosses the placenta of rats, but only 0.01% of the amount administered is incorporated in fetal tissue. Animal studies (rats, mice, rabbits) have shown that fluoride is not a teratogen. Maternal exposure to 12.2 mg fluoride/kg of body weight (rats) or 13.1 mg/kg of body weight (rabbits) did not affect the litter size or fetal weight and did not increase the frequency of skeletal or visceral malformations. There are no adequate and well-controlled studies in pregnant women. However, epidemiological studies conducted in areas with high levels of naturally fluoridated water showed no increase in birth defects. Heavy exposure to fluoride during in utero development may result in skeletal fluorosis which becomes evident in childhood.

Nursing Mothers

It is not known if fluoride is excreted in human milk. However, many drugs are excreted in milk, and caution should be exercised when products containing fluoride are administered to a nursing woman. Reduced milk production was reported in farm-raised fox when the animals were fed a diet containing a high concentration of fluoride (98-137 mg/kg of body weight). No adverse effects on parturition, lactation, or offspring were seen in rats administered fluoride up to 5 mg/kg of body weight.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established. Please refer to the CONTRAINDICATIONS and WARNINGS sections.

Geriatric Use

Of the total number of subjects in clinical studies of 1.1% (w/v) sodium fluoride, 15 percent were 65 and over, while 1 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.5

Adverse Reactions

Allergic reactions and other idiosyncrasies have been rarely reported.

Overdosage

Accidental ingestion of large amounts of fluoride may result in acute burning in the mouth and sore tongue. Nausea, vomiting, and diarrhea may occur soon after ingestion (within 30 minutes) and are accompanied by salivation, hematemesis, and epigastric cramping abdominal pain. These symptoms may persist for 24 hours. If less than 5 mg fluoride/kg body weight (i.e., less than 2.3 mg fluoride/lb body weight) have been ingested, give calcium (e.g., milk) orally to relieve gastrointestinal symptoms and observe for a few hours. If more than 5 mg fluoride/kg body weight (i.e., more than 2.3 mg fluoride/lb body weight) have been ingested, induce vomiting, give orally soluble calcium (e.g., milk, 5% calcium gluconate or calcium lactate solution) and immediately seek medical assistance. For accidental ingestion of more than 15 mg fluoride/kg of body weight (i.e., more than 6.9 mg fluoride/lb body weight), induce vomiting and admit immediately to a hospital facility.

A treatment dose (a thin ribbon) of PreviDent® 5000 Sensitive contains approximately 2.5 mg fluoride. A 3.4 FL OZ (100 mL) bottle contains approximately 575 mg fluoride.

Prevident 5000 Sensitive Dosage and Administration

Follow these instructions unless otherwise instructed by your dental professional:

Adults and children 12 years of age and older: Apply at least 1 inch strip of PreviDent® 5000 Sensitive onto a soft bristle toothbrush. Brush teeth thoroughly for at least 1 minute, expectorate, and rinse mouth thoroughly. Use twice a day (morning and evening) or as recommended by a dentist or physician. Make sure to brush all sensitive areas of the teeth. Children under 12 years of age: Consult a dentist or physician. How is Prevident 5000 Sensitive Supplied

3.4 FL OZ (100 mL) in plastic bottles. Mild Mint: NDC 0126-0070-61

STORAGE

Store at Controlled Room Temperature, 68-77°F (20-25°C)

REFERENCES American Dental Association, Accepted Dental Therapeutics Ed. 40 (Chicago, 1984): 405-407. H.R. Englander et al., JADA 75 (1967): 638-644. H.R. Englander et al., JADA 78 (1969): 783-787. H.R. Englander et al., JADA 83 (1971): 354-358. Data on file, Colgate Oral Pharmaceuticals.

Questions? Comments? Please Call 1-800-962-2345
www.colgateprofessional.com

PRINCIPAL DISPLAY PANEL 100 mL Bottle

NDC 0126-0070-61

Colgate®

PreviDent®
5000ppm

SENSITIVE
1.1% Sodium Fluoride
5% Potassium Nitrate

PRESCRIPTION STRENGTH
TOOTHPASTE FOR SENSITIVE TEETH

MILD MINT

3.4 FL OZ (100 mL)

Rx ONLY

P10000587


PREVIDENT  5000 SENSITIVE
sodium fluoride  gel, dentifrice Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0126-0070 Route of Administration DENTAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sodium fluoride (fluoride ion) Sodium fluoride 12.7 mg  in 1 mL Potassium nitrate (Potassium cation) Potassium nitrate 57.5 mg  in 1 mL Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found Product Characteristics Color GREEN Score      Shape Size Flavor PEPPERMINT Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0126-0070-61 100 mL In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date Unapproved drug other 07/06/2009
Labeler - Colgate-Palmolive Company (055002195) Revised: 07/2009Colgate-Palmolive Company More Prevident 5000 Sensitive resources Prevident 5000 Sensitive Side Effects (in more detail) Prevident 5000 Sensitive Use in Pregnancy & Breastfeeding 0 Reviews for Prevident 5000 Sensitive - Add your own review/rating Prevident 5000 Sensitive Concise Consumer Information (Cerner Multum) APF Gel Advanced Consumer (Micromedex) - Includes Dosage Information EtheDent Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer) Gel-Kam Rinse MedFacts Consumer Leaflet (Wolters Kluwer) Phos-Flur Cream MedFacts Consumer Leaflet (Wolters Kluwer) PreviDent 5000 Sensitive MedFacts Consumer Leaflet (Wolters Kluwer) Compare Prevident 5000 Sensitive with other medications Prevention of Dental Caries
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Co-codamol 30 / 500 Effervescent Tablets


1. Name Of The Medicinal Product

Co-codamol 30/500 Effervescent Tablets

2. Qualitative And Quantitative Composition

Active Constituents

Paracetamol

500.0mg

Codeine Phosphate Hemihydrate

30.0mg

3. Pharmaceutical Form

Effervescent Tablets.

Co-codamol 30/500 Effervescent Tablets are white bevelled-edge tablets, scored on one face.

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of severe pain.

4.2 Posology And Method Of Administration

Adults:

Two tablets not more frequently than every 4 hours, up to a maximum of 8 tablets in any 24 hour period.

Elderly:

As for adults, however a reduced dose may be required. See warnings.

Children:

Not recommended for children under 12 years of age.

Co-codamol 30/500 Effervescent Tablets are for oral administration.

4.3 Contraindications

Hypersensitivity to paracetamol, codeine or any of the other constituents. Conditions where morphine and opioids are contraindicated eg, acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure and following biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent or within 14 days.

4.4 Special Warnings And Precautions For Use

Each tablet of the soluble formulation contains 388mg sodium (16.87mEquivalents). This sodium content should be taken into account when prescribing for patients in whom sodium restriction is indicated.

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated.

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease.

Patients should be advised not to exceed the recommended dose and not take other paracetamol containing products concurrently.

The risk-benefit of continued use should be assessed regularly by the prescriber.

The leaflet will state in a prominent position in the 'before taking' section:

• Do not take for longer than directed by your prescriber

• Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.

• Taking a painkiller for headaches too often or for too long can make them worse.

The label will state (To be displayed prominently on outer pack – not boxed):

Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the Caucasian population may be ultra-rapid metabolisers.

The leaflet will state in the "Pregnancy and breast-feeding" subsection of section 2 "Before taking your medicine":

Usually it is safe to take co-codamol while breast feeding as the levels of the active ingredients of this medicine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels in their breast milk.

If any of the following side effects develop in you or your baby, stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.

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.

The effects of CNS depressants (including alcohol) may be potentiated by codeine.

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of codeine in human pregnancy, but there is epidemiological evidence for the safety of paracetamol. Both substances have been used for many years without apparent ill consequences and animal studies have not shown any hazard. Nonetheless careful consideration should be given before prescribing the products for pregnant patients. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers.

Paracetamol is excreted in breast milk but not in a clinically significant amount.

At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and are unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

4.8 Undesirable Effects

• Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.

• Prolonged use of a painkiller for headaches can make them worse.

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

There have been very rare occurrences of pancreatitis.

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.

4.9 Overdose

Nausea and vomiting are prominent symptoms of codeine toxicity and if there is evidence of circulatory and respiratory depression, suggested treatment is gastric lavage and catharsis. If CNS depression is severe, assisted ventilation, oxygen and parenteral naloxone may be needed.

Patients in whom oxidative liver enzymes have been induced, including alcoholics and those receiving barbiturates and patients who are chronically malnourished, may be particularly sensitive to the toxic effects of paracetamol in overdose.

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, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is likely in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

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 and any patient who had ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine, which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in the CNS rather than the periphery appears to be more sensitive to it. This may explain paracetamol's lack of appreciable anti-inflammatory activity. Paracetamol also exhibits antipyretic activity.

Codeine is a centrally acting analgesic which produces its effect by its action at opioid-binding sites (?-receptors) within the CNS. It is a full agonist.

5.2 Pharmacokinetic Properties

Following oral administration of two effervescent tablets (ie, a dose of paracetamol 1000mg and codeine phosphate 60mg) the mean maximum plasma concentrations of paracetamol and codeine were 20.4?g/ml and 218.8ng/ml respectively. The mean times to maximum plasma concentrations were 0.34 hours for paracetamol 0.42 hours for codeine phosphate.

The mean AUC for the 10 hours following administration was 50.0?g.ml -1.h for paracetamol and 450.0ng/ml -1.h for codeine.

The bioavailabilities of paracetamol and codeine phosphate when given as the combination are similar to those when they are given separately.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium bicarbonate

Anhydrous citric acid

Anhydrous sodium carbonate

Sorbitol powder

Saccharin sodium

Povidone

Dimethicone

Sodium lauryl sulphate

6.2 Incompatibilities

None known.

6.3 Shelf Life

The shelf life for this product is 48 months in PPFP strips and 36 months in Surlyn laminate strips.

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

PPFP strips in cardboard cartons.

Pack sizes: 4, 12, 30, 60 and 100 tablets.

Surlyn laminate strips in cardboard cartons.

Pack sizes: 4 and 12 tablets.

6.6 Special Precautions For Disposal And Other Handling

The tablets should be dissolved in water before taking.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

8. Marketing Authorisation Number(S)

PL 17780/0046

9. Date Of First Authorisation/Renewal Of The Authorisation

7 August 2001/04 March 2009

10. Date Of Revision Of The Text

02 February 2011

LEGAL CATEGORY

POM


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Metformin 500mg tablets (Aurobindo Pharma Ltd)


1. Name Of The Medicinal Product

Metformin hydrochloride 500 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 500 mg metformin hydrochloride corresponding to 390 mg metformin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, round, biconvex, film-coated tablets with 'A' debossed on one side and '60' debossed on the other side.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycemic control.

• In adults, Metformin film-coated tablets may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.

• In children from 10 years of age and adolescents, Metformin hydrochloride film-coated tablets may be used as monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin hydrochloride as first-line therapy after diet failure (see section 5.1).

4.2 Posology And Method Of Administration

Adults:

Monotherapy and combination with other oral antidiabetic agents:

- The usual starting dose is 500mg or 850mg metformin hydrochloride 2 or 3 times daily given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.

The maximum recommended dose of metformin hydrochloride is 3 g daily, taken as 3 divided doses.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin hydrochloride at the dose indicated above.

Combination with insulin:

Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of 500mg or 850mg metformin hydrochloride 2or3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly:

Due to the potential for decreased renal function in elderly subjects, the metformin hydrochloride dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4).

Children and adolescents:

Monotherapy and combination with insulin

• Metformin hydrochloride film-coated tablets can be used in children from 10 years of age and adolescents.

• The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during meals or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

4.3 Contraindications

• Hypersensitivity to metformin hydrochloride or to any of the excipients.

• Diabetic ketoacidosis, diabetic pre-coma.

• Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).

• Acute conditions with the potential to alter renal function such as:

 

dehydration,

severe infection,

shock,

intravascular administration of iodinated contrast agents (see section 4.4).

• Acute or chronic disease which may cause tissue hypoxia such as:

 

cardiac or respiratory failure,

recent myocardial infarction,

shock

• Hepatic insufficiency, acute alcohol intoxication, alcoholism

• Lactation.

4.4 Special Warnings And Precautions For Use

Lactic acidosis:

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis:

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders as abdominal pain and severe asthenia.

Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin hydrochloride should be discontinued and the patient should be hospitalised immediately (see section 4.9).

Renal function:

As metformin hydrochloride is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:

* at least annually in patients with normal renal function,

* at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diueretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug.

Administration of iodinated contrast agent:

As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin hydrochloride must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Surgery:

Metformin hydrochloride must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.

Children and adolescents:

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin hydrochloride is initiated.

No effect of metformin hydrochloride on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin hydrochloride on these parameters in metformin hydrochloride-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years:

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin hydrochloride in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions:

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin hydrochloride alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or sulfonylureas.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use not recommended

Alcohol:

Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:

fasting or malnutrition;

hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medicinal product.

Iodinated contrast agents (see section 4.4):

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin hydrochloride accumulation and an increased risk of lactic acidosis.

Metformin hydrochloride must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Combinations requiring precautions for use:

Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic medicinal product during therapy with the other medicinal product and upon its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin hydrochloride may be necessary during and after addition or discontinuation of such medicinal products.

4.6 Pregnancy And Lactation

Use in pregnancy:

To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development (see section 5.3).

When a woman plans to become pregnant and during pregnancy, diabetes should not be treated with metformin hydrochloride but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.

Use in lactation:

Metformin hydrochloride is contra-indicated during lactation.

Meformin hydrochloride is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue breast-feeding or to discontinue metformin hydrochloride, taking into account the importance of the medicinal product to the mother.

4.7 Effects On Ability To Drive And Use Machines

Metformin hydrochloride monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when meformin hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).

4.8 Undesirable Effects

The following undesirable effects may occur under treatment with metformin hydrochloride. Frequencies are defined as follows:

Very common (

Common (

Uncommon (

Rare (

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders:

Common: Taste disturbance

Gastrointestinal disorders:

Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin hydrochloride be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Skin and subcutaneous tissue disorders:

Very rare: Skin reactions such as erythema, pruritus and urticaria.

Metabolism and nutrition disorders:

Very rare: Lactic acidosis (see section 4.4.).

Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Hepatobiliary disorders:

Not known: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin hydrochloride discontinuation.

In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

4.9 Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin hydrochloride or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin hydrochloride is haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Blood Glucose lowering drugs, excl Insulins, Biguanides

ATC code: A10BA02

Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin hydrochloride may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization

(3) and delay of intestinal glucose absorption.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical efficacy:

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.

Analysis of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed:

a significant reduction of the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/ 1000 patient-years) versus diet alone (43.3 events/ 1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/ 1000 patient-years), p=0.0034;

a significant reduction of the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

a significant reduction of the absolute risk of overall mortality: metformin hydrochloride 13.5 events/ 1000 patient-years versus diet alone 20.6 events/ 1000 patient –years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/ 1000 patient-years (p=0.021);

a significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)

Benefit regarding clinical outcome has not been shown for metformin hydrochloride used as second-line therapy, in combination with a sulfonylurea.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

5.2 Pharmacokinetic Properties

Absorption:

After an oral dose of metformin hydrochloride, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30 %.

After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption is non-linear.

At the recommended metformin hydrochloride doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 4 microgram/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.

Distribution:

Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 l.

Metabolism:

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of metformin hydrochloride is >400 ml/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride in plasma.

Children and adolescents:

Single dose study: After single doses of metformin hydrochloride 500 mg, paediatric patients have shown similar phamacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Povidone

Magnesium stearate

Film-coating:

Hypromellose

Macrogol

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

4 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

20, 28, 30, 40, 42, 50, 56, 60, 70, 80, 84, 90, 98, 100, 120, 180, 200, 300 or 400 film-coated tablets in blister packs (PVC / PVdC / aluminium), each blister containing 10 or 14 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed off in accordance with local requirements.

7. Marketing Authorisation Holder

Aurobindo Pharma Limited

Ares, Odyssey Business Park

West End Road

South Ruislip HA4 6QD

United Kingdom

8. Marketing Authorisation Number(S)

PL 20532-0173

9. Date Of First Authorisation/Renewal Of The Authorisation

20/03/2009

10. Date Of Revision Of The Text

22/07/2010


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Pentasa Slow Release Tablets 500mg


1. Name Of The Medicinal Product

PENTASA® Slow Release Tablets 500mg

2. Qualitative And Quantitative Composition

Each tablet contains mesalazine 500mg

3. Pharmaceutical Form

Tablet

White-grey to pale-brown, specked round tablets, scored and marked 500mg on one side and 'PENTASA' on the reverse side.

4. Clinical Particulars 4.1 Therapeutic Indications

PENTASA Slow Release Tablets 500mg are indicated for the treatment of mild to moderate exacerbations of ulcerative colitis. For the maintenance of remission of ulcerative colitis.

4.2 Posology And Method Of Administration

Ulcerative Colitis

The tablets must not be crushed or chewed. They may be swallowed whole or broken up. To facilitate swallowing they may be dispersed in 50ml of cold water. Stir and drink immediately.

Adults:

Acute treatment: Individual dosage of up to 4g mesalazine daily in two or three divided doses.

Maintenance treatment: Individual dosage. Recommended dosage, 2g mesalazine once daily.

Children: Not recommended.

Elderly Patients: The usual adult dose applies.

Route of administration: oral.

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 take 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).

Patients on any oral formulation of mesalazine should have renal function monitored, with serum creatinine levels measured prior to treatment start, every 3 months for the first year, then 6 monthly for the next 4 years and annually thereafter. Treatment with mesalazine should be discontinued if renal function deteriorates.

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

(<0.01% )

Blood disorders:

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.

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 tablets consist of ethylcellulose-coated microgranules of mesalazine. Following administration and tablet disintegration the microgranules act as discrete slow-release formulations which allow a continuous release of drug from duodenum to rectum at all enteral pH conditions. The microgranules enter the duodenum within an hour of administration, independent of food co-administration. In healthy volunteers the average small intestinal transit time is approximately 3-4 hours.

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:

Based on urine recovery data in healthy volunteers, 30-50% of the ingested dose is absorbed following oral administration, predominantly from the small intestine. Mesalazine is detectable in plasma approximately 15 minutes following administration. Maximum plasma concentrations are seen 1 - 4 hours post-dose. After a gradual decrease, mesalazine will no longer be detectable 12 hours post-dose. The plasma concentration curve for acetyl mesalazine follows the same pattern, but the concentrations are generally higher and the elimination is slower.

The metabolic ratio of acetyl mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500mg x 3 and 2g x 3 respectively, implying a dose-dependent acetylation which may be subject to saturation.

Mean steady-state plasma concentrations of mesalazine are approximately 2 micromoles/l, 8 micromoles/l and 12 micromoles/l after daily doses of 1.5g, 4g and 6g respectively.

For acetyl mesalazine the corresponding concentrations are 6 micromoles/l, 13 micromoles/l and 16 micromoles/l respectively.

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption is reduced.

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. Due to continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, steady-state is reached after a treatment period of 5 days following oral administration. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

The delivery of mesalazine to its site of action after oral administration is only slightly affected by pathophysiological changes such as diarrhoea and increased bowel activity observed during active inflammatory bowel disease. A reduction in systemic absorption to 20 – 25% of the daily dose has been observed in patients with accelerated intestinal transit. A corresponding increase in faecal excretion has been seen.

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

Ethylcellulose

Magnesium stearate

Talc

Microcrystalline cellulose

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

Blister: Double aluminium foil

Pack size: 100 Tablets

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data 7. Marketing Authorisation Holder

Ferring Pharmaceuticals Ltd.,

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ

8. Marketing Authorisation Number(S)

PL 3194/0044

9. Date Of First Authorisation/Renewal Of The Authorisation

30th March 2004

10. Date Of Revision Of The Text

29th September 2009


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Streptase 1,500,000 IU


CSL Behring

Streptase Injection 1,500,000 (1.5 M) I.U.

(Streptokinase)

Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or nurse. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse. In This Leaflet: 1. What Streptase Injection is and what it is used for 2. Before you are given Streptase Injection 3. How you are given Streptase Injection 4. Possible side effects 5. Storing Streptase Injection 6. Further information What Streptase Injection Is And What It Is Used For

Streptase Injection is a type of medicine called a fibrinolytic agent. It contains a substance called streptokinase, which helps to dissolve blood clots.

Streptase Injection 1.5 M IU strength is used to limit the extent of a heart attack, within 12 hours of the event occurring.

Before You Are Given Streptase Injection You should not be given Streptase Injection if any of the following apply to you: You are allergic to any of the ingredients of Streptase (see section 6 for the ingredients) You are pregnant You have recently had a stroke or a serious head injury You have a brain tumour or a tumour with a risk of bleeding You have a blood clotting disorder or you have recently had internal bleeding You are taking drugs to prevent blood clotting (anticoagulants) You have problems with your blood vessels (e.g. weakness in an artery) You have uncontrollable high blood pressure You have recently had a major operation, in particular on your head (intracranial) or spine (intraspinal) You have inflammation of the pancreas (acute pancreatitis) or inflammation in or around your heart (endocarditis or pericarditis) You have severe liver or kidney damage Special care should be taken with Streptase Injection if: you have recently had severe bleeding in your stomach (e.g. an ulcer) you have recently had a severe injury and have been resuscitated you are at risk of severe local bleeding, for example if you have recently had an invasive operation, (e.g. where you have had a tube inserted into your body) you have recently had a baby, miscarriage or abortion you have a disease of your urogenital tract (the parts of your body used for excretion and reproduction) you have blood poisoning likely to cause clotting (septic thrombotic disease) you have a disease of the arteries or a disease affecting the blood vessels of your brain (cerebrovascular disease) you have tuberculosis (TB) you have an irregular heart-beat or heart murmur you have been treated with streptokinase before or have had a recent infection with the streptococcus bacteria (usually a throat infection), you may have high levels of antibodies against the active ingredient, streptokinase. These antibodies will block the action of streptokinase in your body and so your doctor may choose to use a different type of fibrinolytic agent.

Your doctor should consider the above points before you are given Streptase Injection.

Taking or using other medicines

If you are taking or have recently been taking drugs which prevent blood clotting (anticoagulants), there will be an increased risk of bleeding (haemorrhage).

Pregnancy and breast-feeding

You should not be given Streptase Injection if you are pregnant or have recently had a baby, miscarriage or abortion, unless there is no safer alternative.

Breast milk should be discarded if you have received Streptase Injection within the last 24 hours.

How You Are Given Streptase Injection Streptase Injection will usually be given to you by infusion into a vein (drip). It may also be infused into an artery supplying blood to your heart.

Your doctor may recommend that you also take a low dose of aspirin for about 4 weeks to help thin your blood.

If you are given more Streptase Injection than you should have

If you are given too much Streptase Injection over a long period, you may be at risk of another thrombosis (blood clot). Symptoms of a thrombosis are listed in the side effects section below.

Possible Side Effects

Like all medicines, Streptase Injection can have side-effects, although not everybody gets them.

Very common side effects (affect more than 1 in 10 people) Development of antibodies (proteins in the blood which help to fight disease) against streptokinase, the active ingredient of Streptase Injection Common side effects (affect less than 1 in 10 people) Bleeding at the injection site, bruising of the skin, bleeding into the gut, reproductive and urinary systems, nosebleed Allergic reactions e.g. skin rash, flushing, itching, blistering (may also affect the tongue and throat), difficulty breathing, low blood pressure (you may feel faint) Slow or fast heart-beat Feeling or being sick, diarrhoea, stomach pain Headache, muscle pain including back pain, feeling hot or cold, weakness, generally feeling unwell Uncommon effects (affect less than 1 in 100 people) Bleeding into eyes, liver, abdomen or joints, tearing of the spleen Stroke (cerebrovascular haemorrhage) Rare side effects (affect less than 1 in 1,000 people) Dizziness, confusion, agitation Fits Paralysis on one or both sides of the body Very rare side effects (affect less than 1 in 10,000 people) Bleeding into the space around the heart, including tearing of the heart muscle Delayed allergic reactions e.g. serum sickness (shows as pain and swelling in joints and lymph nodes, rash, fall in blood pressure and shock), arthritis, inflammation of blood vessels and kidneys, numbness or pins and needles in the arms or legs Blockage of blood vessels caused by cholesterol crystals Fluid in the lungs (not caused by heart failure) Inflammation in the eyes

The following events have been reported in patients being treated with Streptase Injection, but may not have been due to the medicine:irregular heart-beat, chest pain, lack of oxygen to the heart, heart failure, heart attack, heart shock, inflammation around the heart, fluid around the heart, stopping of heart-beat, heart valve inefficiency, blockage of a blood vessel.

If you receive a lot of Streptase, you may be at risk of a thrombosis (blood clot).

Symptoms of a thrombosis include: Unusual pain or swelling in your legs Sudden sharp pain in your chest Sudden difficulty breathing An unusual, severe or long-lasting headache Dizziness or fainting

If you have any of the side-effects listed in this section, or any other unusual or unexpected side-effects, tell your doctor or nurse immediately.

Storing Streptase Injection

You will not normally be asked to store your medicine as it will be given to you by a doctor.

Keep out of the reach and sight of children.

Do not store above 25 °C. Do not freeze.

After the injection has been prepared it may be kept in a fridge at 2 to 8 ?C for up to 24 hours.

Do not use this medicine after the expiry date shown on the carton and vial label.

Further Information What Streptase Injection contains

The active substance is:

Streptokinase (1.5 Million International Units (IU))

Other ingredients are:

human albumin sodium-L-hydrogen glutamate monohydrate polygeline

Streptase Injection comes as a powder in glass containers, and will be mixed with a liquid to make a solution before use as an infusion.

Each pack contains one vial with 1.5 million IU streptokinase.

Marketing Authorisation Holder CSL Behring UK Limited Hayworth House Market Place Haywards Heath West Sussex RH16 1DB UK Manufacturer CSL Behring GmbH Emil-von-Behring-Strasse 76 35041 Marburg Germany

This leaflet was last approved on: 04/2008

For further information contact

CSL Behring UK Limited Hayworth House Market Place Haywards Heath West Sussex RH16 1DB UK Telephone number:01444 447 405

This leaflet was last approved on: 05/2009


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Co-amoxiclav for Injection 500 / 100mg


1. Name Of The Medicinal Product

Co-amoxiclavfor Injection 500/100mg

2. Qualitative And Quantitative Composition

Each vial contains 500mg amoxicillin (as sodium salt) and 100mg clavulanic acid (as potassium salt).

Each 600mg vial of co-amoxiclav contains 0.5mmol of potassium and 1.55mmol of sodium (approx).

3. Pharmaceutical Form

Powder for solution for injection or infusion.

Co-amoxiclav for Injection 500/100mg is a white or almost white powder.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of the following bacterial infections when caused by amoxicillin-resistant but amoxicillin-clavulanate susceptible organisms (see section 5.1):

Upper and Lower Respiratory Tract Infections, including :

• otitis media

• acute sinusitis

• acute exacerbations of chronic bronchitis

• community-acquired pneumonia

Upper and Lower Urinary Tract Infections

Skin and Soft Tissue Infections

Genito-Urinary Tract Infections including septic abortion, pelvic or puerperal sepsis, intra-abdominal sepsis

Consideration should be given to the official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Dosages for the treatment of infection

Adults and children over 12 years

Usually 1.2g eight hourly. In more serious infections, increase frequency to six-hourly intervals.

Children 3 months – 12 years

Usually 30mg/kg* co-amoxiclav eight hourly. In more serious infections, increase frequency to six-hourly intervals.

Children 0-3 months

30mg/kg* co-amoxiclav every 12 hours in premature infants and in full-term infants during the perinatal period, increasing to eight hours thereafter.

*Each 30mg co-amoxiclav provides 25mg of amoxicillin and 5mg of clavulanic acid.

Each 600mg vial of co-amoxiclav contains 0.5mmol of potassium and 1.55mmol of sodium (approx).

Adult dosage for surgical prophylaxis

The usual dose is 1.2g co-amoxiclav injection given at the induction of anaesthesia. Operations where there is a high risk of infection, e.g. colorectal surgery, may require three, and up to four doses of 1.2g of co-amoxiclav injection in a 24 hour period. These doses are usually given at 0, 8, 16 (and 24) hours. This regimen can be continued for several days if the procedure has a significantly increased risk of infection.

Clear clinical signs of infection at operation will require a normal course of intravenous or oral co-amoxiclav therapy post-operatively.

Dosage in renal impairment

Adults

Mild impairment (creatinine clearance >30 ml/min): No change in dosage.

Moderate impairment (creatinine clearance 10-30 ml/min): 1.2g IV stat., followed by 600mg IV 12 hourly.

Severe impairment (creatinine clearance <10 ml/min): 1.2g IV stat., followed by 600mg IV 24 hourly. Dialysis decreases serum concentrations of co-amoxiclav and an additional 600mg IV dose may need to be given during dialysis and at the end of dialysis.

Children

Similar reductions in dosage should be made for children.

Dosage in hepatic impairment

Dose with caution. Monitor hepatic function at regular intervals. There are, as yet, insufficient data on which to base a dosage recommendation.

Co-amoxiclav may not be used in patients with severe hepatic impairment and in patients in whom hepatic functional impairment has occurred on previous therapy with Co-amoxiclav (see section 4.3 and 4.4). Liver function parameters should be checked at regular intervals in patients with signs of hepatic lesions and a change of therapy should be given considerations if these parameters exacerbate on treatment.

Administration

Co-amoxiclav injection may be administered either by intravenous injection or by intermittent infusion. Therapy can be started parenterally and continued with an oral preparation.

Co-amoxiclav injection should be given by slow intravenous injection over a period of three to four minutes and used within 20 minutes of reconstitution. It may be injected directly into a vein or via a drip tube.

Alternatively, co-amoxiclav intravenous may be infused in Water for Injections Ph Eur or Sodium Chloride Intravenous Injection BP (0.9% w/v). Add, without delay, 600 mg reconstituted solution to 50 ml infusion fluid or 1.2 g reconstituted solution to 100 ml infusion fluid (e.g. using a minibag or in-line burette). Infuse over 30-40 minutes and complete within four hours of reconstitution.

Any residual antibiotic solutions should be discarded.

Co-amoxiclav Injection is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solution should, therefore, not be added to such infusions but may be injected into the drip tubing over a period of three to four minutes.

It is not suitable for intramuscular administration. Duration of therapy should be appropriate to the indication and should not exceed 14 days without review.

4.3 Contraindications

Hypersensitivity to the constituents, amoxicillin and clavulanic acid. Penicillin hypersensitivity. Attention should be paid to possible cross-sensitivity with other ?-lactam antibiotics, e.g. penicillins, cephalosporins, carbapenems, monobactams due to the danger of anaphylactic shock. Consequently a careful history should be taken in regard to allergic reaction before commencing treatment. Co-amoxiclav should not be given to patients with a verified hypersensitivity to any beta-lactam drug.

A previous history of co-amoxiclav or penicillin-associated jaundice/hepatic dysfunction.

Co-amoxiclav may not be used in patients with severe hepatic impairment and in patients in whom hepatic functional impairment has occurred onprevioustherapy with co-amoxiclav, for example cholestatic jaundice induced by co-amoxiclav or penicillin.

Patients with infectious mononucleosis (glandular fever) and patients with lymphatic leukaemia have a higher risk of exanthema and consequently co-amoxiclav injection should not be administered during these diseases to treat concomitant bacterial infections.

4.4 Special Warnings And Precautions For Use

Although severe allergic reactions are more likely in patients who have experienced beta-lactam hypersensitivity, these may occur in the absence of any such history. In such cases treatment should be discontinued immediately and appropriate management instituted.

Co-amoxiclav should be used with caution in patients with allergic diathesis, including asthma, since such patients may have a higher risk of allergic reactions to co-amoxiclav.

Patients with evidence of hepatic dysfunction should be treated with caution. Liver function parameters should be monitored in patients with signs or symptoms of hepatic impairment. Discontinuation of therapy should be considered in case of deterioration of liver function parameters during treatment.

In long term use (more than 10-14 days), regular monitoring of renal and hepatic function is recommended.

Prolonged use of co-amoxiclav, or other broadspectrum antibiotics, may lead to superinfections due to an overgrowth of non-susceptible organisms and yeasts.

In case of severe and persistent diarrhoea, the possibility of pseudomembraneous colitis must be considered, in which case therapy should be discontinued.

In patients with renal impairment, excretion of co-amoxiclav will be delayed and depending on the degree of the impairment, it may be necessary to reduce the total daily dosage (see section 4.2).

The presence of high urinary concentrations of amoxicillin can cause precipitation of the product in urinary catheters. Therefore, catheters should be visually inspected at intervals.

At high doses, adequate fluid intake and urinary output must be maintained to minimise the possibility of amoxicillin crystalluria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Other bacterial agents : There is a possibility that the antibacterial action of amoxicillin could be antagonised on co-administration with macrolides, tetracyclines, sulphonamides or chloramphenicol.

Probenecid : By inhibiting the renal elimination of amoxicillin (but not clavulanic acid) the concomitant administration of probenecid leads to an increase in the concentrations of amoxicillin in serum and bile.

Allopurinol : Concomitant administration of allopurinol may promote the occurrence of allergic cutaneous reactions.

Digoxin: An increase in the absorption of digoxin is possible on concurrent administration with amoxicillin.

Co-amoxiclav / disulfiram : Co-amoxiclav should not be used concurrently with disulfiram.

Methotrexate : Concomitant administration with methotrexate may lead to an increase in toxicity of methotrexate.

Anticoagulants: Concomitant administration of amoxicillin and coumarin anticoagulants, such as warfarin, may increase the incidence of bleeding.

Oral hormonal contraceptives : Administration of amoxicillin can transiently decrease the plasma level of oestrogens and progesterone and may reduce the efficacy of oral contraceptives. Patients should be advised to use supplemental non-hormonal contraceptive measures.

Other forms of interaction : Amoxicillin may produce false positive results in glucose determination tests and tests for urobilinogen performed with nonenzymatic methods. Likewise the urobilinogen test can be affected.

Amoxicillin may decrease the amount of urinary estriol in pregnant women. Diarrhoea may decrease the absorption of other drugs and consequently have a negative influence on their effectivity.

Forced diuresis will lead to an increased elimination of amoxicillin resulting in decreased serum concentrations.

4.6 Pregnancy And Lactation

Reproduction studies in animals (mice and rats) with orally and parenterally administered co-amoxiclav have shown no teratogenic effects. There is limited experience of the use of co-amoxiclav in human pregnancy. As with all medicines, use should be avoided in pregnancy, especially during the first trimester, unless considered essential by the physician.

Co-amoxiclav may be administered during the period of lactation. With the exception of the risk of sensitisation, associated with the excretion of trace quantities in breast milk, there are no known detrimental effects for the breast-fed infant.

4.7 Effects On Ability To Drive And Use Machines

Co-amoxiclav may sometimes be associated with side effects (such as rarely dizziness and even less often convulsions) that may impair the ability to drive a vehicle, to operate machinery and/or work safely (see section 4.8).

4.8 Undesirable Effects

The most commonly reported adverse drug reactions are hypersensitivity reactions:

Common (

• Cutaneous reactions such as exanthema, pruritus, urticaria; the typical morbilliform exanthema occurs 5-11 days after start of therapy. Immediate appearance of urticaria indicates an allergic reaction to amoxicillin and therapy should therefore be discontinued.

Rare (

• Angioneurotic oedema (Quincke's oedema)

• Erythema multiforme syndrome

• Stevens-Johnson syndrome

• Eosinophilia

• Drug fever

• Laryngeal oedema

• Serum sickness

• Haemolytic anaemia

• Allergic vasculitis

• Interstitial nephritis

• Anaphylactic shock

Other possible side effects

Blood disorders:

There have been isolated reports of leucopenia, granulocytopenia, thrombocytopenia, pancytopenia, anaemia, myelosuppression, agranulocytosis, prolongation of bleeding time and prolongation of prothrombin time. However, these changes were reversible on discontinuation of therapy.

Gastrointestinal disorders:

Common (

Gastric complaints, nausea, loss of appetite, vomiting, flatulence, soft stools, diarrhoea, enanthemas (particularly in the region of the mouth), dry mouth, taste disturbances. These effects on the gastrointestinal system are mostly mild and frequently disappear either during the treatment or very soon after completion of therapy. The occurrence of these side-effects can generally be reduced by taking amoxicillin during meals or with some food. If severe and persistent diarrhoea occurs, the rare possibility of pseudomembraneous colitis should be considered. The administration of anti-peristaltic drug is contraindicated.

Very rare (< 0.01%)

Development of a black tongue.

Liver disorders:

Uncommon (

Moderate and transient increase of liver enzymes. Rare reports of hepatitis and cholestatic jaundice.

Renal disorders:

Uncommon (

Acute interstitial nephritis may occur in rare cases.

CNS disorders:

CNS effects have been seen rarely. They include hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Other undesirable effects

Prolonged and repeated use of the preparation can result in superinfections and colonisation with resistant organisms or yeasts such as oral and vaginal candidiasis.

4.9 Overdose

Symptoms of overdosage

In the event of overdosage, gastrointestinal symptoms, such as nausea, vomiting and diarrhoea and disturbances of the fluid and electrolyte balance are possible. Also, convulsions may exist.

Management of overdosage

There is no specific antidote for overdose. Treatment consists of haemodialysis and symptomatic measures paying particular attention to the water and electrolyte balance, especially if there are any gastro-intestinal symptoms. Administration of medicinal charcoal and gastric lavage are useful only in cases of very high overdose (> 250mg/kg). In case of severe renal insufficiency, Co-amoxiclav can be eliminated from the circulation via haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Antibiotic/chemotherapeutic (penicillin with broad spectrum of action) (JOICR).

Mechanism of Action

Amoxicillin:

Amoxicillin is an acid-stable aminopenicillin that is susceptible to hydrolysis by common ?-lactamase enzymes.

Clavulanic acid:

Clavulanic acid is a ?-lactam molecule that is able to inhibit many of the most commonly occurring ?-lactamases such as staphylococcal penicillinases and enzymes of the TEM, OXA, SHV families (including many of the extended spectrum ?-lactamases of these groups). Thus, combination of amoxicillin with clavulanic acid maintains the activity of the aminopenicillin against organisms that produce sufficient quantities of these enzymes that would otherwise render inactive.

However, clavulanic acid is not able to inhibit the AmpC (Class 1) ?-lactamases that may be produced by certain Gram-negative bacilli or the metallo-?-lactamases (such as carbapenemases). Therefore, organisms that are normally susceptible to amoxicillin but have acquired the ability to produce any if these enzymes in amounts sufficient to render amoxicillin inactive would not be susceptible to Co-amoxiclav.

Antibacterial Spectrum

MIC Breakpoints

The MIC breakpoints according to the NCCLS criteria and methodology that separates susceptible (S) organisms from those that are immediately susceptible (I) or resistant (R) are:

• Enterobacteriaceae : S

I = 16/8 mg/L

R

• Staphylococci : S

R

• Haemophilus influenzae : S

R

• Streptococcus pneumoniae: S

I = 1/0.5 mg/L

R

BSAC criteria are as follows (Expressed as amoxicillin) :

• Enterobacteriaceae: S

R

• In UTI: S

R

• Haemophilus influenzae,

Moraxella catarrhalis: S

R

Spectrum of action of Co-amoxiclav

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only approximate guidance on the probabilities whether micro-organisms will be susceptible to Co-amoxiclav or not. As far as possible the information on the European range of acquired resistance for the individual micro-organism is indicated in brackets.

Micro-organisms

Resistance prevalence in the EU*

SUSCEPTIBLE

 

 

Gram-positive aerobes

 

 

E.faecalis

 

S.aureus methicillin-susceptible

 

S.pneumoniae

0% - 26%*

S.pyogenes

 

 

Gram-negative organisms

 

 

E.coli

5 – 20% *

K.pneumoniae

7% *

H.influenzae

2%

M.catarrhalis

 

 

P.mirabilis

N.gonorrhoeae

Up to 34% *

Anaerobes

 

 

B.fragilis

 

 

C.perfringens

 

 

Peptostreptococcus spp

 

 

RESISTANT

 

 

Gram-positive organisms

 

 

E.faecium

 

S.aureus methicillin-resistant

 

Gram-negative organisms

 

 

E.aerogenes

 

 

E.cloacae

 

 

M.morganii

 

 

P.aeroginosa

 

 

Serratia spp.

 

 

P.rettgeri

 

 

Others

 

 

Legionellae

 

 

Chlamydia spp.

 

 

Mycoplasma spp.

 

 

Ricketsia spp.

 

 

* It is recommended that local information on the epidemiology of resistant micro-organisms should be consulted.

Resistance

Organisms that are normally resistant to amoxicillin by non-beta-lactamase-mediated mechanisms (such as impermability, altered penicillin-binding proteins or drug efflux pumps) or via the manufacture of enzymes that arenotinhibited by clavulanic acid would also be resistant to amoxicillin/clavulanate.

5.2 Pharmacokinetic Properties

Amoxicillin:

The absolute bioavailability of amoxicillin depends on the dose and ranges between approximately 72 and 94%. Absorption is not affected by intake of food. Peak plasma concentrations are present about 1 to 2 hours after administration of amoxicillin. The apparent distribution volume ranges between approximately 0.3 and 0.4 l/kg and binding to serum proteins is approximately 17 – 20%. Amoxicillin diffuses through the placental barrier and a small fraction is excreted into breast milk.

Amoxicillin is largely excreted through the kidneys (52 ± 15% of a dose in unchanged form within 7 hours) and a small fraction is excreted in the bile. Total clearance ranges between approximately 250 and 370 ml/min. The serum half-life of amoxicillin in subjects with intact renal function is approximately 1 hour (0.9 – 1.2h), in patients with creatinine clearance ranging between 10 and 30ml/min it is about 6 hours and in anuria it ranges between 10 and 15 hours.

Clavulanic acid:

The absolute bioavailability of clavulanic acid of approximately 60% differs markedly from individual to individual. Absorption is not affected by intake of food. Peal concentrations of clavulanic acid are present after approximately 1 to 2 hours. The apparent distribution volume is about 0.2 l/kg and the serum protein binding rate is approximately 22%. Clavulanic acid diffuses through the placental barrier. No exact data are as yet available in regard to excretion into breast milk.

The substance is partly metabolised (approximately 50 – 70%) and is about 40% is eliminated through the kidneys (18 – 38% of the dose is unchanged form). The total clearance is approximately 260 ml/min. The serum half-life of clavulanic acid in subjects with intact renal function is approximately 1 hour, in patients with creatinine clearance ranging from 20 and 70ml/min it is approximately 2.6 hours and in anuria it ranges between 3 and 4 hours.

Pharmacologically relevant pharmacokinetic interaction between amoxicillin and clavulanic acid have not been observed so far. Both amoxicillin and clavulanic acid are haemodialysable.

5.3 Preclinical Safety Data

a) Acute toxicity

Investigations of the acute toxicity (LD50) of amoxicillin and clavulanic acid in adult animals and neonates have confirmed very low toxicity potential. The LD50 of clavulanic acid (potassium salt) is determined by the potassium content.

Administration of clavulanic acid (potassium salt) together with amoxicillin does not result in any unexpected or synergistic toxicity.

b) Chronic toxicity / subchronic toxicity

Extensive studies of the chronic toxicity have been carried out based on international standards. Solely after high doses (corresponding to 20- to 50- fold the maximal human dose) were mild haematological and blood-chemical changes observed which regressed completely following discontinuation of the therapy.

c) Mutagenic and tumorigenic potential

In-vitro and in-vivo studies did not reveal any signs of any mutagenic effects of the combination of amoxicillin and clavulanic acid.

d) Reproductive toxicity

After treatment of various infections in pregnant women (approximately 560 pregnancies) with Co-amoxiclav no increased occurrence of malformations was observed. Amoxicillin and clavulanic acid diffuse through the placenta and are excreted into breast milk (probable elimination of clavulanic acid into breast milk).

6. Pharmaceutical Particulars 6.1 List Of Excipients

None

6.2 Incompatibilities

Co-amoxiclav Injection should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.

If co-amoxiclav is prescribed concurrently with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions.

6.3 Shelf Life

Two years

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep container in the outer carton.

6.5 Nature And Contents Of Container

Clear 10ml glass vials (Ph.Eur. Type II) with a grey bromobutyl stopper and aluminium-propylene flip-off cap.

6.6 Special Precautions For Disposal And Other Handling

To reconstitute dissolve in 10 ml Water for Injections Ph Eur. (Final volume 10.5 ml.)

For single use. Discard any unused product immediately after use.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing Authorisation Number(S)

PL 29831/0044

PA 1339/5/1

9. Date Of First Authorisation/Renewal Of The Authorisation

3 March 2008 (UK)

13 June 2009 (IE)

10. Date Of Revision Of The Text

March 2008


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Tranexamic Acid 500mg Tablets (Sandoz Limited )


1. Name Of The Medicinal Product

Tranexamic Acid 500 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 500mg Tranexamic Acid.

For excipients, see 6.1.

3. Pharmaceutical Form

Tablet.

White, capsule shaped tablet embossed with 'T500' on one side and a break line on the other side.

4. Clinical Particulars 4.1 Therapeutic Indications

Tranexamic Acid 500mg Tablets are indicated for short term use for haemorrhage or risk of haemorrhage in those with increased fibrinolysis or fibrinogenolysis. Local fibrinolysis as occurs in the following conditions:

1. a) Prostatectomy and bladder surgery

b) Menorrhagia

c) Epistaxis

d) Conisation of the cervix

e) Traumatic hyphaema

2. Management of dental extraction in haemophiliacs.

3. Hereditary angioneurotic oedema.

4.2 Posology And Method Of Administration

Route of administration: Oral.

Adults:

Local Fibrinolysis: The recommended standard dose is 15-25mg/kg bodyweight (i.e. 2-3 tablets) two to three times daily. For the indications listed below the following doses may be used:

1a Prostatectomy: Prophylaxis and treatment of haemorrhage in high risk patients should commence per- or post-operatively with tranexamic acid injection; thereafter 2 tablets three to four times daily until macroscopic haematuria is no longer present.

1b Menorrhagia: Recommended dosage is 2 tablets 3 times daily as long as needed for up to 4 days. If very heavy menstrual bleeding, dosage may be increased. A total dose of 4g daily (8 tablets) should not be exceeded. Treatment with Tranexamic acid should not be initiated until menstrual bleeding has started.

1c Epistaxis: When repeated bleeding is anticipated oral therapy (2 tablets three times daily) should be administered for 7 days.

1d Cervix Conisation: 3 tablets three times daily.

1e Traumatic Hyphaema: 2-3 tablets 3 times daily. The dose is based on 25mg/kg three times a day.

2. Haemophilia: In the management of dental extractions 2-3 tablets every eight hours. The dose is based on 25mg/kg.

3. Hereditary angioneurotic oedema: Some patients are aware of the onset of illness; suitable treatment for these patients is intermittently 2-3 tablets two to three times daily for some days. Other patients are treated continuously at this dosage.

Children:

In children, for current approved indications as described in section 4.1, the dosage is in the region of 20 mg/kg/day. However, data on efficacy, posology and safety for these indications are limited.

Elderly:

No reduction in dosage is necessary unless there is evidence of renal failure (see guidelines below).

Renal Impairment

By extrapolation from clearance data relating to the intravenous dosage form, the following reduction in the oral dosage is recommended for patients with mild to moderate renal insufficiency:

Serum Creatinine (?mol/l)

Oral Dose

Dose Frequency

120-249

15 mg/kg body weight

twice daily

250-500

15 mg/kg body weight

daily

4.3 Contraindications

• Hypersensitivity to tranexamic acid or any of the other ingredients.

• Active thromboembolic disease.

• History of venous or arterial thrombosis.

• Fibrinolytic conditions following consumption coagulopathy.

• Severe renal impairment (risk of accumulation).

• History of convulsions.

4.4 Special Warnings And Precautions For Use

Caution is advised in treating those with massive haematuria from the upper urinary tract, especially in haemophiliacs, as there have been some cases of ureteric obstruction.

Not to be used when disseminated intravascular coagulation is in progress.

The blood levels are increased in patients with renal insufficiency. Therefore a dose reduction is recommended (see Section 4.2, Posology and Method of Administration).

In those patients requiring long term administration of tranexamic acid, such as those with hereditary angioneurotic oedema, regular eye examinations (e.g. visual acuity, slit lamp, intraocular pressure, visual fields) and liver function tests should be performed.

Patients who experience visual disturbance should be withdrawn from treatment.

Patients with irregular menstrual bleeding should not use tranexamic acid until the cause of irregular bleeding has been established. If menstrual bleeding is not adequately reduced by Tranexamic Acid Tablets, an alternative treatment should be considered.

Patients with a previous thromboembolic event and a family history of thromboembolic disease (patients with thrombophilia) should use Tranexamic Acid Tablets only if there is a strong medical indication and under strict medical supervision.

The use of tranexamic acid in cases of increased fibrinolysis due to disseminated intravascular coagulation is not recommended.

Clinical experience with Tranexamic Acid Tablets in menorrhagic children under 15 years of age is not available.

The indications and method of administration indicated above should be followed strictly:

• In case of haematuria of renal origin, there is a risk of mechanical anuria due to formation of a ureteral clot.

• In renal insufficiency leading to a risk of accumulation, the dosage of tranexamic acid should be reduced according to the serum creatinine level.

- serum creatinine between120 and 250 ?mol/l,: TXA iv 10 mg/kg twice daily.

- serum creatinine between 250 and 500 ?mol/l: TXA iv 10 mg/kg once daily (every 24 hours).

- serum creatinine > 500 ?mol/l, TXA iv 10 mg/kg every other day (every 48 hours).

• Before use of TXA, risk factors of thromboembolic disease should be investigated.

• Tranexamic acid should be administered with care in patients receiving oral contraceptives because of the increased risk of thrombosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tranexamic Acid will counteract the thrombolytic effect of fibrinolytic preparations.

4.6 Pregnancy And Lactation

Pregnancy: There is no evidence from animal studies that tranexamic acid has any teratogenic effect, however, the usual caution with use of drugs in pregnancy should be observed.

Tranexamic acid crosses the placenta.

Lactation: Tranexamic acid passes into breast milk to a concentration of approximately one hundredth of the concentration in the maternal blood. An antifibrinolytic effect in the infant is unlikely.

4.7 Effects On Ability To Drive And Use Machines

Tranexamic Acid has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency.

Frequencies are defined as: very common (=1/l0), common (=1/100 to <1/10), uncommon (=1/1000 to <1/100), rare ( =1/10,000 to <1/1000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Immune system disorders

Very rare: Hypersensitivity reactions including anaphylaxis

Nervous System Disorders

Very rare: convulsions, particularly in case of misuse

Eye disorders

Rare: Colour vision disturbances, retinal vein/artery occlusion

Vascular disorders

Rare: Thromboembolic events

Very rare: Arterial or venous thrombosis at any sites. Malaise with hypotension, with or without loss of consciousness (generally following a too fast intravenous injection, exceptionally after oral administration).

Gastro-intestinal disorders

Very rare: Digestive effects such as nausea, vomiting and diarrhoea.

Skin and subcutaneous tissue disorders

Rare: Allergic skin reactions

4.9 Overdose

No cases of overdosage have been reported. Symptoms may be nausea, vomiting, orthostatic symptoms and/or hypotension. Initiate vomiting, then stomach lavage, and charcoal therapy. Maintain a high fluid intake to promote renal excretion. There is a risk of thrombosis in predisposed individuals. Anticoagulant treatment should be considered.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Tranexamic acid is an antifibrinolytic compound which is a potent competitive inhibitor of the activation of plasminogen to plasmin. At much higher concentrations it is a non-competitive inhibitor of plasmin. The inhibitory effect of tranexamic acid in plasminogen activation by urokinase has been reported to be 6-100 times and by streptokinase 6-40 times greater than that of aminocaproic acid. The antifibrinolytic activity of tranexamic acid is approximately ten times greater than that of aminocaproic acid.

5.2 Pharmacokinetic Properties

Following oral administration, 1.13% and 39% of the administered dose were recovered after 3 and 24 hours respectively. Tranexamic acid administered parenterally is distributed in a two-compartment model. Tranexamic acid crosses the placenta, and may reach one hundredth of the serum peak concentration in the milk of lactating women. Tranexamic acid crosses the blood brain barrier.

Following intravenous administration, the biological half-life of tranexamic acid has been determined to be 1.9 hours and 2.7 hours.

5.3 Preclinical Safety Data

No additional information.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Microcrystalline cellulose

Hydroxypropyl cellulose L-HPC LH11

Purified talc

Hydrogenated vegetable Oil

Magnesium stearate

Silica, colloidal anhydrous

Povidone

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

Blister strips of aluminium foil and PVC/PVdC, 12 tablets per blister.

Pack size of 60.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0391

9. Date Of First Authorisation/Renewal Of The Authorisation

12 March 2003

10. Date Of Revision Of The Text

06/2011 (To be amended after approval)


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Diloxanide Tablets 500mg (Sovereign Medical)


1. Name Of The Medicinal Product

Diloxanide Tablets 500mg

2. Qualitative And Quantitative Composition

Active ingredient

Quantity

Diloxanide Furoate

500 mg

3. Pharmaceutical Form

A flat, white tablet, scored and with a characteristic engraving E/F on one face.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of acute and chronic intestinal amoebiasis.

4.2 Posology And Method Of Administration

Adults: One tablet three times daily for ten days.

Children: 20 mg/kg bodyweight daily in divided doses for ten days. Furamide is not suitable for use in children weighing less than 25 kg.

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

If required, a second course of treatment may be prescribed.

4.3 Contraindications

Hypersensitivity to diloxanide furoate.

4.4 Special Warnings And Precautions For Use

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically-significant drug interactions known.

4.6 Pregnancy And Lactation

The safety of Furamide during pregnancy and lactation has not been established and use during these periods should therefore be avoided.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

No serious side effects have been reported and the bacterial flora of the gut is not upset. Flatulence sometimes occurs but may usually be disregarded. Occasionally, vomiting, pruritus and urticaria may occur.

4.9 Overdose

Furamide tablets are unlikely to constitute a hazard in overdosage. In severe overdosage, early gastric lavage is recommended. There is no specific antidote. Treatment should be symptomatic and supportive.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Diloxanide furoate is a luminal amoebicide acting principally in the bowel lumen, although its mode of action is not known.

5.2 Pharmacokinetic Properties

In the gut, diloxanide furoate is largely, if not wholly, hydrolysed into diloxanide and furoic acid under the combined action of bacterial and gut esterases. After absorption, diloxanide is very rapidly conjugated to form a glucuronide. In circulating blood, it is present to about 99% as a glucuronide and 1% as free diloxanide. Diloxanide is predominantly excreted in the urine. It is believed that the unabsorbed diloxanide is the active anti-amoebic substance, up to 10% remaining in the gut which is subsequently excreted as diloxanide in the faeces.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Maize starch, pregelatinized maize starch, dried maize starch, magnesium stearate, purified water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

A white aluminium tube with a polythene foam disc and a white aluminium screw cap with flowed-in PVC. Pack size: 15 tablets.

A white polythene cylindrical bottle and white polypropylene screw cap fitted with a waxed aluminium-faced pulpboard liner. Pack size: 30 tablets.

A rectangular amber-glass bottle with a white tin-plate screw cap fitted with a waxed aluminium-faced pulpboard liner. Pack size: 250 tablets.

A white polythene cylindrical bottle and white polypropylene screw cap fitted with a waxed aluminium-faced pulpboard liner. Pack size: 250 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data 7. Marketing Authorisation Holder

Waymade PLC

Sovereign House

Miles Gray Road

Basildon, Essex, SS14 3FR

United Kingdom

8. Marketing Authorisation Number(S)

PL 06464/0900

9. Date Of First Authorisation/Renewal Of The Authorisation

17 November 1999

10. Date Of Revision Of The Text

29 February 2000

Legal Category

POM


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Tranexamic Acid 500mg Tablets (Sandoz Limited)


1. Name Of The Medicinal Product

Tranexamic Acid 500mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 500mg Tranexamic Acid.

For excipients, see 6.1.

3. Pharmaceutical Form

Tablet.

White, capsule shaped tablet embossed with 'T500' on one side and a break line on the other side.

4. Clinical Particulars 4.1 Therapeutic Indications

Tranexamic Acid 500mg Tablets are indicated for short term use for haemorrhage or risk of haemorrhage in those with increased fibrinolysis or fibrinogenolysis. Local fibrinolysis as occurs in the following conditions:

1. a) Prostatectomy and bladder surgery

b) Menorrhagia

c) Epistaxis

d) Conisation of the cervix

e) Traumatic hyphaema

2. Management of dental extraction in haemophiliacs. 3. Hereditary angioneurotic oedema. 4.2 Posology And Method Of Administration

Route of administration: Oral.

Adults:

Local Fibrinolysis: The recommended standard dose is 15-25mg/kg bodyweight (i.e. 2-3 tablets) two to three times daily. For the indications listed below the following doses may be used:

1a Prostatectomy: Prophylaxis and treatment of haemorrhage in high risk patients should commence per- or post-operatively with tranexamic acid injection; thereafter 2 tablets three to four times daily until macroscopic haematuria is no longer present. 1b Menorrhagia: Recommended dosage is 2 tablets 3 times daily as long as needed for up to 4 days. If very heavy menstrual bleeding, dosage may be increased. A total dose of 4g daily (8 tablets) should not be exceeded. Treatment with Tranexamic acid should not be initiated until menstrual bleeding has started. 1c Epistaxis: When repeated bleeding is anticipated oral therapy (2 tablets three times daily) should be administered for 7 days. 1d Cervix Conisation: 3 tablets three times daily. 1e Traumatic Hyphaema: 2-3 tablets 3 times daily. The dose is based on 25mg/kg three times a day. 2. Haemophilia: In the management of dental extractions 2-3 tablets every eight hours. The dose is based on 25mg/kg. 3. Hereditary angioneurotic oedema: Some patients are aware of the onset of illness; suitable treatment for these patients is intermittently 2-3 tablets two to three times daily for some days. Other patients are treated continuously at this dosage.

Children:

This should be calculated according to bodyweight at 25mg/kg per dose at the adult dosing frequencies.

Elderly:

No reduction in dosage is necessary unless there is evidence of renal failure (see guidelines below).

Renal Impairment

By extrapolation from clearance data relating to the intravenous dosage form, the following reduction in the oral dosage is recommended for patients with mild to moderate renal insufficiency:

Serum Creatinine( ?mol/l)

Oral Dose

Dose Frequency

120-249

15 mg/kg body weight

twice daily

250-500

15 mg/kg body weight

daily

4.3 Contraindications

Hypersensitivity to tranexamic acid or any of the other ingredients.

Active thromboembolic disease.

Severe renal failure because of risk of accumulation.

4.4 Special Warnings And Precautions For Use

Caution is advised in treating those with massive haematuria from the upper urinary tract, especially in haemophiliacs, as there have been some cases of ureteric obstruction.

The blood levels are increased in patients with renal insufficiency. Therefore a dose reduction is recommended (see Section 4.2, Posology and Method of Administration).

In those patients requiring long term administration of tranexamic acid, such as those with hereditary angioneurotic oedema, regular eye examinations (e.g. visual acuity, slit lamp, intraocular pressure, visual fields) and liver function tests should be performed.

Patients with irregular menstrual bleeding should not use tranexamic acid until the cause of irregular bleeding has been established. If menstrual bleeding is not adequately reduced by Tranexamic Acid Tablets, an alternative treatment should be considered.

Patients with a previous thromboembolic event and a family history of thromboembolic disease (patients with thrombophilia) should use Tranexamic Acid Tablets only if there is a strong medical indication and under strict medical supervision.

The use of tranexamic acid in cases of increased fibrinolysis due to disseminated intravascular coagulation is not recommended.

Clinical experience with Tranexamic Acid Tablets in menorrhagic children under 15 years of age is not available.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Tranexamic Acid will counteract the thrombolytic effect of fibrinolytic preparations.

4.6 Pregnancy And Lactation

Pregnancy: There is no evidence from animal studies that tranexamic acid has any teratogenic effect, however, the usual caution with use of drugs in pregnancy should be observed.

Tranexamic acid crosses the placenta.

Lactation: Tranexamic acid passes into breast milk to a concentration of approximately one hundredth of the concentration in the maternal blood. An antifibrinolytic effect in the infant is unlikely.

4.7 Effects On Ability To Drive And Use Machines

Tranexamic Acid has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Gastrointestinal disorders (nausea, vomiting, diarrhoea) may occur but disappear when the dosage is reduced.

Rare instances of colour vision disturbances have been reported. Patients who experience disturbance of colour vision should be withdrawn from treatment.

Rare cases of thromboembolic events have been reported.

Rare cases of allergic skin reactions have also been reported.

4.9 Overdose

No cases of overdosage have been reported. Symptoms may be nausea, vomiting, orthostatic symptoms and/or hypotension. Initiate vomiting, then stomach lavage, and charcoal therapy. Maintain a high fluid intake to promote renal excretion. There is a risk of thrombosis in predisposed individuals. Anticoagulant treatment should be considered.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Tranexamic acid is an antifibrinolytic compound which is a potent competitive inhibitor of the activation of plasminogen to plasmin. At much higher concentrations it is a non-competitive inhibitor of plasmin. The inhibitory effect of tranexamic acid in plasminogen activation by urokinase has been reported to be 6-100 times and by streptokinase 6-40 times greater than that of aminocaproic acid. The antifibrinolytic activity of tranexamic acid is approximately ten times greater than that of aminocaproic acid.

5.2 Pharmacokinetic Properties

Following oral administration, 1.13% and 39% of the administered dose were recovered after 3 and 24 hours respectively. Tranexamic acid administered parenterally is distributed in a two-compartment model. Tranexamic acid crosses the placenta, and may reach one hundredth of the serum peak concentration in the milk of lactating women. Tranexamic acid crosses the blood brain barrier.

Following intravenous administration, the biological half-life of tranexamic acid has been determined to be 1.9 hours and 2.7 hours.

5.3 Preclinical Safety Data

No additional information.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Microcrystalline cellulose

Hydroxypropyl cellulose L-HPC LH11

Purified talc

Hydrogenated vegetable Oil

Magnesium stearate

Silica, colloidal anhydrous

Povidone

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

Blister strips of aluminium foil and PVC/PVdC, 12 tablets per blister.

Pack size of 60.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

8. Marketing Authorisation Number(S)

PL 04416/0391

9. Date Of First Authorisation/Renewal Of The Authorisation

12 March 2003

10. Date Of Revision Of The Text

June 2007


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