SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tagamet Syrup

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The syrup contains 200 mg cimetidine in each 5 ml dose.

3 PHARMACEUTICAL FORM

A clear, orange-coloured, peach-flavoured syrup.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

‘Tagamet’ is a histamine H2-receptor antagonist which rapidly inhibits both basal and stimulated gastric secretion of acid and reduces pepsin output.

‘Tagamet’ is indicated in the treatment of duodenal and benign gastric ulceration, including that associated with non-steroidal anti-inflammatory agents, recurrent and stomal ulceration, oesophageal reflux disease and other conditions where reduction of gastric acid by ‘Tagamet’ has been shown to be beneficial: persistent dyspeptic symptoms with or without ulceration, particularly meal-related upper abdominal pain, including such symptoms associated with non-steroidal anti-inflammatory agents; the prophylaxis of gastrointestinal haemorrhage from stress ulceration in critically ill patients; before general anaesthesia in patients thought to be at risk of acid aspiration (Mendelson's) syndrome, particularly obstetric patients during labour; to reduce malabsorption and fluid loss in the short bowel syndrome; and in pancreatic insufficiency to reduce degradation of enzyme supplements. ‘Tagamet’ is also recommended in the management of the Zollinger-Ellison syndrome.

4.2 Posology and method of administration

The total daily dose should not normally exceed 2.4g. Dosage should be reduced in patients with impaired renal function (see section 4.4).

Adults:

Oral: For patients with duodenal or benign gastric ulceration, a single daily dose of 800mg at bedtime is recommended. Otherwise the usual dosage is 400mg twice a day with breakfast and at bedtime. Other effective regimens are 200mg three times a day with meals and 400mg at bedtime (1.0g/day) and, if inadequate, 400mg four times a day (1.6 g/day) also with meals and at bedtime.

Symptomatic relief is usually rapid. Treatment should be given initially for at least four weeks (six weeks in benign ulcer, eight weeks in ulcer associated with continued non-steroidal anti-inflammatory agents). Most ulcers will have healed by that stage, but those which have not will usually do so after a further course of treatment.

Treatment may be continued for longer periods in those patients who may benefit from reduction of gastric secretion and the dosage may be reduced in those who have responded to treatment, for example to 400mg at bedtime or 400mg in the morning and at bedtime.

In patients with benign peptic ulcer disease, relapse may be prevented by continued treatment, usually with 400mg at bedtime; 400mg in the morning and at bedtime has also been used.

In oesophageal reflux disease, 400mg four times a day, with meals and at bedtime, for four to eight weeks is recommended to heal oesophagitis and relieve associated symptoms.

In patients with very high gastric acid secretion (e.g. Zollinger-Ellison syndrome) it may be necessary to increase the dose to 400mg four times a day, or in occasional cases further.

Antacids can be made available to all patients until symptoms disappear.

In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients, doses of 200-400mg can be given every four to six hours, by oral or nasogastric routes.

In patients thought to be at risk of acid aspiration syndrome an oral dose of 400mg can be given 90-120 minutes before induction of general anaesthesia or, in obstetric practice, at the start of labour. While such a risk persists, a dose of up to 400mg may be repeated at four hourly intervals as required up to the usual daily maximum of 2.4g. Tagamet Syrup should not be used. The usual precautions to avoid acid aspiration should be taken.

In the short bowel syndrome, e.g. following substantial resection for Crohn's disease, the usual dosage range (see above) can be used according to individual response.

To reduce degradation of pancreatic enzyme supplements, 800-1600mg a day may be given according to response in four divided doses, one to one and a half hours before meals.

Elderly: The normal adult dosage may be used unless renal function is markedly impaired. (See section 4.4).

Children: Experience in children is less than that in adults. In children more than one year old, Tagamet 25-30mg/kg body weight per day in divided doses may be administered.

The use of Tagamet in infants under one year old is not yet fully evaluated; 20mg/kg body weight per day in divided doses has been used.

4.3 Contraindications

Hypersensitivity to Cimetidine.

4.4 Special warnings and precautions for use

Dosage should be reduced in patients with impaired renal function according to creatinine clearance. The following dosages are suggested: creatinine clearance of 0-15ml per minute, 200mg twice a day; 15 to 30ml per minute, 200mg three times a day; 30 to 50ml per minute, 200mg four times a day; over 50ml per minute, normal dosage. Cimetidine is removed by haemodialysis, but not to any significant extent by peritoneal dialysis.

Clinical trials of over six years’ continuous treatment and more than 15 years’ widespread use have not revealed unexpected adverse reactions related to long-term therapy. The safety of prolonged use is not fully established and care should be taken to observe periodically patients given prolonged treatment.

‘Tagamet’ treatment can mask the symptoms and allow transient healing of gastric cancer. The potential delay in diagnosis should particularly be borne in mind in patients of middle age and over with new or recently changed dyspeptic symptoms.

Care should be taken that patients with a history of peptic ulcer, particularly the elderly, being treated with Tagamet and a non-steroidal anti-inflammatory agent are observed regularly.

Due to possible interaction with coumarins, close monitoring of prothrombin time is recommended when cimetidine is concurrently used.

Co-administration of therapeutic agents with a narrow therapeutic index, such as phenytoin or theophylline, may require dosage adjustment when starting or stopping concomitantly administered cimetidine (see Section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Tagamet can prolong the elimination of drugs metabolised by oxidation in the liver.

Although pharmacological interactions between cimetidine and a number of drugs have been demonstrated e.g. diazepam and propranolol, only those with oral anticoagulants, phenytoin, theophylline and intravenous lidocaine appear, to date, to be of clinical significance. Close monitoring of patients on Tagamet receiving oral anticoagulants or phenytoin is recommended and a reduction in the dosage of these drugs may be necessary.

In patients on drug treatment or with illnesses that could cause falls in blood cell count, the possibility that H₂-receptor antagonism could potentiate this effect should be borne in mind.

Cimetidine has the potential to affect the absorption, metabolism or renal excretion of other drugs which is particularly important when drugs with a narrow therapeutic index are administered concurrently. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment (see Section 4.4).

Interactions may occur by several mechanisms including:

1)    Inhibition of certain cytochrome P450 enzymes (including CYP1A2, CYP2C9, CYP2D6 and CYP3A3/A4, and CYP2C18); Inhibition of these enzymes may result in increased plasma levels of certain drugs including warfarin-type coumarin anticoagulants (e.g. warfarin), tricyclic antidepressants (e.g. amitriptyline), class I antiarrhythmics (e.g. lidocaine), calcium channel blockers (e.g. nifedipine, diltiazem), oral sulfonylureas (e.g. glipizide), phenytoin, theophylline and metoprolol.

2)    Competition for renal tubular secretion; this may result in increased plasma levels of certain drugs including procainamide, metformin, ciclosporin and tacrolimus.

3)    Alteration of gastric pH; the bioavailability of certain drugs may be affected. This can result in either an increase in absorption (e.g. atazanavir) or a decrease in absorption (e.g. some azole antifungals such as ketoconazole, itraconazole or posaconazole).

4)    Unknown mechanisms; Cimetidine may potentiate the myelosuppressive effects (e.g. neutropenia, agranulocytosis) of chemotherapeutic agents such as carmustine, fluorouracil, epirubicin, or therapies such as radiation. Isolated cases of clinically relevant interactions have been documented with narcotic analgesics (e.g. morphine).

4.6 Fertility, Pregnancy and lactation

Although tests in animals and clinical evidence have not revealed any hazards from the administration of ‘Tagamet’ during pregnancy or lactation, both animal and human studies have shown that it does cross the placental barrier and is excreted in milk. As with most drugs, the use of ‘Tagamet’ should be avoided during pregnancy and lactation unless essential.

4.7 Effects on ability to drive and use machines

Not applicable

4.8 Undesirable effects

Adverse experiences with cimetidine are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000).

Blood and lymphatic system disorders

Uncommon: Leukopenia

Rare: Thrombocytopenia, aplastic anaemia

Very rare: Pancytopenia, agranulocytosis

Immune system disorders

Very rare: Anaphylaxis. Anaphylaxis is usually cleared on withdrawal of the

drug.

Psychiatric disorders

Uncommon: Depression, confusional states, hallucinations. Confusional states, reversible within a few days of withdrawing cimetidine, have been reported, usually in elderly or ill patients.

Nervous system disorders

Common: Headache, dizziness

Cardiac disorders

Uncommon: Tachycardia Rare: Sinus bradycardia Very rare: Heart block

Gastrointestinal disorders

Common: Diarrhoea

Very rare: Pancreatitis. Pancreatitis cleared on withdrawal of the drug.

Hepatobiliary disorders

Uncommon: Hepatitis

Rare: Increased serum transaminase levels. Hepatitis and increased serum transaminase levels cleared on withdrawal of the drug.

Skin and subcutaneous tissue disorders

Common: Skin rashes

Very rare: Reversible alopecia and hypersensitivity vasculitis.

Hypersensitivity

vasculitis usually cleared on withdrawal of the drug.

Musculoskeletal and connective tissue disorders

Common: Myalgia Very rare: Arthralgia

Renal and urinary disorders

Uncommon: Increases in plasma creatinine

Rare: Interstitial nephritis. Interstitial nephritis cleared on withdrawal of the drug. Small increases in plasma creatinine have been reported, unassociated with changes in glomerular filtration rate. The increases do not progress with continued therapy and disappear at the end of therapy.

Reproductive system and breast disorders

Uncommon: Gynaecomastia and reversible impotence. Gynaecomastia is usually reversible upon discontinuation of cimetidine therapy. Reversible impotence has been

reported particularly in patients receiving high doses (e.g. in Zollinger-Ellison Syndrome). However, at regular dosage, the incidence is similar to that in the general population.

Very rare: Galactorrhoea

General disorders and administration site conditions

Common: Tiredness

Very rare: Fever. Fever cleared on withdrawal of the drug.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Acute overdosage of up to 20g has been reported several times with no significant ill-effects. Induction of vomiting and/or gastric lavage may be employed together with symptomatic and supportive therapy.

5.1 Pharmacodynamic properties

Cimetidine is a histamine H2-receptor antagonist which rapidly inhibits both basal and stimulated gastric secretion of acid and reduces pepsin output.

5.2 Pharmacokinetic properties

Cimetidine is well absorbed after oral administration, metabolised in the liver and excreted mainly through the kidney with a half-life of about two hours. The effects on acid secretion are of longer duration.

5.3 Preclinical safety data

Not applicable

6.1    List of excipients

The syrup contains saccharin sodium, hydrochloric acid (E507), ethyl alcohol, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol, sodium chloride, disodium hydrogen phosphate (E339), sorbitol (E420), sucrose, Sunset Yellow (E110), peach flavour, Mafco Magnasweet 180, ethylene oxide and propylene oxide polymer and water. The sodium content per 5ml of syrup is 12.8mg.

6.2    Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25 °C

Nature and contents of container

Amber glass or white opaque HDPE bottles with screw cap containing 600 ml.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

Essential Pharma 7 Egham Business Village Crabtree Road Egham, Surrey TW20 8RB United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 41871/0005

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/07/2008

10    DATE OF REVISION OF THE TEXT

28/01/2016