Tagamet Injection

1. Name Of The Medicinal Product

Tagamet® Injection

2. Qualitative And Quantitative Composition

Tagamet Injection contains 200 mg cimetidine in 2 ml.

3. Pharmaceutical Form

Ampoules containing 200 mg cimetidine in 2 ml solution.

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 seriously 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

Tagamet is usually given orally, but parenteral dosing may be substituted for all or part of the recommended oral dose in cases where oral dosing is impracticable or considered inappropriate.

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

ADULTS

Tagamet may be given intramuscularly or intravenously.

The dose by intramuscular injection is normally 200 mg, which may be repeated at four- to six-hourly intervals.

The usual dosage for intravenous administration is 200 - 400 mg, which may be repeated four to six-hourly.

If direct intravenous injection cannot be avoided, 200 mg should be given slowly over at least five minutes, and may be repeated four to six-hourly. Rapid intravenous injection has been associated with cardiac arrest and arrhythmias. For critically ill patients and patients with cardiovascular impairment, or if a larger dose is needed, the dose should be diluted and given over at least 10 minutes. In such cases infusion is preferable.

For intermittent intravenous infusion, Tagamet may be given at a dosage of 200 mg to 400 mg every 4 to 6 hours.

If continuous intravenous infusion is required, Tagamet may be given at an average rate of 50 to 100 mg/hour over 24 hours.

In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients, doses of 200 - 400 mg can be given every four to six hours by oral, nasogastric or parenteral routes. By direct intravenous injection a dose of 200 mg should not be exceeded: see above.

In patients thought to be at risk of acid aspiration syndrome an oral dose of 400 mg 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 400 mg may be repeated (parenterally if appropriate) at four-hourly intervals as required up to the usual daily maximum of 2.4 g. The usual precautions to avoid acid aspiration should be taken.

To reduce degradation of pancreatic enzyme supplements, 800 - 1600 mg 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 - 30 mg/kg body weight per day in divided doses may be administered.

The use of Tagamet in infants under one year old is not fully evaluated; 20 mg/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

Rapid intravenous injection of cimetidine (less than 5 minutes) should be avoided as there have been rare associations with cardiac arrest and arrhythmias. Transient hypotension has also been observed, particularly in critically ill patients (see Section 4.2).

Dosage should be reduced in patients with impaired renal function according to creatinine clearance. The following dosages are suggested: creatinine clearance of 0 to 15 ml per minute, 200 mg twice a day; 15 to 30 ml per minute, 200 mg three times a day; 30 to 50 ml per minute, 200 mg four times a day; over 50 ml per minute, normal dosage.

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, however, 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.

In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired pneumonia. A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of H₂ receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.63 (95% CI, 1.07-2.48).

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

Coadministration 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 with a number of drugs (e.g. diazepam, propranolol) have been demonstrated, 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, quinidine), 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, quinidine, 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 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: Increases in serum transaminase levels

Hepatitis and increases in serum tranaminase 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.

4.9 Overdose

Acute over-dosage of up to 20 grams 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. Pharmacological Properties

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 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. Pharmaceutical Particulars

6.1 List Of Excipients

The injection contains hydrochloric acid (E507) and water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Five years.

6.4 Special Precautions For Storage

Store ampoules below 30°C, protected from light.

6.5 Nature And Contents Of Container

2 ml clear glass ampoules in boxes of 20.

6.6 Special Precautions For Disposal And Other Handling

Tagamet is compatible with electrolyte and dextrose solutions commonly used for intravenous infusion.

Administrative Data

7. Marketing Authorisation Holder

Smith Kline & French Laboratories Ltd

Great West Road, Brentford, Middlesex TW8 9GS.

trading as:

GlaxoSmithKline UK,

Stockley Park West,

Uxbridge, Middlesex, UB11 1BT

8. Marketing Authorisation Number(S)

PL 0002/0059R

9. Date Of First Authorisation/Renewal Of The Authorisation

4 September 2002

10. Date Of Revision Of The Text

14 August 2008

11. Legal Status

POM.