TAGAMET Tablets 200 mg; TAGAMET Tablets 400 mg; TAGAMET Tablets 800 mg; TAGAMET Syrup 200 mg/5 mL; TAGAMET Ampoules 200 mg; TAGAMET *I.V. 400 (Premix Intravenous solution in **‘VIAFLEX’Plastic Container)

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

TAGAMET Tablets 200 mg
TAGAMET Tablets 400 mg
TAGAMET Tablets 800 mg
TAGAMET Syrup 200 mg/5 mL
TAGAMET Ampoules 200 mg
TAGAMET *I.V. 400 (Premix Intravenous solution in **‘VIAFLEX’Plastic Container)

SCHEDULING STATUS:
S4

PROPRIETARY NAMES
(and dosage form):

TAGAMET Tablets 200 mg
TAGAMET Tablets 400 mg
TAGAMET Tablets 800 mg
TAGAMET Syrup 200 mg/5 mL
TAGAMET Ampoules 200 mg
TAGAMET *I.V. 400 (Premix Intravenous solution in **‘VIAFLEX’Plastic Container)

COMPOSITION:
The chemical name of cimetidine is:
N"-Cyano-N-methyl-N'-[2[(5-melhyl-1H-imidazol-4-yl)methyl]-thio]-ethyl]guanidine.

Each TAGAMET pale green round tablet contains 200 mg cimetidine.
Each TAGAMET pale green oblong-shaped tablet contains 400 mg cimetidine.
Each TAGAMET pale green elliptical-shaped tablet contains 800 mg cimetidine.
5 mL TAGAMET syrup contains 200 mg cimetidine as the hydrochloride.

	Preserved with methyl p-hydroxybenzoate 0,10% m/v and propyl p-hydroxybenzoate 0,02% m/v.
	Contains ethyl alcohol 2,9% v/v.

Each TAGAMET ampoule contains 200 mg cimetidine in 2 mL solution.
Each TAGAMET premix i/v solution in ‘VIAFLEX’plastic container contains 400 mg cimetidine in 100 mL 0,9% m/v sodium chloride.

PHARMACOLOGICAL CLASSIFICATION:
A 11 4 3 Antacids : Other

PHARMACOLOGICAL ACTION:
TAGAMET inhibits both the stimulated and basal secretion of gastric acid and reduces pepsin output. It competitively inhibits the action of histamine at the histamine H2-receptor and is thus a histamine H2-receptor antagonist.
Studies have shown the degree of inhibition of basal acid secretion to vary between 80 and 100% and of stimulated acid secretion between 56 and 98% with a duration of up to 5 hours, depending on the dosage and the type of stimulation.

Pharmacokinetics
TAGAMET is rapidly absorbed after oral administration. The half-life of TAGAMET is approximately 2 hours. The principal route of excretion is the urine.

INDICATIONS:
TAGAMET is in indicated in:
The treatment of duodenal and benign gastric ulceration and peptic oesophagitis, recurrent ulceration; stomal ulceration and other conditions where reduction of gastric acid secretion has been shown to be beneficial.
Maintenance therapy for periods of up to one year in those patients with recurrence of duodenal ulceration after short-term therapy.
TAGAMET is indicated in the management of those patients who are at high risk from haemorrhage of the upper gastro-intestinal tract due to hepatic failure and treatment with immuno-suppressive agents, following kidney transplant.
Management of pathological hypersecretion such as Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas.
Erosive gastro-oesophageal reflux disease (G.O.R.D.)

CONTRA-INDICATIONS:
TAGAMET is contra indicated in any patients who are known to have hypersensitivity to the drug.

DOSAGE AND DIRECTIONS FOR USE:
ADULTS:
TAGAMET may be administered by mouth, by intramuscular injection, by intravenous injection or by slow intravenous infusion, the total daily dosage by any route should not normally exceed 2.4 grams.

ORAL:

	1. Active Ulcer:
	In active duodenal, benign gastric and stomal ulceration:
	The usual dose is 200 mg three times a day with meals and 400 mg at bedtime. 400 mg twice a day with breakfast and at bedtime has also been shown to be effective. The preferred dose is 200 mg three times a day with meals and 400 mg at bedtime.
	If there is inadequate symptomatic improvement or other evidence of continuing ulceration, this dose may be increased to 400 mg four times a day taken with meals and at bedtime. Treatment should be continued for at least four weeks, even if symptomatic relief has been achieved in a shorter time.
	In duodenal ulcer
	The efficacy of a single bedtime dose of 800 mg has been shown to be comparable to that of a daily dose of 800 mg divided in two administrations (400 mg in the morning and 400 mg at bedtime).
	2. Maintenance treatment:
	Prophylaxis of Recurrent Ulcer:
	In patients with a history of recurrent duodenal ulceration relapse after healing is prevented during treatment at reduced dosage for a period of up to 1 year. It is recommended after healing, to continue treatment at reduced dosage for as long as the physician deems necessary to prevent a relapse.
	A maintenance dose of 400 mg at bedtime has been shown to confer protection against recurrence after duodenal ulceration. During this period of 1 year while on maintenance treatment; some patients may require 400 mg twice a day.
	3. In the management of those patients who are at high risk from haemorrhage of the upper gastro-intestinal tract due to hepatic failure and or treatment with immuno-suppressive agents, following kidney transplant:
	Patients with hepatic failure who are at risk from haemorrhage can be treated with normal doses of TAGAMET. The usual dose 200 mg three times a day with meals and 400 mg at bedtime. It may be necessary to increase the dose to 400 mg four times a day.
	For the dosage for patients following kidney transplant, please refer to “Side effects and special precautions”.
	4. Hypersecretory conditions such as Zollinger-Ellison Syndrome:
	The usual dose is 200 mg three times a day with meals and 400 mg at bedtime, but it may be necessary to increase the dose to 400 mg four times a day. In some patients it may be necessary to administer TAGAMET more frequently. Doses should be adjusted to individual need and should continue as long as clinically indicated.
	5. Gastro-oesophageal reflux disease (GORD); (including peptic oesophagitis).
	In Peptic Oesophagitis
	400 mg four times a day, taken with meals and at bedtime for up to 12 weeks is recommended. 0,8 to 1,6 g/day, depending on the degree of severity of the condition, may be used. A single bedtime dose of 800 mg may be effective in patients with peptic oesophagitis. 400 mg Twice daily in the morning and at bedtime has also been shown to be effective.
	Severe cases may require up to 1,6 g/day given in divided doses.
	In GORD
	The recommended dosage to heal reflux oesophagitis and relieve symptoms is 400 mg bd with meals, up to 12 weeks. The doses and regimen for parenteral administration in patients with GORD have not been established.

Since TAGAMET may not always give immediate symptomatic relief, antacids should be made available to patients as needed for relief of pain.

PARENTERAL:
ADULTS:
Where required parenteral administration may be used. The dose by intravenous injection or intramuscular injection is normally 200 mg.
Which should be given slowly over at least 2 minutes and may be repeated at 4 –6 hourly intervals.
Transient pain at the site of intramuscular injection has been reported. In the event that intravenous injection is necessary 200 mg TAGAMET injection should be diluted in 0,9% sodium chloride (or other compatible) solution to a total volume of 20 mL and given very SLOWLY. This dose may be repeated at 4 – 6 hourly intervals. This method of administration should be avoided in patients with cardiovascular disease. If a larger dose is required, or if the patient has cardiovascular impairment, intravenous infusion is recommended.

For intermittent intravenous infusion, the contents of one TAGAMET premix IV solution in a ‘Vitaflex’plastic container (containing cimetidine 400 mg in 100 mL 0,9% m/v sodium chloride) should be infused over 30 minutes to 1 hour, and may be repeated every 4 –6 hours. Continuous intravenous infusion may be used; the average infusion rate should ordinarily not exceed 50 –100 mg/hour over 24 hours.

Do not add supplementary medication or diluent.

The total daily dosage by any route should normally not exceed 2,4 g. TAGAMET has been shown to be compatible with dextrose and normal saline solutions for intravenous infusion. TAGAMET injectable is stable for 1 week at normal room temperature when added to or diluted with most commonly used intravenous solutions eg Sodium Chloride Injection (0,9%), Dextrose Injection (5% or 10%), Lactated Ringers Solution. TAGAMET IV 400 containers should be replaced at least every 24 hours.

CHILDREN:
Clinical experience in children is limited. Therefore, TAGAMET therapy cannot be recommended in children unless in the judgement of the physician, anticipated benefits outweigh the potential risk. In limited experience, 20 to 40 mg/kg per day has been administered in divided doses orally or parenterally. There is no evidence of clinical use in babies and TAGAMET should therefore not be given to infants under one year of age.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Diarrhoea, tiredness, dizziness, rash, which may be severe, and reversible alopecia have been reported in patients during treatment with TAGAMET.

Gynaecomastia which may be reversible has been reported. Reversible impotence has been reported in rare instances.
Decreased white cell counts in TAGAMET treated patients including agranulocytosis have been reported including reports of occurrence on rechallenge. Cases of thrombocytopenia, granulocytopenia, pancytopenia and aplastic anaemia have also been reported. Other side effects which have been reported are allergic reactions, arthralgia, myalgia, and headache.
Rare occurrences of anaphylaxis have been reported in patients treated with H2 antagonists.
Cases of reversible confusional states, slurred speech, hallucinations, and coma have been reported usually in children, elderly and/or severely ill patients, such as those with renal insufficiency or organic brain syndrome. Bradycardia, tachycardia and AV heart block have been reported with TAGAMET. Reversible increases in plasma creatinine may occur. Increases in serum transaminase and cases of hepatitis, fever and interstitial nephritis and pancreatitis which cleared on withdrawal of the drug, have been reported. TAGAMET has been administered to patients with impaired renal function. A transient rise in blood urea and serum creatinine concentration were found in patients with moderate renal failure.

Dosage adjustment for patients with impaired renal function:
In patients with impaired renal function, dosage should be reduced according to creatinine clearance.
The following dosages are suggested:

Creatinine clearance of	0 –15 mL/minute, 200 mg twice a day;
	15 –30 mL/minute, 200 mg three times a day;
	30 –50 mL/minute, 200 mg four times a day;
	over 50 mL/minute, normal dose.

Circulating cimetidine levels are reduced by haemodialysis. Therefore, the drug should be administered at the end of dialysis.

Special Precautions:
Cases of cardiac arrest, cardiac arrhythmias and hypotension have been reported following the rapid administration of TAGAMET Injection by intravenous bolus. Intravenous injections of cimetidine should be given slowly and intravenous infusion is recommended in patients with cardiovascular impairment.
The possibility of malignancy in gastric ulcer should be excluded since the symptoms may respond to TAGAMET treatment.
Glucose handling may be impaired after long-term cimetidine administration, therefore caution should be observed in the treatment of diabetics or elderly patients with cimetidine.

Interactions:
Anticholinergic agents should not be administered concurrently with cimetidine for maintenance treatment because of the possibility of interactions.
TAGAMET apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, chlordiazepoxide, diazepam, lignocaine, nifedipine and theophylline; thereby delaying elimination and increasing blood levels of these medicines.
Since clinically significant interactions have been reported with the warfarin anticoagulants close monitoring of prothrombin time is recommended, and adjustment of the anti-coagulant dose may be necessary when TAGAMET is administered concomitantly.
Interaction with phenytoin, theophylline, lignocaine and calcium channel blockers, has also been reported to produce adverse clinical effects.
Increased plasma levels of nifedipine have been reported during concomitant cimetidine administration.
For concomitant administration of these two medicines, cautious titration of nifedipine is advised.
Doses of the medicines mentioned above and other similarly metabolised medicines may require adjustments when starting or stopping concomitantly administered TAGAMET, to maintain safe, optimum therapeutic blood levels.

Use in Pregnancy and Lactation:
The safety of TAGAMET in pregnancy has not been established in pregnancy. TAGAMET crosses the placenta barrier and is excreted in human milk. The use of TAGAMET should be avoided during pregnancy unless essential.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Acute overdosage of up to 100 tablets (20 grams) has been reported several times with no signiticant ill effects. Induction of vomiting and/or gastric lavage may be employed together with symptomatic and supportive therapy.

IDENTIFICATION:

Tablets 200 mg	:	Pale green, film-coated tablets, engraved TAGAMET on obverse and SK&F 200 on reverse.
Tablets 400 mg	:	Pale green, oblong shaped, film-coated tablets with convex faces and flat sides with TAGAMET imprinted on one face and SK&F 400 on the other face.
Tablets 800 mg	:	Pale green, elliptical, biconvex film-coated tablets with bevelled edges, bearing a raised elliptical portion, surrounded by a groove, on each face, SK&F and T800 is embossed on one face of the tablet.
Syrup	:	Clear, orange-coloured peach flavoured syrup.
Ampoules	:	Clear solution.
I V. 400	:	(Premix Intravenous solution in ‘VIAFLEX’plastic container)
	:	Clear solution.

PRESENTATION:
TAGAMET is available as:

Tablets	:	200 mg tablets in securitainers of 150 and 60.
	:	400 mg tablets in securitainers of 60 and/or blister packs in strips of 10.
	:	800 mg tablets in securitainers of 30.
Syrup	:	In bottles containing 200 mL.
Ampoules	:	2 mL ampoules in packs of 10.
I.V. 400	:	100 mL ‘VIAFLEX’plastic containers in packs of 20.

STORAGE INSTRUCTIONS:
Store at room temperature below 25 °C.
Protect from light.

KEEP OUT OF REACH OF CHILDREN

TAGAMET Injection is stable for one week at room temperature when added to or diluted with most commonly used intravenous solutions, e.g. Sodium Chloride Injection (0,9%), Dextrose Injection (5% or 10%), Lactated Ringers Solution.

TAGAMET I.V. 400 (Premix Intravenous solution ** ‘VIAFLEX’Plastic Container) should be replaced at least every 24 hours.

REGISTRATION NUMBERS:

TAGAMET TABLETS 200 mg	:	J/11.4.3/307
TAGAMET TABLETS 400 mg	:	P/11.4.3/173
TAGAMET TABLETS 800 mg	:	T/11.4.3/22
TAGAMET SYRUP 200 mg/5 mL	:	J/11.4.3/308
TAGAMET AMPOULES 200 mg	:	J/11.4.3/309
TAGAMET I.V. 400	:	S/11.4.3/328

NAME AND BUSINESS ADDRESS OF THE APPLICANT
SmithKline Beecham Pharmaceuticals (Pty) Ltd
6 Carey Street
Wynberg Ext. 6
Johannesburg

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
3 August 1993

	* Manufactured and Distributed by Adcock Ingram Critical Care Limited; Sabax Road; Aeroton; Johannesburg
	Under licence from Baxter Travenol Laboratories Inc. Deerfield, Illinois, USA
	for SmithKline Beecham Pharmaceuticals (Pty) Limited
	TAGAMET is a Registered Trademark of SmithKline Beecham Pharmaceuticals (Pty) Ltd
	** ‘VIAFLEX’is a Registered Trademark of Baxter Travenol Laboratories Inc.