Cimetidine Tablets 400mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Cimetidine Tablets 400mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Cimetidine 400mg
For excipients, see section 6.1
3 PHARMACEUTICAL FORM
Greenish-yellow, film-coated, capsule shaped tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Cimetidine 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 cimetidine 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 gastro-intestinal 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. Cimetidine is also recommended in the management of the Zollinger-Ellison syndrome.
4.2 Posology and method of administration Adults:
Duodenal or benign gastric ulceration: A single daily dose of 800mg at bedtime is recommended. Otherwise, the usual dose is 400mg twice a day with breakfast and at bedtime; and if inadequate, 400mg four times a day (1.6g/day) also with meals and at bedtime.
Treatment should be given initially for at least four weeks (six weeks in benign gastric ulcer, eight weeks in ulcer associated with continued nonsteroidal anti-inflammatory agents) even if symptomatic relief has been achieved sooner. Most ulcers will have healed by that stage, but those which have not, 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.
Benign peptic ulcer disease: In patients who have responded to the initial course, relapse may be prevented by continued treatment, usually with 400mg at bedtime; 400mg in the morning and at bedtime has also been used.
Esophageal 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.
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.
Prophylaxis of hemorrhage from stress ulceration in seriously ill patients: doses of 200- 400mg can be given every four to six hours.
Risk of acid aspiration syndrome: an oral dose of 400mg can be given 90 to 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. The usual precautions to avoid acid aspiration should be taken.
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: 800mg to 1600mg a day may be given according to response in four divided doses, one to one and a half hours before meals.
The total daily dose should not normally exceed 2.4g. Dosage should be reduced in patients with impaired renal function (see section 4.4).
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, cimetidine 25 - 30mg/kg body weight per day in divided doses may be administered.
Additional information on special populations: The use of cimetidine in infants under one year is not fully evaluated; 20mg/kg body weight per day in divided doses has been used. Cimetidine tablets are not an appropriate formulation for infants and young children.
Administration'. Oral; the tablets should be swallowed with a drink of water.
4.3 Contraindications
Hypersensitivity to Cimetidine or to any of the excipients.
4.4 Special warnings and precautions for use
Dosage should be reduced in patients with hepatic impairment and also in patients with impaired renal function, according to creatinine clearance. The following dosages are suggested: creatinine clearance of 0 to 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 of 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.
Care should be taken that patients with a history of peptic ulcer, particularly the elderly, being treated with cimetidine and a non-steroidal antiinflammatory agent are observed regularly.
Before initiating therapy with this preparation for any gastric ulceration, malignancy should be excluded by endoscopy and biopsy, if possible, because cimetidine can relieve the symptoms and help the superficial healing of the gastric cancer. The consequences of potential delay in diagnosis should be borne in mind especially in middle aged patients or over, with new or recently changed dyspeptic symptoms.
4.5 Interaction with other medicinal products and other forms of interaction
Cimetidine can prolong the elimination of drugs metabolized by oxidation in the liver.
It should be avoided in patients stabilized on anticoagulants (e.g. warfarin), antiepileptics (e.g. phenytoin) xanthines (e.g. theophylline).
Caution should be taken in patients taking anti-arrhythmics (e.g. lidocaine) and ciclosporin.
In patients on drug treatment or those with illnesses that could cause fall in blood cell count, the possibility that an H2-receptor antagonism could potentiate this effect should be borne in mind.
4.6 Pregnancy and lactation
Although tests in animals and clinical evidence have not revealed any hazards from the administration of cimetidine during pregnancy or lactation, both animal and human studies have shown that it does cross the placental barrier, and is excreted in milk. The use of this preparation during pregnancy and lactation should be avoided unless considered essential.
4.7
Effects on ability to drive and use machines
None known
4.8 Undesirable effects
Adverse reactions have been infrequent, diarrhea and other gastrointestinal disturbances, dizziness or rash, usually mild and transient, and tiredness have been reported. Gynaecomastia has been reported and is almost always reversible on discontinuing treatment. Biochemical or biopsy evidence of reversible liver damage has been reported occasionally, as have rare cases of hepatitis. Reversible confusional states have occurred, usually in elderly or already very ill patients, e.g. those with renal failure.
Hallucination has been reported rarely; depression has been reported infrequently.
Thrombocytopenia and leucopenia, including agranulocytosis (see Section 4.5), reversible on withdrawal of treatment, have been reported rarely; pancytopenia and aplastic anaemia have been reported very rarely.
There have been very rare reports of interstitial nephritis, acute pancreatitis, fever, headache, myalgia, arthralgia, sinus bradycardia, tachycardia and heart block, all reversible on withdrawal of treatment. In common with other H2-receptor antagonists, there have been very rare reports of anaphylaxis. Rare cases of hypersensitivity vasculitis have been reported. These usually clear on withdrawal of the drug.
Alopecia has been reported but no causal relationship has been established. Reversible impotence has also been very rarely reported but no causal relationship has been established at usual therapeutic doses. Isolated increases of plasma creatinine have been of no clinical significance.
4.9 Overdose
Acute overdosage of up to 20g of cimetidine 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
Pharmacotherapeutic group: H2-receptor antagonists ATC code: A02B A01
Cimetidine, one of the H2 blockers is a reversible, competitive antagonist of the actions of histamine on H2 receptors. It is highly selective in its action and is virtually without effect on H1 receptors or, indeed on receptors for other autacoids or drugs. The most prominent of the effects of histamine that are mediated by H2 receptors is stimulation of gastric acid secretion and they interfere remarkably little with physiological functions other than gastric secretion.
Cimetidine inhibits gastric acid secretion elicited by histamine or other H2 agonists in a dose-dependent, competitive manner; the degree of inhibition parallels the plasma concentration of the drug over a wide range. In addition, the H2 blockers inhibit gastric secretion elicited by muscarinic agonists or by gastrin, although this effect is not always complete.
This breadth of inhibitory effect is not due to non-specific actions at the receptors for these other secretagogues. Rather, this effect, which is noncompetitive and indirect, appears to indicate either that these two classes of secretagogues utilise histamine as the final common mediator or, more probably, that ongoing histaminergic stimulation of the parietal cell is important for amplification of the stimuli provided by ACh or gastrin when they act on their own discrete receptors. Receptors for all three secretagogues are present on the parietal cell. The ability of H2 blockers to suppress responses to all three physiological secretagogues makes them potent inhibitors of all phases of gastric acid secretion. Thus these drugs will inhibit basal (fasting) secretion and nocturnal secretion and also that stimulated by food, sham feeding, fundic distension, insulin, or caffeine. The H2 blockers reduce both the volume of gastric juice secreted and its hydrogen ion concentration. Output of pepsin, which is secreted by the chief cells of the gastric glands (mainly under cholinergic control), generally falls in parallel with the reduction in volume of the gastric juice. Secretion of intrinsic factor is also reduced, but it is normally secreted in great excess, and absorption of vitamin B12 is usually adequate even during long-term therapy with H2 blockers.
Concentrations of gastrin in plasma are not significantly altered under fasting conditions; however, the normal prandial elevation of gastrin concentration may be augmented, apparently as a consequence of a reduction in the negative feedback that is normally provided by acid.
5.2 Pharmacokinetic properties
Cimetidine is rapidly and virtually completely absorbed. Absorption is little impaired by food or by antacids. Peak concentrations in plasma are attained in about 1 to 2 hours. Hepatic first-pass metabolism results in bioavailabilities of about 60% for cimetidine. The elimination half-life is about 2 to 4 hours. Cimetidine is eliminated primarily by the kidneys, and 60% or more may appear in the urine unchanged; much of the rest is oxidation products. Small amounts are recovered in the stool.
5.3 Preclinical safety data
Not available
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose Povidone
Sodium lauryl sulphate Maize starch Sodium starch glycollate Magnesium stearate Hypromellose
Macrogol 400 Titanium dioxide (E 171)
Yellow lake (E104)
Blue lake (E132)
Carnauba wax
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
The tablets are presented in aluminium blisters, strips of which are contained within a printed cardboard carton, containing 30, 56 or 60 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Dexcel®-Pharma Ltd 7 Sopwith Way Drayton Fields, Daventry Northamptonshire NN11 8PB UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 14017/0002
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/08/2011
10 DATE OF REVISION OF THE TEXT
24/08/2011