Cimetidine 200mg/5ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Cimetidine 200mg/5ml Oral Solution
2. Qualitative and Quantitative Composition
Cimetidine 200mg/5ml For excipients see 6.1.
3. Pharmaceutical Form
Oral Solution
Clear yellow/orange colour with odour of peppermint and peach
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 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. Cimetidine is also recommended in the management of the Zollinger-Ellison syndrome.
4.2 Posology and method of administration
For oral administration only.
The total daily dose should not exceed 2.4g. Dosage should be reduced in patients with impaired renal function (see Special warnings and precautions for use)
Adults: 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 (1.6g/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 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 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.
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. Since cimetidine may not give immediate symptomatic relief, 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.
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.
Treatment should be avoided before general anaesthesia and in management of labour.
To reduce degradation of pancreatic enzyme supplements, 800-1600mg a day may be given according to response in four divided doses, 1- 1/ hours before meals.
Elderly:
The normal adult dosage may be used unless renal function is markedly impaired (See special warnings and precautions for use).
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 by the oral route.
The use of cimetidine in infants under one year old is not fully evaluated; 20mg/kg body weight per day in divided doses has been used.
4.3. Contra-Indications
Hypersensitivity to cimetidine or any of the other ingredients listed.
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 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’ 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.
Before initiating therapy with this preparation for any gastric ulceration, malignancy should be excluded by endoscopy and biopsy if possible, because cimetidine 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 cimetidine and a non-steroidal antiinflammatory agent are observed regularly.
Ingredients in the formulation
The product contains sunset yellow E110 which may cause allergic reactions including asthma. Allergy is more common in those people who are allergic to aspirin.
Cimetidine 200mg/5ml Oral Solution contains methyl and propyl hydroxybenzoates (preservatives) which may cause allergic reactions (possibly delayed).
The product also contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Contained in this product is propylene glycol which may cause alcohol-like symptoms
4.5. Interaction with other Medicinal Products and other forms of Interaction
Cimetidine 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 cimetidine 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. 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. As with most drugs, the use of cimetidine 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
Over 56 million patients have been treated with cimetidine world-wide and adverse reactions have been infrequent.
Blood and the lymphatic system disorders
Thrombocytopenia and leucopenia, including agranulocytosis (see Special warnings and precautions for use), reversible on withdrawal of treatment, have been reported rarely; pancytopenia and aplastic anaemia have been reported very rarely.
Immune
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.
Endocrine Disorders
Gynaecomastia has been reported and is always reversible on discontinuing treatment.
There have been rare reports of acute pancreatitis which is reversible on withdrawal of treatment.
Psychiatric Disorders
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.
Cardiac
There are rare reports of sinus bradycardia, tachycardia and heart block which are all reversible on withdrawal of treatment.
Hepato-biliary disorders
Biochemical or biopsy evidence of reversible liver damage has been reported occasionally as have rare cases of hepatitis.
Musculoskeletal, connective tissue and bone disorders
There have been rare reports of myalgia and arthralgia which is reversible on
withdrawal of treatment.
Renal and Urinary Disorders
Isolated increases of plasma creatinine have been of no clinical significance. There have been very rare reports of interstitial nephritis which is reversible on withdrawal.
Reproductive system and breast disorders
Reversible impotence has also been very rarely reported but no causal relationship has been established at usual therapeutic doses.
General Disorders
Diarrhoea, dizziness or rash, usually mild or transient, and tiredness have been reported.
There are rare reports of fever and headache which are reversible on withdrawal of treatment.
Alopecia has been reported but no causal relationship has been established.
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 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Cimetidine is a histamine H2-receptor antagonist; 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 the 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 gastric 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 -3 hours. The effects on acid secretion are of longer duration. 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
Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.
6.1. List of excipients
Methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol, liquid maltitol (containing sorbitol), hydrochloric acid, disodium hydrogen phosphate anhydrous(E339), saccharin sodium, ammonium glycyrrhizinate, peach flavour, peppermint flavour, sunset yellow (E110) and purified water.
6.2. Incompatibilities
Not applicable.
6.3. Shelf life
Closed - 18 months Once open - 1 month
6.4. Special precautions for storage
Do not store above 25°C.
6.5. Nature and contents of container
Bottle: Amber (Type III) glass
Closures:a) HDPE, EPE wadded, tamper evident screw cap.
b) HDPE, EPE wadded, tamper evident, child resistant closure.
Pack Size: 300ml
6.6. Instruction for use and handling
Not applicable
7. MARKETING AUTHORISATION HOLDER
Rosemont Pharmaceuticals Ltd Rosemont House
Yorkdale Industrial Park Braithwaite Street Leeds LS11 9XE United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 00427/0131
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27/02/2009
10 DATE OF REVISION OF THE TEXT
06/06/2012