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Cimetidine USP in:
200mg Tablet: round, biconvex, pale green, film-coated tablets of 9mm diameter, scored on one side and embossed NOVO 200 on the same side.
400mg Tablet: oval, biconvex, pale green, film-coated tablets, 15mm in length, embossed NOVO on one side and 400 on the other.
800mg Tablet: oval, biconvex, pale green, film-coated tablets, 19mm in length, embossed NOVO on one side and 800 on the other.
Cimetidine is a selective antagonist of histamine at gastric H2-receptor sites. It is not an anti-cholinergic agent. Cimetidine reduces both daytime and basal (fasting) gastric acid secretion, also inhibiting gastric acid secretion stimulated by food, histamine, pentagastrin, insulin and caffeine.
Cimetidine administered orally inhibits histamine-evoked gastric acid secretion in a dose dependent manner, the degree of inhibition paralleling closely the concentration of medicine in the blood. Clinical studies indicate that a dose regimen of 300mg cimetidine four times daily given with meals and at bedtime results in an 80% or higher inhibition of 24 hour gastric acid secretion.
Cimetidine reduces both the volume of gastric secretion and its hydrogen ion concentration. Total pepsin output generally falls in parallel with the reduced volume of gastric secretion. The medicine has no consistent effect on the rate of gastric emptying, lower oesophageal sphincter pressure or pancreatic secretion.
Cimetidine concentrations between 0.5-1.0 mcg/mL are required to suppress gastric acid secretion under basal or pentagastrin stimulated conditions. Attempts to correlate cimetidine plasma concentrations or any pharmacodynamic parameters to duodenal ulcer healing have so far failed. Prediction of therapeutic response from pharmacokinetic data, therefore, is disappointing.
Cimetidine also inhibits hepatic cytochrome P-450 and P-448 mixed function oxidase systems, antagonises dihydrotestosterone (antiandrogenic action), and may enhance gastromucosal defense and healing in acid-related disorders, particularly stress-induced ulceration and bleeding, by increasing production of gastric mucous, content of mucous glycoprotein, mucosal secretion of bicarbonate, gastric mucosal blood flow, endogenous mucosal prostaglandin synthesis, and rate of epithelial cell renewal.
Cimetidine is rapidly but incompletely absorbed, only 60-70% of a single oral dose reaching the circulation. The absorption of cimetidine may be delayed by the presence of food, however, the extent of absorption and hence bioavailability is unchanged. Peak plasma concentrations are achieved within 1 to 1.5 hours, and the plasma half-life is approximately 2 hours. In a study in fasting healthy male adult volunteers, peak whole blood cimetidine levels of 1.22mcg/mL (Cmax) were attained at 1.64h (Tmax) following the administration of a single 300mg cimetidine tablet. The measured elimination half-life was 2.9 hours and the Area Under the Curve (AUC) was 4.67mcgh/mL.
Studies in patients with peptic ulcers indicate that similar values are found overall for bioavailability parameters, however, there is greater intersubject variation than seen in healthy volunteers. Other studies in patients with Billroth I or Billroth II gastrectomies indicate: a delay in absorption, compared to control subjects, which is significant in Billroth II patients; and significant increases in the AUC's for both patient groups compared to controls. There was no difference in the maximum attained plasma concentration of cimetidine and half-life, however, concentrations above the effective concentration of 0.5mcg/mL were maintained for significantly longer in the Billroth I and II gastrectomy patients than in the controls. It is postulated that the increase in AUC is due to reduced gut wall metabolism.
Further studies in healthy subjects indicate that there is a good relationship between oral dose and AUC. In 10 patients the AUC from a 400mg dose was found to be 2.05 ± 0.23 times the AUC of a 200mg dose. Similarly, in another 10 subjects the AUC of an 800mg dose was found to be 2.1 times that of a 400mg dose. This indicates linearity of both absorption and clearance of cimetidine between 200-800mg. After continuous administration of cimetidine, reproducible blood levels have been demonstrated up to 2 years after the first investigation.
Cimetidine distributes widely and extensively throughout the majority of body fluids, organs and tissues in man. Approximately 70% of the total body content of cimetidine will be found in skeletal muscle, 5-10% in the liver, GI tract and bone, 1-5% in the kidney, lung and blood and <1% in the pancreas, heart, salivary glands, brain and cerebro-spinal fluid. No cimetidine enters fat. Cimetidine can enter the cerebrospinal fluid (CSF), the mean CSF to serum ratios ranging from 0.03-0.18 in the absence of renal or hepatic disease. Where such disease is present the ratio has been measured to be 0.28-0.5. Plasma protein binding of cimetidine is 18-26.3% at concentrations between 0.05-50mcg/ml. In subjects with peptic ulcer disease it has been assessed as 13-25% (mean 19%). This is well below the critical value of 80% above which changes in unbound drug concentration due to altered protein binding become important. Cimetidine is also taken up into red cells. Cimetidine is eliminated from the body by renal, metabolic and biliary processes with the renal component contributing the most to the total elimination. After oral administration of cimetidine in one study, 82-96% of the dose was recovered in urine and 7.1-12.8% in faeces.
The amount of unchanged cimetidine recovered in the urine varies with age averaging between 65-75% of a dose in young adults whereas it is 45-60% of the dose in the elderly. This may be reduced by a further amount in patients with peptic ulcer disease, however, the extent of renal elimination is unchanged by long term administration. The elimination of unchanged cimetidine into bile is negligible, while elimination of cimetidine metabolites has not been determined.
Metabolism of cimetidine represents only 25-40% of the total elimination of cimetidine and 3 metabolic products are known. These are: cimetidine sulphoxide, hydroxymethyl cimetidine and guanylurea cimetidine. The latter may be formed non-enzymatically as an in-vitro degradation product. A further metabolite cimetidine-N'-glucuronide has been detected and if confirmed would represent the major urinary metabolite of cimetidine at 24% recovery. The sulphoxide metabolite can account for between 7-14% of the urinary recovery, the hydroxymethyl metabolite about 4% and the guanylurea metabolite <2%.
Animal studies indicate that cimetidine sulphoxide may be reduced back to cimetidine although the importance of this is unknown. Age does have an important bearing on the pharmacokinetics of cimetidine, renal clearance being greater in the young than the elderly. The exception is possibly neonates where depressed tubular function is expected to give a low total clearance, however, no specific studies have been performed to confirm this. Published studies show that the total plasma clearance correlates well with age (r2 = 0.8) showing a decrease by half between the ages of 30 and 65 years. Accompanying this decrease in total clearance is an increase in the time during which cimetidine concentrations exceed the level at which gastric acid secretion is inhibited by 50%. There is also a linear relation between the morning trough plasma concentration of cimetidine and age.
A combination of the above indicates that the high incidence of cimetidine side effects in the elderly patient could be due to their reduced ability to clear cimetidine and that smaller doses should be used.
The effects of renal insufficiency have also been investigated and, in general, it can be said that there is no change in the fraction of dose absorbed, volume of distribution or non-renal clearance. However, renal clearance can be less than 10% of normal thereby reducing total plasma clearance by approximately one third and prolonging the half-life 3-fold. It is recommended that doses be adjusted according to creatinine clearance. In patients requiring haemodialysis no extra dose is required at the end of dialysis since less than 20% of a dose is dialysed.
Chronic liver disease is frequently associated with peptic ulcer disease and a high incidence of side effects attributable to cimetidine has been reported in patients with liver cirrhosis. Studies indicate that in liver cirrhosis the non-renal (metabolic) clearance of cimetidine is reduced, leading to increased levels in patients with severe but not mild liver disease. Again the dose should be adjusted based on creatinine clearance. In patients with both renal and hepatic disease, reductions in both renal and non-renal cimetidine clearance indicate that the half-life of cimetidine may be up to 10 x that of normal necessitating a drastic reduction in dose.
Cimetidine can cross the placenta and is detectable in the foetus in considerable concentration. It is also secreted into breast milk and may reach the infant in amounts of several milligrams daily.
CYTINE tablets are indicated for the treatment of the following conditions where reduction of gastric acid secretion is expected to be beneficial: gastric and duodenal ulcer, reflux oesophagitis, upper GI haemorrhage, Zollinger Ellison syndrome.
Its ability to inhibit acid secretion also means that cimetidine may be used for the prophylaxis of gastrointestinal haemorrhage as a consequence of stress ulceration and in patients at risk of acid aspiration during general anaesthesia. Cimetidine may also be used to reduce malabsorption and fluid loss in patients with short bowel syndrome and to reduce the degradation of enzyme supplements given to patients with pancreatic insufficiency.
CYTINE tablets are for oral administration. Daytime doses should generally be taken with meals. The total daily dose should not exceed 2.4g.
Acute Duodenal Ulcer: 800mg at night. This dose should be given initially for at least 4 weeks in the case of duodenal and for at least 6 weeks in the case of gastric ulcers. Where appropriate a maintenance dose of 400mg may then be given. If required antacids may be administered concurrently with cimetidine for the relief of pain. The use of higher or more frequent doses does not improve the prophylactic effectiveness of cimetidine.
Benign Gastric Ulcer: 800mg at night. Healing occurs in 4 weeks in most cases.
Reflux Oesophagitis: 400mg twice daily in mild to moderate cases or up to 400mg four times daily in severe cases for up to 12 weeks.
Zollinger-Ellison Syndrome: 200mg three times daily with meals and 400mg at bedtime, increased to 400mg four times daily if necessary.
Children: 20-40mg/kg bodyweight daily.
Patients with Impaired Renal and/or Hepatic Function: The dose should be reduced in such patients, the adjustment being made in accordance with creatinine clearance.
Creatinine Clearance
0-15mL/min: 200mg twice daily.
15-30mL/min: 200mg three times daily.
30-50mL/min: 200mg four times daily.
>50mL/min: normal dosage.
Elderly: For duodenal or benign gastric ulcer:
65-75 years: 600mg daily.
75-85 years: 400mg daily.
> 85 years: 200mg daily.
Hypersensitivity to cimetidine.
Use in Pregnancy and Nursing Mothers: The safety of cimetidine in the treatment of conditions requiring a reduction in gastric acid secretion during pregnancy has not been established although individual reports indicate cimetidine is unlikely to cause abnormality.
Reproduction studies in rats, mice and rabbits have revealed no evidence of impaired fertility or harm to the foetus due to cimetidine. Cimetidine crosses the placental barrier and is secreted in the milk of animals.
It could possibly suppress gastric acidity, inhibit medicine metabolism, and cause CNS stimulation in the nursing infant. It has been found that very high acute and chronic milk/plasma ratios occur with the use of cimetidine.
If the administration of cimetidine is considered to be necessary in pregnant or lactating patients or women of child-bearing potential its use requires that potential benefits be weighed against possible hazards to the patient and foetus.
Use in Children: Clinical experience with cimetidine tablets in children is limited. Although a dosage regimen of 20-40mg/kg daily in four divided doses is quoted, it is essential that the potential benefits are weighed against the potential risks before cimetidine is used.
Use in the Elderly: Since the total plasma clearance is reduced in the elderly with an increase in duration of concentration above 0.5mcg/mL it is recommended that lower doses be used in the elderly.
Use in Impaired Renal Function: Cimetidine is excreted by the kidney and in the presence of renal impairment, the renal clearance of cimetidine may be decreased resulting in elevated blood levels. Dosage should be reduced in the presence of impaired renal function ( see dosage and administration ).
Use in Gastric Ulcer: Before giving cimetidine to patients with gastric ulcer, the possibility of malignancy should be excluded since cimetidine may mask symptoms and delay diagnosis.
Acute Toxicity:
| Oral LD50 mg/kg | |
|---|---|
| Rat Mice |
5000 2600 |
Long Term Toxicity Studies:
Rats: Oral repeated dose studies in rats at dosage levels of 150, 378 and 950mg/kg cimetidine for periods up to 12 months have been reported. Few adverse effects were noted at all dose levels and no significant differences between the groups were observed in body weight, food consumption, blood chemistry, urinalysis or ophthalmoscopy. The livers of the 950mg/kg dose group were heavier than those of controls. This was attributed to increased metabolic work load. After 12 months dosing there was a reduction in the size of prostates of the rats in all dosed groups and a reduction in the size of testes and seminal vesicles of the top dose group. No histopathological abnormalities were attributable to cimetidine treatment.
Dogs: Oral repeat dose studies in beagle dogs at dose levels of 37, 41, 112, 144, 336 and 504mg/kg for periods up to 12 months have been reported.
At the highest dose 504mg/kg, marked tachycardia was noted and a rapid weight loss during the first 2 weeks of treatment, necessitating temporary dose reduction to 336mg/kg and subsequent sequential dose increase to 504mg/kg at week 12.
Two female dogs had to be killed before the end of the test (1 in week 4, the other in week 33). Histological examination showed centrilobular degeneration in the liver and tubular nephrosis in the kidneys.
Occasional, but not progressive elevations of serum transaminases and SAP were seen in other dogs of this dose group and minor degenerative changes were observed in the centrilobular areas of the liver in animals killed after 6 months dosing with 504mg/kg.
At the 336mg/kg dose level, occasional but non-progressive elevation of some serum enzymes was observed. Tachycardia was observed during the early weeks of the test. Male dogs killed after 6 months dosing at all cimetidine dose levels showed a reduction in the size of prostates. In dogs killed after 12 months, the reduction of the prostate size was found not to be progressive although some reduced development of glandular elements was noted in all males of the 504 and 336mg/kg groups and 2 of 6 males in the 144mg/kg group.
Carcinogenicity Studies:
Rats: A 24 month oral cimetidine toxicity and carcinogenicity study in rats at dose levels of 150, 378 and 950mg/kg was performed. Cimetidine appeared to produce changes involving the liver and the male reproductive organs.
Hepatic changes included increased liver weights at doses of 372mg/kg or more, and centrilobular vacuolation, cellular enlargement, focal necrosis and bile duct hyperplasia at a dose of 950mg/kg. Changes involving the male reproductive organs included reduced prostate and seminal vesicle weights and seminal vesicle atrophy at 150mg/kg or more, testicular seminiferous tubule atrophy at 370mg/kg or more, and seminal vesicle distension, epididymal atrophy, and reduced prostatic secretory activity at 950mg/kg.
Cimetidine treated groups had a lower incidence of mammary tumour (benign and malignant) formation and a lower incidence of benign pituitary tumour formation compared to the control groups. Neither of these effects, however, occurred in a dose-related manner or attained statistical significance. Cimetidine administration was also associated with an increased incidence (statistically significant) of benign Leydig cell tumours of the testes in comparison to the control groups. The tumours were common in both control and medicine treated groups, and did not increase in a dose related manner in medicine treated animals.
In this study non-tumour Leydig cell morphology was normal in cimetidine treated groups. It was concluded that the higher statistically significant incidence (apparent only in aged rats) of benign Leydig cell tumours seen in cimetidine treated groups compared to controls probably represented a chance occurrence and did not imply a tumorigenic risk for man.
Dogs: A gastric cancer study in 18 male and female dogs receiving 144mg/kg oral cimetidine/day and a mean dose of 1.14mg/day nitrite and 37.3mg/day nitrate in their food intake for 40 months is reported. Biopsies taken from the gastric mucosa after termination of the study showed no pathological changes.
The study indicated that there was no endoscopic or histopathological evidence of neoplasia, preneoplasia or hyperplasia of the gastric mucosa in dogs exposed to cimetidine and concomitant nitrite and nitrate in food for 40 months.
Reproductive Studies: Segments I and III reproductive studies were performed in rats and Segment II reproductive studies were performed in mice, rats and rabbits. Oral doses of 100 to 950mg/kg were used. No significant medicine related adverse effects on reproductive parameters or teratogenicity were noted. Mating performance and fertility were not impaired. Offspring of dosed mates were normal and there were no dose-related effects on litter parameters.
In dosed females there was no effect on oestrous cycles, mating performance, fertility, maternal weight gain or perinatal behaviour. No effects were noted on pre- or post-implantation losses, litter size, viability or foetal development. There was no dose-related effect on survival and weight gain in the young of naturally delivered litters.
Central Nervous System: Mental confusion or delirium with dizziness, drowsiness, slurred speech, flushing and sweating are the most common symptoms reported in the clinical literature. Visual hallucinations, brainstem dysfunction, depression and coma have also been reported.
The occurrence of cimetidine-induced confusional states is rare but definitely correlated to cimetidine use. High cimetidine dosage, old age, renal impairment, liver disease, or previous psychiatric disease are often associated factors noted with cimetidine CNS toxicity.
Gastrointestinal: Mild to severe transient diarrhoea. Mild elevations in SGOT have been reported but any liver function abnormality has not been considered severe enough to warrant cimetidine withdrawal. Abrupt discontinuation of cimetidine has been implicated in perforation of duodenal, oesophageal and gastric ulcers. There is no firm evidence, however, that recurrences of ulcer disease occur sooner or more severely in patients withdrawn from other forms of treatment. Gastritis and erosive duodenitis during cimetidine therapy have been described. Rare cases of hepatitis, pancreatitis and paralytic ileus resolving on cimetidine withdrawal have been reported.
Cardiovascular: Severe bradycardia following the use of cimetidine has been reported.
Endocrine: Gynaecomastia with and without elevated prolactin levels has been reported. Galactorrhoea with elevated prolactin levels have also been reported in females only. Decreased libido and impotence during cimetidine treatment has been described.
Haematology: Cimetidine has been implicated in several cases of agranulocytosis, pancytopenia and thrombocytopenia. Rare cases of aplastic anaemia have also been reported.
Renal: Transient serum creatinine level increases without evidence of deterioration of renal function have been reported. Rare cases of interstitial nephritis have been reported.
Skin: Skin rash, giant urticaria, Stevens-Johnson Syndrome and psoriasis secondary to cimetidine have been reported.
Miscellaneous: Fever and muscular pain have been reported.
Clinical studies have indicated that the hepatic metabolism of some benzodiazepines (chlordiazepoxide and diazepam) may be inhibited when used concurrently with cimetidine over a period of time resulting in increased plasma levels of these agents. Caution should be exercised and dosage adjustment of the benzodiazepine may be necessary.
The concurrent use of cimetidine with coumarin-type anticoagulants may prolong prothrombin times. Higher warfarin plasma levels have been observed when warfarin is administered concomitantly with cimetidine. Caution is advised and dosage adjustment of the anticoagulant may be necessary.
Phenytoin haematologic toxicity may be potentiated when used concurrently with cimetidine because of increased plasma levels. The monitoring of peripheral blood counts is recommended. Blood levels of salicylates may be increased when used concurrently with cimetidine. Theophylline hepatic metabolism may be decreased with concurrent cimetidine administration resulting in delayed theophylline elimination and increased blood levels. Theophylline dosage adjustment may be necessary.
The hepatic metabolism of propranolol and lignocaine may also be reduced with concurrent cimetidine administration leading to increased blood levels. The dosage of these medications may require adjustment when starting or stopping concomitantly administered cimetidine, to maintain safe, optimum therapeutic blood levels.
Increased blood concentrations of some anti-arrhythmics, some beta-blockers and some vasodilators have also been reported.
Signs of cimetidine intoxication reported include CNS disturbances including dizziness, confusion, disorientation and drowsiness. Sweating, flushing, tachycardia and impaired respiration may also be present.
The CNS side effects develop predominantly in elderly patients, and those with severe renal or hepatic impairment. In such cases CSF cimetidine concentrations are elevated due to a combination of high plasma concentration and increased permeability of the blood-brain barrier seen in liver disease. The usual measures to remove unabsorbed medicine from the gastrointestinal tract, clinical monitoring and supportive therapy are recommended. In the event of respiratory failure, artificial respiration should be instituted.
Protect from light and moisture.
Prescription Medicine.
Bottles of 30 tablets
Cimetidine is N"-cyano-N-methyl-N'[2[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl] guanidine. Its molecular formula and weight are C10H16N6S and 252.3 respectively.
Douglas Pharmaceuticals Ltd
P.O. Box 45-027, AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
1 September 1999