Cimetidine 400 MG Oral Tablet
Generic Name: CIMETIDINE
Brand Name: Cimetidine
- Substance Name(s):
- CIMETIDINE
DRUG INTERACTIONS
Drug Interactions Cimetidine tablets, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline, and metronidazole, thereby delaying elimination and increasing blood levels of these drugs.
Clinically significant effects have been reported with the warfarin anticoagulants; therefore, close monitoring of prothrombin time is recommended, and adjustment of the anticoagulant dose may be necessary when cimetidine tablets are administered concomitantly.
Interaction with phenytoin, lidocaine, and theophylline has also been reported to produce adverse clinical effects.
However, a crossover study in healthy subjects receiving either 300 mg 4 times daily or 800 mg at bedtime of cimetidine tablets concomitantly with a 300 mg twice-daily dose of theophylline extended-release tablets demonstrated less alteration in steady-state theophylline peak serum levels with the 800 mg at bedtime regimen, particularly in subjects aged 54 years and older.
Data beyond 10 days are not available.
(Note: All patients receiving theophylline should be monitored appropriately, regardless of concomitant drug therapy.) Dosage of the drugs mentioned above and other similarly metabolized drugs, particularly those of low therapeutic ratio or in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping the concomitant administration of cimetidine tablets to maintain optimum therapeutic blood levels.
Alteration of pH may affect absorption of certain drugs (e.g., ketoconazole).
If these products are needed, they should be given at least 2 hours before cimetidine administration.
Additional clinical experience may reveal other drugs affected by the concomitant administration of cimetidine tablets.
OVERDOSAGE
Studies in animals indicate that toxic doses are associated with respiratory failure and tachycardia that may be controlled by assisted respiration and the administration of a beta-blocker.
Reported acute ingestions orally of up to 20 grams have been associated with transient adverse effects similar to those encountered in normal clinical experience.
The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.
There have been reports of severe CNS symptoms, including unresponsiveness, following ingestion of between 20 and 40 grams of cimetidine, and extremely rare reports following concomitant use of multiple CNS-active medications and ingestion of cimetidine at doses less than 20 grams.
An elderly, terminally ill dehydrated patient with organic brain syndrome receiving concomitant antipsychotic agents and 4,800 mg of cimetidine intravenously over a 24-hour period experienced mental deterioration with reversal on discontinuation of cimetidine.
There have been two deaths in adults who were reported to have ingested over 40 grams orally on a single occasion.
DESCRIPTION
Cimetidine is a histamine H 2 -receptor antagonist.
Chemically it is N” -cyano- N -methyl- N’ -[2-[[(5-methyl-1 H -imidazol-4-yl)methyl]thio]-ethyl]guanidine.
Its structural formula is: Cimetidine contains an imidazole ring, and is chemically related to histamine.
Cimetidine has a bitter taste and characteristic odor.
Solubility Characteristics Cimetidine is soluble in alcohol, slightly soluble in water, very slightly soluble in chloroform and insoluble in ether.
Each tablet, for oral administration, contains 200 mg, 300 mg, 400 mg or 800 mg cimetidine, USP.
Inactive ingredients are: croscarmellose sodium, crospovidone, hypromellose, lecithin, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium alginate, sodium lauryl sulfate, titanium dioxide, triacetin, vanillin, FD&C Blue No.
1 Aluminum Lake, FD&C Yellow No.
6 Aluminum Lake and D&C Yellow No.
10 Aluminum Lake.
Structural Formula
CLINICAL STUDIES
CLINICAL TRIALS Duodenal Ulcer Cimetidine tablets have been shown to be effective in the treatment of active duodenal ulcer and, at reduced dosage, in maintenance therapy following healing of active ulcers.
Active Duodenal Ulcer Cimetidine tablets accelerate the rate of duodenal ulcer healing.
Healing rates reported in U.S.
and foreign controlled trials with cimetidine tablets are summarized below, beginning with the regimen providing the lowest nocturnal dose.
Table 3.
Duodenal Ulcer Healing Rates with Various Dosage Regimens of Cimetidine Tablets Averages from controlled clinical trials.
Regimen 300 mg 4 times daily 400 mg twice daily 800 mg at bedtime 1600 mg at bedtime Week 4 68% 73% 80% 86% Week 6 80% 80% 89% – Week 8 – 92% 94% – A U.S., double-blind, placebo-controlled, dose-ranging study demonstrated that all once-daily at bedtime regimens of cimetidine tablets were superior to placebo in ulcer healing and that 800 mg of cimetidine tablets at bedtime healed 75% of patients at 4 weeks.
The healing rate with 800 mg at bedtime was significantly superior to 400 mg at bedtime (66%) and not significantly different from 1600 mg at bedtime (81%).
In the U.S.
dose-ranging trial, over 80% of patients receiving 800 mg of cimetidine tablets at bedtime experienced nocturnal pain relief after one day.
Relief from daytime pain was reported in approximately 70% of patients after 2 days.
As with ulcer healing, the 800 mg dose at bedtime was superior to 400 mg at bedtime and not different from 1,600 mg at bedtime.
In foreign, double-blind studies with 800 mg of cimetidine tablets at bedtime, 79% to 85% of patients were healed at 4 weeks.
While short-term treatment with cimetidine tablets can result in complete healing of the duodenal ulcer, acute therapy will not prevent ulcer recurrence after cimetidine tablets have been discontinued.
Some follow-up studies have reported that the rate of recurrence once therapy was discontinued was slightly higher for patients healed on cimetidine tablets than for patients healed on other forms of therapy; however, the patients treated with cimetidine tablets generally had more severe disease.
Maintenance Therapy in Duodenal Ulcer Treatment with a reduced dose of cimetidine tablets have been proven effective as maintenance therapy following healing of active duodenal ulcers.
In numerous placebo-controlled studies conducted worldwide, the percent of patients with observed ulcers at the end of 1 year’s therapy with 400 mg of cimetidine tablets at bedtime was significantly lower (10% to 45%) than in patients receiving placebo (44% to 70%).
Thus, from 55% to 90% of patients were maintained free of observed ulcers at the end of 1 year with 400 mg of cimetidine tablets at bedtime.
Factors such as smoking, duration and severity of disease, gender, and genetic traits may contribute to variations in actual percentages.
Trials of other anti-ulcer therapy, whether placebo-controlled, positive-controlled or open, have demonstrated a range of results similar to that seen with cimetidine tablets.
Active Benign Gastric Ulcer Cimetidine tablets have been shown to be effective in the short-term treatment of active benign gastric ulcer.
In a multicenter, double-blind U.S.
study, patients with endoscopically confirmed benign gastric ulcer were treated with 300 mg of cimetidine tablets 4 times a day or with placebo for 6 weeks.
Patients were limited to those with ulcers ranging from 0.5 to 2.5 cm in size.
Endoscopically confirmed healing at 6 weeks was seen in significantly* more patients treated with cimetidine tablets than in patients receiving placebo, as shown below: Table 4.
Rate of Endoscopically Confirmed Gastric Ulcer Healing Cimetidine Tablets (300 mg, 4 times daily) Placebo Week 2 14/63 (22%) 7/63 (11%) Total at week 6 43/65 (66%) p < 0.05 30/67 (45%) In a similar multicenter U.S.
study of the 800 mg bedtime oral regimen, the endoscopically confirmed healing rates were: Table 5.
Rate of Endoscopically Confirmed Gastric Ulcer Healing Cimetidine Tablets (800 mg at bedtime) Placebo Total at week 6 63/83 (76%) p = 0.005 44/80 (55%) Similarly, in worldwide double-blind clinical studies, endoscopically evaluated benign gastric ulcer healing rates were consistently higher with cimetidine tablets than with placebo.
Gastroesophageal Reflux Disease In 2 multicenter, double-blind, placebo-controlled studies in patients with gastroesophageal reflux disease (GERD) and endoscopically proven erosions and/or ulcers, cimetidine tablets were significantly more effective than placebo in healing lesions.
The endoscopically confirmed healing rates were: Table 6.
Rate of Endoscopically Confirmed Healing of Erosions and/or Ulcers Trial Cimetidine Tablets (800 mg twice daily) Cimetidine Tablets (400 mg 4 times daily) Placebo p-Value (800 mg twice daily vs.
placebo) 1 Week 6 45% 52% 26% 0.02 Week 12 60% 66% 42% 0.02 2 Week 6 50% 20% <0.01 Week 12 67% 36% <0.01 In these trials cimetidine tablets were superior to placebo by most measures in improving symptoms of day- and night-time heartburn, with many of the differences statistically significant.
The 4 times-daily regimen was generally somewhat better than the twice-daily regimen where these were compared.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome): Cimetidine tablets significantly inhibited gastric acid secretion and reduced occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis, and multiple endocrine adenomas.
Use of cimetidine tablets were also followed by healing of intractable ulcers.
HOW SUPPLIED
Cimetidine Tablets, USP are available containing 200 mg, 300 mg, 400 mg or 800 mg of cimetidine, USP.
The 200 mg tablets are green, film-coated, five-sided, house-shaped, unscored tablets debossed with M on one side and 53 on the other side.
They are available as follows: NDC 0378-0053-01 bottles of 100 tablets The 300 mg tablets are green, film-coated, five-sided, house-shaped, unscored tablets debossed with M on one side and 317 on the other side.
They are available as follows: NDC 0378-0317-01 bottles of 100 tablets The 400 mg tablets are green, film-coated, five-sided, house-shaped, partially scored tablets debossed with M on one side and 372 on the other side.
They are available as follows: NDC 0378-0372-01 bottles of 100 tablets The 800 mg tablets are green, film-coated, oval, partially scored tablets debossed with M 541 across the partial score.
They are available as follows: NDC 0378-0541-01 bottles of 100 tablets Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from light.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Revised: 7/2019 CIM:R14
INDICATIONS AND USAGE
Cimetidine tablets are indicated in: 1.
Short-term treatment of active duodenal ulcer.
Most patients heal within 4 weeks and there is rarely reason to use cimetidine tablets at full dosage for longer than 6 to 8 weeks (see DOSAGE AND ADMINISTRATION: Duodenal Ulcer ).
Concomitant antacids should be given as needed for relief of pain.
However, simultaneous administration of cimetidine tablets and antacids is not recommended, since antacids have been reported to interfere with the absorption of cimetidine.
2.
Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of active ulcer.
Patients have been maintained on continued treatment with cimetidine tablets 400 mg at bedtime for periods of up to 5 years.
3.
Short-term treatment of active benign gastric ulcer.
There is no information concerning usefulness of treatment periods of longer than 8 weeks.
4.
Erosive gastroesophageal reflux (GERD).
Erosive esophagitis diagnosed by endoscopy.
Treatment is indicated for 12 weeks for healing of lesions and control of symptoms.
The use of cimetidine tablets beyond 12 weeks has not been established (see DOSAGE AND ADMINISTRATION: GERD ).
5.
The treatment of pathological hypersecretory conditions (i.e., Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).
PEDIATRIC USE
Pediatric Use Clinical experience in children is limited.
Therefore, therapy with cimetidine tablets cannot be recommended for children under 16, unless, in the judgement of the physician, anticipated benefits outweigh the potential risks.
In very limited experience, doses of 20 to 40 mg/kg/day have been used.
PREGNANCY
Pregnancy Teratogenic Effects.
Pregnancy Category B Reproduction studies have been performed in rats, rabbits and mice at doses up to 40 times the normal human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cimetidine tablets.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
NUSRING MOTHERS
Nursing Mothers Cimetidine is secreted in human milk and, as a general rule, nursing should not be undertaken while a patient is on a drug.
DOSAGE AND ADMINISTRATION
Duodenal Ulcer Active Duodenal Ulcer Clinical studies have indicated that suppression of nocturnal acid is the most important factor in duodenal ulcer healing (see CLINICAL PHARMACOLOGY: Antisecretory Activity: Acid Secretion ).
This is supported by recent clinical trials (see CLINICAL TRIALS: Duodenal Ulcer: Active Duodenal Ulcer ).
Therefore, there is no apparent rationale, except for familiarity with use, for treating with anything other than a once-daily at bedtime dosage regimen.
In a U.S.
dose-ranging study of 400 mg at bedtime, 800 mg at bedtime and 1600 mg at bedtime, a continuous dose-response relationship for ulcer healing was demonstrated.
However, 800 mg at bedtime is the dose of choice for most patients, as it provides a high healing rate (the difference between 800 mg at bedtime and 1,600 mg at bedtime being small), maximal pain relief, a decreased potential for drug interactions (see PRECAUTIONS: Drug Interactions ) and maximal patient convenience.
Patients unhealed at 4 weeks, or those with persistent symptoms, have been shown to benefit from 2 to 4 weeks of continued therapy.
It has been shown that patients who both have an endoscopically demonstrated ulcer larger than 1.0 cm and are also heavy smokers (i.e., smoke 1 pack of cigarettes or more per day) are more difficult to heal.
There is some evidence which suggests that more rapid healing can be achieved in this subpopulation with 1,600 mg of cimetidine tablets at bedtime.
While early pain relief with either 800 mg at bedtime or 1,600 mg at bedtime is equivalent in all patients, 1,600 mg at bedtime provides an appropriate alternative when it is important to ensure healing within 4 weeks for this subpopulation.
Alternatively, approximately 94% of all patients will also heal in 8 weeks with 800 mg of cimetidine tablets at bedtime.
Other regimens of cimetidine tablets in the United States which have been shown to be effective are: 300 mg 4 times daily, with meals and at bedtime, the original regimen with which U.S.
physicians have the most experience, and 400 mg twice daily, in the morning and at bedtime (see CLINICAL TRIALS: Duodenal Ulcer: Active Duodenal Ulcer ).
Concomitant antacids should be given as needed for relief of pain.
However, simultaneous administration of cimetidine tablets and antacids is not recommended, since antacids have been reported to interfere with the absorption of cimetidine.
While healing with cimetidine tablets often occurs during the first week or two, treatment should be continued for 4 to 6 weeks unless healing has been demonstrated by endoscopic examination.
Maintenance Therapy for Duodenal Ulcer In those patients requiring maintenance therapy, the recommended adult oral dose is 400 mg at bedtime.
Active Benign Gastric Ulcer The recommended adult oral dosage for short-term treatment of active benign gastric ulcer is 800 mg at bedtime, or 300 mg 4 times a day with meals and at bedtime.
Controlled clinical studies were limited to 6 weeks of treatment (see CLINICAL TRIALS ).
A dose of 800 mg at bedtime is the preferred regimen for most patients based upon convenience and reduced potential for drug interactions.
Symptomatic response to cimetidine tablets does not preclude the presence of a gastric malignancy.
It is important to follow gastric ulcer patients to assure rapid progress to complete healing.
Erosive Gastroesophageal Reflux Disease (GERD) The recommended adult oral dosage for the treatment of erosive esophagitis that has been diagnosed by endoscopy is 1,600 mg daily in divided doses (800 mg twice daily or 400 mg 4 times daily) for 12 weeks.
The use of cimetidine tablets beyond 12 weeks has not been established.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome) Recommended adult oral dosage: 300 mg 4 times a day with meals and at bedtime.
In some patients it may be necessary to administer higher doses more frequently.
Doses should be adjusted to individual patient needs, but should not usually exceed 2,400 mg per day and should continue as long as clinically indicated.
Dosage Adjustment for Patients with Impaired Renal Function Patients with severely impaired renal function have been treated with cimetidine tablets.
However, such usage has been very limited.
On the basis of this experience the recommended dosage is 300 mg every 12 hours orally.
Should the patient’s condition require, the frequency of dosing may be increased to every 8 hours or even further with caution.
In severe renal failure, accumulation may occur and the lowest frequency of dosing compatible with an adequate patient response should be used.
When liver impairment is also present, further reductions in dosage may be necessary.
Hemodialysis reduces the level of circulating cimetidine tablets.
Ideally, the dosage schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.