Pepcid (Famotidine)

PEPCID® PEPCID® I.V.

MSD

Famotidine

Histamine H2 Receptor Antagonist

Action And Clinical Pharmacology: Famotidine is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity is inhibition of gastric juice secretion. Famotidine reduces the acid and pepsin content, as well as the volume, of basal, nocturnal, and stimulated gastric secretion.

In both normal volunteers and hypersecretors, famotidine inhibited basal nocturnal and daytime gastric secretion, as well as secretion stimulated by a variety of stimuli, such as pentagastrin and food.

After oral administration, the onset of the antisecretory effect occurred within 1 hour; the maximum effect was dose-dependent, occurring within 1 to 3 hours. Duration of inhibition of secretion was 10 to 12 hours. After i.v. administration, the maximum effect was achieved within 30 minutes. Single i.v. doses of 10 and 20 mg inhibited basal nocturnal secretion for a period of 10 to 12 hours. The 20 mg dose was associated with the longest duration of action in most subjects.

Single oral doses of 20 and 40 mg inhibited basal nocturnal acid secretion in all subjects; mean gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. Similar doses given in the morning suppressed food-stimulated acid secretion in all subjects, with mean suppression of 76% and 84%, respectively, 3 to 5 hours after drug, and of 25% and 30%, respectively, 8 to 10 hours after drug; however, in some subjects who received the 20 mg dose, the antisecretory effect was dissipated earlier, within 6 to 8 hours. There was no cumulative effect with repeated doses. The basal nocturnal intragastric pH was raised by evening doses of 20 and 40 mg of famotidine to mean values of 5.0 and 6.4, respectively. When famotidine was given in the morning, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg was raised to about 5.0.

Fasting and postprandial serum gastrin levels may be slightly elevated during periods of drug antisecretory effect and with chronic therapy an increase in gastric bacterial flora may occur. Gastric emptying and exocrine pancreatic function are not affected by famotidine.

The presence of gastroesophageal reflux disease appears to correlate best with the percentage of time over 24 hours during which the esophagus is exposed to acid. In gastroesophageal reflux disease patients, 20 mg twice a day and 40 mg twice a day of famotidine reduced intraesophageal acid exposure into the normal range as measured by 24 hour intraesophageal pH monitoring. In clinical studies of gastroesophageal reflux disease patients with endoscopically verified erosive or ulcerative esophagitis, 40 mg twice a day was more effective than 20 mg twice a day in healing esophageal lesions. Both dosage regimens were superior to placebo.

Systemic pharmacologic effects of famotidine in the CNS, cardiovascular, respiratory or endocrine systems have not been found to date. Serum prolactin levels do not rise after i.v. bolus doses of 20 mg famotidine and no antiandrogenic effects have been detected.

Pharmacokinetics: Famotidine is incompletely absorbed. The bioavailability of oral doses is 40 to 45% . Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. Famotidine undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1 to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of famotidine in plasma is protein bound. Famotidine has an elimination half-life of 2.5 to 3.5 hours. It is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion.

Twenty-five to 30% of an oral dose and 65 to 70% of an i.v. dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide. There is a close relationship between creatinine clearance values and the elimination half-life of famotidine. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, elimination half-life may exceed 20 hours and adjustment of dosing intervals may be necessary (see Precautions and Dosage). In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine.

Indications And Clinical Uses: Tablets: The treatment of the following conditions where a controlled reduction of gastric secretion is required: treatment of acute duodenal ulcer; prophylactic use in duodenal ulcer; treatment of acute benign gastric ulcer; treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome); treatment of gastroesophageal reflux disease (GERD); maintenance of remission of patients with GERD.

Injection: In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage form for short-term use in patients who are unable to take oral medication.

Contra-Indications: Hypersensitivity to any component of this medication.

Precautions: Patients with Severe Renal Insufficiency: Dosing intervals may need to be prolonged in patients with advanced renal insufficiency.

Drug Interactions: Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man have included warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic blood flow and/or hepatic drug extraction has been tested and no significant effects have been found. In addition, studies with famotidine have shown no augmentation of expected blood alcohol levels resulting from alcohol ingestion.

Gastric Ulcer: Gastric malignancy should be excluded prior to initiation of therapy of gastric ulcer with famotidine. Symptomatic response of gastric ulcer to therapy does not preclude the presence of gastric malignancy.

Pregnancy: Reproductive studies have been performed in rats and rabbits at oral doses of up to 2 000 and 500 mg/kg/day, respectively (approximately 2 500 and 625 times the maximum recommended human dose, respectively), and have revealed no evidence of impaired fertility or harm to the fetus due to famotidine. There are, however, no adequate or well-controlled studies in pregnant women.

Since the safe use of famotidine in pregnant women has not been established, the benefits of treatment should be weighed against potential risks.

Lactation: Famotidine is detectable in human milk. Nursing mothers should either stop this drug or should stop nursing.

Children: Safety and effectiveness in children have not been established.

Geriatrics: No dosage adjustment is required based on age.

Adverse Reactions: Famotidine is usually well tolerated; most adverse effects have been mild and transient. The adverse effects listed below have been reported during clinical trials in 2 333 patients. In those controlled clinical trials in which famotidine was compared to placebo, the overall incidence of adverse experiences in the group which received famotidine 40 mg at bedtime, was similar to the placebo group. No antiandrogenic or other adverse hormonal effects have been observed.

The following adverse effects have been reported at a rate of greater than 1% in patients on therapy with famotidine in controlled clinical trials, and may be causally related to the drug: headache (4.6%), dizziness (1.2%), constipation (1.2%) and diarrhea (1.6%).

Other reactions have been reported in clinical trials but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.

Gastrointestinal (8.0%): nausea 1.6%, vomiting 0.9%, anorexia 0.5%, abdominal discomfort 0.3%, dry mouth 0.2%.

CNS/Psychiatric (7.3%): insomnia 0.6%, somnolence 0.4%, anxiety 0.3%, paresthesia 0.3%, depression 0.2%, libido decreased 0.1%.

Respiratory (4.4%): bronchospasm

Body as a Whole (3.0%): fatigue 0.6%, asthenia 0.3%, fever 0.2%.

Musculoskeletal (1.7%): musculoskeletal pain 0.1%, arthralgia 0.1%.

Skin (1.7%): pruritus 0.4%, rash 0.3%, alopecia 0.2%, flushing 0.2%, acne 0.1%, dry skin 0.1%.

Cardiovascular (1.0%): palpitations 0.2%.

Special Senses (0.9%): taste disorder 0.1%, tinnitus 0.1%, orbital edema
Urogenital (0.9%).

The adverse reactions reported for the tablets may also occur with the i.v. In addition, transient irritation at the injection site has been observed with the i.v.

The following additional adverse reactions have been reported since the drug was marketed: urticaria, liver enzymes abnormalities, cholestatic jaundice, anaphylaxis and angioedema. Toxic epidermal necrolysis has been reported very rarely with H2-receptor antagonists.

The following adverse reactions have been reported; however, a causal relationship to therapy with famotidine has not been established: agitation, confusion, hallucinations, grand mal seizures, rare cases of impotence, thrombocytopenia, pancytopenia, leukopenia and agranulocytosis.

Gynecomastia has been reported rarely. In most cases that were followed up, it was reversible after discontinuing treatment.

Laboratory Abnormalities: Laboratory parameters may be affected during treatment with famotidine, but the changes are usually not considered serious. Among the laboratory changes that were reported during clinical trials were increases in AST, ALT, BUN, and serum creatinine. These changes were rarely of clinical significance.

Only 3 patients had to be discontinued from therapy because of laboratory adverse experiences, however laboratory abnormalities were present at baseline.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no experience to date with deliberate overdosage. Doses of up to 800 mg/day have been employed in patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.

The oral LD50 of famotidine in male and female rats and mice was>5 000 mg/kg.

Dosage And Administration: Duodenal Ulcer: Acute Therapy: The recommended adult oral dosage of famotidine for acute duodenal ulcer is 40 mg once a day at bedtime. Treatment should be given for 4 to 8 weeks, but the duration of treatment may be shortened if healing can be documented. Healing occurs within 4 weeks in most cases of duodenal ulcer.

Maintenance Therapy: For the prevention of recurrence of duodenal ulcer, it is recommended that therapy be continued with a dose of 20 mg once a day at bedtime, for a duration of up to 6 to 12 months depending on the severity of the condition.

Benign Gastric Ulcer: Acute Therapy: The recommended adult oral dosage for acute benign gastric ulcer is 40 mg once a day at bedtime. Treatment should be given for 4 to 8 weeks, but the duration of treatment may be shortened if healing can be documented.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome): The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg every 6 hours. In some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. Doses up to 800 mg/day have been administered to some patients with severe Zollinger-Ellison syndrome.

Gastroesophageal Reflux Disease: The recommended dosage for the symptomatic relief of gastroesophageal reflux disease is 20 mg of famotidine twice a day.

For the treatment of esophageal erosion or ulceration associated with gastroesophageal reflux disease, the recommended dosage is 40 mg of famotidine twice a day.

For the maintenance of remission of patients with GERD, the recommended dosage is 20 mg of famotidine twice a day.

I.V. Administration: In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, famotidine injection may be administered. The recommended dosage is 20 mg every 12 hours.

I.V. injection therapy should be changed to oral treatment as soon as the acute situation is under control.

Concomitant Use with Antacids: Antacids may be given concomitantly if needed.

Severe Renal Insufficiency: In patients with advanced renal insufficiency, i.e., with a creatinine clearance less than 10 mL/min, the elimination half-life of famotidine may exceed 20 hours reaching approximately 24 hours in anuric patients.

To avoid excess accumulation of the drug, the dosing interval of famotidine may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response. Reconstitution: See Table I.

Famotidine i.v. solutions are compatible with: water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 10% dextrose injection, lactated Ringer’s injection and sodium bicarbonate injection 5%.

Diluted i.v. solutions should be used within 24 hours due to the possibility of microbial contamination during preparation.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Availability And Storage: Tablets: 20 mg: Each beige, D-shaped, film-coated tablet, coded 963, contains: famotidine 20 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, red ferric oxide, starch pregelatinized, talc, titanium dioxide and yellow ferric oxide. Blisters of 30. Store between 15 and 30°C in a tightly closed container. Protect from light.

40 mg: Each light brownish orange, D-shaped, film-coated tablet, coded 964, contains: famotidine 40 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, red ferric oxide, starch pregelatinized, talc, titanium dioxide and yellow ferric oxide. Gluten- and tartrazine-free. Blisters of 30. Store between 15 and 30°C in a tightly closed container. Protect from light.

I.V.: Each mL of clear, colorless solution for i.v. injection contains: famotidine 10 mg. Also contains L-aspartic acid 4 mg, mannitol 20 mg and water for injection q.s. 1 mL. The multidose injection also contains benzyl alcohol 0.9% added as preservative. Nonpreserved unit dose vials of 2 mL. Packages of 10. Preserved multiple dose vials of 4 mL. Store between 2 and 8°C. Protect from light. If the solution freezes, bring the solution to room temperature; allow sufficient time to solubilize all the components. Should be used within 24 hours due to the possibility of microbial contamination during preparation. (Shown in Product Recognition Section)

PEPCID® PEPCID® I.V. MSD Famotidine Histamine H2 Receptor Antagonist

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