TABLETS
FOR ORAL SUSPENSION
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
The active ingredient in PEPCID* (Famotidine) is a histamine H2-receptor antagonist. Famotidine N’-
(aminosuIfonyI)-3-[[[2[(diaminomethylene)amino]-4-thiazolyl]methyl]thio] propanimidamide. The empirical formula of famotidine is C8H-15N7O2S3 and its molecular weight is 337.43. Its structural formul
a is:
Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid,
slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.
Famotidine is supplied in four dosage forms: PEPCID Tablets, PEPCID for Oral Suspension, PEPCID
Injection and PEPCID Injection Premixed. (See appropriate package circular for information regarding the
intravenous dosage forms.)
Each tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following
inactive ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, magnesium stearate,
microcrystalline cellulose, starch, talc, titanium dioxide.
Each 5 mL of the oral suspensory when prepared as directed contains 40 mg of famotidine and the following
inactive ingredients: citric acid, flavors, microcrystalline cellulose and carboxymethylcellulose sodium, sucrose
and xanthan gum. Added as preservatives are sodium benzoate 0.1%, sodium methylparaben 0.1%, and sodium
propylparaben 0.02%.
GI Effects
PEPCID is a competitive inhibitor of histamine H2-receptors. The primary clinically important
pharmacologic activity of PEPCID is inhibition of gastric secretion. Both the acid concentration and volume of
gastric secretion are suppressed by PEPCID, while changes in pepsin secretion are proportional to volume
output.
In normal volunteers and hypersecretors, PEPCID inhibited basal and nocturnal gastric secretion, as well
as secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect
occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours.
Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours.
After intravenous administration, the maximum effect was achieved within 30 minutes. Single
intravenous doses of 10 and 20 mg inhibited 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 evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects;
mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10
hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean
suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8
to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory
effect was dissipated within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal
intragastric, pH was raised by evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4,
respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after
20 or 40 mg of PEPCID was raised to about 5.
PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and
exocrine pancreatic function were not affected by PEPCID.
Other Effects
Systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted
in clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.)
Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with PEPCID.
Pharmacokinetics
PEPCID is incompletely absorbed. The bioavailability of oral doses is 40-45%. PEPCID Tablets and
PEPCID for Oral Suspension are bioequivalent. Bioavailability may be slightly increased by food, or slightly
decreased by antacids; however, these effects are of no clinical consequence. PEPCID undergoes minimal first-
pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after multiple doses are
similar to those after single doses. Fifteen to 20% of PEPCID in plasma is protein bound. PEPCID has an
elimination half-life of 2.5-3.5 hours. PEPCID is eliminated by renal (65-70%) and metabolic (30-35%) routes.
Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and
65-70% of an intravenous 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 PEPCID.
In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, PEPCID elimination
half-life may exceed 20 hours and adjustment of dose or dosing intervals may be necessary (see
PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID.
Clinical Studies
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer,
orally administered PEPCID was compared to placebo. As shown in Table 1, 70% of patients treated with
PEPCID 40 mg h.s. were healed by week 4.
Table 1 Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers PEPCID PEPCID Placebo 40 mg h.s. 20 mg b.i.d. h.s. (N = 89) (N = 84) (N = 97) Week 2 **32% **38% 17% Week 4 **70% **67% 31% **Statistically significantly different than placebo (p<0.001)
Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with
PEPCID had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with PEPCID
was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed
healed ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving
PEPCID than for patients receiving placebo; patients receiving PEPCID also took less antacid than the patients
receiving placebo.
Long-Term Maintenance
Treatment of Duodenal Ulcers
PEPCID, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind,
multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the
observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the
patients treated with PEPCID. The 89 patients treated with PEPCID had a cumulative observed ulcer incidence
of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These
results were confirmed in an international study where the cumulative observed ulcer incidence within 12 months
in the 307 patients treated with PEPCID was 35.7%, compared to an incidence of 75.5% in the 325 patients
treated with placebo (P<0.01).
Gastric Ulcer
In both a U.S. and an international multicenter, double-blind study in patients with endoscopically
confirmed active benign gastric ulcer, orally administered PEPCID, 40 mg h.s., was compared to placebo h.s.
Antacids were permitted during the studies, but consumption was not significantly different between the PEPCID
and placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with
PEPCID was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6
and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.
Table 2 Patients with Endoscopically Confirmed Healed Gastric Ulcers U.S. Study International Study PEPCID Placebo PEPCID Placebo 40 mg h.s. h.s. 40 mg h.s. h.s. (N = 74) (N = 75) (N = 149) (N = 145) Week 4 45% 39% †47% 31% Week 6 †66% 44% †65% 46% Week 8 ***78% 64% †8O% 54% ***,† Statistically significantly better than placebo (p<=0.05, <=0.01 respectively)
Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients
receiving PEPCID than for patients receiving placebo; however, in neither study was there a statistically
significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD)
Orally administered PEPCID was compared to placebo in a U.S. study that enrolled patients with
symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. PEPCID 20
mg b.i.d. was statistically significantly superior to 40 mg h.s. and to placebo in providing a successful
symptomatic outcome, defined as moderate or excellent improvement of symptoms (Table 3).
Table 3 % Successful Symptomatic Outcome PEPCID PEPCID 20 mg b.i.d. 40 mg h.s. Placebo (N = 154) (N = 149) (N = 73) Week 6 82†† 69 62 †† p<=0.01 vs Placebo
By two weeks of treatment symptomatic success was observed in a greater percentage of patients taking
PEPCID 20 mg b.i.d. compared to placebo (p<=0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in
two additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with
endoscopy. The U.S. study comparing PEPCID 40 mg p.o. b.i.d. to placebo and PEPCID 20 mg p.o. b.i.d.
showed a significantly greater percentage of healing for PEPCID 40 mg b.i.d. at weeks 6 and 12 (Table 4).
Table 4 % Endoscopic Healing - U.S. Study PEPCID PEPCID 40 mg b.i.d. 20 mg b.i.d. Placebo (N = 127) (N = 125) (N = 66) Week 6 48†††,tt 32 18 Week 12 69 †††,t 54 ††† 29 ††† p<=0.01 vs Placebo tp<=0.05 vs PEPCID 20 mg b.i.d. ttp<=0.01 vs PEPCID 20 mg b.i.d.
As compared to placebo, patients who received PEPCID had faster relief of daytime and nighttime
heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn. These
differences were statistically significant.
In the international study, when PEPCID 40 mg p.o. b.i.d., was compared to ranitidine 150 mg p.o. b.i.d.,
a statistically significantly greater percentage of healing was observed with PEPCID 40 mg b.i.d. at week 12
(Table 5). There was, however, no significant difference among treatments in symptom relief.
Table 5 % Endoscopic Healing - International Study PEPCID PEPCID Ranitidine 40 mg b.i.d. 20 mg b.i.d. 150 mg b.i.d. (N = 175) (N = 93) (N = 172) Week 6 48 52 42 Week 12 71ttt 68 60 tttp<=0.05 vs Ranitidine 150 mg b.i.d.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome
with or without multiple endocrine adenomas, PEPCID significantly inhibited gastric acid secretion and
controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid
secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments
were necessary with time in some patients. PEPCID was well tolerated at these high dose levels for prolonged
periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased
prolactin levels, or impotence which were considered to be due to the drug.
PEPCID is indicated in:
1. Short term treatment of active duodenal ulcer. Most patients heal within 4 weeks; there is rarely
reason to use PEPCID at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of
famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer.
Controlled studies have not extended beyond one year.
3. Short term treatment of active benign gastric ulcer. Most patients heal within 6 weeks. Studies have
not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more
than 8 weeks.
4. Short term treatment of gastroesophageal reflux disease (GERD). PEPCID is indicated for short
term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY, Clinical Studies).
PEPCID is also indicated for the short term treatment of esophagitis due to GERD including erosive or
ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY, Clinical Studies).
5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple
endocrine adenomas).
Hypersensitivity to any component of these products.
General
Symptomatic response to therapy with PEPCID does not preclude the presence of gastric malignancy.
Patients with Severe Renal Insufficiency
Longer intervals between doses or lower doses may need to be used in patients with severe renal
insufficiency (creatinine clearance <10 mL/min) to adjust for the longer elimination half-life of famotidine. (See
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) However, currently, no drug-
related toxicity has been found with high plasma concentrations of famotidine.
Information for Patients
The patient should be instructed to shake the oral suspension vigorously for 5-10 seconds prior to each
use. Unused constituted oral suspension should be discarded after 30 days.
Drug Interactions
No drug interactions have been identified. 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 include warfarin, theophylline, phenytoin,
diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested
and no significant effects have been found.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day
(approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of
carcinogenic potential for PEPCID.
Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and
Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo
studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect
was observed.
In studies with rats given oral doses of up to 2000 mg/kg/ day or intravenous doses of up to 200
mg/kg/day fertility and reproductive performance were not affected.
Pregnancy
Pregnancy Category B
Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500
mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no
significant evidence of impaired fertility or harm to the fetus due to PEPCID. While no direct fetotoxic effects
have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were
seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are,
however, no adequate or 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.
Nursing Mothers
Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient
growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least
600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious
adverse reactions in nursing infants from PEPCID, a decision should be made whether to discontinue nursing or
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children have not been established.
Use in Elderly Patients
No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY,
Pharmacokinetics). Dosage adjustment in the case of severe renal impairment may be necessary.
The adverse reactions listed below have been reported during domestic and international clinical trials in
approximately 2500 patients. In those controlled clinical trials in which PEPCID Tablets were compared to
placebo, the incidence o adverse experiences in the group which received PEPCID Tablets, 40 mg at bedtime,
was similar to that in the placebo group.
The following adverse reactions have been reported t occur in more than 1% of patients on therapy with
PEPCID in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%),
constipation (1.2% ) and diarrhea (1.7% ).
The following other adverse reactions have been reported infrequently in clinical trials or since the drug
was marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category
the adverse reactions are listed in order of decreasing severity:
-
Body as a Whole: fever, asthenia, fatigue
Cardiovascular: arrhythmia, AV block, palpitation
Gastrointestinal: Cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, dry mouth
Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia
Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection
Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia
Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; so
mnolence
Respiratory: bronchospasm
Skin: toxic epidermal necrolysis (very rare), alopecia, acne, pruritus, dry skin, flushing
Special Senses: tinnitus, taste disorder
Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled clinical trials, the incidences were not greater than those seen with placebo.
The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension,
PEPCID Injection Premixed or PEPCID Injection.
There is no experience to date with deliberate overdosage. Oral doses of up to 640 mg/day have been
given to 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 greater than 3000 mg/kg and the
minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high
oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting
with 200 mg/kg/day orally. The intravenous LD50 of famotidine for mice and rats ranged from 254 -563 mg/kg
and the minimum lethal single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in
I.V. treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears,
hypotension, tachycardia and collapse.
Duodenal Ulcer
Acute Therapy:. The recommended adult oral dosage for duodenal ulcer is 40 mg once a day at bedtime.
Most patients heal within 4 weeks; there is rarely reason to use PEPCID at full dosage for longer than 6 to 8
weeks. A regimen of 20 mg b.i.d. is also effective.
Maintenance Therapy: The recommended oral dose is 20 mg once a day at bedtime.
Benign Gastric Ulcer
Acute Therapy: The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day
at bedtime.
Gastroesophageal Reflux Disease (GERD)
The recommended oral dosage for treatment of patients with symptoms of GERD is 20 mg b.i.d. for up
to 6 weeks. The recommended oral dosage for the treatment of patients with esophagitis including erosions and
ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks (see CLINICAL
PHARMACOLOGY, Clinical Studies).
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
The dosage of PEPCID in patients with pathological hypersecretory conditions varies with the individual
patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. 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 160 mg q 6 h have been administered to some
patients with severe Zollinger-Ellison Syndrome.
Oral Suspension
PEPCID for Oral Suspension may be substituted for PEPCID Tablets in any of the above indications.
Each five mL contains 40 mg of famotidine after constitution of the powder with 46 mL of Purified Water as
directed.
Directions for Preparing PEPCID for Oral Suspension
Prepare suspension at time of dispensing. Slowly add 46 mL of Purified Water. Shake vigorously for 5-
10 seconds immediately after adding the water and immediately before use.
Stability of PEPCID for Oral Suspension
Unused constituted oral suspension should be discarded after 30 days.
Concomitant Use of Antacids
Antacids may be given concomitantly if needed.
Dosage Adjustment for Patients with Severe Renal Insufficiency
In patients with severe renal insufficiency, i.e., with a creatinine clearance less than 10 mL/min, the
elimination half-life of PEPCID may exceed 20 hours, reaching approximately 24 hours in anuric patients.
Although no relationship o adverse effects to high plasma levels has been established, to
avoid excess accumulation of the drug, the dose of PEPCID may be reduced to 20 mg h.s. or the dosing interval
may be prolonged to 36-48 hours as indicated by the patient’s clinical response.
No. 3535 – PEPCID Tablets, 20 mg, are beige colored, U-shaped, film-coated tablets coded MSD 963 on
one side and PEPCID on the other. They are supplied as follows:
-
NDC 0006-0963-31 unit of use bottles of 30 (6505-01-260-0902, 20 mg 30’s)
NDC 0006-0963-94 unit of use bottles of 90
NDC 0006-0963-58 unit of use bottles of 100
NDC 0006-0963-28 unit dose package of 100
NDC 0006-0963-98 unit of use bottles of 180
NDC 0006-0963-82 bottles of 1,000
NDC 0006-0963-87 bottles of 10,000
NDC 0006-0963-62 unit dose package of 750 (25 x 30 tablets in a punch card).
No. 3536 – PEPCID Tablets, 40 mg, are light brownish-orange, U-shaped, film-coated tablets coded
MSD 964 on one side and PEPCID on the other. They are supplied as follows:
-
NDC 0006-0964-31 unit of use bottles of 30 (6505-01-257-3164, 40 mg 30’s)
NDC 0006-0964-94 unit of use bottles of 90
NDC 0006-0964-58 unit of use bottles of 100
NDC 0006-0964-28 unit dose package of 100 (6505-01-318-0464, 40 mg individually sealed 100’s)
NDC 0006-0964-82 bottles of 1,000
NDC0006-0964-87 bottles of 10,000
NDC 0006-0964-62 unit dose package of 750 (25 x 30 tablets in a punch card).
No. 3538 – PEPCID for Oral Suspension is a white to off-white powder containing 400 mg of famotidine
for constitution. When constituted as directed, PEPCID for Oral Suspension is a smooth, mobile, off-white,
homogeneous suspension with a cherry-banana-mint flavor, containing 40 mg of famotidine per 5 mL.
-
NDC 0006-3538-92, bottles containing 400 mg famotidine.
Storage
Avoid storage of PEPCID Tablets at temperatures above 40oC (104oF).
Avoid storage of the powder for oral suspension at temperatures above 40oC (104oF) After constitution
store the suspension below 30oC (86oF). Do not freeze. Discard unused suspension after 30 days.
