FAMOTIDINE
DESCRIPTION:
The active ingredient in FACID* (Famotidine), is a histamine H2-receptor
antagonist. Famotidine is N'-(aminosulfonyl)-3-(((2-((diaminomethylene)amin o)-
4-thiazolyl)methyl)thio)propanimidamide. The empirical formula of famotidine is
C8H15N7O2S3 and its molecular weight is 337.43.
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.
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,
cornstarch, talc, titanium dioxide.
ACTIONS/CLINICAL PHARMACOLOGY:
GI Effects
FACID is a competitive inhibitor of histamine H2-receptors. The primary
clinically important pharmacologic activity of FACID is inhibition of gastric
secretion. Both the acid concentration and volume of gastric secretion are
suppressed by FACID, while changes in pepsin secretion are proportional to
volume output.
In normal volunteers and hypersecretors, FACID 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.
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 FACID to mean values of 5.0 and 6.4, respectively. When FACID was given
after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20
or 40 mg of FACID was raised to about 5.
FACID had little or no effect on fasting or postprandial serum gastrin levels.
Gastric emptying and exocrine pancreatic function were not affected by FACID.
Other Effects
Systemic effects of FACID 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 FACID.
Pharmacokinetics
FACID is incompletely absorbed. The bioavailability of oral doses is 40-45%.
FACID Tablets and FACID Oral Suspension are bioequivalent. Bioavailability may
be slightly increased by food, or slightly decreased by antacids; however, these
effects are of no clinical consequence. FACID 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 FACID in plasma is protein bound. FACID has an elimination half- life
of 2.5-3.5 hours. FACID 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 FACID. In patients with severe renal insufficiency,
i.e., creatinine clearance less than 10 mL/min, the elimination half-life of
FACID 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 FACID.
CLINICAL STUDIES:
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically
confirmed duodenal ulcer, orally administered FACID was compared to placebo. As
shown in Table 1, 70% of patients treated with FACID 40 mg h.s. were healed by
week 4.
Table 1
OUTPATIENTS WITH ENDOSCOPICALLY
CONFIRMED HEALED DUODENAL ULCERS
FACID FACID 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 FACID had healed versus 45% of patients treated with
placebo. The incidence of ulcer healing with FACID 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 FACID than for patients receiving placebo;
patients receiving FACID also took less antacid than the patients receiving
placebo.
Long-Term Maintenance
Treatment Of Duodenal Ulcers
FACID, 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 FACID. The 89 patients treated with FACID 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 FACID 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
FACID, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during
the studies, but consumption was not significantly different between the FACID
and placebo groups. As shown in Table 2, the incidence of ulcer healing
(dropouts counted as unhealed) with FACID 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
---------- -------------------
FACID Placebo FACID 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% **80% 54%
----------
*,** Statistically significantly better than placebo
(p =0.05, p =0.01 respectively)
Time to complete relief of daytime and nighttime pain was statistically
significantly shorter for patients receiving FACID 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 FACID 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. FACID 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
FACID FACID
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 FACID 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 FACID 40 mg p.o. b.i.d. to placebo and FACID 20 mg p.o.
b.i.d. showed a significantly greater percentage of healing for FACID 40 mg
b.i.d. at weeks 6 and 12 (Table 4).
Table 4
% ENDOSCOPIC HEALING--U.S. STUDY
FACID FACID
40 mg b.i.d. 20 mg b.i.d. Placebo
------------------------------------------------------------------------------------------------------
(N = 127) (N = 125) (N = 66)
Week 6 48**,++ 32 18
Week 12 69**,+ 54** 29
----------------------------------------------------------------------------------------------------
** p = 0.01 vs Placebo
+ p = 0.05 vs FACID 20 mg b.i.d.
++ p = 0.01 vs FACID 20 mg b.i.d.
As compared to placebo, patients who received FACID 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 FACID 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 FACID 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
FACID FACID 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 71* 68 60
-------------------------------------------------------------------------------------------------------
* p = 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, FACID
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. FACID 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.
INDICATIONS AND USAGE:
FACID is indicated in:
1. Short Term Treatment Of Active Duodenal Ulcer. Most patients heal within 4
weeks; there is rarely reason to use FACID 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). FACID is
indicated for short term treatment of patients with symptoms of GERD (see
ACTIONS/CLINICAL PHARMACOLOGY, Clinical Studies).
FACID is also indicated for the short term treatment of esophagitis due to GERD
including erosive or ulcerative disease diagnosed by endoscopy (see
ACTIONS/CLINICAL PHARMACOLOGY, Clinical Studies).
5. Treatment Of Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison
Syndrome, Multiple Endocrine Adenomas).
CONTRAINDICATIONS:
Hypersensitivity to any component of these products.
PRECAUTIONS:
General
Symptomatic response to therapy with FACID 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 ACTIONS/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
FACID.
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 FACID. 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 FACID, 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 ACTIONS/CLINICAL
PHARMACOLOGY, Pharmacokinetics). Dosage adjustment in the case of severe renal
impairment may be necessary.
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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
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 FACID Tablets were compared to placebo, the
incidence of adverse experiences in the group which received FACID Tablets, 40
mg at bedtime, was similar to that in the placebo group.
The following adverse reactions have been reported to occur in more than 1% of
patients on therapy with FACID 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
FACID 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; somnolence
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 FACID Tablets may also occur with FACID for
Oral Suspension.
OVERDOSAGE:
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.
DOSAGE AND ADMINISTRATION:
Duodenal Ulcer
Acute Therapy: The recommended adult oral dosage for active duodenal ulcer is 40
mg once a day at bedtime. Most patients heal within 4 weeks; there is rarely
reason to use FACID 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
ACTIONS/CLINICAL PHARMACOLOGY, Clinical Studies).
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome,
Multiple Endocrine Adenomas)
The dosage of FACID 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
FACID Oral Suspension may be substituted for FACID 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 FACID 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 FACID 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 FACID may exceed 20 hours,
reaching approximately 24 hours in anuric patients. Although no relationship of
adverse effects to high plasma levels has been established, to avoid excess
accumulation of the drug, the dose of FACID 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.