Overdose
The adverse reactions in overdose cases are similar to
the adverse reactions encountered in normal clinical experience (see ADVERSE
REACTIONS). Oral doses of up to 640 mg/day have been given to adult
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.
Contraindications
Hypersensitivity to any
component of these products. Cross sensitivity in this class of compounds has
been observed. Therefore, PEPCID should not be administered to patients with a
history of hypersensitivity to other H2-receptor antagonists.
Undesirable effects
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 of 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 to
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.
Prolonged QT interval, in patients with impaired renal function, has been
reported very rarely.
Gastrointestinal: cholestatic jaundice, hepatitis,
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: rhabdomyolysis, 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. Convulsions, in patients
with impaired renal function, have been reported very rarely.
Respiratory: bronchospasm, interstitial pneumonia
Skin: toxic epidermal necrolysis/Stevens-Johnson
syndrome (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.
Pediatric Patients
In a clinical study in 35 pediatric patients < 1 year
of age with GERD symptoms [e.g., vomiting (spitting up), irritability
(fussing)], agitation was observed in 5 patients on famotidine that resolved
when the medication was discontinued.
Therapeutic indications
PEPCID is indicated in:
- Short-term treatment of active duodenal ulcer. Most adult
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.
- Maintenance therapy for duodenal ulcer patients at
reduced dosage after healing of an active ulcer. Controlled studies in adults
have not extended beyond one year.
- Short-term treatment of active benign gastric ulcer. Most
adult 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.
- Short-term treatment of gastroesophageal reflux disease
(GERD). PEPCID is indicated for short-term treatment of patients with symptoms
of GERD (see CLINICAL PHARMACOLOGY in adults, 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 in adults, Clinical Studies).
- Treatment of pathological
hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine
adenomas) (see CLINICAL PHARMACOLOGY in adults, Clinical Studies).
Pharmacokinetic properties
). This drug is known to be
substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, care should be taken
in dose selection, and it may be useful to monitor renal function. Dosage
adjustment in the case of moderate or severe renal impairment is necessary (see
PRECAUTIONS,
Patients with Moderate or Severe Renal Insufficiency
and
DOSAGE AND ADMINISTRATION,
Dosage Adjustment for Patients with
Moderate or Severe Renal Insufficiency).
Overdosage & Contraindications
OVERDOSE
The adverse reactions in overdose cases are similar to
the adverse reactions encountered in normal clinical experience (see ADVERSE
REACTIONS). Oral doses of up to 640 mg/day have been given to adult
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.
CONTRAINDICATIONS
Hypersensitivity to any
component of these products. Cross sensitivity in this class of compounds has
been observed. Therefore, PEPCID should not be administered to patients with a
history of hypersensitivity to other H2-receptor antagonists.
Clinical Pharmacology
CLINICAL PHARMACOLOGY
Clinical Pharmacology In Adults
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.
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%. 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, the
elimination half-life of PEPCID may exceed 20 hours and adjustment of dose or
dosing intervals in moderate and severe renal insufficiency may be necessary
(see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant
age-related changes in the pharmacokinetics of PEPCID. However, in elderly
patients with decreased renal function, the clearance of the drug may be
decreased (see PRECAUTIONS, Geriatric Use).
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 40 mg h.s.
(N = 89) |
PEPCID 20 mg b.i.d.
(N = 84) |
Placebo h.s.
(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 40 mg h.s.
(N=74) |
Placebo h.s.
(N=75) |
PEPCID 40 mg h.s.
(N=149) |
Placebo h.s.
(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 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 20 mg b.i.d.
(N=154) |
PEPCID 40 mg h.s.
(N=149) |
Placebo
(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 40 mg b.i.d.
(N=127) |
PEPCID 20 mg b.i.d.
(N=125) |
Placebo
(N=66) |
| Week 6 |
48†††,‡‡ |
32 |
18 |
| Week 12 |
69†††,‡ |
54††† |
29 |
††† p ≤ 0.01 vs Placebo
‡ p ≤ 0.05 vs PEPCID 20 mg b.i.d.
‡‡ p ≤ 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 40 mg b.i.d.
(N=175) |
PEPCID 20 mg b.i.d.
(N=93) |
Ranitidine 150 mg b.i.d.
(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, 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.
Clinical Pharmacology In
Pediatric Patients
Pharmacokinetics
Table 6 presents
pharmacokinetic data from clinical trials and a published study in pediatric
patients ( < 1 year of age; N=27) given famotidine I.V. 0.5 mg/kg and from
published studies of small numbers of pediatric patients (1-15 years of age)
given famotidine intravenously. Areas under the curve (AUCs) are normalized to
a dose of 0.5 mg/kg I.V. for pediatric patients 1-15 years of age and compared
with an extrapolated 40 mg intravenous dose in adults (extrapolation based on
results obtained with a 20 mg I.V. adult dose).
Table 6 : Pharmacokinetic
Parametersa of Intravenous Famotidine
| Age (N=number of patients) |
Area Under the Curve (AUC) (ng-hr/mL) |
Total Clearance (Cl) (L/hr/kg) |
Volume of Distribution (Vd) (L/kg) |
Elimination Half-life (T½) (hours) |
| 0-1 monthc(N=10) |
NA |
0.13 + 0.06 |
1.4 + 0.4 |
10.5 + 5.4 |
| 0-3 monthsd(N=6) |
2688 + 847 |
0.21 + 0.06 |
1.8 + 0.3 |
8.1 + 3.5 |
| > 3-12 monthsd |
1160+474 |
0.49 + 0.17 |
2.3 + 0.7 |
4.5 + 1.1 |
| (N=11) 1-11 yrs (N=20) |
1089 ±834 |
0.54 ± 0.34 |
2.07 ± 1.49 |
3.38 ± 2.60 |
| 11-15 yrs (N=6) |
1140±320 |
0.48 ± 0.14 |
1.5 ± 0.4 |
2.3 ± 0.4 |
| Adult (N=16) |
1726b |
0.39 ± 0.14 |
1.3 ± 0.2 |
2.83 ± 0.99 |
aValues are presented as means ± SD unless indicated
otherwise.
bMean value only.
cSingle center study. dMulticenter study. |
Plasma clearance is reduced and
elimination half-life is prolonged in pediatric patients 0-3 months of age
compared to older pediatric patients. The pharmacokinetic parameters for
pediatric patients, ages > 3 months-15 years, are comparable to those
obtained for adults.
Bioavailability studies of 8
pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5
compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs
of 645 ± 249 ng-hr/mL and 580 ± 60
ng-hr/mL in pediatric patients < 1 year of age (N=5) and in pediatric
patients 11-15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in
adults treated with 40 mg orally.
Pharmacodynamics
Pharmacodynamics of famotidine
were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid Emax
model. These data suggest that the relationship between serum concentration of
famotidine and gastric acid suppression is similar to that observed in one
study of adults (Table 7).
Table 7 : Pharmacodynamics of famotidine using the
sigmoid Emax model
| |
EC50 (ng/mL)* |
| Pediatric Patients |
26 ± 13 |
| Data from one study |
|
| a) healthy adult subjects |
26.5 ± 10.3 |
| b) adult patients with upper GI bleeding |
18.7 ± 10.8 |
| *Serum concentration of
famotidine associated with 50% maximum gastric acid reduction. Values are
presented as means ± SD. |
Five published studies (Table
8) examined the effect of famotidine on gastric pH and duration of acid
suppression in pediatric patients. While each study had a different design,
acid suppression data over time are summarized as follows:
Table 8
| Dosage |
Route |
Effecta |
Number of Patients (age range) |
| 0.5 mg/kg, single dose |
I.V. |
gastric pH > 4 for 19.5 hours (17.3, 21.8)c |
11 (5-19 days) |
| 0.3 mg/kg, single dose |
I.V. |
gastric pH > 3.5 for 8.7 ± 4.7b hours |
6 (2-7 years) |
| 0.4-0.8 mg/kg |
I.V. |
gastric pH > 4 for 6-9 hours |
18 (2-69 months) |
| 0.5 mg/kg, single dose |
I.V. |
a > 2 pH unit increase above baseline in gastric pH for > 8 hours |
9 (2-13 years) |
| 0.5 mg/kg b.i.d. |
I.V. |
gastric pH > 5 for 13.5 ± 1.8b hours |
4 (6-15 years) |
| 0.5 mg/kg b.i.d. |
oral |
gastric pH > 5 for 5.0 ± 1.1b hours |
4 (11-15 years) |
aValues reported in published literature.
bMeans ± SD.
cMean
(95% confidence interval). |
The duration of effect of
famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one
study to be longer in pediatric patients < 1 month of age than in older
pediatric patients. This longer duration of gastric acid suppression is
consistent with the decreased clearance in pediatric patients < 3 months of
age (see Table 6).
Fertility, pregnancy and lactation
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.
Special warnings and precautions for use
WARNINGS
No information provided
PRECAUTIONS
General
Symptomatic response to therapy with PEPCID does not
preclude the presence of gastric malignancy.
Patients With Moderate Or Severe Renal Insufficiency
Since CNS adverse effects have been reported in patients
with moderate and severe renal insufficiency, longer intervals between doses or
lower doses may need to be used in patients with moderate (creatinine clearance
< 50 mL/min) or severe (creatinine clearance < 10 mL/min) renal
insufficiency to adjust for the longer elimination half-life of famotidine (see
CLINICAL PHARMACOLOGY in adults and DOSAGE AND ADMINISTRATION).
Prolonged QT interval has been reported very rarely in patients with impaired
renal function whose dose/dosing interval of famotidine may not have been
adjusted appropriately.
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 Patients < 1 Year Of Age
Use of PEPCID in pediatric patients < 1 year of age is
supported by evidence from adequate and well-controlled studies of PEPCID in
adults, and by the following studies in pediatric patients < 1 year of age.
Two pharmacokinetic studies in pediatric patients < 1
year of age (N=48) demonstrated that clearance of famotidine in patients > 3
months to 1 year of age is similar to that seen in older pediatric patients
(1-15 years of age) and adults. In contrast, pediatric patients 0-3 months of
age had famotidine clearance values that were 2- to 4-fold less than those in
older pediatric patients and adults. These studies also show that the mean
bioavailability in pediatric patients < 1 year of age after oral dosing is
similar to older pediatric patients and adults. Pharmacodynamic data in
pediatric patients 0-3 months of age suggest that the duration of acid
suppression is longer compared with older pediatric patients, consistent with
the longer famotidine half-life in pediatric patients 0-3 months of age. (See CLINICAL
PHARMACOLOGY In Pediatric Patients, Pharmacokinetics and Pharmacodynamics.)
In a double-blind, randomized, treatment-withdrawal
study, 35 pediatric patients < 1 year of age who were diagnosed as having
gastroesophageal reflux disease were treated for up to 4 weeks with famotidine
oral suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous
famotidine formulation was available, no patients were treated with intravenous
famotidine in this study. Also, caregivers were instructed to provide
conservative treatment including thickened feedings. Enrolled patients were
diagnosed primarily by history of vomiting (spitting up) and irritability
(fussiness). The famotidine dosing regimen was once daily for patients < 3
months of age and twice daily for patients ≥ 3 months of age. After 4
weeks of treatment, patients were randomly withdrawn from the treatment and
followed an additional 4 weeks for adverse events and symptomatology. Patients
were evaluated for vomiting (spitting up), irritability (fussiness) and global
assessments of improvement. The study patients ranged in age at entry from 1.3
to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white
and 6% were black. Most patients (27/35) continued into the
treatment-withdrawal phase of the study. Two patients discontinued famotidine
due to adverse events. Most patients improved during the initial treatment
phase of the study. Results of the treatment-withdrawal phase were difficult to
interpret because of small numbers of patients. Of the 35 patients enrolled in
the study, agitation was observed in 5 patients on famotidine that resolved
when the medication was discontinued; agitation was not observed in patients on
placebo (see ADVERSE REACTIONS, Pediatric Patients).
These studies suggest that a starting dose of 0.5
mg/kg/dose of famotidine oral suspension may be of benefit for the treatment of
GERD for up to 4 weeks once daily in patients < 3 months of age and twice
daily in patients 3 months to < 1 year of age; the safety and benefit of
famotidine treatment beyond 4 weeks have not been established. Famotidine
should be considered for the treatment of GERD only if conservative measures
(e.g., thickened feedings) are used concurrently and if the potential benefit
outweighs the risk.
Pediatric Patients 1-16 years Of Age
Use of PEPCID in pediatric patients 1-16 years of age is
supported by evidence from adequate and well-controlled studies of PEPCID in
adults, and by the following studies in pediatric patients: In published
studies in small numbers of pediatric patients 1-15 years of age, clearance of
famotidine was similar to that seen in adults. In pediatric patients 11-15
years of age, oral doses of 0.5 mg/kg were associated with a mean area under
the curve (AUC) similar to that seen in adults treated orally with 40 mg.
Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5
mg/kg were associated with a mean AUC similar to that seen in adults treated
intravenously with 40 mg. Limited published studies also suggest that the
relationship between serum concentration and acid suppression is similar in
pediatric patients 1-15 years of age as compared with adults. These studies
suggest a starting dose for pediatric patients 1-16 years of age as follows:
Peptic Ulcer - 0.5 mg/kg/day p.o. At Bedtime Or Divided
b.i.d. Up To 40 mg/day.
Gastroesophageal Reflux Disease with or without
esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided
b.i.d. up to 40 mg b.i.d.
While published uncontrolled studies suggest
effectiveness of famotidine in the treatment of gastroesophageal reflux disease
and peptic ulcer, data in pediatric patients are insufficient to establish
percent response with dose and duration of therapy. Therefore, treatment
duration (initially based on adult duration recommendations) and dose should be
individualized based on clinical response and/or pH determination (gastric or
esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric
patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day
for GERD with or without esophagitis including erosions and ulcerations.
Geriatric Use
Of the 4,966 subjects in clinical studies who were
treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects
(1.7%) were greater than 75 years of age. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects.
However, greater sensitivity of some older individuals cannot be ruled out.
No dosage adjustment is required based on age (see CLINICAL
PHARMACOLOGY in adults, Pharmacokinetics). This drug is known to be
substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, care should be taken
in dose selection, and it may be useful to monitor renal function. Dosage
adjustment in the case of moderate or severe renal impairment is necessary (see
PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency
and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with
Moderate or Severe Renal Insufficiency).
Dosage (Posology) and method of 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 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 adult 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 adult
patients with symptoms of GERD is 20 mg b.i.d. for up to 6 weeks. The
recommended oral dosage for the treatment of adult 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 in adults,
Clinical Studies).
Dosage For Pediatric Patients < 1 Year Of Age
Gastroesophageal Reflux Disease (GERD)
See PRECAUTIONS, Pediatric Patients < 1 year
of age.
The studies described in PRECAUTIONS, Pediatric Patients
< 1 year of age suggest the following starting doses in pediatric patients
< 1 year of age: Gastroesophageal Reflux Disease (GERD) -0.5 mg/kg/dose of
famotidine oral suspension for the treatment of GERD for up to 8 weeks once
daily in patients < 3 months of age and 0.5 mg/kg/dose twice daily in
patients 3 months to < 1 year of age. Patients should also be receiving
conservative measures (e.g., thickened feedings). The use of intravenous
famotidine in pediatric patients < 1 year of age with GERD has not been
adequately studied.
Dosage For Pediatric Patients 1-16 Years Of Age
See PRECAUTIONS, Pediatric Patients 1-16 years
of age.
The studies described in PRECAUTIONS, Pediatric Patients
1-16 years of age suggest the following starting doses in pediatric patients
1-16 years of age:
Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or
divided b.i.d. up to 40 mg/day.
Gastroesophageal Reflux Disease with or without
esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided
b.i.d. up to 40 mg b.i.d.
While published uncontrolled studies suggest
effectiveness of famotidine in the treatment of gastroesophageal reflux disease
and peptic ulcer, data in pediatric patients are insufficient to establish
percent response with dose and duration of therapy. Therefore, treatment
duration (initially based on adult duration recommendations) and dose should be
individualized based on clinical response and/or pH determination (gastric or
esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric
patients 1-16 years of age have employed doses up to 1 mg/kg/day for peptic
ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions
and ulcerations.
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 adult
patients with severe Zollinger-Ellison Syndrome.
Concomitant Use Of Antacids
Antacids may be given concomitantly if needed.
Dosage Adjustment For Patients With Moderate Or Severe
Renal Insufficiency
In adult patients with moderate (creatinine clearance
< 50 mL/min) or severe (creatinine clearance < 10 mL/min) renal
insufficiency, the elimination half-life of PEPCID is increased. For patients
with severe renal insufficiency, it may exceed 20 hours, reaching approximately
24 hours in anuric patients. Since CNS adverse effects have been reported in
patients with moderate and severe renal insufficiency, to avoid excess
accumulation of the drug in patients with moderate or severe renal
insufficiency, the dose of PEPCID may be reduced to half the dose or the dosing
interval may be prolonged to 36-48 hours as indicated by the patient's clinical
response.
Based on the comparison of pharmacokinetic parameters for
PEPCID in adults and pediatric patients, dosage adjustment in pediatric
patients with moderate or severe renal insufficiency should be considered.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
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 of 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 to
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.
Prolonged QT interval, in patients with impaired renal function, has been
reported very rarely.
Gastrointestinal: cholestatic jaundice, hepatitis,
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: rhabdomyolysis, 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. Convulsions, in patients
with impaired renal function, have been reported very rarely.
Respiratory: bronchospasm, interstitial pneumonia
Skin: toxic epidermal necrolysis/Stevens-Johnson
syndrome (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.
Pediatric Patients
In a clinical study in 35 pediatric patients < 1 year
of age with GERD symptoms [e.g., vomiting (spitting up), irritability
(fussing)], agitation was observed in 5 patients on famotidine that resolved
when the medication was discontinued.
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.
