5 Warnings and Precautions

5.1 Central Nervous System Adverse Reactions

Central nervous system (CNS) adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy, have been reported in elderly patients and patients with moderate and severe renal impairment treated with Famotidine. Since famotidine blood levels are higher in patients with renal impairment than in patients with normal renal function, dosage adjustments are recommended in patients with renal impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

5.2 Concurrent Gastric Malignancy

In adults, symptomatic response to therapy with Famotidine does not preclude the presence of gastric malignancy. Consider evaluation for gastric malignancy in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with Famotidine.

6 Adverse Reactions

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Famotidine was studied in 7 US and international placebo- and-active- controlled trials in approximately 2500 patients [see Clinical Studies (14)]. A total of 1442 patients were treated with Famotidine, including 302 treated with 40 mg twice daily, 456 treated with 20 mg twice daily, 461 treated with 40 mg once daily, and 396 treated with 20 mg once daily. The population was 17-91 years old, fairly well distributed between gender and race, however the predominant race treated was Caucasian.
The following adverse reactions occurred in greater than or equal to 1% of Famotidine-treated patients: headache, dizziness and constipation.
The following other adverse reactions were reported in less than 1% of patients in clinical trials:
Body as a Whole: fever, asthenia, fatigue
Cardiovascular: palpitations
Gastrointestinal: elevated liver enzymes, vomiting, nausea, abdominal discomfort, anorexia, dry mouth
Hematologic: thrombocytopenia
Hypersensitivity: orbital edema, rash, conjunctival injection, bronchospasm
Musculoskeletal: musculoskeletal pain, arthralgia
Nervous System/Psychiatric: seizure, hallucinations, depression, anxiety, decreased libido, insomnia, somnolence
Skin: pruritus, dry skin, flushing
Special Senses: tinnitus, taste disorder
Other: impotence

6.2 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of famotidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular: arrhythmia, AV block, prolonged QT interval
Gastrointestinal: cholestatic jaundice, hepatitis
Hematologic: agranulocytosis, pancytopenia, leukopenia
Hypersensitivity: anaphylaxis, angioedema, facial edema, urticaria
Musculoskeletal: rhabdomyolysis, muscle cramps
Nervous System/Psychiatric: confusion, agitation, paresthesia
Respiratory: interstitial pneumonia
Skin: toxic epidermal necrolysis/Stevens-Johnson syndrome

7 Drug Interactions

7.1 Drugs Dependent on Gastric pH for Absorption

Famotidine can reduce the absorption of other drugs, due to its effect on reducing intragastric acidity, leading to loss of efficacy of the concomitant drug.
Concomitant administration of Famotidine with dasatinib, delavirdine mesylate, cefditoren, and fosamprenavir is not recommended.
See the prescribing information for other drugs dependent on gastric pH for absorption for administration instructions, including atazanavir, erlotinib, ketoconazole, itraconazole, ledipasvir/sofosbuvir, nilotinib, and rilpivirine.

7.2 Tizanidine (CYP1A2 Substrate)

Although not studied clinically, famotidine is considered a weak CYP1A2 inhibitor and may lead to substantial increases in blood concentrations of tizanidine, a CYP1A2 substrate. Avoid concomitant use with Famotidine. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

14 Clinical Studies

14.1 Active Duodenal Ulcer

In a U.S. multicenter, double-blind trial in adult outpatients with endoscopically confirmed duodenal ulcer (DU), orally-administered Famotidine was compared to placebo. As shown in Table 4, 70% of patients treated with Famotidine 40 mg tablets at bedtime were healed by Week 4. Most patients DU healed within 4 weeks.
Patients not healed by Week 4 were continued in the trial. By Week 8, 83% of patients treated with Famotidine had healed DU, compared to 45% of patients treated with placebo. The incidence of DU healing with Famotidine was greater than with placebo at each time point based on proportion of endoscopically confirmed healed DUs. Trials have not assessed the safety of Famotidine in uncomplicated active DU for periods of more than 8 weeks.

Table 4: Patients with Endoscopically-Confirmed Healed Duodenal Ulcers

ap<0.001 vs. placebo
In this study, time to relief of daytime and nocturnal pain was shorter for patients receiving Famotidine than for patients receiving placebo; patients receiving Famotidine also took less antacid than patients receiving placebo.

14.2 Active Gastric Ulcer

In both a U.S. and an international multicenter, double-blind trials in patients with endoscopically-confirmed active gastric ulcer (GU), orally- administered Famotidine 40 mg at bedtime was compared to placebo. Antacids were permitted during the trials, but consumption was not significantly different between the Famotidine and placebo groups.
As shown in Table 5, the incidence of GU healing confirmed by endoscopy (dropouts counted as unhealed) with Famotidine was greater than placebo at Weeks 6 and 8 in the U.S. trial, and at Weeks 4, 6 and 8 in the international trial. In these trials, most Famotidine-treated patients healed within 6 weeks. Trials have not assessed the safety of Famotidine in uncomplicated active GU for periods of more than 8 weeks.
Table 5: Patients with Endoscopically-Confirmed Healed Gastric Ulcers

ap≤0.01 vs. placebo bp≤0.05 vs. placebo

Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving Famotidine than for patients receiving placebo; however, neither trial demonstrated a statistically significant difference in the proportion of patients whose pain was relieved by the end of the trial (Week 8).

14.3 Symptomatic Gastroesophageal Reflux Disease (GERD)

Orally-administered Famotidine was compared to placebo in a U.S. trial that enrolled patients with symptoms of GERD and without endoscopic evidence of esophageal erosion or ulceration. As shown in Table 6, patients treated with Famotidine 20 mg twice daily had greater improvement in symptomatic GERD than patients treated with 40 mg at bedtime or placebo.
Table 6: Patients with Improvement of Symptomatic GERD (N=376)

ap≤0.01 vs. placebo

14.4 Erosive Esophagitis Due to GERD

Healing of endoscopically-verified erosion and symptomatic improvement were studied in a U.S. and an international double-blind trials. Healing was defined as complete resolution of all erosions visible with endoscopy. The U.S. trial comparing orally-administered Famotidine 40 mg twice daily to placebo and orally administered Famotidine 20 mg twice daily showed a significantly greater percentage of healing of erosive esophagitis for Famotidine 40 mg tablets twice daily at Weeks 6 and 12 (Table 7).

Table 7: Patients with Endoscopic Healing of Erosive Esophagitis - U.S. Study (N=318)

ap0.01 vs. placebo bp0.01 vs. Famotidine tablets 20 mg twice daily
cp0.05 vs. Famotidine tablets 20 mg twice daily

As compared to placebo, patients in the U.S. trial who received Famotidine tablets had faster relief of daytime and nighttime heartburn, and a greater percentage of Famotidine-treated patients experienced complete relief of nighttime heartburn. These differences were statistically significant.
In the international trial, when orally-administered Famotidine 40 mg tablets twice daily was compared to orally-administered ranitidine 150 mg twice daily, a statistically significantly greater percentage of healing of erosive esophagitis was observed with Famotidine 40 mg tablets twice daily at Week 12 (Table 8). There was, however, no significant difference in symptom relief among treatment groups.
Table 8: Patients with Endoscopic Healing of Erosive Esophagitis- International Study(N=440)

ap≤0.05 vs ranitidine 150 mg twice daily

14.5 Pathological Hypersecretory Conditions

In trials of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine neoplasias, Famotidine significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered Famotidine dosages from 20 mg to 160 mg every 6 hours maintained basal acid secretion below 10 mEq/hour; initial dosages were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients.

14.6 Risk Reduction of Duodenal Ulcer Recurrence

Two randomized, double-blind, multicenter trials in patients with endoscopically-confirmed healed DUs demonstrated that patients receiving treatment with orally-administered Famotidine
20 mg tablets at bedtime had lower rates of DU recurrence, as compared with placebo.
• In the U.S. trial, DU recurrence within 12 months was 2.4 times greater in patients treated
with placebo than in the patients treated with Famotidine tablets. The Famotidine-treated 89
patients had a cumulative observed DU recurrence rate of 23%, compared to a 57% in the
89 patients receiving placebo (p<0.01).
• In the international trial, the cumulative observed DU recurrence within 12 months in the 307
Famotidine-treated patients was 36%, compared to 76% in the 325 patients who received
placebo (p<0.01).
Controlled trials have not extended beyond one year.

17 Patient Counseling Information

Central Nervous System (CNS) Adverse Reactions
Advise elderly patients and those with moderate and severe renal impairment of the risk of CNS adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy [see Warnings and Precautions (5.1)]. Report symptoms immediately to a healthcare provider.
QT Prolongation
Advise patients with moderate and severe renal impairment of the risk of QT interval prolongation [see Use in Specific Populations (8.6)]. Report new cardiac symptoms, such as palpitations, fainting and dizziness or lightheadedness immediately to a healthcare provider.
Administration
Advise patients:
• Take Famotidine tablets once daily before bedtime or twice daily in the morning and before bedtime, as recommended.
• Famotidine tablets may be taken with or without food.
• Famotidine tablets may be given with antacids.

12 Clinical Pharmacology

12.1 Mechanism of Action

Famotidine is a competitive inhibitor of histamine-2 (H2) receptors. The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output.

12.2 Pharmacodynamics

Adults
Famotidine inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration of Famotidine, 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 mg and 40 mg was 10 to 12 hours.
Single evening oral doses of 20 mg 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 to 8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 mg and 40 mg of Famotidine tablets to mean values of 5.0 and 6.4, respectively. When Famotidine was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 mg or 40 mg of Famotidine tablets was raised to about 5.
Famotidine tablets had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by Famotidine tablets.
In clinical pharmacology studies, systemic effects of Famotidine tablets in the CNS, cardiovascular, respiratory or endocrine systems were not noted. Also, no anti-androgenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with Famotidine tablets.
Pediatric Patients
Pharmacodynamics of famotidine, assessed by gastric pH, were evaluated in 5 pediatric patients 2 to 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 adults (see Table 3).

Table 3: Serum Concentrations of Famotidine Associated with Gastric Acid Reduction in Famotidine-Treated Pediatric and Adult Patients****a

aUsing the Sigmoid Emax model, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means ± SD.
In a study examining the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients, four pediatric patients ages 11 to 15 years of age using the oral formulation at a dose of 0.5 mg/kg, maintained a gastric pH above 5 for 13.5 ± 1.8 hours.

12.3 Pharmacokinetics

Absorption
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.
Peak famotidine plasma levels occur in 1 to 3 hours. Plasma levels after multiple dosages are similar to those after single doses.
Distribution
Fifteen to 20% of famotidine in plasma is protein bound.
Elimination
Metabolism
Famotidine undergoes minimal first-pass metabolism. Twenty-five to 30% of an oral dose was recovered in the urine as unchanged compound. The only metabolite identified in humans is the S-oxide.
Excretion
Famotidine has an elimination half-life of 2.5-3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/minute, indicating some tubular excretion.
Specific Populations
Pediatric Patients
Bioavailability studies of 8 pediatric patients (11 to 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 per kg achieved AUCs of 580 ± 60 ng•hr/mL in pediatric patients 11 to 15 years of age, compared to 482 ± 181 ng•hr/mL in adults treated with 40 mg orally.
Patients with Renal Impairment
In adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the systemic exposure (AUC) of famotidine increased at least 5-fold. In patients with moderate renal impairment (creatinine clearance between 30 to 60 mL/minute), the AUC of famotidine increased at least 2-fold [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].
Drug Interaction Studies
Human Organic Anion Transporter (OAT) 1 and 3: In vitro studies indicate that famotidine is a substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg), an inhibitor of OAT1 and OAT3, with a single oral 20 mg dose of famotidine in 8 healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ng•hr/mL and the maximum serum concentration (Cmax) increased from 73 to 113 ng/mL. Renal clearance, urinary excretion rate and amount of famotidine excreted unchanged in urine were decreased. The clinical relevance of this interaction is unknown.
Multidrug and Toxin Extrusion Protein 1 (MATE-1): An in vitro study showed that famotidine is an inhibitor of MATE-1. However, no clinically significant interaction with metformin, a substrate for MATE-1, was observed.
CYP1A2: Famotidine is a weak CYP1A2 inhibitor.

16 How Supplied/Storage and Handling

Famotidine 20 mg tablets are white, round, film-coated tablets engraved with CTI 121 on one side, supplied as follows:

NDC 68788-7853-3 bottles of 30
NDC 68788-7853-6 bottles of 60
NDC 68788-7853-9 bottles of 90
NDC 68788-7853-4 bottles of 14

Storage
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Dispense in a tight, light-resistant container.