ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The most common adverse reactions are: headache, dizziness, constipation, and diarrhea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.PEPCID was studied in US and international placebo- and active-controlled trials in approximately 2500 patients [see Clinical Studies (14)]. total of 1442 patients were treated with PEPCID, 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 PEPCID-treated patients: headache, dizziness and constipation.The following other adverse reactions were reported in less than 1% of patients in clinical trials:Body as Whole: fever, asthenia, fatigueCardiovascular: palpitationsGastrointestinal: elevated liver enzymes, vomiting, nausea, abdominal discomfort, anorexia, dry mouthHematologic: thrombocytopeniaHypersensitivity: orbital edema, rash, conjunctival injection, bronchospasmMusculoskeletal: musculoskeletal pain, arthralgiaNervous System/Psychiatric: seizure, hallucinations, depression, anxiety, decreased libido, insomnia, somnolenceSkin: pruritus, dry skin, flushingSpecial Senses: tinnitus, taste disorderOther: impotence. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of famotidine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular: arrhythmia, AV block, prolonged QT intervalGastrointestinal: cholestatic jaundice, hepatitisHematologic: agranulocytosis, pancytopenia, leukopeniaHypersensitivity: anaphylaxis, angioedema, facial edema, urticariaMusculoskeletal: rhabdomyolysis, muscle crampsNervous System/Psychiatric: confusion, agitation, paresthesiaRespiratory: interstitial pneumoniaSkin: toxic epidermal necrolysis/Stevens-Johnson syndrome.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Famotidine is 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 PEPCID inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration of PEPCID, 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 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, to hours after administration, and 25% and 30%, respectively, to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated within to 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 PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at and hours after 20 mg 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. In clinical pharmacology studies, systemic effects of PEPCID 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 PEPCID. Pediatric Patients Pharmacodynamics of famotidine, assessed by gastric pH, were evaluated in pediatric patients 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 PEPCID-Treated Pediatric and Adult PatientsUsing the Sigmoid Emax model, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means +- SD. EC50 (ng/mL)aPediatric Patients26 +- 13Adults Healthy adult subjects26.5 +- 10.3 Adult patients with upper GI bleeding18.7 +- 10.8In 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 dose of 0.5 mg/kg, maintained gastric pH above 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 to 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 pediatric patients (11 to 15 years of age) showed 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 ngohr/mL in pediatric patients 11 to 15 years of age, compared to 482 +- 181 ngohr/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) and 3: In vitro studies indicate that famotidine is substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg), an inhibitor of OAT1 and OAT3, with single oral 20 mg dose of famotidine in healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ngohr/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 (MATE-1): An in vitro study showed that famotidine is an inhibitor of MATE-1. However, no clinically significant interaction with metformin, substrate for MATE-1, was observed. CYP1A2: Famotidine is weak CYP1A2 inhibitor.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Active Duodenal Ulcer In U.S. multicenter, double-blind trial in adult outpatients with endoscopically confirmed duodenal ulcer (DU), orally administered PEPCID was compared to placebo. As shown in Table 4, 70% of patients treated with PEPCID 40 mg at bedtime were healed by Week 4. Most patients DU healed within weeks. Patients not healed by Week were continued in the trial. By Week 8, 83% of patients treated with PEPCID had healed DU, compared to 45% of patients treated with placebo. The incidence of DU healing with PEPCID was greater than with placebo at each time point based on proportion of endoscopically confirmed healed DUs. Trials have not assessed the safety of PEPCID in uncomplicated active DU for periods of more than weeks.Table 4: Patients with Endoscopically Confirmed Healed Duodenal UlcersPEPCID40 mg at bedtime (N=89)PEPCID20 mg twice daily (N=84)Placebo at bedtime (N=97)Week 232%p<0.001 vs. placebo 38% 17%Week 470% 67% 31%In this study, time to relief of daytime and nocturnal pain was shorter for patients receiving PEPCID than for patients receiving placebo; patients receiving PEPCID also took less antacid than patients receiving placebo.. 14.2 Active Gastric Ulcer In both U.S. and an international multicenter, double-blind trials in patients with endoscopically confirmed active gastric ulcer (GU), orally administered PEPCID 40 mg at bedtime was compared to placebo. Antacids were permitted during the trials, but consumption was not significantly different between the PEPCID and placebo groups. As shown in Table 5, the incidence of GU healing confirmed by endoscopy (dropouts counted as unhealed) with PEPCID was greater than placebo at Weeks and in the U.S. trial, and at Weeks 4, and in the international trial. In these trials, most PEPCID-treated patients healed within weeks. Trials have not assessed the safety of PEPCID in uncomplicated active GU for periods of more than weeks.Table 5: Patients with Endoscopically Confirmed Healed Gastric UlcersU.S. Study (N=149)International Study (N=294)PEPCID40 mg at bedtime (N=74)Placebo at bedtime (N=75)PEPCID40 mg at bedtime (N=149)Placebo at bedtime (N=145)Week 445%39%47%p<=0.01 vs. placebo 31%Week 666% 44%65% 46%Week 878%p<=0.05 vs. placebo 64%80% 54%Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving PEPCID than for patients receiving placebo; however, neither trial demonstrated 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 PEPCID was compared to placebo in 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 PEPCID 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)PEPCID 20 mg twice daily (N=154)PEPCID 40 mg at bedtime (N=149)Placebo at bedtime (N=73)Week 682%69%62%. 14.4 Erosive Esophagitis due to GERD Healing of endoscopically verified erosion and symptomatic improvement were studied in 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 PEPCID 40 mg twice daily to placebo and orally administered PEPCID 20 mg twice daily showed significantly greater percentage of healing of erosive esophagitis for PEPCID 40 mg twice daily at Weeks and 12 (Table 7).Table 7: Patients with Endoscopic Healing of Erosive Esophagitis U.S. Study (N=318)PEPCID40 mg twice daily (N=127)PEPCID20 mg twice daily (N=125)Placebotwice daily (N=66)Week 648%p<=0.01 vs. placebo p<=0.01 vs. PEPCID 20 mg twice daily 32%18%Week 1269% p<=0.05 vs. PEPCID 20 mg twice daily 54% 29%As compared to placebo, patients in the U.S. trial who received PEPCID had faster relief of daytime and nighttime heartburn, and greater percentage of PEPCID-treated patients experienced complete relief of nighttime heartburn. These differences were statistically significant. In the international trial, when orally administered PEPCID 40 mg twice daily was compared to orally administered ranitidine 150 mg twice daily, statistically significantly greater percentage of healing of erosive esophagitis was observed with PEPCID 40 mg 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)PEPCID40 mg twice daily (N=175)PEPCID20 mg twice daily (N=93)Ranitidine150 mg twice daily (N=172)Week 648%52%42%Week 1271%p<=0.05 vs ranitidine 150 mg twice daily 68%60%. 14.5 Pathological Hypersecretory Conditions In trials of patients with pathological hypersecretory conditions such as Zollinger-Ellison syndrome with or without multiple endocrine neoplasias, PEPCID significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered PEPCID dosages from 20 mg to 160 mg every 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 PEPCID 20 mg at bedtime had lower rates of DU recurrence, as compared with placebo. oIn 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 PEPCID. The 89 PEPCID-treated patients had cumulative observed DU recurrence rate of 23%, compared to 57% in the 89 patients receiving placebo (p<0.01). oIn the international trial, the cumulative observed DU recurrence within 12 months in the 307 PEPCID-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.. oIn 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 PEPCID. The 89 PEPCID-treated patients had cumulative observed DU recurrence rate of 23%, compared to 57% in the 89 patients receiving placebo (p<0.01). oIn the international trial, the cumulative observed DU recurrence within 12 months in the 307 PEPCID-treated patients was 36%, compared to 76% in the 325 patients who received placebo (p<0.01).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage Table shows the recommended dosage of PEPCID 20 mg and 40 mg tablets in adult and pediatric patients weighing 40 kg and greater with normal renal function. The use of PEPCID 20 mg and 40 mg tablets is not recommended in pediatric patients weighing less than 40 kg because the lowest available strength (20 mg) exceeds the recommended dose for these patients. Use another famotidine formulation for pediatric patients weighing less than 40 kg.Table 1: Recommended Dosage and Duration of PEPCID Tablets in Adult and Pediatric Patients 40 kg and Greater with Normal Renal FunctionIndicationRecommended DosageRecommended DurationActive duodenal ulcer (DU)40 mg once daily; or 20 mg twice dailyBoth dosages demonstrated effectiveness in clinical trials [see Clinical Studies (14)]. Up to weeksIn clinical trials, the majority of patients healed within weeks. For patients who do not heal after weeks, consider an additional to weeks of treatment [see Clinical Studies (14.1)]. Longer treatment durations have not been studied in clinical trials [see Clinical Studies (14.1, 14.2, 14.3)]. Active gastric ulcer40 mg once dailyUp to weeks Symptomatic nonerosive GERD20 mg twice dailyUp to weeks Erosive esophagitis diagnosed by endoscopy20 mg twice daily; or 40 mg twice dailyUp to 12 weeksPathological hypersecretory conditionsIn pediatric patients, the safety and effectiveness of PEPCID have not been established for the reduction of the risk of duodenal ulcer recurrence or for treatment of pathological hypersecretory conditions [see Use in Specific Populations (8.4)]. Starting dosage: 20 mg every hours; adjust dosage to individual patient needs Maximum dosage 160 mg every hoursAs clinically indicatedReduction of the risk of DU recurrence 20 mg once daily1 year or as clinically indicated. 2.2 Dosage in Renal Impairment Dosage adjustments of PEPCID are recommended for patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/min) [see Use in Specific Populations (8.6)]. Table shows the recommended maximum dosage of PEPCID 20 mg or 40 mg tablets for patients with renal impairment, by indication. Use the lowest effective dose. Some dosage adjustments may require switching to other formulations of famotidine (e.g., oral suspension, lower dose tablet).Table 2: Recommended Maximum Dosage of PEPCID Tablets in Adult and Pediatric Patients 40 kg and Greater with Moderate and Severe Renal ImpairmentIndicationRecommended Maximum DosagesCreatinine clearance 30 to 60 mL/minuteCreatinine clearance less than 30 mL/minuteActive duodenal ulcer (DU)20 mg once daily; or 40 mg every other day20 mg every other dayAn alternate dosage regimen is 10 mg once daily. Since 20 mg or 40 mg tablet strength cannot be used for this dosage regimen, use an alternate famotidine formulation. Active gastric ulcer20 mg once daily; or 40 mg every other day20 mg every other day Symptomatic nonerosive GERD20 mg once daily20 mg every other day Erosive esophagitis diagnosed by endoscopyDosage adjustments for renal impairment are provided for both dosing regimens (20 mg twice daily and 40 mg twice daily) which showed effectiveness for the treatment of erosive esophagitis in clinical trials [see Clinical Studies (14.4)]. 20 mg once daily; or 40 mg every other day20 mg every other day 40 mg once daily 20 mg once daily Pathological hypersecretory conditionsIn pediatric patients, the safety and effectiveness of PEPCID have not been established for the reduction of the risk of duodenal ulcer recurrence or for treatment of pathological hypersecretory conditions see Use in Specific Populations (8.4)]. Avoid useDoses required to treat pathological hypersecretory conditions may exceed the maximum doses evaluated in patients with impaired renal function. The risk for increased adverse reactions in renally impaired patients treated with PEPCID for pathological hypersecretory conditions is unknown. Reduction of the risk of DU reccurrence20 mg every other day (see footnote)Recommended dosage regimen is 10 mg every other day. Since 20 mg or 40 mg strength cannot be used for this dosage regimen, use an alternate famotidine formulation. 2.3 Administration Instructions oTake PEPCID once daily before bedtime or twice daily in the morning and before bedtime, as recommended.oPEPCID may be taken with or without food [see Clinical Pharmacology (12.3)].PEPCID may be given with antacids.. oTake PEPCID once daily before bedtime or twice daily in the morning and before bedtime, as recommended.. oPEPCID may be taken with or without food [see Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oDrugs Dependent on Gastric pH for Absorption: Systemic exposure of the concomitant drug may be significantly reduced leading to loss of efficacy. See full prescribing information for list of interacting drugs. (7.1)oTizanidine (CYP1A2) Substrate: Potential for substantial increases in blood concentrations of tizanidine resulting in hypotension, bradycardia or excessive drowsiness; avoid concomitant use, if possible. (7.2). oDrugs Dependent on Gastric pH for Absorption: Systemic exposure of the concomitant drug may be significantly reduced leading to loss of efficacy. See full prescribing information for list of interacting drugs. (7.1). oTizanidine (CYP1A2) Substrate: Potential for substantial increases in blood concentrations of tizanidine resulting in hypotension, bradycardia or excessive drowsiness; avoid concomitant use, if possible. (7.2). 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 PEPCID 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 weak CYP1A2 inhibitor and may lead to substantial increases in blood concentrations of tizanidine, CYP1A2 substrate. Avoid concomitant use with PEPCID. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE PEPCID tablets are indicated in adult and pediatric patients 40 kg and greater for the treatment of: oactive duodenal ulcer (DU). oactive gastric ulcer (GU). osymptomatic nonerosive gastroesophageal reflux disease (GERD). oerosive esophagitis due to GERD, diagnosed by biopsy.PEPCID tablets are indicated in adults for the: otreatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). reduction of the risk of duodenal ulcer recurrence.. oactive duodenal ulcer (DU). oactive gastric ulcer (GU). osymptomatic nonerosive gastroesophageal reflux disease (GERD). oerosive esophagitis due to GERD, diagnosed by biopsy.. otreatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias). PEPCID is histamine-2 (H2) receptor antagonist indicated (1):In adult and pediatric patients 40 kg and greater for the treatment of:oactive duodenal ulcer (DU).oactive gastric ulcer.osymptomatic nonerosive gastroesophageal reflux disease (GERD).oerosive esophagitis due to GERD, diagnosed by biopsy.In adults for the:otreatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison osyndrome, multiple endocrine neoplasias).oreduction of the risk of DU recurrence.. oactive duodenal ulcer (DU).. oactive gastric ulcer.. osymptomatic nonerosive gastroesophageal reflux disease (GERD).. oerosive esophagitis due to GERD, diagnosed by biopsy.. otreatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison osyndrome, multiple endocrine neoplasias).. oreduction of the risk of DU recurrence.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Adults PEPCID inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration of PEPCID, 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 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, to hours after administration, and 25% and 30%, respectively, to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated within to 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 PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at and hours after 20 mg 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. In clinical pharmacology studies, systemic effects of PEPCID 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 PEPCID. Pediatric Patients Pharmacodynamics of famotidine, assessed by gastric pH, were evaluated in pediatric patients 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 PEPCID-Treated Pediatric and Adult PatientsUsing the Sigmoid Emax model, serum concentrations of famotidine associated with 50% maximum gastric acid reduction are presented as means +- SD. EC50 (ng/mL)aPediatric Patients26 +- 13Adults Healthy adult subjects26.5 +- 10.3 Adult patients with upper GI bleeding18.7 +- 10.8In 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 dose of 0.5 mg/kg, maintained gastric pH above for 13.5 +- 1.8 hours.

PHARMACOKINETICS SECTION.

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 to 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 pediatric patients (11 to 15 years of age) showed 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 ngohr/mL in pediatric patients 11 to 15 years of age, compared to 482 +- 181 ngohr/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) and 3: In vitro studies indicate that famotidine is substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg), an inhibitor of OAT1 and OAT3, with single oral 20 mg dose of famotidine in healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ngohr/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 (MATE-1): An in vitro study showed that famotidine is an inhibitor of MATE-1. However, no clinically significant interaction with metformin, substrate for MATE-1, was observed. CYP1A2: Famotidine is weak CYP1A2 inhibitor.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryAvailable data with H2-receptor antagonists, including famotidine, in pregnant women are insufficient to establish drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse development effects were observed with oral administration of famotidine at doses up to approximately 243 and 122 times, respectively, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis (see Data).The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal DataReproductive 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 intravenous 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 (about 49 times the recommended human dose of 80 mg per day, based on body surface area) 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.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage Table shows the recommended dosage of PEPCID 20 mg and 40 mg tablets in adult and pediatric patients weighing 40 kg and greater with normal renal function. The use of PEPCID 20 mg and 40 mg tablets is not recommended in pediatric patients weighing less than 40 kg because the lowest available strength (20 mg) exceeds the recommended dose for these patients. Use another famotidine formulation for pediatric patients weighing less than 40 kg.Table 1: Recommended Dosage and Duration of PEPCID Tablets in Adult and Pediatric Patients 40 kg and Greater with Normal Renal FunctionIndicationRecommended DosageRecommended DurationActive duodenal ulcer (DU)40 mg once daily; or 20 mg twice dailyBoth dosages demonstrated effectiveness in clinical trials [see Clinical Studies (14)]. Up to weeksIn clinical trials, the majority of patients healed within weeks. For patients who do not heal after weeks, consider an additional to weeks of treatment [see Clinical Studies (14.1)]. Longer treatment durations have not been studied in clinical trials [see Clinical Studies (14.1, 14.2, 14.3)]. Active gastric ulcer40 mg once dailyUp to weeks Symptomatic nonerosive GERD20 mg twice dailyUp to weeks Erosive esophagitis diagnosed by endoscopy20 mg twice daily; or 40 mg twice dailyUp to 12 weeksPathological hypersecretory conditionsIn pediatric patients, the safety and effectiveness of PEPCID have not been established for the reduction of the risk of duodenal ulcer recurrence or for treatment of pathological hypersecretory conditions [see Use in Specific Populations (8.4)]. Starting dosage: 20 mg every hours; adjust dosage to individual patient needs Maximum dosage 160 mg every hoursAs clinically indicatedReduction of the risk of DU recurrence 20 mg once daily1 year or as clinically indicated.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryAvailable data with H2-receptor antagonists, including famotidine, in pregnant women are insufficient to establish drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse development effects were observed with oral administration of famotidine at doses up to approximately 243 and 122 times, respectively, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis (see Data).The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.DataAnimal DataReproductive 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 intravenous 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 (about 49 times the recommended human dose of 80 mg per day, based on body surface area) 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.. 8.2 Lactation Risk SummaryThere are limited data available on the presence of famotidine in human breast milk. There were no effects on the breastfed infant. There are no data on famotidine effects on milk production. Famotidine is present in the milk of lactating rats (see Data).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for famotidine and any potential adverse effects on the breastfed child from PEPCID or from the underlying maternal condition.DataAnimal DataTransient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of famotidine at least 600 times the usual human dose.. 8.4 Pediatric Use The safety and effectiveness of PEPCID have been established in pediatric patients for the treatment of peptic ulcer disease (i.e., duodenal ulcer, gastric ulcer) and GERD (i.e., symptomatic nonerosive GERD, erosive esophagitis as diagnosed by endoscopy). The use of PEPCID and the recommended dosage of PEPCID in these pediatric patients is supported by evidence from adequate and well-controlled studies of PEPCID in adults and published pharmacokinetic and pharmacodynamic data in pediatric patients [see Dosage and Administration (2.1), Clinical Pharmacology (12.2, 12.3)]. In pediatric patients, the safety and effectiveness for the treatment of pathological hypersecretory conditions and reduction of risk of duodenal ulcer recurrence have not been established.PEPCID 20 and 40 mg tablets are not recommended for use in pediatric patients weighing less than 40 kg because these tablet strengths exceed the recommended dose for these patients [see Dosage and Administration (2.1)]. For pediatric patients weighing less than 40 kg, consider another famotidine formulation (e.g., oral suspension, lower dose tablet).. 8.5 Geriatric Use Of the 1442 PEPCID-treated patients in clinical studies, approximately 10% were 65 and older. In these studies, no overall differences in safety or effectiveness were observed between elderly and younger patients. In postmarketing experience, CNS adverse reactions have been reported in elderly patients with and without renal impairment receiving PEPCID [see Warnings and Precautions (5.1)]. Famotidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to PEPCID may be greater in elderly patients, particularly those with impaired renal function [see Use in Specific Populations (8.6)]. In general, use the lowest effective dose of PEPCID for an elderly patient and monitor renal function [see Dosage and Administration (2.2)]. 8.6 Renal Impairment CNS adverse reactions and prolonged QT intervals have been reported in patients with moderate and severe renal impairment [see Warnings and Precautions (5.1)]. The clearance of famotidine is reduced in adults with moderate and severe renal impairment compared to adults with normal renal function [see Clinical Pharmacology (12.3)]. No dosage adjustment is needed in patients with mild renal impairment (creatinine clearance greater than or equal to 60 mL/minute). Dosage reduction is recommended in adult and pediatric patients greater than or equal to 40 kg with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Dosage and Administration (2.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oCentral Nervous System (CNS) Adverse Reactions: Elderly patients and patients with renal impairment at increased risk; reduce the dosage. (2.2, 5.1, 8.5, 8.6)oGI Malignancy: Absence of GI symptoms does not preclude the presence of gastric malignancy; evaluate prior to initiating therapy. (5.2). oCentral Nervous System (CNS) Adverse Reactions: Elderly patients and patients with renal impairment at increased risk; reduce the dosage. (2.2, 5.1, 8.5, 8.6). oGI Malignancy: Absence of GI symptoms does not preclude the presence of gastric malignancy; evaluate prior to initiating therapy. (5.2). 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 PEPCID. 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 PEPCID does not preclude the presence of gastric malignancy. Consider evaluation for gastric malignancy in adult patients who have suboptimal response or an early symptomatic relapse after completing treatment with PEPCID.