Famotidine

INDICATIONS AND USAGE Famotidine Injection is supplied as a premixed solution in GALAXY plastic containers and is intended for intravenous use only. Famotidine Injection is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for short term use in patients who are unable to take oral medication for the following conditions: 1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks. 2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled studies in adults have not extended beyond one year. 3. 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. 4. Short term treatment of gastroesophageal reflux disease (GERD). Famotidine is indicated for short term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ). Famotidine 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 ). 5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ).

DOSAGE AND ADMINISTRATION Recommended adult dosage by indication (2.1) : Active DU 40 mg once daily; or 20 mg twice daily Active GU 40 mg once daily Symptomatic Nonerosive GERD 20 mg twice daily Erosive Esophagitis due to GERD 20 mg twice daily; or 40 mg twice daily Pathological Hypersecretory Conditions 20 mg every 6 hours; adjust to patient needs; maximum 160 mg every 6 hours Risk Reduction of DU Recurrence 20 mg once daily Recommended pediatric dosage by indication (2.2) : Peptic Ulcer Disease 1 year to less than 17 years Starting dosage 0.5 mg/kg once daily; or 0.25 mg/kg twice daily; may increase to 1 mg/kg once daily at bedtime or 0.5 mg/kg twice daily; Maximum of 40 mg per day GERD Birth to less than 3 months Starting dosage 0.5 mg/kg once daily; may increase to 1 mg/kg once daily 3 months to less than 1 year Starting dosage 0.5 mg/kg twice daily; may increase to 1 mg/kg twice daily; Maximum of 40 mg per day GERD with or without esophagitis and ulcerations 1 year to less than 17 years 0.5 mg/kg twice daily Maximum of 40 mg twice daily See full prescribing information for complete dosing information in adults and pediatrics, recommended treatment duration by indication, and dosage adjustment for adult patients with renal impairment. (2.1 , 2.2 , 2.3) Administration (2.3) : Take once daily before bedtime or twice daily in the morning and before bedtime with or without food. 2.1 Recommended Dosage in Adults The recommended dosage and duration of Famotidine for oral suspension in adults with normal renal function is shown in Table 1. Table 1: Recommended Dosage and Duration of Famotidine for Oral Suspension a in Adults with Normal Renal Function Indication Recommended Dosage Recommended Duration Active DU 40 mg once daily; or 20 mg twice daily b Up to 8 weeks c,d Active GU 40 mg once daily Up to 8 weeks d Symptomatic nonerosive GERD 20 mg twice daily Up to 6 weeks d Erosive esophagitis due to GERD, diagnosed by endoscopy 20 mg twice daily; or 40 mg twice daily b Up to 12 weeks Pathological hypersecretory conditions Starting dosage: 20 mg every 6 hours; adjust dosage to individual patient needs Maximum dosage 160 mg every 6 hours As clinically indicated Reduction of the risk of DU recurrence 20 mg once daily 1 year c,d or as clinically indicated a After preparation, the concentration of famotidine oral suspension is 8 mg/mL [see DOSAGE AND ADMINISTRATION (2.3) ] b Both dosages demonstrated effectiveness in clinical trials [see CLINICAL STUDIES (14) ]. c In clinical trials, the majority of patients healed within 4 weeks. For patients who do not heal after 4 weeks, consider an additional 2 to 4 weeks of treatment [see CLINICAL STUDIES (14.1) ]. d Longer treatment durations have not been studied in clinical trials [see CLINICAL STUDIES (14.1 , 14.2 , 14.3) ]. 2.2 Recommended Dosage in Pediatric Patients The recommended dosage and duration of famotidine for oral suspension in pediatric patients with normal renal function is shown in Table 2. Table 2: Recommended Dosage and Duration of Famotidine for Oral Suspension a in Pediatric Patients with Normal Renal Function Indication Pediatric Age Range Recommended Dosage a Duration Peptic Ulcer Disease 1 year to less than 17 years Starting dosage 0.5 mg/kg once daily; or 0.25 mg/kg twice daily. May increase to 1 mg/kg once daily at bedtime or 0.5 mg/ kg twice daily Maximum of 40 mg per day 8 weeks b GERD Birth to less than 3 months Starting dosage 0.5 mg/kg once daily. May increase to 1 mg/kg once daily b Up to 8 weeks b,c,d 3 months to less than 1 year Starting dosage 0.5 mg/kg twice daily. May increase to 1 mg/kg twice daily c Maximum of 40 mg per day GERD with or without esophagitis and ulcerations 1 year to less than 17 years 0.5 mg/kg twice daily Maximum of 40 mg twice daily 6 to 12 weeks b a After preparation, the concentration of famotidine oral suspension is 8 mg/mL [see DOSAGE AND ADMINISTRATION (2.3) ] b Treatment duration based on adult recommendations (see Table 1). Individualize the dose and duration based upon clinical response an/or pH determinations (gastric or esophageal) and endoscopy. c Use conservative measures (e.g., thickened feedings) concurrently [see USE IN SPECIFIC POPULATIONS (8.4) ]. d After 4 weeks of treatment re-evaluate the patient. Consider an additional 4 weeks of treatment if treatment benefit outweighs potential risks. 2.3 Recommended Dosage in Adults with Renal Impairment Recommended dosage adjustments for adults with moderate to severe renal impairment (creatinine clearance less than 60 mL/min) by indication are shown in Table 3. Use the lowest effective dosage [see USE IN SPECIFIC POPULATIONS (8.6) ]. A safe and effective dosage has not been established in pediatric patients with renal impairment. Table 3: Recommended Maximum Dosage of Famotidine for Oral Suspension in Adults with Moderate and Severe Renal Impairment Indication Recommended Maximum Dosages Creatinine clearance 30 to 60 mL/minute Creatinine clearance less than 30 mL/minute Active DU 20 mg once daily; or 40 mg every other day 10 mg once daily; or 20 mg every other day Active GU 20 mg once daily; or 40 mg every other day 10 mg once daily; or 20 mg every other day Symptomatic nonerosive GERD 20 mg once daily 10 mg once daily; or 20 mg every other day Erosive esophagitis due to GERD, diagnosed by endoscopy a 20 mg once daily; or 40 mg every other day b 40 mg once daily b 10 mg once daily; or 20 mg every other day b 20 mg once daily b Pathological hypersecretory conditions Avoid use b Reduction of the risk of DU recurrence 10 mg once daily; or 20 mg every other day 10 mg every other day a Dosage 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)]. b The dosage required to treat pathological hypersecretory conditions may exceed the maximum dosage evaluated in patients with impaired renal function. The risk for increased adverse reactions in renally impaired patients treated with famotidine for oral suspension for pathological hypersecretory conditions is unknown. 2.4 Administration Instructions Preparation of Constituted Suspension by a Healthcare Provider Prior to Dispensing Prior to dispensing, constitute famotidine for oral suspension by slowly adding 46 mL of Purified Water to the bottle. Shake vigorously for 5 to 10 seconds immediately after adding the water. The constituted suspension contains 40 mg of famotidine per 5 mL, and should be a smooth, mobile, white to off-white, and homogeneous suspension. Administration and Storage of Constituted Suspension Shake the bottle of constituted famotidine for oral suspension vigorously for 5 to 10 seconds prior to each use. Take famotidine for oral suspension once daily before bedtime or twice daily in the morning and before bedtime, as recommended. Famotidine for oral suspension may be taken with or without food [see CLINICAL PHARMACOLOGY (12.3) ] . Famotidine for oral suspension may be given with antacids. Store the constituted suspension at 25°C (77°F). Protect from freezing. Discard unused constituted suspension after 30 days. 2.1 Recommended Dosage in Adults The recommended dosage and duration of Famotidine for oral suspension in adults with normal renal function is shown in Table 1. Table 1: Recommended Dosage and Duration of Famotidine for Oral Suspension a in Adults with Normal Renal Function Indication Recommended Dosage Recommended Duration Active DU 40 mg once daily; or 20 mg twice daily b Up to 8 weeks c,d Active GU 40 mg once daily Up to 8 weeks d Symptomatic nonerosive GERD 20 mg twice daily Up to 6 weeks d Erosive esophagitis due to GERD, diagnosed by endoscopy 20 mg twice daily; or 40 mg twice daily b Up to 12 weeks Pathological hypersecretory conditions Starting dosage: 20 mg every 6 hours; adjust dosage to individual patient needs Maximum dosage 160 mg every 6 hours As cl

Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDS. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal GI events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ibuprofen and famotidine tablet in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ibuprofen and famotidine tablet is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDS. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ibuprofen and famotidine tablet until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Active Bleeding When active and clinically significant bleeding from any source occurs in patients receiving ibuprofen and famotidine tablet, the treatment should be withdrawn. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. 5.4 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including ibuprofen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ibuprofen and famotidine tablet immediately, and perform a clinical evaluation of the patient. 5.5 Hypertension NSAIDs, including ibuprofen and famotidine tablet, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.6 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors,

Ibuprofen and famotidine tablet is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or famotidine or any components of the drug product [see Warnings and Precautions (5.8, 5.11)]. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.8, 5.10)]. In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. Ibuprofen and famotidine tablet should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists. Cross sensitivity with other H2-receptor antagonists has been observed.

See Table 3 for clinically significant drug interactions with ibuprofen. Table 3: Clinically Significant Drug Interactions with Ibuprofen and Famotidine Drugs That Interfere with Hemostasis Clinical Impact: Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ibuprofen and famotidine tablet with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.16)]. Aspirin Clinical Impact: Pharmacodynamic (PD) studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric-coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once-daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology (12.2)]. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. Concomitant use of ibuprofen and famotidine tablet and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.3)]. Ibuprofen and famotidine tablet is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of ibuprofen and famotidine tablet and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of ibuprofen and famotidine tablet and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.7)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ibuprofen and famotidine tablet with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.7)]. Digoxin Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ibuprofen and famotidine tablet and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ibuprofen and famotidine tablet and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ibuprofen and famotidine tablet and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of ibuprofen and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of ibuprofen and famotidine tablet and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of ibuprofen and famotidine tablet with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of ibuprofen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of ibuprofen and famotidine tablet and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between permetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Drugs Dependent on Gastric pH for Absorption Clinical Impact Because famotidine lowers intra-gastric acidity, this may result in reduced absorption and loss of efficacy of concomitant drugs. Intervention Concomitant administration of ibuprofen and famotidine tablet is not recommended with dasatinib, delavirdine mesylate, cefditoren, and fosamprenavir. For administration instructions of other drugs whose absorption is dependent on gastric pH, refer to their prescribing information (e.g., atazanavir, erlotinib, ketoconazole, itraconazole, nilotinib, ledipasvir/sofosbuvir, and rilpivirine). Tizanidine (CYP1A2 Substrate) Clinical Impact Famotidine is considered a weak CYP1A2 inhibitor and may lead to substantial increases in blood concentrations of tizanidine, a CYP1A2 substrate. Intervention Avoid concomitant use with ibuprofen and famotidine tablet. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] Hepatotoxicity [see Warnings and Precautions (5.4)] Hypertension [see Warnings and Precautions (5.5)] Heart Failure and Edema [see Warnings and Precautions (5.6)] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.7)] Anaphylactic Reactions [see Warnings and Precautions (5.8)] Seizures [see Warnings and Precautions (5.9)] Serious Skin Reactions [see Warnings and Precautions (5.11)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.12)] Fetal Toxicity [see Warnings and Precautions (5.13)] Hematologic Toxicity [see Warnings and Precautions (5.14)] Aseptic Meningitis [see Warnings and Precautions (5.18)] Ophthalmological Effects [see Warnings and Precautions (5.19)] 6.1 Clinical Trials 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. The safety of ibuprofen and famotidine tablet was evaluated in 1022 patients in controlled clinical studies, including 508 patients treated for at least 6 months and 107 patients treated for approximately 1 year. Patients treated with ibuprofen and famotidine tablet ranged in age from 39 to 80 years (median age 55 years), with 67% female, 79% Caucasian, 18% African-American, and 3% other races. Two randomized, active-controlled clinical studies (Study 301 and Study 303) were conducted for the reduction of the risk of development of ibuprofen-associated, upper gastrointestinal ulcers in patients who required use of ibuprofen, which included 1022 patients on ibuprofen and famotidine tablet and 511 patients on ibuprofen alone. Approximately 15% of patients were on low-dose aspirin. Patients were assigned randomly, in a 2:1 ratio, to treatment with either ibuprofen and famotidine tablet or ibuprofen 800 mg three times a day for 24 consecutive weeks. Three serious cases of acute renal failure were observed in patients treated with ibuprofen and famotidine tablet in the two controlled clinical trials. All three patients recovered to baseline levels after discontinuation of ibuprofen and famotidine tablet. Additionally, increases in serum creatinine were observed in both treatment arms in the two clinical studies. Many of these patients were taking concomitant diuretics and/or angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. There were patients with a normal baseline serum creatinine level who developed abnormal values in the controlled trials as presented in Table 1. Table 1: Shift Table of Serum Creatinine, Normal** to Abnormal*** in Controlled Studies Study 301 Study 303 Baseline Post-Baseline* Ibuprofen and famotidine tablet N=414 % (n) Ibuprofen N=207 % (n) Ibuprofen and famotidine tablet N=598 % (n) Ibuprofen N=296 % (n) Normal** Abnormal*** 4% (17) 2% (4) 2%(15) 4% (12) *At any point after baseline level **serum creatinine normal range is 0.5 – 1.4 mg/dL or 44-124 micromol/L *** serum creatinine >1.4 mg/dL Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%), from pooled data from the two controlled studies are presented in Table 2. Table 2: Incidence of Adverse Reactions in Controlled Studies Ibuprofen and famotidine tablet N=1022 Ibuprofen N=511 % % Blood and lymphatic system disorders Anemia 2 1 Gastrointestinal disorders Nausea 6 5 Dyspepsia 5 8 Diarrhea 5 4 Constipation 4 4 Abdominal pain upper 3 3 Gastroesophageal reflux disease 2 3 Vomiting 2 2 Stomach discomfort 2 2 Abdominal pain 2 2 General disorders and administration site conditions Edema peripheral 2 2 Infections and infestations Upper respiratory tract infection 4 4 Nasopharyngitis 2 3 Sinusitis 2 3 Bronchitis 2 1 Urinary tract infection 2 2 Influenza 2 2 Musculoskeletal and connective tissue disorders Arthralgia 1 2 Back pain 2 1 Nervous system disorders Headache 3 3 Respiratory, thoracic and mediastinal disorders Cough 2 2 Pharyngolaryngeal pain 2 1 Vascular disorders Hypertension 3 2 In controlled clinical studies, the discontinuation rate due to adverse events for patients receiving ibuprofen and famotidine tablet and ibuprofen alone were similar. The most common adverse reactions leading to discontinuation from ibuprofen and famotidine tablet therapy were nausea (0.9%) and upper abdominal pain (0.9%). There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment. 6.2 Postmarketing Experience Ibuprofen Skin and Appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). The following adverse reactions have been identified during post-approval use of ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Cardiac disorders: myocardial infarction Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain General disorders and administration site conditions: pyrexia, pain, fatigue, asthenia, chest pain, drug ineffective, edema peripheral Musculoskeletal and connective tissue disorders: arthralgia Nervous system disorders: headache, dizziness Psychiatric disorders: depression, anxiety Renal and urinary disorders: renal failure acute Respiratory, thoracic, and mediastinal disorders: dyspnea Vascular disorders: hypertension Famotidine The following adverse reactions have been identified during post-approval use of famotidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Blood and lymphatic system disorders: anemia, thrombocytopenia Gastrointestinal disorders: nausea, diarrhea, vomiting, abdominal pain General disorders and administration site conditions: pyrexia, condition aggravated, asthenia, drug ineffective, chest pain, fatigue, pain, edema peripheral Hepatobiliary disorders: hepatic function abnormal Infections and infestations: pneumonia, sepsis Investigations: platelet count decreased, aspartate aminotransferase increased, alanine aminotransferase increased, hemoglobin decreased Metabolism and nutrition disorders: decreased appetite Nervous system disorders: dizziness, headache Respiratory, thoracic, and mediastinal disorders: dyspnea Vascular disorders: hypotension

CLINICAL PHARMACOLOGY IN ADULTS GI Effects Famotidine is a competitive inhibitor of histamine H 2 -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. In normal volunteers and hypersecretors, famotidine 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 mg and 40 mg was 10 to 12 hours. After intravenous administration, the maximum effect was achieved within 30 minutes. Single intravenous doses of 10 mg and 20 mg inhibited nocturnal secretion for a period of 10 to 12 hours. The 20 mg dose was associated with the longest duration of action in most subjects. Single evening oral doses of 20 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 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 was raised to about 5. Famotidine had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by famotidine. Other Effects Systemic effects of famotidine in the central nervous system (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 (T 4 ) and testosterone, were not altered after treatment with famotidine. Pharmacokinetics Orally administered famotidine is incompletely absorbed, and its bioavailability is 40 to 45%. Famotidine undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1 to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of famotidine in plasma is protein bound. Famotidine has an elimination half-life of 2.5 to 3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 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 famotidine. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of famotidine 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 famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use ). Clinical Studies The majority of clinical study experience involved oral administration of famotidine tablets, and is provided herein for reference. Duodenal Ulcer In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered famotidine was compared to placebo. As shown in Table 1, 70% of patients treated with famotidine 40 mg h.s. were healed by week 4. Table 1 Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers Famotidine 40 mg h.s. (N=89) Famotidine 20 mg b.i.d. (N=84) Placebo h.s. (N=97) Week 2 Statistically significantly different than placebo (p < 0.001) 32% 38% 17% Week 4 70% 67% 31% Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with famotidine had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with famotidine 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 famotidine than for patients receiving placebo; patients receiving famotidine also took less antacid than the patients receiving placebo. Long-Term Maintenance Treatment of Duodenal Ulcers Famotidine, 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 famotidine. The 89 patients treated with famotidine 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 famotidine 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 famotidine, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during the studies, but consumption was not significantly different between the famotidine and placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with famotidine 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 Famotidine 40 mg h.s. (N=74) Placebo h.s. (N=75) Famotidine 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 famotidine 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 famotidine 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. Famotidine 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 Famotidine 20 mg b.i.d. (N=154) Famotidine 40 mg h.s. (N=149) Placebo (N=73) Wee