Boxed Warning (Black Box)
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1) ] . Ibu...
IBUPROFEN AND FAMOTIDINE
IBUPROFEN AND FAMOTIDINE
Manufacturer: Aurobindo Pharma Limited
Clinical information
Indications & Usage
1 INDICATIONS AND USAGE Ibuprofen and famotidine tablet, a combination of the NSAID ibuprofen and the histamine H 2 -receptor antagonist famotidine, is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers, which in the clinical trials was defined as a gastric and/or duodenal ulcer, in patients who are taking ibuprofen for those indications. The clinical trials primarily enrolled patients less than 65 years of age without a prior history of gastrointestinal ulcer. Controlled trials do not extend beyond 6 months [see Clinical Studies (14) , Use in Specific Populations (8.5) ] . Ibuprofen and famotidine tablet, a combination of a nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and the histamine H 2 -receptor antagonist famotidine, is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers, which in the clinical trials was defined as a gastric and/or duodenal ulcer, in patients who are taking ibuprofen for those indications. The clinical trials primarily enrolled patients less than 65 years of age without a prior history of gastrointestinal ulcer. Controlled trials do not extend beyond 6 months. ( 1 )
Dosage & Administration
2 DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of ibuprofen and famotidine tablets and other treatment options before deciding to use ibuprofen and famotidine tablets. Use ibuprofen at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ] . The recommended daily dose of ibuprofen and famotidine 800 mg/26.6 mg is a single tablet administered orally three times per day. Ibuprofen and famotidine tablets should be swallowed whole, and should not be cut to supply a lower dose. Do not chew, divide, or crush tablets. Patients should be instructed that if a dose is missed, it should be taken as soon possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. Do not substitute ibuprofen and famotidine tablet with the single-ingredient products of ibuprofen and famotidine. One ibuprofen and famotidine tablet administered orally three times per day. ( 2 ) Use ibuprofen at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2 ) Do not substitute ibuprofen and famotidine tablet with the single-ingredient products of ibuprofen and famotidine. ( 2 )
Contraindications
4 CONTRAINDICATIONS Ibuprofen and famotidine tablets are 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 tablets should not be administered to patients with a history of hypersensitivity to other H 2 -receptor antagonists. Cross sensitivity with other H 2 -receptor antagonists has been observed. Known hypersensitivity to ibuprofen or famotidine or any components of the drug product. ( 4 ) History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. ( 4 ) In the setting of CABG surgery. ( 4 ) Known hypersensitivity to other H 2 -receptor antagonists. ( 4 )
Safety
Adverse Reactions
6 ADVERSE REACTIONS 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) ] Most common adverse reactions (≥1% and greater than ibuprofen alone) are nausea, diarrhea, constipation, upper abdominal pain, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 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 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 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 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 in the two controlled clinical trials. All three patients recovered to baseline levels after discontinuation of ibuprofen and famotidine. 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 * At any point after baseline level ** serum creatinine normal range is 0.5 to 1.4 mg/dL or 44 to 124 micromol/L *** serum creatinine >1.4 mg/dL Study 301 Study 303 Baseline Post-Baseline* Ibuprofen and famotidine N=414 % (n) Ibuprofen N=207 % (n) Ibuprofen and famotidine N=598 % (n) Ibuprofen N=296 % (n) Normal** Abnormal*** 4% (17) 2% (4) 2%(15) 4% (12) 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 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 and ibuprofen alone were similar. The most common adverse reactions leading to discontinuation from ibuprofen and famotidine 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 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 Skin and Appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE) 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
Drug Interactions
7 DRUG INTERACTIONS 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 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 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 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 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 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 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 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 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 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 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 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 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 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. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine. See full prescribing information for a list of clinically important drug interactions. ( 7 )
Additional information
Description
11 DESCRIPTION Ibuprofen and famotidine tablets are supplied as a tablet for oral administration which combines the nonsteroidal anti-inflammatory drug, ibuprofen, and the histamine H 2 -receptor antagonist, famotidine. Ibuprofen, USP is (±)-2-( p- isobutylphenyl)propionic acid. Its chemical formula is C 13 H 18 O 2 and molecular weight is 206.28. Ibuprofen, USP is a white to off-white, crystalline powder, having a slight, characteristic odor, that is very soluble in alcohol, in methanol, in acetone and in chloroform; slightly soluble in ethyl acetate and practically insoluble in water. Its structural formula is: Famotidine, USP is N'- (aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. Its chemical formula is C 8 H 15 N 7 O 2 S 3 and molecular weight is 337.45. Famotidine, USP is a white to pale yellowish white crystalline powder that is freely soluble in dimethyl formamide, glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, practically insoluble in acetone, in alcohol, in chloroform, in ether and in ethyl acetate. Its structural formula is: Each ibuprofen and famotidine tablet contains ibuprofen, USP (800 mg) and famotidine, USP (26.6 mg). The inactive ingredients in ibuprofen and famotidine tablets include: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, palmitic acid, polyethylene glycol, polysorbate 80, polyvinyl alcohol, povidone, stearic acid, talc and titanium dioxide. The imprinting ink contains black iron oxide, propylene glycol and shellac glaze in ethanol. Chemical Structure Chemical Structure
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Ibuprofen and famotidine tablets, 800 mg/26.6 mg, are white in color, biconvex, oval shaped film-coated tablet with slight blister surface, imprinted with “G3” on one side and plain on the other side and supplied as: Bottle of 90 tablets NDC 59651-908-90 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
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Frequently Asked Questions
What is ibuprofen and famotidine used for?+
Ibuprofen and famotidine is used for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as to decrease the risk of developing upper gastrointestinal ulcers. It combines the pain-relieving properties of ibuprofen with the stomach-protecting properties of famotidine. Consult a doctor to determine if this medication is right for your specific condition.
How long does it take for ibuprofen and famotidine to start working?+
Ibuprofen and famotidine can start to relieve pain and reduce inflammation within a few hours of taking the medication. However, it may take several days to a week to experience the full effects of the medication. Consult a doctor if you have any questions or concerns about the effectiveness of the medication.
Can I take ibuprofen and famotidine with other medications?+
It is generally not recommended to take ibuprofen and famotidine with other medications, such as blood thinners or other NSAIDs, without consulting a doctor first. Combining medications can increase the risk of side effects or interactions. Consult a doctor to determine if it is safe to take ibuprofen and famotidine with your other medications.
What are the common side effects of ibuprofen and famotidine?+
Common side effects of ibuprofen and famotidine include stomach upset, nausea, and diarrhea. More serious side effects can include stomach ulcers, kidney damage, and increased risk of heart attack or stroke. Consult a doctor if you experience any side effects or have concerns about the safety of the medication.
Can I stop taking ibuprofen and famotidine if my symptoms improve?+
It is generally not recommended to stop taking ibuprofen and famotidine without consulting a doctor first, even if your symptoms improve. Stopping the medication abruptly can cause a rebound effect, where your symptoms return or worsen. Consult a doctor to determine the best course of treatment and when it is safe to stop taking the medication.
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