FAMOTIDINE Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
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 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. See full prescribing information for a list of clinically important drug interactions. ( 7 )
Contraindications
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 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 )
Related Warnings
AND PRECAUTIONS Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.4 ) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. ( 5.5 , 7 )
Heart
Failure and Edema: Avoid use of ibuprofen and famotidine tablets in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. ( 5.6 )
Active
Bleeding: Active and clinically significant bleeding from any source can occur; discontinue ibuprofen and famotidine tablets if active bleeding occurs. ( 5.3 )
Renal
Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration or hypovolemia. Avoid use of ibuprofen and famotidine tablets in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. ( 5.7 )
Anaphylactic
Reactions: Seek emergency help if an anaphylactic reaction occurs. ( 5.8 ) Exacerbation of Asthma Related to Aspirin Sensitivity: Ibuprofen and famotidine tablets are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin-sensitivity). ( 5.10 )
Serious Skin
Reactions: Discontinue ibuprofen and famotidine tablets at first appearance of skin rash or other signs of hypersensitivity ( 5.11 ).
Drug
Reaction with Eosinophilia and Systematic Symptoms (DRESS): Discontinue and evaluate clinically ( 5.12 ).
Fetal
Toxicity: Limit use of NSAIDs, including Ibuprofen and famotidine tablets, between about 20 weeks to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 5.13 , 8.1 )
Hematologic
Toxicity: Monitor hemoglobin or hematocrit in patient with any signs or symptoms of anemia. ( 5.14 )
5.1 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>.
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 days to 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 tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ibuprofen and famotidine tablets are 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 months to 6 months and in about 2% to 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 tablets 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 tablets, 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 tablets immediately and perform a clinical evaluation of the patient.
5.5 Hypertension NSAIDs, including ibuprofen and famotidine tablets, 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. 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 or angiotensin receptor blockers [ARBs]) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. Avoid the use of ibuprofen and famotidine tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ibuprofen and famotidine tablets are used in patients with severe heart failure, monitor patients for signs and symptoms of worsening heart failure.
5.7 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of ibuprofen and famotidine tablets in patients with advanced renal disease. The renal effects of ibuprofen and famotidine tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating ibuprofen and famotidine tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration or hypovolemia during use of ibuprofen and famotidine tablets <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. Avoid the use of ibuprofen and famotidine tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If ibuprofen and famotidine tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
5.8 Anaphylactic Reactions Ibuprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.8 )]</span>. Seek emergency help if an anaphylactic reaction occurs.
5.9 Seizures Central nervous system (CNS) adverse effects including seizures, delirium and coma have been reported with famotidine in patients with moderate (creatinine clearance < 50 mL/min) and severe renal insufficiency (creatinine clearance < 10 mL/min) and the dosage of the famotidine component in ibuprofen and famotidine tablets is fixed. Therefore, ibuprofen and famotidine tablets are not recommended in patients with creatinine clearance < 50 mL/min.
5.10 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ibuprofen and famotidine tablets are contraindicated in patients with this form of aspirin sensitivity <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . When ibuprofen and famotidine tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.11 Serious Skin Reactions NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of ibuprofen and famotidine tablets at the first appearance of skin rash or any other sign of hypersensitivity. Ibuprofen and famotidine tablets are contraindicated in patients with previous serious skin reactions to NSAIDs <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.
5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen and famotidine tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ibuprofen and famotidine tablets and evaluate the patient immediately.
5.13 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including ibuprofen and famotidine tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including ibuprofen and famotidine tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal
Renal Impairment Use of NSAIDs, including ibuprofen and famotidine tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ibuprofen and famotidine tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ibuprofen and famotidine tablets treatment is needed for a pregnant woman. Discontinue ibuprofen and famotidine tablets if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations ( 8.1 )].