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Ibuprofen and Famotidine Tablet

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


Cardiovascular Risk

  • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

  • Ibuprofen is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk

  • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

 

1. DESCRIPTION

Ibuprofen and famotidine tablet for oral administration combines the nonsteroidal anti-inflammatory agent, ibuprofen, and the histamine H2-receptor antagonist, famotidine.

Ibuprofen is a nonsteroidal anti-inflammatory agent. Chemically, it is (±) - 2 - (p - isobutylphenyl) propionic acid. The structural formula is represented below:

Ibuprofen: Molecular formula: C13H18O2 - Molecular weight: 206.28

Ibuprofen is a white powder with a melting point of 74-77˚ C and is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone.

Famotidine is histamine H2-receptor antagonist. Chemically, it is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. The structural formula is:

Famotidine: Molecular formula: C8H15N7O2S3 - Molecular weight: 337.45

Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.

Each ibuprofen and famotidine tablet contains ibuprofen, USP (800 mg) and famotidine, USP (26.6 mg) and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, purified water, povidone, titanium dioxide, polyethylene glycol, polysorbate 80, polyvinyl alcohol, hypromellose, talc, FD&C Blue #2/Indigo Carmine Aluminum Lake, and FD&C Blue #1/Brilliant Blue FCF Aluminum Lake.

2. INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ibuprofen and famotidine and other treatment options before deciding to use ibuprofen and famotidine tablet. Use the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions, Drug Interactions and Use in Specific Populations].

Ibuprofen and famotidine tablet, a combination of the NSAID ibuprofen and the histamine H2-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 Use in Specific Populations].

3. DOSAGE AND ADMINISTRATION

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.

4. CONTRAINDICATIONS

• Ibuprofen and famotidine should not be given to patients who have experienced asthma, urticaria, or allergic reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylaxis with NSAIDs have been reported in such patients [see Warnings and Precautions and Drug Interactions].

• Ibuprofen and famotidine is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions].

• Ibuprofen and famotidine is contraindicated in patients in late stages of pregnancy [see Warnings and Precautions].

• Ibuprofen and famotidine 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.

5. MECHANISM OF ACTION

Ibuprofen and famotidine is fixed-combination tablet of ibuprofen and famotidine

Ibuprofen possesses analgesic and antipyretic activities. Its mode of action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.

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

Systemic effects of famotidine in the CNS, cardiovascular, respiratory, or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with ibuprofen and famotidine. Reproductive studies conducted with ibuprofen in rats and rabbits have not demonstrated evidence of developmental abnormalities. Reproductive studies with famotidine have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day (approximately 243 and 122 times the recommended human dose, respectively, based on body surface area) and in both species at intravenous (I.V.) doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (approximately 49 times the recommended human dose based on body surface area) or higher. There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. Ibuprofen and famotidine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided [see Warnings and Precautions].

6.2 Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of ibuprofen and famotidine on labor and delivery in pregnant women are unknown.

6.3 Nursing Mothers

It is not known whether ibuprofen is excreted in human milk.

Famotidine is secreted into breast milk of lactating rats. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 300 times the usual human dose of famotidine. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from ibuprofen and famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

6.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

6.5 Geriatric Use

The clinical trials primarily enrolled patients less than 65 years of age. Of the 1022 subjects in clinical studies of ibuprofen and famotidine, 18% (249 subjects) were 65 years of age or older.

Famotidine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and adjusting dose interval, and it may be useful to monitor renal function [see Warnings and Precautions].

As with any NSAIDs, caution should be exercised in treating the elderly (65 years old and older). Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of NSAIDs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions].

Ibuprofen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of NSAIDs [see Warnings and Precautions].

6.6 Renal Insufficiency

In adult patients with renal insufficiency (creatinine clearance < 50 mL/min), the elimination half-life of famotidine is increased. Since CNS adverse effects have been reported in patients with creatinine clearance < 50 mL/min and the dosage of the famotidine component in ibuprofen and famotidine tablet is fixed, ibuprofen and famotidine tablet is not recommended in these patients [see Warnings and Precautions].

7. WARNINGS AND PRECAUTIONS

7.1 Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets, of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events [see Warnings and Precautions].

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 [see Contraindications].

7.2 Hypertension

NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ibuprofen and famotidine tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy [see Drug Interactions].

7.3 Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Ibuprofen and famotidine tablets should be used with caution in patients with fluid retention or heart failure.

7.4 Risk of Gastrointestinal Ulceration, Bleeding, and Perforation

NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets, can cause serious gastrointestinal (GI) adverse reactions including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse reactions 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 occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for 1 year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs, including ibuprofen and famotidine tablets, should be prescribed with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs, including ibuprofen and famotidine tablets, include concomitant use of oral corticosteroids, anticoagulants, antiplatelet drugs (including low-dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI reactions are in elderly or debilitated patients, and, therefore, special care should be taken in treating this population with ibuprofen and famotidine tablets.

To minimize the potential risk for an adverse GI reaction in patients treated with an NSAID, the shortest possible duration should be used. Patients and physicians should remain alert for signs and symptoms of GI ulcers and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. This should include discontinuation of the NSAID until a serious GI adverse reaction is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of concurrent use of an NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding [see Drug Interactions]. Although these studies focused on upper gastrointestinal bleeding, bleeding at other sites cannot be ruled out.

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.

Because serious GI tract ulcers and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their complete blood count (CBC) and chemistry profile checked periodically.

Symptomatic response to therapy with ibuprofen and famotidine tablets does not preclude the presence of gastric malignancy.

7.5 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.

7.6 Renal Injury

Long-term administration of NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets, 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, heart failure, liver dysfunction, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors, and the elderly. If clinical signs (e.g., azotemia, hypertension, and/or proteinuria) and symptoms consistent with renal disease develop, ibuprofen and famotidine tablets should be discontinued. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state [see Adverse Reactions and Use in Specific Populations].

7.7 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 tablet is not recommended in patients with creatinine clearance < 50 mL/min.

7.8 Anaphylaxis

Anaphylaxis may occur in patients without known prior exposure to ibuprofen, which is a component of ibuprofen and famotidine tablets. Ibuprofen and famotidine should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications and Warnings and Precautions]. Emergency help should be sought in cases where anaphylaxis, which may have a fatal outcome, occurs.

7.9 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. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications and Adverse Reactions].

7.10 Pregnancy

Starting at 30 weeks gestation, ibuprofen and famotidine tablets should be avoided by pregnant women because it may cause premature closure of the ductus arteriosus [see Contraindications and Use in Specific Population].

7.11 Hepatic Injury

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ibuprofen, which is a component of ibuprofen and famotidine tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen and famotidine tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ibuprofen and famotidine tablets should be discontinued.

7.12 Anemia

Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen which is a component of ibuprofen and famotidine tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ibuprofen and famotidine tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

7.13 Inhibition of Platelet Aggregation

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ibuprofen and famotidine tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

7.14 Pre-existing Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and NSAIDs has been reported in such aspirin-sensitive patients, ibuprofen and famotidine tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

7.15 Concomitant NSAID Use

Ibuprofen and famotidine tablet contains ibuprofen as one of its active ingredients. It should not be used with other ibuprofen-containing products.

The concomitant use of NSAIDs, including aspirin, with ibuprofen and famotidine tablets may increase the risk of adverse events [see Adverse Reactions, Drug Interactions].

7.16 Aseptic Meningitis

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen, which is a component of ibuprofen and famotidine tablets. Although it is probably more likely to occur in patients with systemic lupus erythematosus (SLE) and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on ibuprofen and famotidine tablets, the possibility of its being related to ibuprofen should be considered.

7.17 Corticosteroid Treatment

Ibuprofen and famotidine tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

7.18 Masking of Inflammation and Fever

The pharmacological activity of ibuprofen and famotidine tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.

7.19 Visual Disturbances

Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving ibuprofen and famotidine tablets, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.

8. ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular events [see Boxed Warning and Warnings and Precautions]

• Gastrointestinal effects [see Boxed Warning and Warnings and Precautions]

• Renal injury [see Warnings and Precautions]

• Seizures [see Warnings and Precautions]

• Anaphylaxis [see Warnings and Precautions]

• Skin reactions [see Warnings and Precautions]

• Corticosteroid treatment [see Warnings and Precautions]

• Masking of inflammation and fever [see Warnings and Precautions]

• Hepatic injury [see Warnings and Precautions]

• Hematological effects [see Warnings and Precautions]

• Pre-existing asthma [see Warnings and Precautions]

• Aseptic meningitis [see Warnings and Precautions]

8.1 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets in the two controlled clinical trials. All three patients recovered to baseline levels after discontinuation of ibuprofen and famotidine tablets. 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 – 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 tablets 800 mg/26.6 mg administered orally three times per day.

Ibuprofen 800 mg administered orally three times per day.

In controlled clinical studies, the discontinuation rate due to adverse events for patients receiving ibuprofen and famotidine tablets 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.

8.2 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

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: hyoptension

9. OVERDOSAGE

No data are available with regard to overdose of ibuprofen and famotidine tablets. Findings related to the individual active substances are listed below.

Ibuprofen

Approximately 1 1/2 hours after the reported ingestion of from 7 to 10 ibuprofen tablets (400 mg), a 19-month-old child weighing 12 kg was seen in the hospital emergency room, apneic and cyanotic, responding only to painful stimuli. This type of stimulus, however, was sufficient to induce respiration. Oxygen and parenteral fluids were given; a greenish-yellow fluid was aspirated from the stomach with no evidence to indicate the presence of ibuprofen. Two hours after ingestion the child's condition seemed stable; she still responded only to painful stimuli and continued to have periods of apnea lasting from 5 to 10 seconds. She was admitted to intensive care and sodium bicarbonate was administered as well as infusions of dextrose and normal saline. By 4 hours post-ingestion she could be aroused easily, sit by herself, and respond to spoken commands. Blood level of ibuprofen was 102.9 μg/mL approximately 8.5 hours after accidental ingestion. At 12 hours she appeared to be completely recovered.

In two other reported cases where children (each weighing approximately 10 kg) accidentally, acutely ingested approximately 120 mg/kg, there were no signs of acute intoxication or late sequelae. Blood level in one child 90 minutes after ingestion was 700 μg/mL — about 10 times the peak levels seen in absorption-excretion studies.

A 19-year-old male who had taken 8,000 mg of ibuprofen over a period of a few hours complained of dizziness, and nystagmus was noted. After hospitalization, parenteral hydration and 3 days bed rest, he recovered with no reported sequelae.

In cases of acute overdosage, the stomach should be emptied by vomiting or lavage, though little drug will likely be recovered if more than 1 hour has elapsed since ingestion. Because the drug is acidic and is excreted in the urine, it is theoretically beneficial to administer alkali and induce diuresis. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption and reabsorption of ibuprofen tablets.

Famotidine

The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience. Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the GI tract, the patient should be monitored, and supportive therapy should be employed.

10. DRUG INTERACTIONS

Co-administration of ibuprofen (800 mg) and famotidine (40 mg) increased ibuprofen Cmax by 15.6% but did not affect its AUC, and increased famotidine AUC and Cmax by 16% and 22%, respectively.

Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested, and no significant effects have been found.

10.1 Warfarin-Type Anticoagulants

Several short-term controlled studies failed to show that ibuprofen significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, because bleeding has been reported when ibuprofen and other NSAIDs have been administered to patients on coumarin-type anticoagulants, prescribers should be cautious when administering ibuprofen to patients on anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone [see Warnings and Precautions].

10.2 Aspirin

When ibuprofen, which is a component of ibuprofen and famotidine tablets, is administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen is not altered. The clinical significance of this interaction is not known. As with other NSAIDs, the concurrent use of aspirin and ibuprofen and famotidine tablets may increase the risk of adverse events [see Warnings and Precautions, Adverse Reactions].

10.3 ACE-Inhibitors

Reports suggest that ibuprofen, a component of ibuprofen and famotidine tablets, may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking ibuprofen and famotidine tablets concomitantly with ACE-inhibitors. During concomitant therapy with ibuprofen and famotidine tablets, the patient should be observed closely for signs of renal failure [see Warnings and Precautions].

10.4 Diuretics

Clinical studies, as well as postmarketing observations, have shown that ibuprofen, which is a component of ibuprofen and famotidine tablets, can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with ibuprofen and famotidine tablets, the patient should be observed closely for signs of renal failure [see Warnings and Precautions], as well as to assure diuretic efficacy.

10.5 Lithium

Ibuprofen, which is a component of ibuprofen and famotidine tablets, produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of 11 normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 20% during this period of concomitant ibuprofen drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

10.6 Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

10.7 Selective Serotonin Reuptake Inhibitors (SSRIs)

There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs including COX-2 selective inhibitors. Caution should be used when NSAIDs are administered concomitantly with SSRIs [see Warnings and Precautions].

10.8 Cholestyramine

As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of ibuprofen, a component of ibuprofen and famotidine tablets.

11. PHARMACOKINETICS

Absorption

Ibuprofen and famotidine are rapidly absorbed after a single dose administration of ibuprofen and famotidine tablet. Mean Cmax values for ibuprofen are 45 μg/mL and are reached approximately 1.9 hours after oral administration of ibuprofen and famotidine tablet. The Cmax and AUC0-24 hrs values for the 800 mg of ibuprofen contained in a ibuprofen and famotidine tablet are bioequivalent to the values for 800 mg of ibuprofen administered alone. Cmax values for famotidine were 61 ng/mL and are reached at approximately 2 hours after oral administration of ibuprofen and famotidine tablet.

A high-fat meal reduced famotidine Cmax and AUC by approximately by 15% and 11%, respectively, and reduced ibuprofen AUC by approximately 14% but did not change Cmax. Food delayed famotidine Tmax and ibuprofen Tmax by approximately 1 hour and 0.2 hour, respectively.

Distribution

Ibuprofen is extensively bound to plasma proteins.

Fifteen to 20% of famotidine in plasma is protein bound.

Metabolism

The only metabolite of famotidine identified in man is the S-oxide.

Excretion

Ibuprofen is eliminated from the systemic circulation with a mean half-life (t½) value of 2 hours following administration of a single dose of ibuprofen and famotidine tablet.

Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose.

Studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the urine within 24 hours as metabolite A (25%), (+)-2-[p-(2-hydroxymethyl-propyl) phenyl] propionic acid and metabolite B (37%), (+)-2-[p-(2-carboxypropyl)phenyl] propionic acid; the percentages of free and conjugated ibuprofen were approximately 1% and 14%, respectively.

Famotidine is eliminated from the systemic circulation with a mean t½ value of 4 hours following administration of a single dose of ibuprofen and famotidine tablet.

Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound.

Special Populations

Gender: The effects of gender on the pharmacokinetics of ibuprofen or famotidine after administration of ibuprofen and famotidine tablets have not been evaluated.

Age: The effects of age on the pharmacokinetics of ibuprofen or famotidine after administration of ibuprofen and famotidine tablets have not been evaluated.

Pediatrics: The pharmacokinetics of ibuprofen or famotidine after administration of ibuprofen and famotidine tablets have not been evaluated in a pediatric population considering the doses of ibuprofen and famotidine in ibuprofen and famotidine tablets are targeted for use in an adult population.

Renal impairment: There is a close relationship between creatinine clearance values and the elimination t½ of famotidine, which is a component of ibuprofen and famotidine tablets. In patients with creatinine clearance < 50 mL/min, the elimination t½ of famotidine is increased and may exceed 20 hours. Therefore, ibuprofen and famotidine tablet is not recommended in patients with creatinine clearance < 50 mL/min. [see Warnings and Precautions].

Hepatic impairment: The effects of hepatic impairment on the pharmacokinetics of ibuprofen or famotidine after administration of ibuprofen and famotidine tablets have not been evaluated [see Warnings and Precautions].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: DUEXIS, by HORIZON PHARMA.

b) Generic drugs: None.

2) How Supplied:

DUEXIS (ibuprofen and famotidine) tablets, 800 mg/26.6 mg, are light blue, oval, biconvex, film-coated tablets debossed with “HZT” on one side and supplied as:

Bottle of 90 tablets - NDC Number: 75987-010-03

3) Storage:

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature].

Rx only

Rev 04/11