Ibuprofen and Famotidine Tablets

DUEXIS (ibuprofen and famotidine) is supplied as a tablet for oral administration which combines the nonsteroidal anti-inflammatory drug, ibuprofen, and the histamine H2-receptor antagonist, famotidine.

Ibuprofen is (±)-2-(p-isobutylphenyl)propionic acid. Its chemical formula is C13H18O2 and molecular weight is 206.28. Ibuprofen is a white powder that is very slightly soluble in water ( < 1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. Its structural formula is:

Famotidine is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. Its chemical formula is C8H15N7O2S3 and molecular weight is 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. Its structural formula is:

Each DUEXIS tablet contains ibuprofen, USP (800 mg) and famotidine, USP (26.6 mg). The inactive ingredients in DUEXIS include: 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.

Dosage Forms And Strengths

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

Storage And Handling

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:

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

Distributed by: Horizon Pharma USA Inc., Lake Forest, IL 60045 For more information, go to www.DUEXIS.com or call 1-866-479-6742. Revised: Jun 2017

Mechanism Of Action

DUEXIS is a fixed-combination tablet of ibuprofen and famotidine. The ibuprofen component has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of the ibuprofen component of DUEXIS, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Ibuprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to an increase of prostaglandins in peripheral tissues.

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.

Pharmacokinetics

Ibuprofen and famotidine are rapidly absorbed after a single dose administration of DUEXIS. Mean Cmax values for ibuprofen are 45 μg/mL and are reached approximately 1.9 hours after oral administration of DUEXIS. The Cmax and AUC0-24hours values for the 800 mg of ibuprofen contained in a DUEXIS 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 DUEXIS.

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.

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 DUEXIS.

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 DUEXIS.

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.

Specific Populations

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

Hepatic impairment: The effects of hepatic impairment on the pharmacokinetics of ibuprofen or famotidine after administration of DUEXIS have not been evaluated [see WARNINGS AND PRECAUTIONS].

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

Drug Interaction Studies

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.

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS].

Probenecid, An inhibitor Of Organic Aniton Transporter 1 (OAT1) And OAT3

In vitro studies indicate that famotidine is a substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg) with a single oral 20 mg dose of famotidine in 8 healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ngxhr/mL and the maximum serum concentration (Cmax) increased from 73 to 113 ng/mL. Renal clearance, urinary excretion rate and amount of famotidine excreted unchanged in urine were decreased. The clinical relevance of this interaction is unknown.

Metformin: Famotidine is a selective inhibitor of multidrug and toxin extrusion transporter 1 (MATE-1) but no clinical significant interaction with metformin, a substrate for MATE-1, was observed.

Clinical Studies

Two multicenter, double-blind, active-controlled, randomized, 24-week studies of DUEXIS were conducted in patients who were expected to require daily administration of an NSAID for at least the coming 6 months for conditions such as the following: osteoarthritis, rheumatoid arthritis, chronic low back pain, chronic regional pain syndrome, and chronic soft tissue pain. Patients were assigned randomly, in approximately a 2:1 ratio, to treatment with either DUEXIS or ibuprofen (800 mg) three times a day for 24 consecutive weeks. A total of 1533 patients were enrolled and ranged in age from 39 to 80 years (median age 55 years) with 68% females. Race was distributed as follows: 79% Caucasian, 18% African-American, and 3% Other. Approximately 15% of the patients in Studies 301 and 303 were taking concurrent low-dose aspirin (less than or equal to 325 mg daily), 18% were 65 years of age or older, and 6% had a history of previous upper gastrointestinal ulcer. Although H. pylori status was negative at baseline, H. pylori status was not reassessed during the trials.

Studies 301 and 303 compared the incidence of upper gastrointestinal (gastric and/or duodenal) ulcer formation in a total 930 patients taking DUEXIS (ibuprofen and famotidine) and 452 patients taking ibuprofen only, either as a primary or secondary endpoint. In both trials, DUEXIS was associated with a statistically significantly reduction in the risk of developing upper gastrointestinal ulcers compared to taking ibuprofen only during the 6 month study period. The data are presented below in Tables 4 and 5. Two analyses for each endpoint were conducted. In one analysis patients who terminated early, without an endoscopic evaluation within 14 days of their last dose of study drug, were classified as not having an ulcer. In the second analysis, those patients were classified as having an ulcer. Both analyses exclude patients who terminated study prior to the first scheduled endoscopy at 8 weeks.

Table 4: Overall Incidence Rates of Patients Who Developed at Least One Upper Gastrointestinal or Gastric Ulcer -Study 301

Table 5: Overall Incidence Rate of Patients Who Developed at Least One Gastric or Upper Gastrointestinal Ulcer -Study 303

Subgroup analyses of patients who used low-dose aspirin (less than or equal to 325 mg daily), were 65 years and older, or had a prior history of gastrointestinal ulcer are summarized as follows:

Of the 1022 patients in clinical studies of DUEXIS, 15% (213 patients) used low-dose aspirin and the results were consistent with the overall findings of the study. In these clinical studies 16% of patients who used low-dose aspirin who were treated with DUEXIS developed an upper gastrointestinal ulcer compared to 35% of those patients who received only ibuprofen.

The clinical trials primarily enrolled patients less than 65 years without a prior history of gastrointestinal ulcer. Of the 1022 patients in clinical studies of DUEXIS, 18% (249 patients) were 65 years of age or older. In these clinical studies, 23% of patients 65 years of age and older who were treated with DUEXIS developed an upper gastrointestinal ulcer compared to 27% of those patients who received only ibuprofen [see Use in Specific Populations].

Of the 1022 patients in clinical studies of DUEXIS, 6% had a prior history of gastrointestinal ulcer. In these clinical studies, 25% of patients with a prior history of gastrointestinal ulcer who were treated with DUEXIS developed an upper gastrointestinal ulcer compared to 24% of those patients who received only ibuprofen.

You should not use this medication if you are allergic to ibuprofen (Advil, Motrin), famotidine (Pepcid), aspirin, other NSAIDs (non-steroidal anti-inflammatory drugs), or other stomach acid reducers (such as Tagamet, Zantac, or Axid).

Do not use famotidine and ibuprofen if you are more than 29 weeks (7 months) pregnant. Taking ibuprofen during this time may harm the unborn baby.

Before you take this medicine, tell your doctor if you have a stomach or intestinal disorder, heart disease, high blood pressure, asthma, nasal polyps, liver or kidney disease, lupus, a bleeding or blood-clotting disorder, or a history of heart attack, stroke, or blood clot. Also tell your doctor if you smoke.

Ibuprofen may cause life-threatening heart or circulation problems such as heart attack or stroke, especially if you use it long term. Do not use famotidine and ibuprofen just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Get emergency medical help if you have chest pain, weakness, shortness of breath, slurred speech, or problems with vision or balance.

Ibuprofen may also cause serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and can occur without warning, especially in older adults.

Call your doctor at once if you have symptoms of stomach bleeding such as black, bloody, or tarry stools, or coughing up blood or vomit that looks like coffee grounds.

Do not use famotidine and ibuprofen just before or after heart bypass surgery (coronary artery bypass graft, or CABG).

Ibuprofen may cause life-threatening heart or circulation problems such as heart attack or stroke, especially if you use it long term.

Ibuprofen may also cause serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and can occur without warning, especially in older adults.

You should not use this medication if you are allergic to ibuprofen (Advil, Motrin) or famotidine (Pepcid), or if you have:

• a history of asthma, hives, or severe allergic reaction after taking aspirin or another NSAID, such as naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others;
• if you are allergic to other stomach acid reducers such as ranitidine (Zantac), cimetidine (Tagamet), or nizatidine (Axid); or
• if you are more than 29 weeks (7 months) pregnant.

To make sure you can safely take famotidine and ibuprofen, tell your doctor if you have any of these other conditions:

• Crohn's disease, inflammatory bowel disease, or ulcerative colitis;
• a history of heart attack, stroke, or blood clot;
• heart disease, congestive heart failure, high blood pressure;
• a history of stomach ulcers or bleeding;
• asthma;
• polyps in your nose;
• liver or kidney disease;
• systemic lupus erythematosus (SLE);
• a bleeding or blood clotting disorder; or
• if you smoke.

Famotidine and ibuprofen can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

FDA pregnancy category C. Do not take this medicine if you are more than 7 months pregnant. Taking ibuprofen during this time may harm the unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using famotidine and ibuprofen.

Do not give this medicine to a child without the advice of a doctor.

• Rheumatoid Arthritis (RA)