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Duexis

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Duexis

CLINICAL PHARMACOLOGY

Mechanism of Action

DUEXIS 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.

Pharmacodynamics

No pharmacodynamic studies were conducted.

Pharmacokinetics

Absorption

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.

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 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-(2carboxypropyl)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.

Special Populations

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

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

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.

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].

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].

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 3 and 4. 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 3: Overall Incidence Rates of Patients Who Developed at Least One Upper Gastrointestinal or Gastric Ulcer -Study 301

  DUEXIS % (n/N) Ibuprofen % (n/N) P-valuea
Primary endpoint
Upper gastrointestinal ulcer* 10.5% (40/380) 20.0% (38/190) 0.002
Upper gastrointestinal ulcer** 22.9% (87/380) 32.1% (61/190) 0.02
Secondary endpoint
  Gastric ulcer* 9.7% (37/380) 17.9% (34/190) 0.005
  Gastric ulcer** 22.4% (85/380) 30.0% (57/190) 0.052
aCochran-Mantel-Haenszel test
* Classifying early terminated patients as NOT having an ulcer
** Classifying patients who early terminated due to an adverse event, were lost to follow-up, discontinued due to the discretion of the sponsor or the investigator, or did not have an endoscopy performed within 14 days of their last dose of study drug, as having an ulcer

Table 4: Overall Incidence Rate of Patients Who Developed at Least One Gastric or Upper Gastrointestinal Ulcer -Study 303

  DUEXIS % (n/N) Ibuprofen % (n/N) P-valuea
Primary endpoint
  Gastric ulcer* 8.7% (39/447) 17.6% (38/216) 0.0004
  Gastric ulcer** 17.4% (78/447) 31.0% (67/216) < 0.0001
Secondary endpoint
Upper gastrointestinal ulcer* 10.1% (45/447) 21.3% (46/216) < 0.0001
Upper gastrointestinal ulcer** 18.6% (83/447) 34.3% (74/216) < 0.0001
aCochran-Mantel-Haenszel test
* Classifying early terminated patients as NOT having an ulcer
** Classifying patients who early terminated due to an adverse event, were lost to follow-up, discontinued due to the discretion of the sponsor or the investigator, or did not have an endoscopy performed within 14 days of their last dose of study drug, as having an ulcer

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 subjects in clinical studies of DUEXIS, 18% (249 subjects) 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 subjects 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.

Last reviewed on RxList: 1/31/2013
This monograph has been modified to include the generic and brand name in many instances.

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