Gemfibrozil 600 mg Tablet, 60-count — NDC 16714-101-02 (Billing 16714-0101-02)

WARNINGS 1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil and clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000 subjects with previous myocardial infarction were treated for five years with clofibrate.

There was no difference in mortality between the clofibrate-treated subjects and 3000 placebo-treated subjects, but twice as many clofibrate-treated subjects developed cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the World Health Organization (WHO), 5000 subjects without known coronary heart disease were treated with clofibrate for five years and followed one year beyond. There was a statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo-treated control group during the trial period.

The excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of clofibrate-treated subjects for gallbladder disease was confirmed. Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up (see CLINICAL PHARMACOLOGY ).

Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil primarily due to cancer deaths observed during the open-label extension. During the five year primary prevention component of the Helsinki Heart Study, mortality from any cause was 44 (2.2%) in the gemfibrozil group and 43 (2.1%) in the placebo group; including the 3.5 year follow-up period since the trial was completed, cumulative mortality from any cause was 101 (4.9%) in the gemfibrozil group and 83 (4.1%) in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo).

Because of the more limited size of the Helsinki Heart Study, the observed difference in mortality from any cause between the gemfibrozil and placebo groups at Year-5 or at Year-8.5 is not statistically significantly different from the 29% excess mortality reported in the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary heart disease related mortality showed an excess in the group originally randomized to gemfibrozil at the 8.5 year follow-up (65 gemfibrozil versus 45 placebo noncoronary deaths).

The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized groups. In addition, there were 16 basal cell carcinomas in the group originally randomized to gemfibrozil and 9 in the group originally randomized to placebo (p=0.22). There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to gemfibrozil and 18 (0.9%) in the group originally randomized to placebo (p=0.11).

Adverse outcomes, including coronary events, were higher in gemfibrozil patients in a corresponding study in men with a history of known or suspected coronary heart disease in the secondary prevention component of the Helsinki Heart Study (see CLINICAL PHARMACOLOGY ). A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively), clofibrate (400 mg/kg; 1.6 times the human dose, respectively), and gemfibrozil (250 mg/kg; 1.7 times the human dose, respectively).

Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treat… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS In the double-blind controlled phase of the primary prevention component of the Helsinki Heart Study, 2046 patients received gemfibrozil for up to five years. In that study, the following adverse reactions were statistically more frequent in subjects in the gemfibrozil group: Gemfibrozil PLACEBO (N = 2046) (N = 2035) Frequency in percent of subjects Gastrointestinal reactions 34.2

23.8Dyspepsia 19.6

11.9Abdominal pain 9.8

5.6Acute appendicitis 1.2 0.6 (histologically confirmed in most cases where data were available) Atrial fibrillation 0.7

0.1Adverse events reported by more than 1% of subjects, but without a significant difference between groups: Diarrhea 7.2

6.5Fatigue 3.8

3.5Nausea/Vomiting 2.5

2.1Eczema 1.9

1.2Rash 1.7

1.3Vertigo 1.5

1.3Constipation 1.4

1.3Headache 1.2

1.1Gallbladder surgery was performed in 0.9% of gemfibrozil and 0.5% of placebo subjects in the primary prevention component, a 64% excess, which is not statistically different from the excess of gallbladder surgery observed in the clofibrate group compared to the placebo group of the WHO study. Gallbladder surgery was also performed more frequently in the gemfibrozil group compared to the placebo group (1.9% versus 0.3%, p=0.07) in the secondary prevention component. A statistically significant increase in appendectomy in the gemfibrozil group was seen also in the secondary prevention component (6 on gemfibrozil versus 0 on placebo, p=0.014).

Nervous system and special senses adverse reactions were more common in the gemfibrozil group. These included hypesthesia, paresthesias, and taste perversion. Other adverse reactions that were more common among gemfibrozil treatment group subjects but where a causal relationship was not established include cataracts, peripheral vascular disease, and intracerebral hemorrhage.

From other studies it seems probable that gemfibrozil is causally related to the occurrence of MUSCULOSKELETAL SYMPTOMS (see WARNINGS ), and to ABNORMAL LIVER FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS ). Reports of viral and bacterial infections (common cold, cough, urinary tract infections) were more common in gemfibrozil treated patients in other controlled clinical trials of 805 patients. Additional adverse reactions that have been reported for gemfibrozil are listed below by system.

These are categorized according to whether a causal relationship to treatment with gemfibrozil is probable or not established: CAUSAL RELATIONSHIP CAUSAL RELATIONSHIP PROBABLE NOT ESTABLISHED General: weight loss Cardiac: extrasystoles Gastrointestinal: cholestatic jaundice pancreatitis hepatoma colitis Central Nervous System: dizziness confusion somnolence convulsions paresthesia syncope peripheral neuritis decreased libido depression headache Eye: blurred vision retinal edema Genitourinary: impotence decreased male fertility renal dysfunction Musculoskeletal: myopathy myasthenia myalgia painful extremities arthralgia synovitis rhabdomyolysis (see WARNINGS and Drug Interactions under PRECAUTIONS ) Clinical Laboratory: increased creatine phosphokinase positive antinuclear antibody increased bilirubin increased liver transaminases (AST, ALT) increased alkaline phosphatase Hematopoietic: anemia thrombocytopenia leukopenia bone marrow hypoplasia eosinophilia Immunologic: angioedema anaphylaxis laryngeal edema Lupus-like syndrome urticaria vasculitis Integumentary: exfoliative dermatitis alopecia rash photosensitivity dermatitis pruritus Additional adverse reactions that have been reported include cholecystitis and cholelithiasis (see WARNINGS ).

3. Drug Interactions (A) HMG-CoA Reductase Inhibitors: The concomitant administration of gemfibrozil with simvastatin is contraindicated ( see CONTRAINDICATIONS and WARNINGS ). Avoid concomitant use of gemfibrozil with rosuvastatin.

If concomitant use cannot be avoided, initiate rosuvastatin at 5 mg once daily. The dose of rosuvastatin should not exceed 10 mg once daily. The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy.

Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months (see WARNINGS ). There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. (B) Anti-coagulants: CAUTION SHOULD BE EXERCISED WHEN WARFARIN IS GIVEN IN CONJUNCTION WITH GEMFIBROZIL.

THE DOSAGE OF WARFARIN SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN LEVEL HAS STABILIZED. (C) CYP2C8 Substrates: Gemfibrozil is a strong inhibitor of CYP2C8 and may increase exposure of drugs mainly metabolized by CYP2C8 (e.g., dabrafenib, enzalutamide, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone).

Therefore, dosing reduction of drugs that are mainly metabolized by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly (see WARNINGS ). Repaglinide: In healthy volunteers, co-administration with gemfibrozil (600 mg twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7 hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) + itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration 7 hours after the dose.

In addition, gemfibrozil alone or gemfibrozil + itraconazole prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and repaglinide increases the risk of severe hypoglycemia and is contraindicated (see CONTRAINDICATIONS ). Dasabuvir: Co-administration of gemfibrozil with dasabuvir increased dasabuvir AUC and C max (ratios: 11.3 and 2.01, respectively) due to CYP2C8 inhibition.

Increased dasabuvir exposure may increase the risk of QT prolongation, therefore, coadministration of gemfibrozil with dasabuvir is contraindicated (see CONTRAINDICATIONS ). Selexipag: Co-administration of gemfibrozil with selexipag doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of gemfibrozil with selexipag is contraindicated (see CONTRAINDICATIONS ).

Enzalutamide: In healthy volunteers given a single 160 mg dose of enzalutamide after gemfibrozil 600 mg twice daily, the AUC of enzalutamide plus active metabolite (N-desmethyl enzalutamide) was increased by 2.2 fold and corresponding C max was decreased by 16%. Increased enzalutamide exposure may increase the risk of seizures. If co-administration is considered necessary, the dose of enzalutamide should be reduced (see WARNINGS ).

(D) OATP1B1 substrates: Gemfibrozil is an inhibitor of OATP1B1 transporter and may increase exposure of drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly (see WARNINGS ). Combination therapy of gemfibrozil with si… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS 1. Initial Therapy Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal. Before instituting gemfibrozil therapy, every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities.

2. Continued Therapy Periodic determination of serum lipids should be obtained, and the drug withdrawn if lipid response is inadequate after three months of therapy. 3.

Drug Interactions (A) HMG-CoA Reductase Inhibitors: The concomitant administration of gemfibrozil with simvastatin is contraindicated ( see CONTRAINDICATIONS and WARNINGS ). Avoid concomitant use of gemfibrozil with rosuvastatin. If concomitant use cannot be avoided, initiate rosuvastatin at 5 mg once daily.

The dose of rosuvastatin should not exceed 10 mg once daily. The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months (see WARNINGS ).

There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. (B) Anti-coagulants: CAUTION SHOULD BE EXERCISED WHEN WARFARIN IS GIVEN IN CONJUNCTION WITH GEMFIBROZIL. THE DOSAGE OF WARFARIN SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS.

FREQUENT PROTHROMBIN DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN LEVEL HAS STABILIZED. (C) CYP2C8 Substrates: Gemfibrozil is a strong inhibitor of CYP2C8 and may increase exposure of drugs mainly metabolized by CYP2C8 (e.g., dabrafenib, enzalutamide, loperamide, montelukast, paclitaxel, pioglitazone, rosiglitazone). Therefore, dosing reduction of drugs that are mainly metabolized by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly (see WARNINGS ).

Repaglinide: In healthy volunteers, co-administration with gemfibrozil (600 mg twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7 hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) + itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration 7 hours after the dose.

In addition, gemfibrozil alone or gemfibrozil + itraconazole prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and repaglinide increases the risk of severe hypoglycemia and is contraindicated (see CONTRAINDICATIONS ). Dasabuvir: Co-administration of gemfibrozil with dasabuvir increased dasabuvir AUC and C max (ratios: 11.3 and 2.01, respectively) due to CYP2C8 inhibition.

Increased dasabuvir exposure may increase the risk of QT prolongation, therefore, coadministration of gemfibrozil with dasabuvir is contraindicated (see CONTRAINDICATIONS ). Selexipag: Co-administration of gemfibrozil with selexipag doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of gemfibrozil with selexipag is contraindicated (see CONTRAINDICATIONS ).

Enzalutamide: In healthy volunteers given a single 160 mg dose of enzalutamide after gemfibrozil 600 mg twice daily, the AUC of enzalutamide plus active metabolite (N-desmethyl enzalutamide) was increased by 2.2 fold and corresponding C max was decreased by 16%. Increased enzalutamide exposure may increase the risk of seizures. If co-administration is considered necessar… [Excerpted — this section continues on DailyMed.]