GEMFIBROZIL tablet, film coated

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Active ingredient:
GEMFIBROZIL (UNII: Q8X02027X3) (GEMFIBROZIL - UNII:Q8X02027X3)
Available from:
NCS HealthCare of KY, Inc dba Vangard Labs
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Gemfibrozil tablets, USP are indicated as adjunctive therapy to diet for: - Treatment of adult patients with very high elevations of serum triglyceride levels (Types IV and V hyperlipidemia) who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them. Patients who present such risk typically have serum triglycerides over 2000 mg/dL and have elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides below 1000 mg/dL are unlikely to present a risk of pancreatitis. Gemfibrozil tablets, USP therapy may be considered for those subjects with triglyceride elevations between 1000 and 2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000 mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern with massive triglyceride eleva
Product summary:
Gemfibrozil Tablets USP, 600 mg are white to off-white, elliptical, biconvex, film-coated tablets, debossed with ‘E’ on one side and ‘82’ on the other side.             Blistercards of 30                  NDC 0615-8354-39          Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature]. Protect from light and humidity. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 038, India Revised: 07/2018
Authorization status:
Abbreviated New Drug Application
Authorization number:
0615-8354-39

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GEMFIBROZIL- gemfibrozil tablet, film coated

NCS HealthCare of KY, Inc dba Vangard Labs

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Gemfibrozil Tablets, USP

Rx only

DESCRIPTION

Gemfibrozil is a lipid regulating agent. It is available as tablets for oral administration. Each tablet

contains 600 mg gemfibrozil. Each tablet also contains calcium stearate, colloidal silicon dioxide,

hypromellose, low substituted hydroxypropyl cellulose, low viscosity hydroxypropyl cellulose,

microcrystalline cellulose, polyethylene glycol, polysorbate, pregelatinized starch (maize), and titanium

dioxide. The chemical name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, with the following

structural formula:

The molecular formula is C

H O and the molecular weight is 250.35; practically insoluble in water,

soluble in alcohol, in methanol and in chloroform. The melting point is 58° to 61°C. Gemfibrozil USP

is a white or almost white, waxy crystalline solid.

CLINICAL PHARMACOLOGY

Gemfibrozil is a lipid regulating agent which decreases serum triglycerides and very low density

lipoprotein (VLDL) cholesterol, and increases high density lipoprotein (HDL) cholesterol. While

modest decreases in total and low density lipoprotein (LDL) cholesterol may be observed with

gemfibrozil therapy, treatment of patients with elevated triglycerides due to Type IV

hyperlipoproteinemia often results in a rise in LDL-cholesterol. LDL-cholesterol levels in Type IIb

patients with elevations of both serum LDL-cholesterol and triglycerides are, in general, minimally

affected by gemfibrozil treatment; however, gemfibrozil usually raises HDL-cholesterol significantly

in this group. Gemfibrozil increases levels of high density lipoprotein (HDL) subfractions HDL and

HDL , as well as apolipoproteins AI and AII. Epidemiological studies have shown that both low HDL-

cholesterol and high LDL-cholesterol are independent risk factors for coronary heart disease.

In the primary prevention component of the Helsinki Heart Study, in which 4081 male patients between

the ages of 40 and 55 were studied in a randomized, double-blind, placebo-controlled fashion,

gemfibrozil therapy was associated with significant reductions in total plasma triglycerides and a

significant increase in high density lipoprotein cholesterol. Moderate reductions in total plasma

cholesterol and low density lipoprotein cholesterol were observed for the gemfibrozil treatment group

as a whole, but the lipid response was heterogeneous, especially among different Fredrickson types.

The study involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous

history of coronary heart disease. Over the five-year study period, the gemfibrozil group experienced

a 1.4% absolute (34% relative) reduction in the rate of serious coronary events (sudden cardiac deaths

plus fatal and nonfatal myocardial infarctions) compared to placebo, p=0.04 (see Table I). There was a

37% relative reduction in the rate of nonfatal myocardial infarction compared to placebo, equivalent to a

treatment-related difference of 13.1 events per thousand persons. Deaths from any cause during the

double-blind portion of the study totaled 44 (2.2%) in the gemfibrozil randomization group and 43

(2.1%) in the placebo group.

Table I: Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids

in the Helsinki

Heart Study, Years 0 to 5

All Patients

LDL-C>175;

HDL-C>46.4

LDL-C>175;

TG>177

LDL-C>175;

TG>200;

HDL-C<35

lipid values in mg/dL at baseline

P = placebo group; G = gemfibrozil group

difference in rates between placebo and gemfibrozil groups

fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1000 patients over 5

years)

Incidence of Events

41 27

Among Fredrickson types, during the 5-year double-blind portion of the primary prevention component

of the Helsinki Heart Study, the greatest reduction in the incidence of serious coronary events occurred

in Type IIb patients who had elevations of both LDL-cholesterol and total plasma triglycerides. This

subgroup of Type IIb gemfibrozil group patients had a lower mean HDL-cholesterol level at baseline

than the Type IIa subgroup that had elevations of LDL-cholesterol and normal plasma triglycerides. The

mean increase in HDL-cholesterol among the Type IIb patients in this study was 12.6% compared to

placebo. The mean change in LDL-cholesterol among Type IIb patients was -4.1% with gemfibrozil

compared to a rise of 3.9% in the placebo subgroup. The Type IIb subjects in the Helsinki Heart Study

had 26 fewer coronary events per thousand persons over five years in the gemfibrozil group compared

to placebo. The difference in coronary events was substantially greater between gemfibrozil and

placebo for that subgroup of patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol),

triglycerides >200 mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.9 mmol) (see Table I).

Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all subjects who had

participated in the Helsinki Heart Study. At the completion of the Helsinki Heart Study, subjects could

choose to start, stop, or continue to receive gemfibrozil; without knowledge of their own lipid values

or double-blind treatment, 60% of patients originally randomized to placebo began therapy with

gemfibrozil and 60% of patients originally randomized to gemfibrozil continued medication. After

approximately 6.5 years following randomization, all patients were informed of their original treatment

group and lipid values during the five years of the double-blind treatment. After further elective

changes in gemfibrozil treatment status, 61% of patients in the group originally randomized to

gemfibrozil were taking drug; in the group originally randomized to placebo, 65% were taking

gemfibrozil. The event rate per 1000 occurring during the open-label follow-up period is detailed in

Table II.

Table II: Cardiac Events and All-Cause Mortality (events per 1000 patients) Occurring During

the 3.5 Year Open-Label Follow-up to the Helsinki Heart Study

Group:

PDrop

N=215

PN

N=494

PG

N=1283

GDrop

N=221

GN

N=574

GG

N=1207

Cardiac Events

38.8

22.9

22.5

37.2

28.3

25.4

1

2

1

The six open-label groups are designated first by the original randomization (P = placebo, G =

gemfibrozil) and then by the drug taken in the follow-up period (N = Attend clinic but took no drug, G =

gemfibrozil, Drop = No attendance at clinic during open-label).

All-Cause Mortality

41.9

22.3

15.6

72.3

19.2

24.9

Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the group originally

randomized to gemfibrozil versus the originally randomized placebo group and a 20% relative decrease

in cardiac events in the group originally randomized to gemfibrozil versus the originally randomized

placebo group (see Table III). This analysis of the originally randomized “intent-to-treat’’ population

neglects the possible complicating effects of treatment switching during the open-label phase.

Adjustment of hazard ratios, taking into account open-label treatment status from years 6.5 to 8.5, could

change the reported hazard ratios for mortality toward unity.

Table III: Cardiac Events, Cardiac Deaths, Non-Cardiac Deaths, and All-Cause Mortality in the

Helsinki Heart Study, Years 0 to 8.5

Event

Gemfibrozil at Study

Start

Placebo at Study

Start

Gemfibrozil:Placebo

Hazard

Ratio

CI Hazard

Ratio

Intention-to-Treat Analysis of originally randomized patients neglecting the open-label treatment

switches and exposure to study conditions.

Hazard ratio for risk event in the group originally randomized to gemfibrozil compared to the group

originally randomized to placebo neglecting open-label treatment switch and exposure to study

conditions.

95% confidence intervals of gemfibrozil:placebo group hazard ratio.

Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over the 8.5 year period.

Cardiac Events

0.62 to 1.03

Cardiac Deaths

0.98

0.63 to 1.54

Non-Cardiac Deaths

0.95 to 2.05

All-Cause Mortality

0.9 to 1.61

It is not clear to what extent the findings of the primary prevention component of the Helsinki Heart

Study can be extrapolated to other segments of the dyslipidemic population not studied (such as women,

younger or older males, or those with lipid abnormalities limited solely to HDL-cholesterol) or to

other lipid-altering drugs.

The secondary prevention component of the Helsinki Heart Study was conducted over five years in

parallel and at the same centers in Finland in 628 middle-aged males excluded from the primary

prevention component of the Helsinki Heart Study because of a history of angina, myocardial infarction,

or unexplained ECG changes. The primary efficacy endpoint of the study was cardiac events (the sum

of fatal and non-fatal myocardial infarctions and sudden cardiac deaths). The hazard ratio

(gemfibrozil:placebo) for cardiac events was 1.47 (95% confidence limits 0.88 to 2.48, p=0.14). Of the

35 patients in the gemfibrozil group who experienced cardiac events, 12 patients suffered events after

discontinuation from the study. Of the 24 patients in the placebo group with cardiac events, 4 patients

suffered events after discontinuation from the study. There were 17 cardiac deaths in the gemfibrozil

group and 8 in the placebo group (hazard ratio 2.18; 95% confidence limits 0.94 to 5.05, p=0.06). Ten

of these deaths in the gemfibrozil group and 3 in the placebo group occurred after discontinuation from

therapy. In this study of patients with known or suspected coronary heart disease, no benefit from

gemfibrozil treatment was observed in reducing cardiac events or cardiac deaths. Thus, gemfibrozil has

shown benefit only in selected dyslipidemic patients without suspected or established coronary heart

disease. Even in patients with coronary heart disease and the triad of elevated LDL-cholesterol,

1

2

3

elevated triglycerides, plus low HDL-cholesterol, the possible effect of gemfibrozil on coronary

events has not been adequately studied.

No efficacy in the patients with established coronary heart disease was observed during the Coronary

Drug Project with the chemically and pharmacologically related drug, clofibrate. The Coronary Drug

Project was a 6-year randomized, double-blind study involving 1000 clofibrate, 1000 nicotinic acid,

and 3000 placebo patients with known coronary heart disease. A clinically and statistically significant

reduction in myocardial infarctions was seen in the concurrent nicotinic acid group compared to

placebo; no reduction was seen with clofibrate.

The mechanism of action of gemfibrozil has not been definitely established. In man, gemfibrozil has

been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thus

reducing hepatic triglyceride production. Gemfibrozil inhibits synthesis and increases clearance of

VLDL carrier apolipoprotein B, leading to a decrease in VLDL production.

Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol, reduce

incorporation of long-chain fatty acids into newly formed triglycerides, accelerate turnover and

removal of cholesterol from the liver, and increase excretion of cholesterol in the feces. Gemfibrozil

is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1

to 2 hours with a plasma half-life of 1.5 hours following multiple doses.

Gemfibrozil is completely absorbed after oral administration of gemfibrozil tablets, reaching peak

plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by the

timing of meals relative to time of dosing. In one study (ref. 4), both the rate and extent of absorption of

the drug were significantly increased when administered 0.5 hour before meals. Average AUC was

reduced by 14 to 44% when gemfibrozil was administered after meals compared to 0.5 hour before

meals. In a subsequent study, rate of absorption of gemfibrozil was maximum when administered 0.5

hour before meals with the C

50 to 60% greater than when given either with meals or fasting. In this

study, there were no significant effects on AUC of timing of dose relative to meals (see DOSAGE

AND ADMINISTRATION).

Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl

and a carboxyl metabolite. Approximately seventy percent of the administered human dose is excreted in

the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil.

Six percent of the dose is accounted for in the feces. Gemfibrozil is highly bound to plasma proteins

and there is potential for displacement interactions with other drugs (see PRECAUTIONS).

INDICATIONS AND USAGE

Gemfibrozil tablets, USP are indicated as adjunctive therapy to diet for:

1. Treatment of adult patients with very high elevations of serum triglyceride levels (Types IV and V

hyperlipidemia) who present a risk of pancreatitis and who do not respond adequately to a

determined dietary effort to control them. Patients who present such risk typically have serum

triglycerides over 2000 mg/dL and have elevations of VLDL-cholesterol as well as fasting

chylomicrons (Type V hyperlipidemia). Subjects who consistently have total serum or plasma

triglycerides below 1000 mg/dL are unlikely to present a risk of pancreatitis. Gemfibrozil tablets,

USP therapy may be considered for those subjects with triglyceride elevations between 1000 and

2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis.

It is recognized that some Type IV patients with triglycerides under 1000 mg/dL may, through

dietary or alcoholic indiscretion, convert to a Type V pattern with massive triglyceride elevations

accompanying fasting chylomicronemia, but the influence of gemfibrozil tablets, USP therapy on the

risk of pancreatitis in such situations has not been adequately studied. Drug therapy is not indicated

for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma

triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of

plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V

hyperlipoproteinemia.

2. Reducing the risk of developing coronary heart disease only in Type IIb patients without history of

or symptoms of existing coronary heart disease who have had an inadequate response to weight

loss, dietary therapy, exercise, and other pharmacologic agents (such as bile acid sequestrants and

nicotinic acid, known to reduce LDL- and raise HDL-cholesterol) and who have the following triad

of lipid abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol and

elevated triglycerides (see WARNINGS, PRECAUTIONS, and CLINICAL

PHARMACOLOGY). The National Cholesterol Education Program has defined a serum HDL-

cholesterol value that is consistently below 35 mg/dL as constituting an independent risk factor for

coronary heart disease. Patients with significantly elevated triglycerides should be closely

observed when treated with gemfibrozil. In some patients with high triglyceride levels, treatment

with gemfibrozil is associated with a significant increase in LDL-cholesterol. BECAUSE OF

POTENTIAL TOXICITY SUCH AS MALIGNANCY, GALLBLADDER DISEASE,

ABDOMINAL PAIN LEADING TO APPENDECTOMY AND OTHER ABDOMINAL

SURGERIES, AN INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE

44% RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED ALL-

CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND PHARMACOLOGICALLY

RELATED DRUG, CLOFIBRATE, THE POTENTIAL BENEFIT OF GEMFIBROZIL IN

TREATING TYPE IIA PATIENTS WITH ELEVATIONS OF LDL-CHOLESTEROL ONLY IS

NOT LIKELY TO OUTWEIGH THE RISKS. GEMFIBROZIL TABLETS, USP ARE ALSO NOT

INDICATED FOR THE TREATMENT OF PATIENTS WITH LOW HDL-CHOLESTEROL AS

THEIR ONLY LIPID ABNORMALITY.

In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-cholesterol

values at baseline (greater than 46.4 mg/dL), the incidence of serious coronary events was similar for

gemfibrozil and placebo subgroups (see Table I).

The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality.

Excess body weight and excess alcohol intake may be important factors in hypertriglyceridemia and

should be managed prior to any drug therapy. Physical exercise can be an important ancillary measure,

and has been associated with rises in HDL-cholesterol. Diseases contributory to hyperlipidemia such

as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy is

sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial

hypertriglyceridemia. In such cases, discontinuation of estrogen therapy may obviate the need for

specific drug therapy of hypertriglyceridemia. The use of drugs should be considered only when

reasonable attempts have been made to obtain satisfactory results with nondrug methods. If the decision

is made to use drugs, the patient should be instructed that this does not reduce the importance of

adhering to diet.

CONTRAINDICATIONS

1. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.

2. Preexisting gallbladder disease (see WARNINGS).

3. Hypersensitivity to gemfibrozil.

4. Combination therapy of gemfibrozil with simvastatin (see WARNINGS and PRECAUTIONS).

5. Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS).

6. Combination therapy of gemfibrozil with dasabuvir (see PRECAUTIONS).

7. Combination therapy of gemfibrozil with selexipag (see PRECAUTIONS).

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), and gemfibrozil (250 mg/kg; 1.7 times the human dose). 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 treated with

clofibrate; hepatic neoplastic nodules were increased in males and females treated with clofibrate;

hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while

testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs.

2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend toward a

greater prevalence of gallstones during the study within the gemfibrozil treatment group (7.5% versus

4.9% for the placebo group, a 55% excess for the gemfibrozil group). A trend toward a greater

incidence of gallbladder surgery was observed for the gemfibrozil group (17 versus 11 subjects, a

54% excess). This result did not differ statistically from the increased incidence of cholecystectomy

observed in the WHO study in the group treated with clofibrate. Both clofibrate and gemfibrozil may

increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected,

gallbladder studies are indicated. Gemfibrozil therapy should be discontinued if gallstones are found.

Cases of cholelithiasis have been reported with gemfibrozil therapy.

3. Since a reduction of mortality from coronary heart disease has not been demonstrated and because

liver and interstitial cell testicular tumors were increased in rats, gemfibrozil should be administered

only to those patients described in the INDICATIONS AND USAGE section. If a significant serum

lipid response is not obtained, gemfibrozil should be discontinued.

4. Concomitant Anticoagulants – 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.

5. The concomitant administration of gemfibrozil with simvastatin is contraindicated

(see CONTRAINDICATIONS and PRECAUTIONS). Concomitant therapy with gemfibrozil and an

HMG-CoA reductase inhibitor is associated with an increased risk of skeletal muscle toxicity

manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK) levels, and myoglobinuria,

leading in a high proportion of cases to acute renal failure and death. IN PATIENTS WHO HAVE

HAD AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE BENEFIT OF

COMBINED THERAPY WITH GEMFIBROZIL AND an HMG-CoA REDUCTASE INHIBITOR

DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY, RHABDOMYOLYSIS, AND

ACUTE RENAL FAILURE (see PRECAUTIONS, Drug Interactions). The use of fibrates alone,

including gemfibrozil, may occasionally be associated with myositis. Patients receiving gemfibrozil and

complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for

myositis, including serum creatine–kinase level determination. If myositis is suspected or diagnosed,

gemfibrozil therapy should be withdrawn.

6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats

treated with gemfibrozil at 10 times the human dose.

7. CYP2C8 substrates – Gemfibrozil, a strong inhibitor of CYP2C8, may increase exposure of CYP2C8

substrates when administered concomitantly (see PRECAUTIONS, Drug Interactions).

8. OATP1B1 substrates – Gemfibrozil is an inhibitor of organic anion-transporter polyprotein (OATP)

1B1 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

PRECAUTIONS, Drug Interactions). Combination therapy of gemfibrozil with simvastatin or

with repaglinide, which are OATP1B1 substrates, is contraindicated (see CONTRAINDICATIONS).

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). 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) Anticoagulants

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-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 to 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

(ratios: 11.3 and

2.01, respectively) due to CYP2C8 inhibition. Increased dasabuvir exposure may increase the risk of

QT prolongation, therefore, co-administration 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 Cmax 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

simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated (see

CONTRAINDICATIONS).

(E) In vitro studies of CYP enzymes, UGTA enzymes and OATP1B1 transporter:

In vitro studies have shown that gemfibrozil is an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19,

OATP1B1, and UDP-glucuronosyltransferase (UGT) 1A1 and 1A3 (see WARNINGS).

(F) Bile Acid-Binding Resins

Gemfibrozil AUC was reduced by 30% when gemfibrozil was given (600 mg) simultaneously with

resin-granule drugs such as colestipol (5 g). Administration of the drugs two hours or more apart is

recommended because gemfibrozil exposure was not significantly affected when it was administered

two hours apart from colestipol.

(G) Colchicine

Myopathy, including rhabdomyolysis, has been reported with chronic administration of colchicine at

therapeutic doses. Concomitant use of gemfibrozil may potentiate the development of myopathy. Patients

with renal dysfunction and elderly patients are at increased risk. Caution should be exercised when

prescribing gemfibrozil with colchicine, especially in elderly patients or patients with renal

dysfunction.

4. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC).

The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose

male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not

statistically significant (p=0.1). Male rats had a dose-related and statistically significant increase of

benign Leydig cell tumors. The higher dose female rats had a significant increase in the combined

incidence of benign and malignant liver neoplasms.

Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based on

AUC). There were no statistically significant differences from controls in the incidence of liver

tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates.

Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following

gemfibrozil administration to the male rat. An adequate study to test for peroxisome proliferation has not

been done in humans but changes in peroxisome morphology have been observed. Peroxisome

proliferation has been shown to occur in humans with either of two other drugs of the fibrate class

when liver biopsies were compared before and after treatment in the same individual.

Administration of approximately 2 times the human dose (based on surface area) to male rats for 10

weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that this effect

was reversed after a drug-free period of about eight weeks, and it was not transmitted to the offspring.

5. Pregnancy

Gemfibrozil has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3

times the human dose (based on surface area). There are no adequate and well-controlled studies in

pregnant women. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the

potential risk to the fetus.

Administration of gemfibrozil to female rats at 2 times the human dose (based on surface area) before

and throughout gestation caused a dose-related decrease in conception rate, an increase in stillborns,

and a slight reduction in pup weight during lactation. There were also dose-related increased skeletal

variations. Anophthalmia occurred, but rarely.

Administration of 0.6 and 2 times the human dose (based on surface area) of gemfibrozil to female rats

from gestation day 15 through weaning caused dose-related decreases in birth weight and suppressions

of pup growth during lactation.

Administration of 1 and 3 times the human dose (based on surface area) of gemfibrozil to female rabbits

during organogenesis caused a dose-related decrease in litter size and, at the high dose, an increased

incidence of parietal bone variations.

6. Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human

milk and because of the potential for tumorigenicity shown for gemfibrozil in animal studies, a decision

should be made whether to discontinue nursing or to discontinue the drug, taking into account the

importance of the drug to the mother.

7. Hematologic Changes

Mild hemoglobin, hematocrit, and white blood cell decreases have been observed in occasional patients

following initiation of gemfibrozil therapy. However, these levels stabilize during long-term

administration. Rarely, severe anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia have

been reported. Therefore, periodic blood counts are recommended during the first 12 months of

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