Gemfibrozil-300 - Cap Product Monograph

INDICATIONS

GEMFIBROZIL (gemfibrozil) is indicated as an adjunct to diet and other therapeutic measures for:

1. 1. treatment of adult patients with very high serum triglyceride levels, Fredrickson classification Type IV and V hyperlipidemias, who are at a high risk of sequelae and complications (i.e. pancreatitis) from their hyperlipidemia.
2. 2.

   treatment of patients with hypercholesterolemia, Type Ila and lIb mixed dyslipidemias, to regulate lipid levels (reduce serum triglycerides and LDL cholesterol levels and increase

   HDL cholesterol).

GEMFIBROZIL alone may not be adequate therapy in some patients with familial combined hyperlipidemia with Type lIb and IV hyperlipoproteinemia.

Initial therapy for hyperlipidemia should include a specific diet, weight reduction, and an exercise program, and for patients with diabetes mellitus, a good diabetic control.

CONTRAINDICATIONS

1. 1. Hepatic or renal dysfunction, including primary biliary cirrhosis.
2. 2. Pre-existing gallbladder disease. (see Precautions)
3. 3. Hypersensitivity to gemfibrozil.
4. 4. The drug should not be used in pregnant or lactating patients.
5. 5. GEMFIBROZIL is not indicated for the treatment of Type I hyperlipoproteinemia.
6. 6. The concomitant use of gemfibrozil with the oral hypoglycaemic repaglinide is contraindicated (see PRECAUTIONS – Drug Interactions).

WARNINGS

Drug Interactions - When gemfibrozil and lovastatin were used concomitantly, there have been reports of severe myositis with markedly elevated creatinine kinase (CK) and myoglobinuria

(rhabdomyolysis). When myoglobinuria is severe, acute renal failure may ensue. Therefore, lovastatin should not be used concomitantly with gemfibrozil.

Caution should be exercised when anticoagulants are given in conjunction with gemfibrozil. The dosage of the anticoagulant 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.

Gemfibrozil clinically, pharmacologically and chemically shows similarities with clofibrate.

Physicians prescribing gemfibrozil should also be familiar with the risks and benefits of clofibrate. Long-term studies with gemfibrozil have been conducted in rats and mice at one and ten times the human dose. The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas was increased also in low dose males, but the increase was not statistically significant (p>0.05). There were no statistically significant differences from controls in the incidence of liver tumors in female rats and in male and female mice. Liver and testicular cell tumors were increased in male rats.

Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to male rats. Such changes have not been found in the liver of patients treated with this drug.

Toxicology studies in male rats revealed a dose-related increase of benign Leydig cell tumors.

Subcapsular bilateral cataracts occurred in 10% and unilateral in 6.3% of the high dose males.

Cholelithiasis - Gemfibrozil may increase cholesterol excretion into the bile leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. GEMFIBROZIL

(gemfibrozil) therapy should be discontinued if gallstones are found.

Since a reduction of total mortality has not been demonstrated, GEMFIBROZIL should be administered only in those patients described in the Indications section. If a significant serum lipid response is not obtained in 3 months, GEMFIBROZIL should be discontinued.

If GEMFIBROZIL is chosen for treatment, the prescribing physician should discuss the proposed therapy and inform the patient of the expected benefits and potential risks which may be associated with long-term administration (see Precautions).

Safety and efficacy in children have not been established.

Strict birth control procedures must be exercised by women of child-bearing potential. If pregnancy occurs despite birth control procedures, GEMFIBROZIL should be discontinued.

Women who are planning pregnancy should discontinue GEMFIBROZIL several months prior to conception.

Nursing mothers - Because of the potential for tumorigenicity shown for gemfibrozil in rats, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

PRECAUTIONS

Initial Therapy - Before instituting GEMFIBROZIL (gemfibrozil) therapy, attempts should be made to control serum lipids and lipoproteins with appropriate diet, exercise, weight loss in obese patients, and control of diabetes mellitus.

Long-term Therapy - Because long-term administration of gemfibrozil is recommended, pretreatment clinical chemistry studies should be performed to ensure that the patient has elevated serum lipid or low HDL cholesterol levels. Periodic determinations of serum lipids and lipoproteins should be done during gemfibrozil administration, including measurement of LDL-cholesterol/HDL-cholesterol ratio, particularly in Type IV hyperlipoproteinemic patients.

Impairment of Fertility - Administration of approximately three and ten times the human dose 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 8 weeks, and it was not transmitted to their offspring.

Hemoglobin Changes - A mild hemoglobin or hematocrit decrease has been observed in occasional patients following initiation of gemfibrozil therapy. The levels then stabilize during long-term administration. Therefore, a blood count is recommended every two months during the first 12 months of gemfibrozil administration.

Liver Function - Abnormal liver function tests have been observed occasionally during gemfibrozil administration, including elevations of SGOT, SGPT, LDH and alkaline phosphatase. These are usually reversible when gemfibrozil is discontinued. Therefore, periodic liver function studies are recommended and GEMFIBROZIL therapy should be terminated if abnormalities persist.

Hepatobiliary Disease - In patients with a past history of jaundice or hepatic disorder,

GEMFIBROZIL should be used with caution.

Cardiac Arrhythmias - Although no clinically significant abnormalities occurred that could be attributed to gemfibrozil, the possibility exists that such abnormalities may occur.

Drug Interactions – Repaglinide

Serious cases of hypoglycemia have been reported following the concomitant use of repaglinide and gemfibrozil. This was likely due to inhibition of CYP 2C8 by gemfibrozil as evidenced by decreases in blood glucose that were proportional to the dose of gemfibrozil. In healthy volunteers, the levels of repaglinide were significantly increased when co-administered with gemfibrozil. The averaged area under the curve (AUC) was increased 8-fold (range 6- to 15-fold)

and the half-life increased 3-fold. When itraconazole, an inhibitor of CYP 3A4, was also given with gemfibrozil and repaglinide, even greater effects were observed: AUC for repaglinide was increased 19-fold and the half-life increased from 1.3 to 6 hours.

ADVERSE REACTIONS

Pre-Marketing Studies

Gemfibrozil has been carefully evaluated in over 3,000 patients having received the drug in monitored clinical studies prior to marketing. Symptoms reported during the controlled phase in studies of 805 subjects were considered for safety. The symptoms listed in Table 1 are those which occurred in at least 5 patients and all skin reactions whatever their incidence. The principal symptoms for which incidence was greater with gemfibrozil than with placebo involved the gastrointestinal system. Nausea and vomiting, and abdominal and epigastric pain occurred more often in the gemfibrozil group than in the placebo group. However, the incidence was low:

nausea, 4.3% with gemfibrozil versus 3.8% with placebo; vomiting, 2.3% versus 0.8%; abdominal pain, 6.4% versus 4.2%; and, epigastric pain, 3.4% versus 1.7%.

Table 1 - Incidence of Symptoms Reported in Controlled Pre-marketing Studies

_____________________________________________________________________________________

Symptom Gemfibrozil Placebo (n = 529) (n = 236) _____________________________________________________________________________________

Body as a Whole

dizziness 2.8% 4.2% chest pain 2.1% 1.7% fatigue 0.9% 0.4%

Integumentary

rash 2.5% 1.3% pruritis 0.8% 1.3% dermatitis 0.6% 0.4% urticaria 0.2% 0.0%

Musculoskeletal

pain in extremities 1.5% 1.7%

Gastrointestinal

abdominal pain 6.4% 4.2% diarrhea 4.9% 5.1% nausea 4.3% 3.8% epigastric pain 3.4% 1.7% vomiting 2.3% 0.8% flatulence 1.5% 2.1%

Endocrine

gout 0.9% 0.8% CNS

headache 2.3% 4.2% paresthesia 0.9% 0.4%

Special Senses

blurred vision 1.1% 0.8%

Number of Patients Withdrawn

for Clinical Symptoms 1.3% 1.3% _____________________________________________________________________________________

Post–Marketing Study (Helsinki Heart Study)

The long-term safety of gemfibrozil was established in the Helsinki Heart Study, a 5-year primary prevention Phase IV clinical trial. In the double-blind phase of the Helsinki Heart Study, 2,046 patients received gemfibrozil for up to 5 years. Table 2 lists the most frequently reported adverse events and includes those occurring in at least 1% of all subjects treated with gemfibrozil (i.e. 21 or more patients). Dyspepsia and abdominal pain occurred more often in the gemfibrozil group than the placebo group (19.6% versus 11.9% and 9.8% versus 5.6%, respectively, p < 0.05), while all other adverse events were similar in frequency between the two groups.

Table 2 - Incidence of Adverse Events in Controlled Phase of Helsinki Heart Study _____________________________________________________________________________________

Gemfibrozil Placebo Adverse Event (n=2,046) (n=2,035) _____________________________________________________________________________________

Body as a Whole

fatigue 3.8% 3.5% headache 1.2% 1.1%

Digestive System

dyspepsia 19.6% 11.9% abdominal pain 9.8% 5.6% diarrhea 7.2% 6.5% flatulence 5.3% 5.2% nausea and/or vomiting 2.5% 2.1% constipation 1.4% 1.3%

Nervous System

vertigo 1.5% 1.3%

Skin and Appendages

eczema 1.9% 1.2% rash 1.7% 1.3%

No. of Patients Withdrawn

Due to Adverse Events 10.4% 7.3% _____________________________________________________________________________________

SYMPTOMS AND TREATMENT OF OVERDOSAGE

While there has been no reported case of overdosage, symptomatic supportive measures should be taken should it occur.

DOSAGE AND ADMINISTRATION

The recommended dose of GEMFIBROZIL (gemfibrozil) for adults is 1200 mg administered in two divided doses (two 300 mg capsules or one 600 mg tablet twice a day) 30 minutes before the morning and evening meal. The maximum recommended daily dose is 1500 mg.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: gemfibrozil

Chemical name: 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid

Structural Formula:

Molecular formula: C₁₅H₂₂0₃

Molecular weight: 250.35

Description: Gemfibrozil is a white, waxy powder which is stable under ordinary conditions. The melting point is 58 - 61°C. Its solubility is 0.0019%

(w/v) in water and in acid, and over 1% in dilute base.

Composition

In addition to the active ingredient gemfibrozil, each capsule contains the non-medicinal ingredients methylcellulose, colloidal silicon dioxide_, magnesium stearate and croscarmellose sodium. The capsule shell contains the non-medicinal ingredients gelatin, sodium lauryl sulphate, silicon dioxide, sodium metabisulfite, titanium dioxide, FD&C red #3, D&C red #28, FD&C red #40 and FD&C blue #1. The capsule shell is imprinted with edible grey printing ink containing the non-medicinal colourants FD&C blue #2, FD&C yellow #6, FD&C red #40 and FD&C blue #1.

CH₃

CH₃

O(CH₂)₃C(CH₃)₂COOH

In addition to the active ingredient gemfibrozil, each tablet contains the non-medicinal ingredients methylcellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol and titanium dioxide.

Stability and Storage Recommendations

Capsules: Store at room temperature 15-30°C (59-86°F).

Tablets: Store between 15-25°C (59-77°F). Protect from moisture.

AVAILABILITY OF DOSAGE FORMS

GEMFIBROZIL-300 Capsules 300 mg: Each maroon and white capsule, imprinted “PRO 300”, contains 300 mg gemfibrozil. Available in bottles of 100 and 500.

GEMFIBROZIL-600 Tablets 600 mg: Each white, oval, biconvex, film-coated tablet, engraved

“PRO-600” on one side and plain on the other, contains 600 mg gemfibrozil. Available in bottles of 100 and 500 and in unit dose packages of 100.

PHARMACOLOGY

The hypolipidemic activity of gemfibrozil has been demonstrated in laboratory animals, with most of the work done with rats. Studies in normal rats showed that gemfibrozil was 15 times more active than clofibrate in reducing triglycerides at doses as low as 7.5 mg/kg over seven days.

However, it had no effect on total plasma cholesterol at any dose tested because it increased the

HDL fraction by 50% to 70%. Oral doses of 25 mg/kg/day administered to hyperlipidemic rats caused a 75% reduction in the triglyceride level, while clofibrate at four times that dose had no significant effect.

In cholesterol-fed rats with abnormally low HDL cholesterol levels, oral administration of gemfibrozil at doses of 12.5 to 50 mg/kg/day produced elevations in the HDL fraction of 200% to

600%. When lipids were extracted from the liver and measured, it was found that gemfibrozil had caused a dramatic reduction in the liver cholesterol content below the control level at both one and two weeks_, suggesting enhanced removal of previously deposited cholesterol.

The mechanism by which these actions occur has not been firmly established. Additional studies in rats suggest that gemfibrozil inhibits the incorporation of long-chain fatty acids into newly formed triglycerides and inhibits basal adipose tissue lipolysis. Gemfibrozil also inhibits the production and increases the turnover rate of the beta-apolipoprotein moiety of VLDL_, the resulting decrease in VLDL production providing the basis for the drug’s ability to reduce lipid levels.

Gemfibrozil has no significant cardiovascular or central nervous system activity.

CLINICAL PHARMACOLOGY AND PHARMACOKINETICS

Gemfibrozil is well absorbed from the gastrointestinal tract following oral administration to laboratory animals and humans.

In animals, gemfibrozil is excreted in both urine and feces. In rats and dogs, the major route of excretion is fecal, accounting for 47% and 62% of a given dose in the two species, respectively.

In monkeys, urinary excretion predominates, 62% of an administered dose being excreted by that route in four days; fecal excretion accounted for only 2% of the dose.

In human subjects, approximately 70% of a given dose is excreted in the urine, primarily as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is accounted for in the feces. Peak plasma levels occur in one to two hours following single doses. The mean half-life was approximately 1.5 hours following single doses and 1.3 hours following multiple doses. Plasma levels appear proportional to dose and do not demonstrate accumulation across time following multiple doses.

Three metabolic pathways have been identified. The first metabolic pathway is that of conjugation of gemfibrozil and its metabolites. The second, and presumably the principal route, involves hydroxylation of the metamethyl group of gemfibrozil, yielding a benzyl alcohol

(Metabolite II) that undergoes rapid oxidation to a benzoic acid metabolite (Metabolite III, the major metabolite). The third pathway involves hydroxylation of the aromatic ring to a phenol

(Metabolite I) which is further converted to a compound (Metabolite IV) with no intact carboxylic acid function but which is phenolic in nature.

CY2P8 inhibition by gemfibrozil can affect the metabolism of several major cardiovascular drugs such as amiodarone, verapamil, warfarin but also other drugs such as tolbutamide.

Gemfibrozil is also known to potently inhibit CYP2C9 activity. Therefore, CYP2C9 inhibition by gemfibrozil can affect the metabolism of several major cardiovascular drugs such as carvedilol and losartan but also other drugs such as diazepam and phenytoin.

CLINICAL EXPERIENCE

Gemfibrozil versus Placebo

In a large multicentre trial of 427 patients, 108 patients having Fredrickson Type Ila, 107 patients

Type lIb, and 212 patients Type IV hyperlipidemia, the effect of gemfibrozil on lipoprotein fractions was compared to that of placebo. In the initial, controlled phase of the trial, patients were randomly assigned to one of two treatment groups; subjects in group A received placebo for 6 weeks, then received increasing doses of gemfibrozil, 800 mg/day, 1200 mg/day and 1600 mg/day each dose for 6 weeks; those in group B received placebo for the entire period. Following this, the subjects entered a single-blind period in which the subjects in group B received the rising doses of gemfibrozil, and those in group A, after 6 weeks on placebo, entered a long-term, open label phase. The following lipid measurements were made: total cholesterol, triglycerides, very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins

(HDL).

Total Cholesterol: In patients with Type Ila and type lIb hyperlipoproteinemia, gemfibrozil therapy resulted in a statistically significant decrease of total cholesterol with all doses, except the 1200 mg dose among the Type Ila subjects. In patients with type IV hyperlipidemia, gemfibrozil had no significant effect on total cholesterol.

Triglycerides: In all three groups of patients, gemfibrozil therapy resulted in a significant decrease of serum triglyceride levels. At the 1200 mg daily dose, triglycerides were decreased by 44% in type Ila patients, by 45% in the type lIb group, and by 40% in type IV patients.

HDL-Cholesterol: In all three hyperlipoproteinemia types studied_, gemfibrozil therapy was associated with a significant elevation of the high density lipoprotein fraction. At the 1200 mg daily dose in type Ila, lIb and type IV patients, the increase of HDL–cholesterol was 24.6%, 19.5% and 17.4% respectively.

Measurement of HDL-cholesterol to total cholesterol ratio is often employed as a useful parameter in blood lipid profile. This ratio showed a significant increase during gemfibrozil therapy, amounting to 33%, 34% and 23%, respectively, in the three groups studied.

Following the controlled phase of the multicentre trial, 349 subjects entered a long-term open treatment phase with gemfibrozil. Total cholesterol, triglycerides and total LDL-cholesterol levels consistently remained below the baseline placebo values throughout the long-term trial. HDL-cholesterol and the HDL-cholesterol to total cholesterol ratio both consistently remained above the placebo baseline values during the long-term trial. By the end of 12 lunar months of treatment, the improvement in lipid values had increased for nearly every parameter. The greatest changes during the long-term treatment were observed in total cholesterol, LDL-cholesterol, total LDL-cholesterol and HDL-cholesterol to total cholesterol ratio. These results indicate that the improvement achieved during the control period was maintained or increased during the long-term trial.

Gemfibrozil versus Clofibrate

The lipid regulating effect of gemfibrozil was also studied against clofibrate. In a study of

32 patients with type IIa, lIb or type IV hyperlipidemia, 17 patients were treated with gemfibrozil,

1200 mg per day, and 15 patients with clofibrate, 2000 mg per day, for 18 weeks. The two drugs had similar effects on total plasma cholesterol, triglycerides and LDL-cholesterol levels, but gemfibrozil had significantly greater effect in elevating HDL-cholesterol and HDL/total cholesterol ratios. The mean percent increases in HDL-cholesterol levels were 22.4% with gemfibrozil and

8.6% with clofibrate, while the HDL/total cholesterol ratio increased 43.0% with gemfibrozil and

25.9% with clofibrate.

Primary-Prevention Trial (Helsinki Heart Study)

The Helsinki Heart Study investigated the effect of gemfibrozil on the incidence of coronary heart disease (CHD) in a randomized, double-blind, five-year trial in middle-aged men (40 to 55 years of age) who were free of coronary heart symptoms on entry, but were at a high risk because of abnormal levels of blood lipids (i.e. non-HDL-cholesterol > 200 mg/dl). The study was aimed at testing the hypothesis that reducing serum total cholesterol and LDL-cholesterol, and increasing

HDL–cholesterol with gemfibrozil would reduce the incidence of cardiac disease. One group of men (2,046) received 1200 mg (600 mg b.i.d.) of gemfibrozil per day and another group (2,035) received placebo. In terms of Fredrickson types, the subjects entered into the study were distributed as follows:

Treatment

Group Fredrickson Type Total Number

Type IIa Type IIb Type IV Type V

Gemfibrozil 1293 570 182 1 2,046 Placebo 1297 561 177 0 2,035

Serum lipids (i.e. total triglycerides, total cholesterol, LDL-cholesterol, and HDL cholesterol) were measured periodically during the study. Efficacy of treatment was determined by comparing the incidence of cardiovascular endpoints (i.e. fatal and nonfatal myocardial infarction, sudden and unwitnessed cardiac death) on an intent-to-treat basis.

Gemfibrozil caused a marked change in the serum lipid levels of patients. The lipid changes occurred rapidly, being noted during the first 3-months of treatment and persisted over the 5-year treatment period. The percent changes in serum lipid levels of the gemfibrozil group by

Fredrickson type averaged across the 5-year study period relative to baseline are shown in the following table:

% Change From Baseline in Gemfibrozil Group Over 5–Year Period

Serum Lipid

Parameter

Type Ila (n=1,293)

Type IIb (n=570)

Type IV (n=182)

All Subjects (2,046)* Triglycerides

Total Cholesterol

LDL-Cholesterol

HDL-Cholesterol

Non-HDL-Cholesterol

-26.3% -9.2% -11.4% +8.5% -13.5%

-44.3% -8.6% -4.1% +11.7% -12.7%

-49.9% -5.0% +4.8% +9.6% -7.8%

-37.3% -8.7%

-8.2%

+9.0%

-12.5% *One subject was a Fredrickson Type V.

In the gemfibrozil group, decreases of 37%, 9%, 8% and 12.5% occurred in triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol respectively, and HDL-cholesterol increased by 9%. In contrast, changes in serum lipid levels of the placebo group over the 5-years relative to baseline were small and inconsistent. Statistical analyses revealed a significant difference between the gemfibrozil group and placebo group for every lipid parameter at each year and across all years (p<0.001). Statistical differences were also evident for all lipid parameters between treatment groups by Fredickson type at each year and across all years

(p<0.001), with the exception of LDL-cholesterol in Type IV subjects.

The annual frequency of cardiovascular endpoints over the 5-year study period is shown in the table below:

Treatment and Endpoind Year Total Number

(Rate/1,000) 1 2 3 4 5

Number of Subjects Gemfibrozil (N=2,046):

Nonfatal MI*

Fatal MI

Sudden CD*

Unwitnessed CD*

Total

Placebo (N=2,035):

Nonfatal MI

Fatal MI

Sudden CD*

Unwitnessed CD*

Total

45 (22.0)**

6 (2.9)

5 (2.4)

0 (0.0)

56 (27.4)

71 (34.9) 8 (3.9)

4 (2.0)

1 (0.5)

84 (41.3)

* MI = myocardial infarction; CD = cardiac death.

** Three subjects in the gemfibrozil group and 6 in the placebo group died later after surviving previous MI.

The effect of gemfibrozil on the incidence of cardiovascular endpoints was first established during the third year and became more prominent over years 4 and 5 of the study. Analyses of the incidence of cardiovascular endpoints on an intent-to-treat basis revealed that over the 5-year study period, the gemfibrozil group experienced a 34% reduction in the overall incidence of CHD compared to placebo (27.4 per 1,000 in the gemfibrozil group versus 41.3 per 1,000 in the placebo group); in years 3 to 5 of the study, the reduction in CHD was greater than 50%. There was an overall 37% reduction in nonfatal myocardial infarction (22.0 per 1,000 in the gemfibrozil group versus 34.9 per 1,000 in the placebo group) and a 26% reduction in cardiac deaths (14 deaths in total or 6.8 per 1,000 in the gemfibrozil group versus 19 deaths in total or 9.3 per 1,000 in the placebo group). The greatest reduction in incidence of serious cardiac events occurred in

Type lIb patients.

The data from the Helsinki Heart Study suggested that the correlation between changes in lipids

(increasing HDL-cholesterol 8.0% and decreasing LDL-cholesterol 7.3%) and reducing CHD incidence should have brought reductions of 23% and 15% respectively in CHD incidence. When the joint effects of HDL-cholesterol (+8.0%) and LDL-cholesterol (-7.3%) were taken into consideration simultaneously, the predicted reduction in CHD incidence was 28% in the gemfibrozil group.

There was no difference between the groups in the total death rate (all causes) over the 5-year study period.

LITHOGENICITY

Pre-Marketing Study

The effect of gemfibrozil on gallstone formation was studied both in normal volunteers and in hyperlipidemic subjects.

In 10 healthy male volunteers, gemfibrozil and clofibrate were studied according to a cross-over design. Changes in concentrations of bile phospholipid, cholesterol and bile acid were measured and a lithogenic index was calculated. While clofibrate showed a significant potential for lithogenicity, the gemfibrozil results were not significantly different from baseline.

Since the above study suggested a low lithogenic potential for gemfibrozil, further studies were carried out in a group of over 200 patients with dyslipoproteinemias who received gemfibrozil for

2 years or more and who had cholecystograms immediately prior to receiving the drug and at 1-year and 2-year intervals. During the period of study, 5 patients developed radiological evidence of cholelithiasis, an annual incidence of 1.21%. This figure is not different from the incidence of newly observed gallstones in the general population. Based on these data, gemfibrozil does not seem to have a significant lithogenic potential.

Post-Marketing Study

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% in the placebo group). In addition, more patients underwent surgical operations

(cholecystectomy, cholecystotomy, appendectomy) while on gemfibrozil therapy.

TOXICOLOGY

Acute Toxicity

LD₅₀ (mg/kg) Species Sex Oral I.P. Mice M & F 3162 380 Rat M & F 4786 360

The effects of single dose gemfibrozil administration to mice and rats showed that the toxicity of the drug was low. Clinical signs of intolerance were similar for both species and included incoordination, depression, flaccid prostration and dyspnea. The only microscopic change was hepatocellular enlargement.

Two beagle dogs were given increasing daily doses of gemfibrozil over a 49-day period. At a dose level of 500 mg/kg, signs of intolerance, such as occasional vomiting and decreased activity, were observed. As the dose level was increased_, these symptoms became more frequent and prominent, and finally anorexia, weight loss, and incoordination occurred. One dog died following a dose of 875 mg/kg. At autopsy, congestion and focal mucosal hemorrhage were the only prominent gross findings.

Chronic Toxicity

Gemfibrozil was administered to rats and dogs for 12 months. The rats were given daily doses of

30, 150 and 300 mg/kg and the dogs received 25, 150 and 300 mg/kg - the top dose level representing about 15 times the average effective daily human dose.

The 12-month study in rats showed only a dose–related suppression of weight gain. There were fluctuations in hematological and blood biochemical values, but they were neither consistent nor clearly dose-related. Microscopic findings revealed that abnormalities were confined to the liver and consisted primarily of an abundance of microbodies and a marked increase in smooth endoplasmic reticulum in the cell cytoplasm. Such changes are thought to be adaptive rather than degenerative.

In the one–year dog study, gemfibrozil was clinically well–tolerated. Gross autopsy disclosed no drug–related abnormalities. Histopathologic findings revealed that the Increase in microbodies, as observed In rats, was not a prominent feature in the hepatocytes of the dogs.

Tumorigenicity Studies

Gemfibrozil was given as a dietary admixture at daily doses of 30 and 300 mg/kg to two groups of

50 rats of each sex for 2 years, and another group of 50 rats served as untreated controls.

Histologically, 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>0.05) There were no statistically significant differences from controls in the incidence of liver tumors in female rats. Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation following gemfibrozil administration to male rats. Similar changes have not been found in the human liver based on biopsy material.

An 18–month study was conducted in mice. Gemfibrozil at daily doses of 30 and 300 mg/kg was given as a dietary admixture to two groups of 72 mice per sex, and an additional group of 72 mice of each sex served as untreated controls. A number of animals died during the course of the study; these deaths were equally distributed among the different groups and no significant differences in mortality rates were found. There were no significant clinical or ophthalmic changes attributable to gemfibrozil. A slight to moderate weight gain suppression occurred in treated animals in a dose related fashion. No histopathological changes were attributed to gemfibrozil except for slight hypertrophy and increased eosinophilia of hepatocytes in the centrolobular area in high dose males. Tumors occurred randomly and there were no statistically significant differences from controls in the incidence of liver tumors in treated male and female mice.

Reproduction and Teratology Studies

Gemfibrozil was administered in oral doses of approximately 95 and 325 mg/kg/day to male and female rats for 61 and 15 days respectively before mating. Dosing was continued through pregnancy and weaning of offspring. Gemfibrozil produced a dose–related suppression of fertility but had no effect on length of gestation, duration of parturition, litter size, or embryonic or fetal wastage. Treated males were responsible for the reduced fertility rate, probably because of the marked suppression of weight gain they experienced.

Gemfibrozil was administered to pregnant rats and rabbits during the critical period of organogenesis. Rats were given gemfibrozil in the diet in doses of 81 and 281 mg/kg on days 6 through 15 of gestation.

Artificially inseminated rabbits were given gemfibrozil by gavage at 60 and 200 mg/kg on days 6 through 18 of gestation. Examination of fetuses removed from treated rats and rabbits one day before expected parturition disclosed no significant effects on either litter or fetal characteristics, nor were significant malformations found among almost 400 offspring from 36 litters of treated rats or 100 fetuses from 22 litters of treated rabbits.

Mutagenicity

Gemfibrozil was studied under standard test conditions for point mutations by the Ames test.

Five strains of Salmonella typhimurium and 3 concentrations of gemfibrozil, (100, 500 and 2500 mcg/plate), with and without metabolic activation, were tested. The resultant number of revertant colonies, in the presence or absence of metabolic activation, was not increased over control at any concentration tested in the five strains. It was concluded that gemfibrozil showed no mutagenic potential in the five strains of Salmonella tested.

BIBLIOGRAPHY

1. 1. Borresen A-L, Berg K, Dahlen G, Gillnas T, Ericson C. The effect of gemfibrozil on human serum apolipoproteins and on serum reserve cholesterol binding capacity (SRCBC). Artery 1981; 9:77-86.
2. 2. Dahlen G, Gillnas T, Borresen A-L, Berg K, Ericson C. Effect of gemfibrozil on serum lipid levels. Artery 1980; 7:224-231.
3. 3.

   de Salcedo I, Gorringe JAL, Luis Silva J, Santos JA. Gemfibrozil in a group of diabetics.

   Proc Roy Soc Med 1976; 69 (Suppl 2):64-70.

4. 4. Elkeles RS, Ashwell M, Priest R, Durrant M. The effect of CI-719 on lipolysis in rat adipose tissue. Proc Roy Soc Med 1976; 69 (Suppl 2):98-100.
5. 5. Fenderson RW, Deutsch S, Menachemi E, Chin B, Samuel P. Effect of gemfibrozil on serum lipids in man. Angiology 1982; 33:581-593.
6. 6.

   Hodges RM, Marcus EL. Safety of gemfibrozil (Lopid) in clinical use. Res Clin Forum 1982;

   4:35-40.

7. 7. Kaukola S, Manninen V, Malkonen M, Ehnholm C. Gemfibrozil in the treatment of dyslipidemias in middle–aged survivors of myocardial infarction. Acta Med Scand 1981; 209:69-73.
8. 8. Kesaniemi YA, Grundy SM. Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. JAMA 1984; 251:2241-2246.
9. 9.

   Kissebah AH, Adams PA, Wynn V. Lipokinetic studies with gemfibrozil (CI-719). Proc Roy

   Soc Med 1976; 69 (Suppl 2):94-97.

10. 10. Komatsu T, Yamazaki H, Asahi S, et al. Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol: Roles of cytochromes P450 2C9, 2C19, and 3A4. Drug Metabol Disposition 2000;28(11):1361-8.
11. 11. Konttinen A, Kuisma I, Ralli R, Pohjola S, Ojala K. The effect of gemfibrozil on serum lipids in diabetic patients. Ann Clin Res 1979; 11:240-245.
12. 12. Kurtz SM, Fitzgerald JE, Fisken RA, Schardein JL, Reutner TH, et al. Toxicological studies on gemfibrozil. Proc Roy Soc Med 1976; 69 (Suppl 2):15-23.
13. 13.

    Lewis JE. Long–term use of gemfibrozil (Lopid) in the treatment of dyslipidemia. Angiology

    1982; 33:603-612.

14. 14. Lewis JE. Multicenter Collaborative Study Group. Clinical use of gemfibrozil: a controlled multicenter trial. Pract Cardiol 1983; 9:99-118.
15. 15. Manninen V, Malkonen M, Eisalo A, Virtamo J, Tuomilehto J, et al. Gemfibrozil in the treatment of dyslipidemia: a 5–year follow–up study. Acta Med Scand 1982; (Suppl-668):82-87.
16. 16.

    Maxwell RE, Nawrocki JW, Uhlendorf PD. Effects of gemfibrozil (CI-719), gemcadiol (CI-

    720), clofibrate and U-41792 on cholesterol distribution in rat plasma fractions obtained by polyanion precipitation. Artery 1978; 4:303-313.

17. 17. Nash DT. Gemfibrozil - a new lipid-lowering agent. J Med 1980; 11:107-116.
18. 18.

    Nash DT. Hyperlipoproteinemia, artherosclerosis and gemfibrozil. Angiology 1982; 33:594-

    602.

19. 19.

    Nash DT. Clinical investigation of gemfibrozil: gemfibrozil versus clofibrate. Cardiovasc Rev

    Rep 1982; 3:1207-1214.

20. 20. Niemi M, Neuvonen PJ, Kivistö KT. Effect of gemfibrozil on the pharmacokinetic and pharmacodynamics of glimepiride. Clin Pharmacol Ther 2001;70:439-45.
21. 21. Nye ER, Sutherland WHF, Temple WA. The treatment of hyperlipoproteinemia with gemfibrozil compared with placebo and clofibrate. NZ Med J 1980; 92:345-349.
22. 22.

    Ohyama K, Nakajima M, Nakamura S, et al. A significant role of human cytochrome P450

    2C8 in amiodarone N-deethylation: An approach to predict the contribution with relative activity factor. Drug Metabol Disposition 2000;28(11):1303-10.

23. 23.

    Okerholm RA, Keeley FJ, Peterson FE, Glazko AJ. The metabolism of gemfibrozil. Proc Roy

    Soc Med 1976; 69 (Suppi 2):11-14.

24. 24. Oldham HG, Clarke SE. In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+) and S(-)-carvedilol. Drug Metabol Disposition 1997;25(8):970-7.
25. 25. Rodney G, Uhlendorf P, Maxwell RE. The hypolipidaemic effect of gemfibrozil (CI-719) in laboratory animals. Proc Roy Soc Med 1976; 69 (Suppl 2):6-10.
26. 26. Samuel P. Effects of gemfibrozil on serum lipids. Am J Med 1983; 74 (5A) :23-27.
27. 27. Schwandt P, Weisweiler P, Neureuther G. Serum lipoprotein lipids after gemfibrozil treatment. Artery 1979; 5:117-124.
28. 28. Seed M, Niththyananthan R, Wynn V. Long–term treatment of hyperlipidemia with gemfibrozil. Res Clin Forum 1982;4:55-68.
29. 29. Tracy TS, Korzekwa KR, Gonzalez FJ, et al. Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharmacol 1999;47:545-52.
30. 30. Tuomilehto J, Salonen J, Kuusisto P, Virtamo J, Manninen V, et al. A clofibrate–controlled trial of gemfibrozil in the treatment of hyperlipidaemlas. Proc Roy Soc Med 1976; 69 (Supp 2):38-40.
31. 31.

    Wen X, Wang JS, Backman JT, et al. Gemfibrozil is a potent inhibitor of human cytochrome

    P450 2C9. Drug Metabolism Disposition 2001;29(11):1359-61.