GEMFIBROZIL
DESCRIPTION:
Lopid(R) (gemfibrozil tablets, USP) is a lipid regulating agent.
The empirical formula is C15H22O3 and the molecular weight is 250.35; the
solubility in water and acid is 0.0019% and in dilute base it is greater than
1%. The melting point is 58 deg- 61 deg C. Gemfibrozil is a white solid which is
stable under ordinary conditions.
ACTIONS/CLINICAL PHARMACOLOGY:
Lopid (gemfibrozil tablets, USP) 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 Lopid
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 Lopid
treatment; however, Lopid usually raises HDL-cholesterol significantly in this
group. Lopid increases levels of high density lipoprotein (HDL) subfractions
HDL2 and HDL3, 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 (REF. 1,2), in
which 4081 male patients between the ages of 40 and 55 were studied in a
randomized, double-blind, placebo- controlled fashion, Lopid 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 Lopid 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 5-year study period, the
Lopid 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 Lopid randomization group and 43 (2.1%) in the
placebo group.
TABLE I
Reduction in CHD Rates (events per 1000 patients) by Baseline
Lipids(1) in the Helsinki Heart Study, Years 0-5(2)
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All LDL-C > 175; LDL-C > 175; LDL-C > 175;
Patients HDL-C > 46.4 TG > 177 TG > 200;
HDL-C < 35
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P L Dif(3) P L Dif P L Dif P L Dif
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Incidence of
Events(4) 41 27 14 32 29 3 71 44 27 149 64 85
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1 lipid values in mg/dL at baseline
2 P=placebo group; L=Lopid group
3 difference in rates between placebo and Lopid groups
4 fatal and nonfatal myocardial infarctions plus sudden cardiac deaths
(events per 1000 patients over 5 years)
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 Lopid 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 5 years in
the gemfibrozil group compared to placebo. The difference in coronary events was
substantially greater between Lopid 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 (<0.90 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 Lopid; without knowledge of their own lipid values or
double-blind treatment, 60% of patients originally randomized to placebo began
therapy with Lopid and 60% of patients originally randomized to Lopid continued
medication. After approximately 6.5 years following randomization, all patients
were informed of their original treatment group and lipid values during the 5
years of the double-blind treatment. After further elective changes in Lopid
treatment status, 61% of patients in the group originally randomized to Lopid
were taking drug; in the group originally randomized to placebo, 65% were taking
Lopid. 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(1)
Group: PDrop PN PL LDrop LN LL
N=215 N=494 N=1283 N=221 N=574 N=1207
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Cardiac
Events 38.8 22.9 22.5 37.2 28.3 25.4
All-Cause
Mortality 41.9 22.3 15.6 72.3 19.2 24.9
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1 The six open-label groups are designated first by the original
randomization (P = placebo, L = Lopid) and then by the drug taken in the
follow-up period (N = Attend clinic but took no drug, L = Lopid, Drop =
No attendance at clinic during open-label).
Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in
the group originally randomized to Lopid versus the originally randomized
placebo group and a 20% relative decrease in cardiac events in the group
originally randomized to Lopid 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, Year 0-8.5.(1)
Lopid:
Event Lopid Placebo Placebo
at Study at Study Hazard Cl Hazard(3)
Start Start Ratio(2) Ratio
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Cardiac
Events(4) 110 131 0.80 0.62-1.03
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Cardiac
Deaths 36 38 0.98 0.63-1.54
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Non-Cardiac
Deaths 65 45 1.40 0.95-2.05
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All-Cause
Mortality 101 83 1.20 0.90-1.61
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1 Intention-to-Treat Analysis of originally randomized patients neglecting
the open-label treatment switches and exposure to study conditions.
2 Hazard ratio for risk of event in the group originally randomized to Lopid
compared to the group originally randomized to placebo neglecting
open-label treatment switch and exposure to study condition.
3 95% confidence intervals of Lopid:placebo group hazard ratio.
4 Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over
the 8.5 year period.
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 5 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
(REF. 3). 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 (Lopid:placebo) for cardiac events was 1.47 (95% confidence limits
0.88-2.48, p = 0.14). Of the 35 patients in the Lopid 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 Lopid group and 8 in the placebo group (hazard ratio 2.18; 95%
confidence limits 0.94-5.05, p = 0.06). Ten of these deaths in the Lopid 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 Lopid treatment was observed in reducing cardiac events or cardiac deaths.
Thus, Lopid 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, elevated
triglycerides, plus low HDL-cholesterol, the possible effect of Lopid 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, Lopid has been shown to inhibit peripheral lipolysis and to decrease the
hepatic extraction of free fatty acids, thus reducing hepatic triglyceride
production. Lopid 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. Lopid 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.
Plasma levels appear proportional to dose and do not demonstrate accumulation
across time following multiple doses.
Lopid 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.
INDICATIONS AND USAGE:
Lopid (gemfibrozil tablets, USP) is 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.
Lopid 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 Lopid 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 (REF.
4).
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
ACTIONS/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 (REF. 5).
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 NONCORONARY 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. LOPID IS 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 46.4mg/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.
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 5 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 5 years and followed one year beyond. There was
a statistically significant, 44%, higher age-adjusted total mortality in the
clofibrate-treated than in a comparable placebo- treated control group during
the trial period. The excess mortality was due to a 33% increase in
noncardiovascular 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 Lopid and placebo group is
not statistically significantly different from the 29% excess mortality reported
in the clofibrate group in the separate WHO study at the 9 year follow-up (see
ACTIONS/CLINICAL PHARMACOLOGY). Noncoronary heart disease related mortality
showed an excess in the group originally randomized to Lopid primarily due to
cancer deaths observed during the open-label extension.
During the 5 year primary prevention component of the Helsinki Heart Study
mortality from any cause was 44 (2.2%) in the Lopid 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 Lopid 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 Lopid 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 9 year follow-up. Noncoronary heart disease related
mortality showed an excess in the group originally randomized to Lopid at the
8.5 year follow-up (65 Lopid 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 Lopid and 9 in the group randomized to
placebo (p = 0.22). There were 30 (1.5%) deaths attributed to cancer in the
group originally randomized to Lopid 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 ACTIONS/CLINICAL PHARMACOLOGY.)
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 Lopid treatment group (7.5% vs 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 Lopid group (17 vs 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. Lopid therapy should be discontinued if gallstones are found.
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, Lopid should be administered only to those patients described
in the INDICATIONS AND USAGE section. If a significant serum lipid response is
not obtained, Lopid should be discontinued.
4. Concomitant Anticoagulants--Caution should be exercised when anticoagulants
are given in conjunction with Lopid. 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.
5. Concomitant therapy with Lopid and Mevacor(R) (lovastatin) has been
associated with rhabdomyolysis, markedly elevated creatine kinase (CK) levels
and myoglobinuria, leading in a high proportion of cases to acute renal failure.
IN VIRTUALLY ALL PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE TO
EITHER DRUG ALONE, ANY POTENTIAL LIPID BENEFIT OF COMBINED THERAPY WITH
LOVASTATIN AND GEMFIBROZIL DOES NOT OUTWEIGH THE RISKS OF SEVERE MYOPATHY,
RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE (see Drug Interactions). The use of
fibrates alone, including Lopid, may occasionally be associated with myositis.
Patients receiving Lopid 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, Lopid 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.
PRECAUTIONS:
1. INITIAL THERAPY--Laboratory studies should be done to ascertain that the
lipid levels are consistently abnormal. Before instituting Lopid 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 3 months of
therapy.
3. DRUG INTERACTIONS--(A) HMG-COA REDUCTASE INHIBITORS: Rhabdomyolysis has
occurred with combined gemfibrozil and lovastatin therapy. It may be seen as
early as 3 weeks after initiation of combined therapy or after several months.
In most subjects who have had an unsatisfactory lipid response to either drug
alone, the possible benefit of combined therapy with lovastatin (or other HMG-
CoA reductase inhibitors) and gemfibrozil does not outweigh the risks of severe
myopathy, rhabdomyolysis, and acute renal failure. 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 ANTICOAGULANTS ARE GIVEN IN
CONJUNCTION WITH LOPID. 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.
4. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY--LONG-TERM STUDIES HAVE
BEEN CONDUCTED IN RATS AT 0.2 and 2 times the human dose (based on surface area,
mg/meter(square)). Based on two- week toxicokinetic studies, exposure (AUC) of
the dose groups was estimated to be 0.2 and 1.3 times the human exposure. 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 1 times the human dose
(based on surface area). Based on two-week toxicokinetic studies, exposure (AUC)
of the two dose groups was estimated to be 0.1 and 0.7 times the human exposure.
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 Lopid 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 0.6 and 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 CATEGORY C--Lopid 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) but no developmental toxicity or teratogenicity among offspring of either
species. There are no adequate and well- controlled studies in pregnant women.
Lopid should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Administration of Lopid to female rats at 0.6 and 2 times the human dose (based
on surface area) before and throughout gestation caused a dose- related decrease
in conception rate and, at the high dose, 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
Lopid 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 Lopid
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 Lopid 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
Lopid 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 Lopid administration.
8. LIVER FUNCTION--Abnormal liver function tests have been observed occasionally
during Lopid administration, including elevations of AST (SGOT), ALT (SGPT),
LDH, bilirubin, and alkaline phosphatase. These are usually reversible when
Lopid is discontinued. Therefore periodic liver function studies are recommended
and Lopid therapy should be terminated if abnormalities persist.
9. KIDNEY FUNCTION--There have been reports of worsening renal insufficiency
upon the addition of Lopid therapy in individuals with baseline plasma
creatinine >2.0 mg/dL. In such patients, the use of alternative therapy should
be considered against the risks and benefits of a lower dose of Lopid.
10. PEDIATRIC USE--Safety and efficacy in pediatric patients have not been
established.
DRUG INTERACTIONS:
(A) HMG-COA REDUCTASE INHIBITORS: Rhabdomyolysis has occurred with combined
gemfibrozil and lovastatin therapy. It may be seen as early as 3 weeks after
initiation of combined therapy or after several months. In most subjects who
have had an unsatisfactory lipid response to either drug alone, the possible
benefit of combined therapy with lovastatin (or other HMG-CoA reductase
inhibitors) and gemfibrozil does not outweigh the risks of severe myopathy,
rhabdomyolysis, and acute renal failure. 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 ANTICOAGULANTS ARE GIVEN IN
CONJUNCTION WITH LOPID. 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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
In the double-blind controlled phase of the primary prevention component of the
Helsinki Heart Study, 2046 patients received Lopid for up to 5 years. In that
study, the following adverse reactions were statistically more frequent in
subjects in the Lopid group:
LOPID PLACEBO
(N=2046) (N=2035)
Frequency in
percent of subjects
Gastrointestinal reactions 34.2 23.8
Dyspepsia 19.6 11.9
Abdominal pain 9.8 5.6
Acute appendicitis 1.2 0.6
(histologically confirmed in most
cases where data were available)
Atrial fibrillation 0.7 0.1
Adverse events reported by more than 1% of subjects, but without a significant
difference between groups:
Diarrhea 7.2 6.5
Fatigue 3.8 3.5
Nausea/Vomiting 2.5 2.1
Eczema 1.9 1.2
Rash 1.7 1.3
Vertigo 1.5 1.3
Constipation 1.4 1.3
Headache 1.2 1.1
GALLBLADDER SURGERY was performed in 0.9% of Lopid 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
compared to the placebo group of the WHO study. Gallbladder surgery was also
performed more frequently in the Lopid group compared to placebo (1.9% vs 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 vs 0 on placebo, p = 0.014).
Nervous system and special senses adverse reactions were more common in the
Lopid group. These included hypesthesia, paresthesias, and taste perversion.
Other adverse reactions that were more common among Lopid 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 Lopid 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 Lopid 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 positive antinuclear
phosphokinase antibody
increased bilirubin
increased liver
transaminases (AST
(SGOT), ALT (SGPT))
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
dermatitis
pruritus
DOSAGE AND ADMINISTRATION:
The recommended dose for adults is 1200 mg administered in two divided doses 30
minutes before the morning and evening meal.
OVERDOSAGE:
There have been reported cases of overdosage with Lopid. In one case a 7 year
old child recovered after ingesting up to 9 grams of Lopid. Symptomatic
supportive measures should be taken should an overdose occur.
REFERENCES:
1. Frick MH, Elo O, Haapa K, et al: Helsinki Heart Study: Primary prevention
trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;
317:1237-1245.
2. Manninen V, Elo O, Frick MH, et al: Lipid alterations and decline in the
incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988;
260:641-651.
3. Frick MH, Heinonen OP, et al: Efficacy of Gemfibrozil in Dyslipidemic
Subjects with suspected Heart Disease. An Ancillary Study in the Helsinki Heart
Study Frame Population. Annals Of Medicine 1993; 25:41-45.
4. Nikkila EA: Familial lipoprotein lipase deficiency and related disorders of
chylomicron metabolism. In Stanbury J.B. et al. (eds.): The Metabolic Basis Of
Inherited Disease, 5th ed., McGraw-Hill, 1983, Chap. 30, pp. 622-642.
5. Report of the National Cholesterol Education Program Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol. Arch Int Med
1988;148:36-69.
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