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the drug withdrawn if lipid response is inadequate after three months of therapy.
3. Drug Interactions–(A) HMG-CoA reductase inhibitors: The risk of myopathy and
rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase
inhibitor therapy (see CONTRAINDICATIONS). 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 (refs. 8, 9, 10, 11). (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 ANTI-COAGULANTS 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.
(C ) Repaglinide: In vivo data from a study that evaluated the co-administration of
gemfibrozil with repaglinide in healthy subjects resulted in a significant increase in
repaglinide blood levels. Patients taking repaglinide should not start taking gemfibrozil;
patients taking gemfibrozil should not start taking repaglinide. Concomitant use may
result in enhanced and prolonged blood glucose-lowering effects of repaglinide. Caution
should be used in patients already on repaglinide and gemfibrozil – blood glucose levels
should be monitored and repaglinide dose adjustment may be needed. Rare post
marketing events of serious hypoglycemia have been reported in patients taking
repaglinide and gemfibrozil together. In this same study, gemfibrozil and itraconazole
had a synergistic metabolic inhibitory effect on repaglinide. Therefore, patients taking
repaglinide and gemfibrozil should not take itraconazole.
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 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 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). 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 at2 times the human dose (based on surface area)
before and throughout gestation caused a dose-related decrease in conception rate and,
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.