**LOPID^^\
(Gemfibrozil Tablets, USP)**

**DESCRIPTION**

LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is
available as tablets for oral administration. Each tablet contains 600
mg gemfibrozil. Each also contains calcium stearate, NF; candelilla wax,
FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF;
hydroxypropylmethylcellulose, USP; methylparaben, NF; Opaspray white;
polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF;
colloidal silicon dioxide, NF; pregelatinized starch, NF. The chemical
name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, with the
following structural formula:

![](media/image1.png){width="2.525in" height="1.0666666666666667in"}

The empirical formula is C~15~H~22~O~3~ 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° -61° C. Gemfibrozil is a
white solid which is stable under ordinary conditions.

**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 HDL~2~
and HDL~3~, 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 (refs.
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 five-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^

<table>
<colgroup>
<col style="width: 16%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="3"><p>All</p>
<p>Patients</p></td>
<td colspan="3"><p>LDL-C&gt;175;</p>
<p>HDL-C&gt;46.4</p></td>
<td colspan="3"><p>LDL-C&gt;175;</p>
<p>TG&gt;177</p></td>
<td colspan="3"><p>LDL-C&gt;175;</p>
<p>TG&gt;200;</p>
<p>HDL-C&lt;35</p></td>
</tr>
<tr class="even">
<td></td>
<td>P</td>
<td>L</td>
<td>Dif<sup>3</sup></td>
<td>P</td>
<td>L</td>
<td>Dif</td>
<td>P</td>
<td>L</td>
<td>Dif</td>
<td>P</td>
<td>L</td>
<td>Dif</td>
</tr>
<tr class="odd">
<td>Incidence of</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Events<sup>4</sup></td>
<td>41</td>
<td>27</td>
<td>14</td>
<td>32</td>
<td>29</td>
<td>3</td>
<td>71</td>
<td>44</td>
<td>27</td>
<td>149</td>
<td>64</td>
<td>85</td>
</tr>
</tbody>
</table>

> ^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 five 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
five 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
> HeartStudy^1^

  ----------- ---------- --------- ---------- ---------- ---------- ----------
  Group:      PDrop      PN        PL         LDrop      LN         LL

              N=215      N=494     N=1283     N=221      N=574      N=1207

  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
  ----------- ---------- --------- ---------- ---------- ---------- ----------

> ^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, Years 0-8.5^1^

  --------------- ------------ ----------- ------------------- ------------
  Event           LOPID        Placebo     LOPID:Placebo       

                  at Study     at Study    Hazard              Cl Hazard

                  Start        Start       Ratio^2^            Ratio^3^

  Cardiac                                                      

  Events^4^       110          131         0.80                0.62-1.03

  Cardiac                                                      

  Deaths          36           38          0.98                0.63-1.54

  Non-Cardiac                                                  

  Deaths          65           45          1.40                0.95-2.05

  All-Cause                                                    

  Mortality       101          83          1.20                0.90-1.61
  --------------- ------------ ----------- ------------------- ------------

> ^1^Intention-to-Treat Analysis of originally randomized patients
> neglecting the open-label treatment switches and exposure to study
> conditions.
>
> ^2^Hazard ration for risk 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 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 (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.

Gemfibrozil is completely absorbed after oral administration of LOPID
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 14-44%
when LOPID was administered after meals compared to 0.5 hour before
meals. In a subsequent study (ref. 4), rate of absorption of LOPID was
maximum when administered 0.5 hour before meals with the Cmax 50-60%
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).

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.
Gemfibrozil is highly bound to plasma proteins and there is potential
for displacement interactions with other drugs (see PRECAUTIONS).

**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. 5).

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 (ref. 6). 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. 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 46.4
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\. Combination therapy of LOPID with cerivastatin due to the increased
risk of myopathy and rhabdomyolysis (see WARNINGS).

2\. Hepatic or severe renal dysfunction, including primary biliary
cirrhosis.

3\. Preexisting gallbladder disease (see WARNINGS).

4\. Hypersensitivity to gemfibrozil.

**[WARNINGS]{.mark}**

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 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 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 nine year follow-up (see 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 five 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 nine 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 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), 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 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. Cases of cholelithiasis have been reported with gemfibrozil
therapy (ref. 7).

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 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. **Because of an observed marked increased risk of
myopathy and rhabdomyolysis, the specific combination of LOPID and
cerivastatin is absolutely contraindicated (see**
**CONTRAINDICATIONS)**. IN PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID
RESPONSE TO EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH
LOPID AND HMG-CoA REDUCTASE INHIBITORS OTHER THAN CERIVASTATIN DOES NOT
OUTWEIGH THE RISKS OF SEVERE MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL
FAILURE (refs. 8, 9, 10, 11) (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 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.

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.

**[ADVERSE REACTIONS]{.mark}**

In the double-blind controlled phase of the primary prevention component
of the Helsinki Heart Study, 2046 patients received LOPID for up to five
years. In that study, the following adverse reactions were statistically
more frequent in subjects in the LOPID group:

![](media/image2.png){width="4.041666666666667in"
height="2.8645833333333335in"}

**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:

![](media/image3.png){width="3.55in" height="5.391666666666667in"}

Additional adverse reactions that have been reported include
cholecystitis and cholelithiasis (ref. 12) (see WARNINGS).

**DOSAGE AND ADMINISTRATION**

The recommended dose for adults is 1200 mg administered in two divided
doses 30 minutes before the morning and evening meal (see CLINICAL
PHARMACOLOGY).

**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.
Symptoms reported with overdosage were abdominal cramps, abnormal liver
function tests, diarrhea, increased CPK, joint and muscle pain, nausea
and vomiting. Symptomatic supportive measures should be taken, should an
overdose occur.

**HOW SUPPLIED**

LOPID (Tablet 737), white, elliptical, film-coated, scored tablets, each
containing 600 mg gemfibrozil, are available as follows:

N 0071-0737-20: Bottles of 60

N 0071-0737-30: Bottles of 500

Parcode^®^ No. 737

Store at controlled room temperature 20° - 25°C (68° - 77°F) \[see
USP\]. Protect from light and humidity.

**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\. Data on file. Parke-Davis; Morris Plains, NJ.

5\. Nikkila EA: Familial lipoprotein lipase deficiency and related
disorders of chylomicron metabolism. In Stanbury JB et al. (eds.): *The
Metabolic Basis of Inherited Disease*, 5th ed., McGraw-Hill, 1983, Chap.
30, pp. 622-642.

6\. 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.

7\. Data on file. Pfizer; NY, NY.

8\. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis
associated with lovastatin/gemfibrozil combination therapy. JAMA
1990;264:71-75.

9\. Bermingham RP, Whitsitt TB, Smart ML et al. Rhabdomyolysis in a
patient receiving the combination of cerivastatin and gemfibrozil. Am J
Health-Syst Pharm 2000;57:461-464.

10\. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking
atorvastatin with gemfibrozil. Am J Cardiol 1998;81:368-369.

11\. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with
simvastatin/gemfibrozil therapy. South Med J 1997;90:546-547.

12\. Data on file. Pfizer; NY, NY.

**Rx only**

Revised June 2002

Manufactured by:\
**Pfizer Pharmaceuticals, Ltd.\
**Vega Baja, PR 00694

> Distributed by:

 Parke-Davis

> Division of Pfizer Inc, NY, NY 10017

©1997-\'02, PPL

69-5829-00-2