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Heart Disease
Heart Attack
Congestive Heart Failure
Generic Drugs
Alternative Heart Disease Treatment |
Heart Disease
Generic Drugs Plavix Side
Effects
SIDE EFFECTS
PLAVIX has been evaluated for safety in more than 11,300 patients, including
over 7,000 patients treated for 1 year or more. The overall tolerability of
PLAVIX was similar to that of aspirin regardless of age, gender and race, with
an approximately equal incidence (13%) of patients withdrawing from treatment
because of adverse reactions. The clinically important adverse events observed
in CAPRIE are discussed below.
Hemorrhagic: In patients receiving PLAVIX in CAPRIE, gastrointestinal
hemorrhage occurred at a rate of 2.0%, and required hospitalization in 0.7%. In
patients receiving aspirin, the corresponding rates were 2.7% and 1.1%,
respectively. The incidence of intracranial hemorrhage was 0.4% for PLAVIX
compared to 0.5% for aspirin.
Neutropenia/ agranulocytosis: Ticlopidine, a drug chemically similar to
PLAVIX, is associated with a 0.8% rate of severe neutropenia (less than 450
neutrophils/ mL). Patients in CAPRIE (see Clinical Trials) were intensively
monitored for neutropenia. Severe neutropenia was observed in six patients, four
on PLAVIX and two on aspirin. Two of the 9599 patients who received PLAVIX and
none of the 9586 patients who received aspirin had neutrophil counts of zero.
One of the four PLAVIX patients was receiving cytotoxic chemotherapy, and
another recovered and returned to the trial after only temporarily interrupting
treatment with PLAVIX. Although the risk of myelotoxicity with PLAVIX thus
appears to be quite low, this possibility should be considered when a patient
receiving PLAVIX demonstrates fever or other sign of infection.
Gastrointestinal: Overall, the incidence of gastrointestinal events (e.
g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving
PLAVIX (clopidogrel bisulfate) was 27. 1%, compared to 29.8% in those receiving
aspirin.
The incidence of peptic, gastric or duodenal ulcers was 0.7% for PLAVIX and 1.2%
for aspirin.
Cases of diarrhea were reported in 4.5% of patients in the PLAVIX group compared
to 3.4% in the aspirin group. However, these were rarely severe (PLAVIX= 0.2%
and aspirin= 0.1%).
The incidence of patients withdrawing from treatment because of gastrointestinal
adverse reactions was 3.2% for PLAVIX and 4.0% for aspirin.
Rash and Other Skin Disorders: The incidence of skin and appendage
disorders in patients receiving PLAVIX was 15.8% (0.7% serious); the
corresponding rate in aspirin patients was 13.1% (0.5% serious).
The overall incidence of patients withdrawing from treatment because of skin and
appendage disorders adverse reactions was 1.5% for PLAVIX and 0.8% for aspirin.
Adverse events occurring in ³2.5% of patients on PLAVIX in the CAPRIE controlled
clinical trial are shown below in table 2 regardless of relationship to PLAVIX.
The median duration of therapy was 20 months, with a maximum of 3 years.
Table 2.
|
Adverse Events Occurring in
³2.5% of PLAVIX Patients
|
|
Body System
Event
|
% Incidence (% Discontinuation)
|
|
PLAVIX
[n= 9599]
|
Aspirin
[n= 9586]
|
| Body as a Whole - general
disorders |
| Chest Pain |
8.3 (0.2)
|
8.3 (0.3)
|
| Accidental Injury |
7.9 (0.1)
|
7.3 (0.1)
|
| Influenza- like symptoms |
7.5 (<0.1)
|
7.0 (<0.1)
|
| Pain |
6.4 (0.1)
|
6.3 (0.1)
|
| Fatigue |
3.3 (0.1)
|
3.4 (0.1)
|
| Cardiovascular disorders,
general |
| Edema |
4.1 (<0.1)
|
4.5 (<0.1)
|
| Hypertension |
4.3 (<0.1)
|
5.1 (<0.1)
|
| Central & peripheral
nervous system disorders |
| Headache |
7.6 (0.3)
|
7.2 (0.2)
|
| Dizziness |
6.2 (0.2)
|
6.7 (0.3)
|
| Gastrointestinal system
disorders |
| Abdominal pain |
5.6 (0.7)
|
7.1 (1.0)
|
| Dyspepsia |
5.2 (0.6)
|
6.1 (0.7)
|
| Diarrhea |
4.5 (0.4)
|
3.4 (0.3)
|
| Nausea |
3.4 (0.5)
|
3.8 (0.4)
|
| Metabolic & nutritional
disorders |
| Hypercholesterolemia |
4.0 (0)
|
4.4 (<0.1)
|
| Musculo- skeletal system
disorders |
| Arthralgia |
6.3 (0.1)
|
6.2 (0.1)
|
| Continued |
| Back Pain |
5.8 (0.1)
|
5.3 (<0.1)
|
| Platelet, bleeding, &
clotting disorders |
| Purpura |
5.3 (0.3)
|
3.7 (0.1)
|
| Epistaxis |
2.9 (0.2)
|
2.5 (0.1)
|
| Psychiatric disorders |
| Depression |
3.6 (0.1)
|
3.9 (0.2)
|
| Respiratory system
disorders |
| Upper resp tract infection |
8.7 (<0.1)
|
8.3 (<0.1)
|
| Dyspnea |
4.5 (0.1)
|
4.7 (0.1)
|
| Rhinitis |
4.2 (0.1)
|
4.2 (<0.1)
|
| Bronchitis |
3.7 (0.1)
|
3.7 (0)
|
| Coughing |
3.1 (<0.1)
|
2.7 (<0.1)
|
| Skin & appendage
disorders |
| Rash |
4.2 (0.5)
|
3.5 (0.2)
|
| Pruritus |
3.3 (0.3)
|
1.6 (0.1)
|
| Urinary system disorders |
| Urinary tract infection |
3.1 (0)
|
3.5 (0.1)
|
Incidence of discontinuation, regardless of relationship to therapy, is shown
in parentheses.
Other adverse experiences of potential importance occurring in 1% to 2.5% of
patients receiving PLAVIX (clopidogrel bisulfate) in the CAPRIE controlled
clinical trial are listed below regardless of relationship to PLAVIX. In
general, the incidence of these events was similar in the aspirin- treated
group.
Autonomic Nervous System Disorders: Syncope, Palpitation.
Body as a Whole - general disorders: Asthenia, Hernia.
Cardiovascular disorders: Cardiac failure.
Central and peripheral nervous system disorders: Cramps legs,
Hypoaesthesia, Neuralgia, Paraesthesia, Vertigo.
Gastrointestinal system disorders: Constipation, Vomiting.
Heart rate and rhythm disorders: Fibrillation atrial.
Liver and biliary system disorders: Hepatic enzymes increased.
Metabolic and nutritional disorders: Gout, hyperuricemia, non-
protein nitrogen (NPN) increased.
Musculo- skeletal system disorders: Arthritis, Arthrosis.
Platelet, bleeding & clotting disorders: GI hemorrhage, hematoma, platelets
decreased.
Psychiatric disorders: Anxiety, Insomnia.
Red blood cell disorders: Anemia.
Respiratory system disorders: Pneumonia, Sinusitis.
Skin and appendage disorders: Eczema, Skin ulceration.
Urinary system disorders: Cystitis.
Vision disorders: Cataract, Conjunctivitis.
Other potentially serious adverse events which may be of clinical interest but
were rarely reported (<1%) in patients who received PLAVIX are listed below
regardless of relationship to PLAVIX. In general, the incidence of these events
was similar in the aspirin group.
Body as a whole: Allergic reaction, necrosis ischemic.
Cardiovascular disorders: Edema generalized.
Gastrointestinal system disorders: Gastric ulcer perforated,
gastritis hemorrhagic, upper GI ulcer hemorrhagic.
Liver and Biliary system disorders: Bilirubinemia, hepatitis
infectious, liver fatty. Platelet, bleeding and clotting disorders: hemarthrosis,
hematuria, hemoptysis, hemorrhage intracranial, hemorrhage retroperitoneal,
hemorrhage of operative wound, ocular hemorrhage, pulmonary hemorrhage, purpura
allergic, thrombocytopenia. Red blood cell disorders: Anemia aplastic, anemia
hypochromic.
Reproductive disorders, female: Menorrhagia. Respiratory system
disorders: Hemothorax.
Skin and appendage disorders: Bullous eruption, rash erythematous,
rash maculopapular, urticaria. White cell and reticuloendothelial system
disorders: Agranulocytosis, granulocytopenia, leukemia, leukopenia, neutrophils
decreased.
DRUG INTERACTIONS
Study of specific drug interactions yielded the following results:
Aspirin: Aspirin did not modify the clopidogrel- mediated
inhibition of A.P. induced platelet aggregation. Concomitant administration of
500 mg of aspirin twice a day for 1 day did not significantly increase the
prolongation of bleeding time induced by PLAVIX. PLAVIX potentiated the effect
of aspirin on collagen- induced platelet aggregation. The safety of chronic
concomitant administration of aspirin and PLAVIX has not been established.
Heparin: In a study in healthy volunteers, PLAVIX did not
necessitate modification of the heparin dose or alter the effect of heparin on
coagulation. Coadministration of heparin had no effect on inhibition of platelet
aggregation induced by PLAVIX. The safety of this combination has not been
established, however, and concomitant use should be undertaken with caution.
Nonsteroidal Anti- Inflammatory Drugs (NSAIDs): In healthy
volunteers receiving naproxen, concomitant administration of PLAVIX was
associated with increased occult gastrointestinal blood loss. NSAIDs and PLAVIX
should be coadministered with caution.
Warfarin: The safety of the coadministration of PLAVIX with
warfarin has not been established. Consequently, concomitant administration of
these two agents should be undertaken with caution.
Other Concomitant Therapy: No clinically significant
pharmacodynamic interactions were observed when PLAVIX was coadministered with
atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic
activity of PLAVIX was also not significantly influenced by the coadministration
of phenobarbital, cimetidine or estrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the
coadministration of PLAVIX (clopidogrel bisulfate). At high concentrations in
vitro, clopidogrel inhibits P 450 (2C9). Accordingly, PLAVIX may interfere with
the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide,
fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no
data with which to predict the magnitude of these interactions. Caution should
be used when any of these drugs is coadministered with PLAVIX.
In addition to the above specific interaction studies, patients entered into
CAPRIE received a variety of concomitant medications including diuretics,
beta-blocking agents, angiotensin converting enzyme inhibitors, calcium
antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic
agents, antiepileptic agents and hormone replacement therapy without evidence of
clinically significant adverse interactions.
Drug/ Laboratory Test Interactions
None known.
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