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Heart Disease

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Congestive Heart Failure

Generic Drugs

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Heart Disease 

Generic Drugs

Zocor Side Effects

From Merck

SIDE EFFECTS

In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse experiences attributable to ZOCOR. Adverse reactions have usually been mild and transient. ZOCOR has been evaluated for serious adverse reactions in more than 21,000 patients and is generally well tolerated.

Clinical Adverse Experiences In Adults

Adverse experiences occurring in adults at an incidence of 1% or greater in patients treated with ZOCOR, regardless of causality, in controlled clinical studies are shown in Table 1.

 

TABLE 1 Adverse Experiences in Clinical Studies Incidence 1 Percent or Greater, Regardless of Causality

 

ZOCOR

Placebo

Cholestyramine

 

(N = 1,583)

(N = 157)

(N = 179)

 

%

%

%

Body as a Whole

Abdominal pain

3.2

3.2

8.9

Asthenia

1.6

2.5

1.1

Gastrointestinal

Constipation

2.3

1.3

29.1

Diarrhea

1.9

2.5

7.8

Dyspepsia

1.1

4.5

Flatulence

1.9

1.3

14.5

Nausea

1.3

1.9

10.1

Nervous System/ Psychiatric

Headache

3.5

5.1

4.5

Respiratory

Upper respiratory infection

2.1

1.9

3.4


Scandinavian Simvastatin Survival Study Clinical Adverse Experiences

In 4S involving 4,444 patients treated with 20-40 mg/day of ZOCOR (n=2,221) or placebo (n=2,223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study. The clinical adverse experiences reported as possibly, probably, or definitely drug-related in 0.5% in either treatment group are shown in Table 2.

 

TABLE 2 Drug-Related Clinical Adverse Experiences in 4S Incidence 0.5 Percent or Greater

 

ZOCOR

Placebo

 

(N = 2,221)

(N = 2,223)

 

%

%

Body as a Whole

Abdominal pain

0.9

0.9

Gastrointestinal

Diarrhea

0.5

0.3

Dyspepsia

0.6

0.5

Flatulence

0.9

0.7

Nausea

0.4

0.6

Musculoskeletal

Myalgia

1.2

1.3

Skin

Eczema

0.8

0.8

Pruritus

0.5

0.4

Rash

0.6

0.6

Special Senses

Cataract

0.5

0.8

Heart Protection Study Clinical Adverse Experiences

In HPS (see CLINICAL PHARMACOLOGY, Clinical Studies), involving 20,536 patients treated with ZOCOR 40 mg/day (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with ZOCOR and patients treated with placebo over the mean 5 years of the study. In this large trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse experiences were comparable (4.8% in patients treated with ZOCOR compared with 5.1% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with ZOCOR.

The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with simvastatin therapy.

Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.

Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.

Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.

Reproductive: gynecomastia, loss of libido, erectile dysfunction. Eye: progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, -glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

Laboratory Tests

Marked persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. Muscle pain or dysfunction usually was not reported.

Concomitant Lipid-Lowering Therapy

In controlled clinical studies in which simvastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with simvastatin or cholestyramine. The combined use of simvastatin at doses exceeding 10 mg/day with gemfibrozil should be avoided.

Adolescent Patients (ages 10-17 years)

In a 48-week controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age with heterozygous familial hypercholesterolemia (n=175), the safety and tolerability profile of the group treated with ZOCOR (10-40 mg daily) was generally similar to that of the group treated with placebo, with the most common adverse experiences observed in both groups being upper respiratory infection, headache, abdominal pain, and nausea.

DRUG INTERACTIONS

CYP3A4 Interactions

Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of simvastatin.

Pharmacokinetics.

Itraconazole Ketoconazole Erythromycin Clarithromycin HIV protease inhibitors Nefazodone Cyclosporine

Large quantities of grapefruit juice (>1 quart daily)


Interactions with lipid-lowering drugs that can cause myopathy when given alone

The risk of myopathy is increased by gemfibrozil (see DOSAGE AND ADMINISTRATION) and to a lesser extent by other fibrates and niacin (nicotinic acid) (1 g/day).

Other drug interactions

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil (see WARNINGS, Myopathy/Rhabdomyolysis).

Propranolol: In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of ZOCOR and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.

Digoxin: Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.

Warfarin: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to insure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).


 

 
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