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Canadian Pharmacy |
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Drug Interactions
Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin:
Cytochrome P450 3A4 Inhibitors
In vitro and in vivo data indicate that pravastatin is not metabolized by
cytochrome P450 3A4 to a clinically significant extent. This has been shown
in studies with known cytochrome P450 3A4 inhibitors other examples of cytochrome
P450 3A4 inhibitors are mibefradil, erythromycin and ketoconazole
Diltiazem
It has been noticed that steady-state levels of diltiazem had no effect
on the pharmacokinetics of pravastatin. Study shows, the AUC and Cmax of
another HMG-CoA reductase inhibitor which is known to be metabolized by
cytochrome P450 3A4 increased by factors of 3.6 and 4.3, respectively.
Itraconazole
When given with itraconazole as compared to placebo, the mean AUC and Cmax
for pravastatin were increased by factors of 1.7 and 2.5. The mean t½
was not affected by itraconazole, suggesting that the relatively small increases
in Cmax and AUC were due solely to increased bioavailability rather than
a decrease in clearance, consistent with inhibition of p-glycoprotein transport
by itraconazole. This drug transport system is thought to affect bioavailability
and excretion of HMG-CoA reductase inhibitors, including pravastatin. When
given with itraconazole, the AUC and Cmax of another HMG-CoA reductase inhibitor
which is known to be metabolized by cytochrome P450 3A4 increased by factors
of 19 and 17.
Antipyrine
Since concomitant administration of pravastatin had no effect on the clearance
of antipyrine, interactions with other drugs metabolized via the same hepatic
cytochrome isozymes are not expected.
Cholestyramine/Colestipol
The management of Concomitant resulted in an about 40 to 50% decrease in
the mean AUC of pravastatin. Though, pravastatin was administered 1 hour
before or 4 hours after cholestyramine, there was no clinically significant
decrease in bioavailability.
Warfarin
Related administration of 40 mg pravastatin had no clinically significant
effect on prothrombin time when administered in a study to normal elderly
subjects who were stabilized on warfarin.
Cimetidine
The AUC0-12hr for pravastatin when given with cimetidine was not significantly
different from the AUC for pravastatin when given alone. A significant difference
was observed between the AUC’s for pravastatin when given with cimetidine
compared to when administered with antacid.
Digoxin
In a crossover trial involving 18 healthy male subjects given 20 mg pravastatin
and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters
of digoxin were not affected. The AUC of pravastatin tended to increase,
but the overall bioavailability of pravastatin plus its metabolites SQ 31,906
and SQ 31,945 was not altered.
Cyclosporine
Some investigators have measured cyclosporine levels in patients on pravastatin
(up to 20 mg), and to date, these results indicate no clinically meaningful
elevations in cyclosporine levels. In one single-dose study, pravastatin
levels were found to be increased in cardiac transplant patients receiving
cyclosporine.
Gemfibrozil
In a crossover study in 20 healthy male volunteers given concomitant single
doses of pravastatin and gemfibrozil, there was a significant decrease in
urinary excretion and protein binding of pravastatin. In addition, there
was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite
SQ 31,906. Combination therapy with pravastatin and gemfibrozil is generally
not recommended.
In interaction studies with aspirin, antacids (1 hour prior to Pravachol),
cimetidine, nicotinic acid, or probucol, no statistically significant differences
in bioavailability were seen when Pravachol (pravastatin sodium) was administered.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower
circulating cholesterol levels and, as such, might theoretically blunt adrenal
or gonadal steroid hormone production. Results of clinical trials with pravastatin
in males and postmenopausal females were inconsistent with regard to possible
effects of the drug on basal steroid hormone levels. In a study of 21 males,
the mean testosterone response to human chorionic gonadotropin was significantly
reduced (p<0.004) after 16 weeks of treatment with 40 mg of pravastatin.
However, the percentage of patients showing a ? 50% rise in plasma testosterone
after human chorionic gonadotropin stimulation did not change significantly
after therapy in these patients. The effects of HMG-CoA reductase inhibitors
on spermatogenesis and fertility have not been studied in adequate numbers
of patients. The effects, if any, of pravastatin on the pituitary-gonadal
axis in pre-menopausal females are unknown. Patients treated with pravastatin
who display clinical evidence of endocrine dysfunction should be evaluated
appropriately. Caution should also be exercised if an HMG-CoA reductase
inhibitor or other agent used to lower cholesterol levels is administered
to patients also receiving other drugs (e.g., ketoconazole, spironolactone,
cimetidine) that may diminish the levels or activity of steroid hormones.In
a placebo-controlled study of 214 pediatric patients with HeFH, of which
106 were treated with pravastatin (20 mg in the children aged 8-13 years
and 40 mg in the adolescents aged 14-18 years) for two years, there were
no detectable differences seen in any of the endocrine parameters [ACTH,
cortisol, DHEAS, FSH, LH, TSH, estradiol (girls) or testosterone (boys)]
relative to placebo. There were no detectable differences seen in height
and weight changes, testicular volume changes, or Tanner score relative
to placebo.
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema
and mononuclear cell infiltration of perivascular spaces, were seen in dogs
treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs
were observed at approximately 59 times the human dose of 80 mg/day, based
on AUC. Similar CNS vascular lesions have been observed with several other
drugs in this class.
A chemically similar drug in this class 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 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 which resulted in a mean plasma drug level
similar to that seen with the 60 mg/kg/day dose. |
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Pravachol Articles |
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