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Do I need a prescription for lovastatin?
Mechanism Of Action
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
Lovastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance.
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (Total-C) and LDL-C levels in the lower end of this range.
Lovastatin immediate-release tablets have been shown to reduce elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the highaffinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin immediate-release may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. The independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. The effects of lovastatin immediate-release on lipoprotein (a) [Lp(a)], fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
The appearance of lovastatin in plasma from an Altoprev® extended-release tablet is slower and more prolonged compared to the lovastatin immediate-release formulation.
A pharmacokinetic study carried out with Altoprev® involved measurement of the systemic concentrations of lovastatin (pro-drug), lovastatin acid (active-drug) and total and active inhibitors of HMG-CoA reductase. The pharmacokinetic parameters in 12 hypercholesterolemic subjects at steady state, after 28 days of treatment, comparing Altoprev® 40 mg to lovastatin immediate-release 40 mg, are summarized in Table 3.
Table 3 : Altoprev® vs . Lovastatin Immediate-Release (IR) (Steady-State Pharmacokinetic Parameters at Day 28)
|Drug||Cmax (ng/mL)||Cmin (ng/mL)||Tmax (h)||AUC0-24hr (ng• hr/mL)|
|Altoprev® 40 mg*||5.5||5.8||17.3||13.4||2.6||3.1||9.1||4.3||14.2||11.8||77||87||263||171|
|Lovastatin IR 40 mg**||7.8||11.9||36.2||26.6||0.4||0.7||2.4||2.1||3.3||5.3||45||83||252||186|
|L = lovastatin, LA = lovastatin acid, TI = total inhibitors of HMG-CoA reductase, AI = active inhibitors of HMG-CoA reductase, Cmax= highest observed plasma concentration, Cmin= trough concentration at t = 24 hours after dosing, Tmax = time at which the Cmax occurred, AUC0-24h = area under the plasma concentration-time curve from time 0 to 24 hr after dosing, calculated by the linear trapezoidal rule. |
* Administered at bedtime.
** Administered with the evening meal.
The mean plasma concentration-time profiles of lovastatin and lovastatin acid in patients after multiple doses of Altoprev® or lovastatin immediate-release at day 28 are shown in Figure 1.
Figure 1 : Mean (SD) plasma concentration-time profiles of lovastatin and lovastatin acid in hypercholes terolemic patients (n=12) after 28 days of administration of Altoprev® or lovastatin immediate-release
The extended-release properties of Altoprev® are characterized by a prolonged absorptive phase, which results in a longer T and lower C for lovastatin (pro-drug) and its major metabolite, lovastatin acid, compared to lovastatin immediate-release.
The bioavailability of lovastatin (pro-drug) as measured by the AUC0-24hr was greater for Altoprev® compared to lovastatin immediate-release (as measured by a chemical assay), while the bioavailability of total and active inhibitors of HMG-CoA reductase were equivalent to lovastatin immediate-release (as measured by an enzymatic assay).
With once-a-day dosing, mean values of AUCs of active and total inhibitors at steady state were about 1.8-1.9 times those following a single dose. Accumulation ratio of lovastatin exposure was 1.5 after multiple daily doses of Altoprev® compared to that of a single dose measured using a chemical assay. Altoprev® appears to have dose linearity for doses from 10 mg up to 60 mg per day.
When Altoprev® was given after a meal, plasma concentrations of lovastatin and lovastatin acid were about 0.5 - 0.6 times those found when Altoprev® was administered in the fasting state, indicating that food decreases the bioavailability of Altoprev® . There was an association between the bioavailability of Altoprev® and dosing after mealtimes. Bioavailability was lowered under the following conditions, (from higher bioavailability to lower bioavailability) in the following order: under overnight fasting conditions, before bedtime, with dinner, and with a high fat breakfast. In a multicenter, randomized, parallel group study, patients were administered 40 mg of Altoprev® at three different times; before breakfast, after dinner and at bedtime. Although there was no statistical difference in the extent of lipid change between the three groups, there was a numerically greater reduction in LDL-C and TG and an increase in HDL-C when Altoprev® was administered at bedtime. Results of this study are displayed in Table 4.
Table 4 : Altoprev® 40 mg (Least Squares Mean Percent Changes from Baseline to Endpoint at 4 Weeks of Treatment*)
|N = 22 for the Before Breakfast group, N = 23 for the After Dinner group, and N = 23 for the Before Bedtime group. |
* All changes from baseline are statistically significant.
At steady state in humans, the bioavailability of lovastatin, following the administration of Altoprev®, was 190% compared to lovastatin immediate-release.Lovastatin Immediate-Release
Absorption of lovastatin, estimated relative to an intravenous reference dose in each of four animal species tested, averaged about 30% of an oral dose. Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors.
Distribution: Both lovastatin and its β-hydroxyacid metabolite are highly bound ( > 95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues.
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable.
Metabolism: Metabolism studies with Altoprev® have not been conducted.Lovastatin
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its 6'- hydroxy derivative, and two additional metabolites. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Strong inhibitors of CYP3A can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Lovastatin is a substrate for CYP3A4 [see DRUG INTERACTIONS]. Grapefruit juice contains one or more components that inhibit CYP3A and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study , 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration of lovastatin and its beta-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold respectively (as measured using a chemical assay - liquid chromatography/tandem mass spectrometry). In a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36- fold, respectively, and of lovastatin and its β-hydroxyacid metabolite (measured using a chemical assay - liquid chromatography/tandem mass spectrometry) of 1.94-fold and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
Table 5 : The Effect of Other Drugs on Lovastatin Exposure When Both Were Co-administered
|Coadministered Drug or Grapefruit Juice||Dosing of Co-administered Drug orGrapefruit Juice||Dosing of Lovastatin||AUC Ratio *(with / without co-administered drug) No Effect = 1.00||Cmax Ratio*(with / without co-administered drug) No Effect = 1.00|
|Lovastatin||Lovastatin acidt||Lovastatin||Lovastatin acidt|
|Contraindicated with lovastatin, [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]|
|Itraconazole‡||200 mg QD for 4 days||40 mg on Day 4||§||20||> 25§||13.0|
|100 mg QD for 4 days||40 mg on Day 4||> 14.8§||15.4||14.5||11.5|
|Avoid with lovastatin, [see WARNINGS AND PRECAUTIONS]|
|Cyclosporine||Not describedβ||10 mg QD for 10 days on Day 10||3-to 5-fold||NRa||NRa||NRa|
|Gemfibrozil||600 mg BID for 3 days||40 mg on Day 3||0.96||2.80||0.88||2.81|
|Grapefruit Juice¶ (high dose)||200 mL of double-strength TID for 2 days||80 mg on Day 3||15.3||5.0||11.8||4.0|
|Grapefruit Juice¶ (low dose)||8 oz (about 250 mL)of single-strengthÞ for 4 days||40 mg on Day 3||1.94||1.57||2.26||1.65|
|Avoid taking with > 20 mg lovastatin, [see WARNINGS AND PRECAUTIONS]|
|Diltiazem||120 mg bid ior 14 days||on4 a 0D 2||3.57e||ND||||4.33e||ND|||
|No dosing adjustments required for the following:|
|Propanolol||40 mg BID for 2.5 days||20 mg on Day 2||ND||||0.87||ND||||0.81|
|* Results based on a chemical assay. |
† Lovastatin acid refers to the β-hydroxyacid of lovastatin.
‡ Results could be representative of strong CYP3A inhibitors such as ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone.
§The mean total AUC of lovastatin without itraconazole phase could not be determined due to assay's detection limit.
¶The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
#Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose lovastatin and 30 and 90 minutes following single dose lovastatin on Day 3.
ÞSingle-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and lovastatin was administered in the evening on Day 3.
βCyclosporine-treated post kidney transplant patients with stable graft function, transplanted at least 9 months prior to study.
aNR = Analyte not reported.
eLactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.
||Analyte not determined
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents : In pharmacokinetic studies of lovastatin immediate-release in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.
Excretion: In a single-dose study with Altoprev® , the amounts of lovastatin and lovastatin acid excreted in the urine were below the lower limit of quantitation of the assay (1.0 ng/mL), indicating that negligible excretion of Altoprev® occurs through the kidney.Lovastatin
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
Geriatric: Lovastatin Immediate-Release
In a study with lovastatin immediate-release which included 16 elderly patients between 70-78 years of age who received lovastatin immediate-release 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18- 30 years of age [see Use in Specific Populations].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: In a single dose pharmacokinetic study with Altoprev® , there were no statistically significant differences in pharmacokinetic parameters between men (n=12) and women (n=10), although exposure tended to be higher in men than women.
In clinical studies with Altoprev® , there was no clinically significant difference in LDL-C reduction between men and women.
Renal Impairment: In a study of patients with severe renal impairment (creatinine clearance 10-30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
Hemodialysis : The effect of hemodialysis on plasma levels of lovastatin and its metabolites have not been studied.
Hepatic Impairment: No pharmacokinetic studies with Altoprev® have been conducted in patients with hepatic impairment.
Altoprev® has been shown to reduce Total-C, LDL-C, and TG and increase HDL-C in patients with hypercholesterolemia. Near maximal response was observed after four weeks of treatment and the response was maintained with continuation of therapy for up to 6 months.
In a 12-week, multicenter, placebo-controlled, double-blind, dose-response study in adult men and women 21 to 70 years of age with primary hypercholesterolemia, once daily administration of Altoprev® 10 to 60 mg in the evening was compared to placebo. Altoprev® produced dose related reductions in LDL-C and Total-C. Altoprev® produced mean reductions in TG across all doses that varied from approximately 10% to 25%. Altoprev® produced mean increases in HDL-C across all doses that varied from approximately 9% to 13%.
The lipid changes with Altoprev® treatment in this study, from baseline to endpoint, are displayed in Table 6.
Table 6 : Altoprev® vs. Placebo (Mean Percent Change from Baseline After 12 Weeks )*
|Altoprev® 10 mg||33||-23.8||9.4||-17.9||-17.3|
|Altoprev® 20 mg||34**||-29.6||12.0||-20.9||-13.0|
|Altoprev® 40 mg||33||-35.8||13.1||-25.4||-9.9|
|Altoprev® 60 mg||35||-40.8||11.6||-29.2||-25.1|
|N = the number of patients with values at both baseline and endpoint. |
* Except for the HDL-C elevation with Altoprev® 10 mg, all lipid changes with Altoprev® were statistically significant compared to placebo.
** For LDL-C, 33 patients had values at baseline and endpoint.
The range of LDL-C responses is represented graphically in the following figure (Figure 2):
Figure 2 : Altoprev® vs. Placebo LDL-C Percent Change from Baseline After 12 Weeks
The distribution of LDL-C responses is represented graphically by the boxplots in Figure 2. The bottom line of the box represents the 25th percentile and the top line, the 75th percentile. The horizontal line in the box represents the median and the gray area is the 95% confidence interval for the median.
The range of responses is depicted by the tails and outliers.Expanded Clinical Evaluation Of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in 8,245 patients with hypercholesterolemia [Total-C 240-300mg/dL (6.2 mmol/L-7.6 mmol/L), LDL-C > 160 mg/dL (4.1 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements (see Table 7) observed in lovastatin immediate-release-treated patients were dose-related and significantly different from placebo (p ≤ 0.001). These results were sustained throughout the study.
Table 7 : Lovastatin Immediate-Release (IR) vs . Placebo (Percent Change from Baseline - Average Values Between Weeks 12 and 48)
|DOSAGE||N**||TOTAL-C (mean)||LDL-C (mean)||HDL-C (mean)||LDL-C/ HDL-C (mean)||TOTAL-C/ HDL-C (mean)||TG (median)|
|Lovastatin IR 20mg q.p.m.||1642||-17||-24||+6.6||-27||-21||-10|
|40 mg q.p.m.||1645||-22||-30||+7.2||-34||-26||-14|
|20 mg b.i.d.||1646||-24||-34||+8.6||-38||-29||-16|
|40 mg b.i.d.||1649||-29||-40||+9.5||-44||-34||-19|
|** Patients enrolled|
A total of 365 patients were enrolled in an extension study in which all patients were administered Altoprev® 40 mg or 60 mg once daily for up to 6 months of treatment. The lipid-altering effects of Altoprev® were comparable to what was observed in the dose-response study, and were maintained for up to 6 months of treatment.Specific Populations
In clinical studies with Altoprev®, there were no statistically significant differences in LDL-C reduction in an older population ( ≥ 65 years old), compared to a younger population ( < 65 years old). There were also no statistically significant differences in LDL-C reduction between male and female patients.
Heterozygous Familial HypercholesterolemiaLovastatin Immediate-Release
Lovastatin immediate-release has been shown to be effective in reducing Total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night.
Lovastatin immediate-release was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin immediate-release on lipids and lipoproteins and the safety profile of lovastatin immediaterelease were similar to that demonstrated in studies in nondiabetics. Lovastatin immediate-release had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
Prevention Of Coronary Heart Disease
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a doubleblind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin immediate-release decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up. Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without symptomatic cardiovascular disease with average to moderately elevated Total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated Total- C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C < 35 mg/dL, hypertension, family history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: Total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤ 45 mg/dL for men and ≤ 47 mg/dL for women, and TG of ≤ 400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin immediate-release 20 mg - 40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin immediate-release were titrated to 40 mg daily when their LDL-C remained > 110 mg/dL at the 20-mg starting dose.
Lovastatin immediate-release reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin immediate-release 3.5%, placebo 5.5%; p < 0.001; Figure 3). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin immediate-release, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, lovastatin immediate-release reduced the risk of unstable angina by 32% (1.8% vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7% vs. 2.9%; p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2% vs. 4.8%; p=0.001). Trends in risk reduction associated with treatment with lovastatin immediate-release were consistent across men and women, smokers and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants with ≥ 2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary revascularization procedures (RR 37%). Because there were too few events among those participants with age as their only risk factor in this study, the effect of lovastatin immediate-release on outcomes could not be adequately assessed in this subgroup.
Figure 3 : Acute Major Coronary Events (Primary Endpoint)
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients. In this randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either lovastatin 20 mg - 80 mg daily or placebo. Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to 11% of placebo patients.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double- blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin immediate-release. During these trials the appearance of new opacities was noted in both the lovastatin immediate-release and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin immediate-release on the human lens demonstrated that there were no clinically or statistically significant differences between the lovastatin immediate-release and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.
1. Azie, N, et. al. Clin Pharmacol Ther 1998; 64(4): 369-377.
2. Gullestad, L., et. al. Transplantation Proceedings 1999; 31: 2163-2165.
3. Kantola, T, et al. Clin Pharmacol Ther 1998; 63(4):397-402.
4. Kivisto, K., et.al. Br. J Clin Pharmacol 1998; 46: 49-53.
5. Kyrklund, C. et. al. Clin Pharmacol Ther 2001; 69(5): 340-345.
6. Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy. Reproductive Toxicology. 19(6):439-446. 1996.
7. Neuvonen, P. J. et.al. Clin Pharmacol Ther 1998; 60(1): 54-61.
8. Pan, H. Y. et.al. Br. J Clin Pharmacol 1991; 31: 665-670.
9. Rogers, J. D. et.al. Clin Pharmacol Ther 1999; 66(4): 358-366.
Pregnancy & Lactation
Pregnancy category: X
Lactation: Contraindicated; unsafe
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Altoprev and Pregnancy
Tell your doctor if you are pregnant or plan to become pregnant.
The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.
Altoprev falls into category X. This drug should not be used during pregnancy as it has the potential to cause miscarriage or severe birth defects.
Altoprev may harm your unborn baby.
If you take too much Altoprev, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.
How should I take Altoprev (lovastatin)?
Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Lovastatin is usually taken at bedtime or with an evening meal. If you take lovastatin several times daily, take it with meals. Follow your doctor's instructions.
Do not crush, chew, or break an extended-release tablet. Swallow it whole.
You may need to take lovastatin on a long-term basis for the treatment of high cholesterol. You may need to stop using lovastatin for a short time if you have surgery or a medical emergency. Do not stop taking this medicine unless your doctor tells you to.
You will need frequent blood tests to check your liver function.
Lovastatin is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.
Store at room temperature away from moisture, heat, and light.
Commonly used brand name(s)
In the U.S.
Available Dosage Forms:
- Tablet, Extended Release
Therapeutic Class: Antihyperlipidemic
Pharmacologic Class: HMG-COA Reductase Inhibitor
Before Using Altoprev
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of lovastatin regular tablets for children 10 to 17 years of age. However, safety and efficacy in children younger than 10 years of age have not been established.
Teenage girls taking lovastatin regular tablets should be counseled on appropriate birth control methods to prevent pregnancy.
Appropriate studies have not been performed on the relationship of age to the effects of lovastatin extended-release tablets in the pediatric population. Safety and efficacy have not been established.
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lovastatin in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require an adjustment in the dose for patients receiving lovastatin.
|All Trimesters||X||Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.|
Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.
Interactions with Medicines
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
- Dabigatran Etexilate
- Fenofibric Acid
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
- Oat Bran
- St John's Wort
Interactions with Food/Tobacco/Alcohol
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
- Grapefruit Juice
Other Medical Problems
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
- Alcohol abuse, or history of or
- Diabetes, poorly-controlled or
- Hypothyroidism (an underactive thyroid) or
- Liver disease, history of—Use with caution. May cause side effects to become worse.
- Electrolyte disorder, severe or
- Endocrine disorder, severe or
- Epilepsy (seizures), not well-controlled or
- Hypotension (low blood pressure) or
- Kidney disease, severe or
- Metabolic disorder, severe or
- Sepsis (severe infection)—Patients with these conditions may be at risk for muscle or kidney problems.
- Hypercholesterolemia (high cholesterol in the blood), familial homozygous—Less effective in patients with this condition.
- Liver disease, active or
- Liver enzymes, elevated—Should not be used in patients with these conditions.
Proper Use of lovastatin
This section provides information on the proper use of a number of products that contain lovastatin. It may not be specific to Altoprev. Please read with care.
Take this medicine only as directed by your doctor. Do not take more or less of it, and do not take more or less often than your doctor ordered.
In addition to this medicine, your doctor may change your diet to one that is low in fat, sugar, and cholesterol. Carefully follow your doctor's orders about any special diet.
Take the regular tablet with food. Take the extended-release tablet without food.
Swallow the whole. Do not crush, break, or chew it.
If you are taking danazol (Danocrine®), diltiazem (Cardizem®), dronedarone (Multaq®), or verapamil (Calan®, Isoptin®, Verelan®) together with lovastatin, your lovastatin dose should not be higher than 20 milligrams (mg) per day, unless otherwise directed by your doctor. Do not use more than 40 mg per day of lovastatin together with amiodarone (Cordarone®). When used together with higher doses of lovastatin, these medicines may increase your risk of muscle injury and could result in kidney problems.
Tell your doctor if you drink grapefruit juice. Drinking large amounts of grapefruit juice (more than 1 quart each day) while taking this medicine may increase your risk of muscle injury and could result in kidney problems.
Do not drink large amounts of alcohol with lovastatin. This could cause unwanted effects on the liver.
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For high cholesterol:
- For oral dosage form (extended-release tablets):
- Adults—At first, 20 to 60 milligrams (mg) once a day, in the evening at bedtime and taken as single dose. Your doctor may increase your dose as needed.
- Children—Use and dose must be determined by your doctor.
- For oral dosage form (tablets):
- Adults—At first, 20 milligrams (mg) once a day given with the evening meal. Your doctor may increase your dose as needed. However, the dose is usually not more than 80 mg per day.
- Children 10 to 17 years of age—At first, 10 mg once a day given with the evening meal. Your doctor may increase your dose as needed. However, the dose is usually not more than 40 mg per day.
- Children younger than 10 years of age—Use and dose must be determined by your doctor.
- For oral dosage form (extended-release tablets):
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Altoprev Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:Less common
- Bladder pain
- bloody or cloudy urine
- chest tightness
- dark-colored urine
- difficult, burning, or painful urination
- difficulty with moving
- frequent urge to urinate
- joint pain
- lower back or side pain
- muscle aching, cramps, spasms, or stiffness
- muscle pain, tenderness, or weakness
- pain or tenderness around the eyes and cheekbones
- stuffy or runny nose
- swollen joints
- trouble with breathing
- unusual tiredness or weakness
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:Less common
- Acid or sour stomach
- bloated or full feeling
- blurred vision
- difficulty having a bowel movement (stool)
- excess air or gas in the stomach or intestines
- lack or loss of strength
- passing gas
- stomach discomfort, upset, or pain
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
Consumer Information Use and Disclaimer
- If your symptoms or health problems do not get better or if they become worse, call your doctor.
- Do not share your drugs with others and do not take anyone else's drugs.
- Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
- Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
- Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
- If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
This information should not be used to decide whether or not to take Altoprev or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Altoprev. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
Review Date: October 4, 2017
Warnings and Precautions
Skeletal Muscle Effects
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Altoprev®. These risks can occur at any dose level, but increase in a dose-dependent manner. Predisposing factors for myopathy include advanced age (≥65 years), female gender, renal impairment, and inadequately treated hypothyroidism. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with Altoprev®, or whose dose of Altoprev® is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Altoprev. Altoprev therapy should be discontinued immediately if myopathy is diagnosed or suspected.
Altoprev® therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Altoprev® therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy.
• Drug Interactions that can cause skeletal muscle effects
Strong CYP3A Inhibitors: The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. Co-administration of these drugs with Altoprev is contraindicated. If treatment with strong CYP3A inhibitors is unavoidable, therapy with Altoprev should be suspended during the course of treatment (see Contraindications (4); Clinical Pharmacology (12.3); Drug Interactions (7.1)].
Erythromycin: Co-administration of erythromycin with Altoprev is contraindicated. If treatment with erythromycin is unavoidable, therapy with Altoprev should be suspended during the course of treatment (see Contraindications (4); Drug Interactions (7.2)].
Gemfibrozil: Avoid the combined use of Altoprev with gemfibrozil.
Other lipid-lowering drugs (other fibrates, or lipid-lowering doses (≥ 1 g/day) of niacin: Use caution when prescribing other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin with Altoprev, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered with Altoprev. Carefully weigh the expected benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin against the potential risks of these combinations [see Drug Interactions (7.3)].
Cyclosporine: Avoid the combined use of Altoprev with cyclosporine [see Drug Interactions (7.4)].
Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin: Do not exceed 20 mg of Altoprev daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil. Weigh carefully the benefits of the use of Altoprev in patients receiving danazol, diltiazem, dronedarone or verapamil against the risks of these combinations [see Drug Interactions (7.6)].
Amiodarone: Do not exceed 40 mg of Altoprev daily in patients receiving concomitant therapy with amiodarone. Avoid the combined use of Altoprev at doses exceeding 40 mg daily with amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy. The concomitant use of higher doses of a closely related member of the HMG-CoA reductase inhibitor class with amiodarone increased the risk of myopathy/rhabdomyolysis [see Drug Interactions (7.6)].
Colchicine: There have been cases of myopathy, including rhabdomyolysis, reported in patients receiving lovastatin coadministered with colchicine. Use caution when prescribing Altoprev with colchicine [see Drug Interactions (7.9)].
Ranolazine: Concomitant use of ranolazine and Altoprev may increase the risk of myopathy, including rhabdomyolysis. Consider dose adjustment of Altoprev if coadministering with ranolazine [see Drug Interactions (7.9)].
Prescribing recommendations for interacting agents are summarized in Table 1.
Strong CYP3A inhibitors (e.g.,
Contraindicated with lovastatin
Avoid with lovastatin
Do not exceed 20 mg lovastatin daily
Do not exceed 40 mg lovastatin daily
Avoid grapefruit juice
Liver Enzyme Abnormalities
Increases in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) have been reported with HMG-CoA reductase inhibitors, including Altoprev®.
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials [see Adverse Reactions (6.1)]. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with Altoprev and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Altoprev, promptly interrupt therapy. If an alternate etiology is not found, do not restart Altoprev.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of Altoprev®.
In controlled clinical trials (467 patients treated with Altoprev® and 329 patients treated with lovastatin immediate-release) no meaningful differences in transaminase elevations between the two treatments were observed.
In the EXCEL study [see Clinical Studies (14)], the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin immediate-release, symptomatic liver disease has been reported rarely at all dosages [see Adverse Reactions (6.2)].
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with lovastatin who develop 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., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.
Use in specific populations
Pregnancy Category X
Safety in pregnant women has not been established. Lovastatin immediate-release has been shown to produce skeletal malformations at plasma levels 40 times the human exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose of lovastatin immediate-release).
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to lovastatin immediate-release or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Altoprev® during pregnancy [see Contraindications (4)], treatment should be immediately discontinued as soon as pregnancy is recognized. Altoprev® should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazard.
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human breast milk and because of the potential for serious adverse reactions in nursing infants, women taking Altoprev® should not nurse their infants [see Contraindications (4)].
Safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with Altoprev® is not recommended at this time.
Of the 467 patients who received Altoprev® in controlled clinical studies, 18% were 65 years and older. Of the 297 patients who received Altoprev® in uncontrolled clinical studies, 22% were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Thus, lower starting doses of Altoprev® are recommended for elderly patients. [see Dosage and Administration (2.2)].
In pharmacokinetic studies with lovastatin immediate-release, the mean plasma level of HMG-CoA reductase inhibitory activity was shown to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin immediate-release (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg dosage range [see Clinical Pharmacology (12.3)].
In a study of patients with severe renal impairment (creatinine clearance 10–30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
After oral administration of lovastatin immediate-release to mice the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage with lovastatin immediate-release have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5 g to 6 g.
Until further experience is obtained, no specific treatment of overdosage with Altoprev® can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
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