2.1 Important Dosage and Administration Information

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Take Altoprev orally once daily in the evening.

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The maximum recommended dosage of Altoprev is 60 mg orally once daily.

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Swallow tablets whole. Do not split, crush, or chew the extended-release tablets [see Clinical Pharmacology (12.3)].

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If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.

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The recommended dosage of Altoprev depends on a patient’s indication for usage, LDL-C level, and individual risk for cardiovascular events.

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For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving Altoprev 60 mg daily, prescribe alternative LDL-C-lowering treatment.

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Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating Altoprev, and adjust the dosage if necessary. 

2.2 Recommended Dosage in Adult Patients

The recommended dosage range of Altoprev is 20 to 60 mg once daily in the evening.

2.3 Recommended Dosage in Patients with Renal Impairment

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In patients with severe renal impairment [creatinine clearance (CLcr) <30 mL/min], consider if the benefits of increasing the dosage above 20 mg daily outweighs the increased risk of myopathy and rhabdomyolysis [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

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There are no dosage adjustment recommendations for patients with mild or moderate renal impairment.

2.4 Dosage Modifications Due to Drug Interactions

Concomitant use of Altoprev with the following drugs requires dosage modification of Altoprev [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

Patients Taking Danazol, Diltiazem, Dronedarone, or Verapamil

Do not exceed Altoprev 20 mg daily.

Patients Taking Amiodarone

Do not exceed Altoprev 40 mg daily.

5.1 Myopathy and Rhabdomyolysis

Altoprev may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including Altoprev.

Risk Factors for Myopathy

Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher Altoprev dosage [see Drug Interactions (7.1)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

The concomitant use of strong CYP3A4 inhibitors with Altoprev is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend Altoprev during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of Altoprev with gemfibrozil or cyclosporine is not recommended [see Contraindications (4) and Drug Interactions (7.1)].

Altoprev dosage modifications are recommended for patients taking amiodarone, danazol, diltiazem, dronedarone, and verapamil [see Dosage and Administration (2.4) and Drug Interactions (7.1)].

Lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ranolazine may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].

Use of grapefruit juice is not recommended when taking Altoprev [see Drug Interactions (7.1)].

Discontinue Altoprev if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if Altoprev is discontinued. Temporarily discontinue Altoprev in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Altoprev dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

5.2 Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMGCoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue Altoprev if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have occurred with Altoprev [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the upper limit of normal (ULN) in serum transaminases have occurred in approximately 1.9% of patients receiving Altoprev in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with Altoprev. There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Altoprev.

Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.

Consider liver enzyme testing before Altoprev initiation and when clinically indicated thereafter. Altoprev is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue Altoprev.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Altoprev. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

6.1 Clinical Trial Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials 467 patients were treated with Altoprev with mean exposure of approximately 11.6 weeks. The mean age of the population was 56 years, 43% of the population were female, 86% were White, 6% were Black or African American, 1% were Asian, and 7% were other races [see Clinical Studies (14)]. Adverse reactions occurring in ≥5% of patients in any treatment group are shown in Table 1 below.

Elevations in Liver Enzyme Tests

In the AFCAPS/TexCAPS study, 6,605 patients were treated with lovastatin immediate-release (n=3,304) or placebo (n=3,301). Patients with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times ULN), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups. Elevated transaminases resulted in discontinuation of 6 (0.2%) patients from therapy in the lovastatin immediate-release group and 4 (0.1%) in the placebo group.

In the EXCEL study, the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg daily, 0.9% at 40 mg daily, and 1.5% at 80 mg daily in patients treated with lovastatin immediate-release (not an approved dose of Altoprev) [see Dosage and Administration (2.2)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Altoprev. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skeletal: muscle cramps, myopathy, rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

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

There have been rare post marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

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, urticaria, 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, fatal and non-fatal hepatic failure.

Skin: alopecia, pruritus, lichen planus. 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: alkaline phosphatase, g-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

Respiratory: interstitial lung disease.

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Altoprev 

Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with Altoprev and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Altoprev Effects on Other Drugs

Table 3 presents Altoprev’s effect on other drugs and instructions for preventing or managing them.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Altoprev have not been established in pediatric patients.

8.5 Geriatric Use

Of the 467 patients who received Altoprev in clinical studies, 18% were 65 years and older. In the clinical studies conducted with lovastatin immediate-release (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. 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 [see Clinical Pharmacology (12.3)].

Advanced age (≥65 years) is a risk factor for Altoprev-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving Altoprev for the increased risk of myopathy [see Warnings and Precautions (5.1)].

8.6 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.

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment, consider if the benefits of increasing the dosage above 20 mg daily outweighs the increased risk of myopathy and rhabdomyolysis [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Altoprev is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) and Warnings and Precautions (5.3)].

12.1 Mechanism of Action

Lovastatin is a lactone prodrug that is hydrolyzed in vivo to its active β-hydroxyacid form, an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.2 Pharmacodynamics

Inhibition of HMG-CoA reductase by lovastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of lovastatin is usually achieved by 4 weeks and is maintained after that.

12.3 Pharmacokinetics

Absorption

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 subjects with hypercholesterolemia at steady state, after 28 days of treatment of Altoprev 40 mg, is summarized in Table 4.

The extended-release properties of Altoprev are characterized by a prolonged absorptive phase, which results in a longer Tmax and lower Cmax for lovastatin (pro-drug) and its major metabolite, lovastatin acid, compared to lovastatin immediate-release.

At the 40 mg dose, 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).

Altoprev appears to have dose linearity for doses from 10 mg up to 60 mg per day.

Effect of Food

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 5.

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.

Elimination

Metabolism

Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, an 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.

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 undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.

Specific Populations

Geriatric Patients:

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 (not an approved dose of Altoprev) [see Dosage and Administration (2.2)], 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 (8.5)].

Male and Female Patients

In a single dose pharmacokinetic study with Altoprev, there were no statistically significant differences in pharmacokinetic parameters between males (n=12) and females (n=10), although exposure tended to be higher in males than females.

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.

Drug Interaction Studies

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 (5.1) and Drug Interactions (7)].

Lovastatin is a substrate for CYP3A4 [see Drug Interactions (7)]. 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.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 21-month carcinogenic study in mice with lovastatin immediate-release, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day lovastatin immediate-release dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. [Although mice were given 300 times the human dose (HD) on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of lovastatin immediate-release].

There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans given lovastatin immediate-release. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.

In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day lovastatin immediate-release (doses in rats were 5, 30 and 180 mg/kg/day).

An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.

A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose of lovastatin immediate-release. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls.

No evidence of mutagenicity was observed with lovastatin immediate-release in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.

Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day with lovastatin immediate-release. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.