of one [30:3 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). Endocrine Effects 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. Adverse Reactions The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis and myopathy [see Warnings and Precautions ( 5.1 ) ] Liver enzyme abnormalities [see Warnings and Precautions ( 5.2 ) ] 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 controlled clinical trials with Altoprev , (467 patients with mean exposure to study drug of approximately 11.6 weeks), 3.2% of patients were discontinued due to adverse reactions. This was similar to the discontinuation rate in the placebo (2/34, 5.9%) and lovastatin immediate-release (3.3%) treatment groups. Pooled results from clinical trials with Altoprev show that the most frequently reported adverse reactions in the Altoprev group were infection, headache and accidental injury. Similar incidences of these adverse reactions were seen in the lovastatin and placebo groups. In controlled clinical trials, clinical adverse reactions reported in > 5% of patients in any treatment group are shown in Table 2 below. Table 2 Pooled Controlled Studies TESS by Body System and COSTART Term, Most Common ( 5% in Any Group) Randomized Patients, n= Treatment Placebo 34 Altoprev 467 Mevacor 329 Body System COSTART Term Body as a Whole Infection 3 (9) 52 (11) 52 (16) Accidental Injury 3 (9) 26 (6) 12 (4) Asthenia 2 (6) 12 (3) 6 (2) Headache 2 (6) 34 (7) 26 (8) Back Pain 1 (3) 23 (5) 18 (5) Flu Syndrome 1 (3) 24 (5) 18 (5) Pain 0 14 (3) 17 (5) Digestive Diarrhea 2 (6) 15 (3) 8 (2) Musculoskeletal Arthralgia 2 (6) 24 (5) 20 (6) Myalgia 5 (15) 14 (3) 11 (3) Nervous Dizziness 2 (6) 10 (2) 5 (2) Respiratory Sinusitis 1 (3) 17 (4) 20 (6) Urogenital Urinary Tract Infection 2 (6) 8 (2) 9 (3) Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) In AFCAPS/TexCAPS [see Clinical Pharmacology ( 12 ) ] involving 6,605 participants treated with 20-40 mg/day of lovastatin immediate-release (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin immediate-release was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. 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%)]. The starting dose of lovastatin immediate-release was 20 mg/day; 50% of the lovastatin immediate-release treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin immediate-release with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. 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). Postmarketing Experience The following adverse reactions have been identified during post-approval use of Altoprev and/or are class effects of HMG CoA reductase inhibitors (statins). 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, myalgia, myopathy, rhabdomyolysis, arthralgias. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions ( 5.1 ) ]. Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression. There have been rare postmarketing 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). 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, fatal and non-fatal hepatic failure. 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, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities. Respiratory: interstitial lung disease. Drug Interactions Drug interaction studies have not been performed with Altoprev . The types, frequencies and magnitude of drug interactions that may be encountered when Altoprev is administered with other drugs may differ from the drug interactions encountered with the lovastatin immediate-release formulation. In addition, as the drug exposure with Altoprev 60 mg is greater than that with lovastatin immediate-release 80 mg (maximum recommended dose), the severity and magnitude of drug interactions that may be encountered with Altoprev 60 mg are not known. It is therefore recommended that the following precautions and recommendations for the concomitant administration of lovastatin immediate-release with other drugs be interpreted with caution, and that the monitoring of the pharmacologic effects of Altoprev and/or other concomitantly administered drugs be undertaken where appropriate. Strong CYP 3A Inhibitors Lovastatin is metabolized by CYP3A4 but has no CYP3A inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A. Strong inhibitors of CYP3A (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), increase the risk of myopathy by reducing the elimination of lovastatin. The use of lovastatin with strong CYP3A inhibitors is contraindicated [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 ) ]. Erythromycin Do not use Altoprev concomitantly with erythromycin [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A inhibitors, but which can cause myopathy when given alone. [see Warnings and Precautions ( 5.1 ) ]. Gemfibrozil Avoid the concomitant use of Altoprev with gemfibrozil [see Warnings and Precautions ( 5.1 ) ]. Other fibrates - Use caution when prescribing Altoprev with other fibrates. [see Warnings and Precautions ( 5.1 ) ]. Niacin (nicotinic acid) ( 1 g/day) Use caution when prescribing Altoprev with lipid-modifying ( 1 g/day) doses of niacin. [see Warnings and Precautions ( 5.1 ) ]. Cyclosporine Avoid the concomitant use of Altoprev with cyclosporine [see Warnings and Precautions ( 5.1 ) ] . Danazol, Diltiazem, Dronedarone or Verapamil Do not exceed 20 mg of Altoprev daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone, or verapamil. [ see Dosage and Administration ( 2.3 ),Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 ) ]. Amiodarone Do not exceed 40 mg of Altoprev daily in patients receiving concomitant therapy with amiodarone. [see Dosage and Administration ( 2.3 ),Warnings and Precautions ( 5.1 ) ]. Coumarin Anticoagulants In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. In patients taking anticoagulants, prothrombin time should be determined before starting Altoprev and frequently enough during early therapy to ensure 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 Altoprev is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. Colchicine Cases of myopathy, including rhabdomyolysis have been reported with lovastatin coadministered with colchicine. Exercise caution when prescribing Altoprev with colchicine. Ranolazine The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Exercise caution when prescribing Altoprev with ranolazine. Dose adjustment of Altoprev may be necessary during coadministration with ranolazine. USE IN SPECIFIC POPULATIONS Pregnancy 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/m 2 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 review 2 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. Nursing Mothers 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 ) ]. Pediatric Use 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. Geriatric Use 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 ) ]. Lovastatin Immediate-Release 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 ) ]. 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. [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]. Overdosage After oral administration of lovastatin immediate-release to mice the median lethal dose observed was >15 g/m 2 . 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. Altoprev Description Altoprev lovastatin extended-release tablets contain a cholesterol-lowering agent isolated from a strain of Aspergillus terreus . After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol. Lovastatin is [1 S -[1α( R* ),3α,7β,8β(2 S* ,4 S* ),8aβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C 24 H 36 O 5 and its molecular weight is 404.55. Its structural formula is: Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile. Altoprev extended-release tablets are designed for once-a-day oral administration and deliver 20 mg, 40 mg, or 60 mg of lovastatin. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: acetyltributyl citrate; butylated hydroxy anisole; candellila wax; cellulose acetate; confectioner s sugar (contains corn starch); F D & C yellow # 6; glyceryl monostearate; hypromellose; hypromellose phthalate; lactose; methacrylic acid copolymer, type B; polyethylene glycols (PEG 400, PEG 8000); polyethylene oxides; polysorbate 80; propylene glycol; silicon dioxide; sodium chloride; sodium lauryl sulfate; synthetic black iron oxide; red iron oxide; talc; titanium dioxide and triacetin. Altoprev - Clinical Pharmacology 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. Pharmacodynamics 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 high-affinity 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. Pharmacokinetics Absorption: 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) L = lovastatin, LA = lovastatin acid, TI = total inhibitors of HMG-CoA reductase, AI = active inhibitors of HMG-CoA reductase, C max = highest observed plasma concentration, C min = trough concentration at t = 24 hours after dosing, T max = time at which the C max occurred, AUC 0-24hr = 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. Drug C max (ng/mL) C min (ng/mL) T max (h) AUC 0-24hr (ng hr/mL) L LA TI AI L LA TI AI L LA L LA TI AI 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 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 hypercholesterolemic 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 max and lower C max 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. LDL-C HDL-C TOTAL-C TG Before Breakfast -32.0% 8.4% -22.2% -10.2% After Dinner -34.1% 7.4% -23.6% -11.2% Before Bedtime -36.9% 11.1% -25.5% -19.7% 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 ( 5.1 ), 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 1 , 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 * 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. Þ Single-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. ß Cyclosporine-treated post kidney transplant patients with stable graft function, transplanted at least 9 months prior to study. à NR = Analyte not reported. è Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone. Π Analyte not determined Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Lovastatin AUC Ratio * (with / without coadministered drug) No Effect = 1.00 C max Ratio * (with / without coadministered drug) No Effect = 1.00 Lovastatin Lovastatin acid Lovastatin Lovastatin acid Contraindicated with lovastatin, [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ] 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 ( 5.1 ) ] Cyclosporine Not described ß 10 mg QD for 10 days on Day 10 3- to 5-fold NR à NR à NR à 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-strength Þ 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 ( 5.1 ) ] Diltiazem 120 mg BID for 14 days 20 mg on Day 14 3.57 è ND Π 4.33 è ND Π No dosing adjustments required for the following: Propanolol 40 mg BID for 2.5 days 20 mg on Day 2 ND Π 0.87 ND Π 0.81 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. Specific Populations Geriatric: Lovastati putting forward
TOP Products Altoprev really appropriate
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