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Lovastatin
Overview
What is Lovastatin?
Lovastatin is a cholesterol lowering agent isolated from a strain of . After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and an 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-[1α(*),3α,7β,8β(2*,4*), 8aβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The molecular formula of lovastatin is CHO and its molecular weight is 404.54. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
Each tablet for oral administration, contains 10 mg, 20 mg, or 40 mg of lovastatin. In addition, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. Butylated hydroxyanisole is added as a preservative. The 20 mg tablet also contains D&C Red #30 aluminum lake. The 40 mg tablet also contains D&C Yellow #10 HT aluminum lake.
What does Lovastatin look like?
What are the available doses of Lovastatin?
Sorry No records found.
What should I talk to my health care provider before I take Lovastatin?
Sorry No records found
How should I use Lovastatin?
Therapy with lovastatin should be a component of multiple risk factor intervention in those individuals with dyslipidemia at risk for atherosclerotic vascular disease. Lovastatin should be used in addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has been inadequate to reduce risk.
Primary Prevention Of Coronary Heart Disease:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease:
Hypercholesterolemia:
Adolescent Patients With Heterozygous Familial Hypercholesterolemia:
1. LDL-C remains >189 mg/dL or
2. LDL-C remains > 160 mg/dL
• there is a positive family history of premature cardiovascular disease or
• two or more other CVD risk factors are present in the adolescent patient
General Recommendations:
LDL-C = total-C - [0.2 x (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated total-C. In such cases, lovastatin tablets are not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
After the LDL-C goal has been achieved, if the TG is still ≥ 200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is ≥ 130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy.
Although lovastatin may be useful to reduce elevated LDL-C levels in patients with combined hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality (Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
*** Classification of Hyperlipoproteinemias
The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature cardiovascular disease is summarized below:
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
The patient should be placed on a standard cholesterol-lowering diet before receiving lovastatin and should continue on this diet during treatment with lovastatin (see NCEP Treatment Guidelines for details on dietary therapy). Lovastatin should be given with meals.
Adult Patients:
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin if cholesterol levels fall significantly below the targeted range.
What interacts with Lovastatin?
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see ).
Pregnancy And Lactation
Lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive
What are the warnings of Lovastatin?
Myopathy/Rhabdomyolysis:
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the following:
Potent Inhibitors Of CYP3A4:
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided.
Gemfibrozil, Particularly With Higher Doses Of Lovastatin:
The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with gemfibrozil. The combined use of lovastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination.
Other Lipid-lowering Drugs (Other Fibrates Or ≥ 1 g/day Of Niacin):
The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with other fibrates or ≥ 1 g/day of niacin.
The benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations.
Cyclosporine Or Danazol, With Higher Doses Of Lovastatin:
The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with cyclosporine or danazol.
Amiodarone Or Verapamil:
The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant medication with amiodarone or verapamil
Prescribing recommendations for interacting agents are summarized in Table VI (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; ; ).
Liver Dysfunction:
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
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 and placebo groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of lovastatin was 20 mg/day; 50% of the lovastatin treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin 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 group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to initiation of therapy in patients with a history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawl of therapy with lovastatin is recommended.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal) elevations of serum transaminases have been reported following therapy with lovastatin (see ). These changes appeared soon after initiation of therapy with lovastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.
| Interacting Agents | Prescribing Recommendations |
| Itraconazole | Avoid lovastatin |
| Ketoconazole | |
| Erythromycin | |
| Clarithromycin | |
| Telithromycin | |
| HIV protease inhibitors | |
| Nefazodone | |
| Gemfibrozil | Do not exceed 20 mg lovastatin |
| Other fibrates | |
| Lipid-lowering doses (≥1 g/day)of niacin | |
| Cyclosporine | |
| Danazol | |
| Amiodarone | Do not exceed 40 mg lovastatin daily |
| Verapamil | |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
What are the precautions of Lovastatin?
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see and ). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia:
Information for Patients
Patients should be advised about substances they should not take concomitantly with lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking lovastatin.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.
See and CLINICAL PHARMACOLOGY, Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (>1 quart daily)
Interactions With Lipid-lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy when given alone.
See .
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥ 1 g/day)
Cyclosporine or danazol
Amiodarone or verapamil:
Coumarin anticoagulants:
Propranolol:
Digoxin:
Oral hypoglycemic agents:
Endocrine Function:
CNS Toxicity
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (C) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, 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 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.)
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. 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 (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. 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 in a microbial mutagen test using mutant strains of with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an chromosome aberration study in CHO cells, or an 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. 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.
Pregnancy
Pregnancy Category X: See .
Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations (affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7 times the human dose based on body surface area and in rats results in 5 times the human exposure based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to 0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%, respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and 11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5 mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of greater than 200 prospectively followed pregnancies exposed during the first trimester to lovastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in congenital anomalies over the background incidence.
Maternal treatment with lovastatin may reduce the fetal levels of mevalonate, which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipidlowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, lovastatin should not be used in women who are pregnant, or can become pregnant (see ). Lovastatin 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 hazards. Treatment as soon as pregnancy is recognized.
Reproductive Toxicology
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 lovastatin should not nurse their infants (see ).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience profile generally similar to that of patients treated with placebo. In these limited controlled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See ; ; and should be counseled on appropriate contraceptive methods while on lovastatin therapy (see and ).
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity 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 (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/day dosage range (see ).
What are the side effects of Lovastatin?
Lovastatin is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies:
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see ).
Expanded Clinical Evaluation Of Lovastatin (EXCEL) Study:
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. chest pain; acid regurgitation, dry mouth, vomiting; leg pain, shoulder pain, arthralgia; : insomnia, paresthesia; : alopecia, pruritus; : eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with lovastatin. The value for the placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS):
Concomitant Therapy:
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, g-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
| Placebo (N = 1663)%________ | Lovastatin20 mg q.p.m. (N = 1642) %________ | Lovastatin40 mg q.p.m. (N = 1645)%________ | Lovastatin20 mg b.i.d. (N = 1646)%________ | Lovastatin40 mg b.i.d.(N = 1649)%________ | |
| Asthenia | 1.4 | 1.7 | 1.4 | 1.5 | 1.2 |
| Abdominal pain | 1.6 | 2.0 | 2.0 | 2.2 | 2.5 |
| Constipation | 1.9 | 2.0 | 3.2 | 3.2 | 3.5 |
| Diarrhea | 2.3 | 2.6 | 2.4 | 2.2 | 2.6 |
| Dyspepsia | 1.9 | 1.3 | 1.3 | 1.0 | 1.6 |
| Flatulence | 4.2 | 3.7 | 4.3 | 3.9 | 4.5 |
| Nausea | 2.5 | 1.9 | 2.5 | 2.2 | 2.2 |
| Muscle cramps | 0.5 | 0.6 | 0.8 | 1.1 | 1.0 |
| Myalgia | 1.7 | 2.6 | 1.8 | 2.2 | 3.0 |
| Dizziness | 0.7 | 0.7 | 1.2 | 0.5 | 0.5 |
| Headache | 2.7 | 2.6 | 2.8 | 2.1 | 3.2 |
| Rash | 0.7 | 0.8 | 1.0 | 1.2 | 1.3 |
| Blurred vision | 0.8 | 1.1 | 0.9 | 0.9 | 1.2 |
Adolescent Patients (Ages 10-17 Years):
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the groups treated with lovastatin (10 to 40 mg daily) was generally similar to that of the groups treated with placebo (see and ).
What should I look out for while using Lovastatin?
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see ).
Pregnancy And Lactation
Lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive
What might happen if I take too much Lovastatin?
After oral administration of lovastatin to mice, the median lethal dose observed was >15 g/m.
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 have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with lovastatin can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
How should I store and handle Lovastatin?
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.PHARMACIST:Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008Lovastatin Tablets, USP are available as follows:10 mg — Each white, round, flat faced beveled edge tablet imprinted with on one side and 633 on the other side contains 10 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6590-39),20 mg — Each pink, round, flat faced beveled edge tablet imprinted with on one side and 634 on the other side contains 20 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-5589-39), and 31 (NDC 0615-5589-31).40 mg — Each yellow, round, flat faced beveled edge tablet imprinted with on one side and 635 on the other side contains 40 mg of lovastatin. Tablets are supplied in blisterpacks of 30 (NDC 0615-6551-39).Dispense in a tight, light-resistant container as defined in the USP.Store between 5°-25°C (41°-77°F). Protect from light and store in a well-closed, light-resistant container.Manufactured by:Actavis Elizabeth LLC200 Elmora Avenue, Elizabeth, NJ 07207 USA40-8843Revised — January 2008
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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) 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 in the lower end of this range.
Lovastatin has been shown to reduce both normal and 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 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. Apolipoprotein B also falls substantially during treatment with lovastatin. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that lovastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, lovastatin can produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of lovastatin on Lp(a), fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
Lovastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which 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.
Pharmacokinetics:
in vivo
Following an oral dose of C-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. Plasma concentrations of total radioactivity (lovastatin plus C-metabolites) peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours post-dose. Absorption of lovastatin, estimated relative to an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral dose. 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. 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. Following administration of lovastatin tablets the coefficient of variation, based on between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in the general circulation.
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.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its 6’-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state between the second and third days of therapy and were about 1.5 times those following a single dose. When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on average about two-thirds those found when lovastatin was administered immediately after a standard test meal.
In a study of patients with severe renal insufficiency (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.
In a study including 16 elderly patients between 70-78 years of age who received lovastatin 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 ).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due, in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see and ).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see ). Grapefruit juice contains one or more components that inhibit CYP3A4 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 a mean increase in the serum concentration of lovastatin and its β-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 - high performance liquid chromatography]. 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 an enzyme inhibition assay 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 - different from that used in the first** study] 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.
______________
**Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4): 397-402.
Clinical Studies In Adults:
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia, lovastatin, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo. Lovastatin consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-C/HDL-C ratio. In addition, lovastatin produced increases of variable magnitude in HDL-C, and modestly decreased VLDL-C and plasma TG (see Tables I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table I.
Lovastatin was compared to cholestyramine in a randomized open parallel study. The study was performed with patients with hypercholesterolemia who were at high risk of myocardial infarction. Summary results are presented in Table II.
Lovastatin was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin on lipids and lipoproteins and the safety profile of lovastatin were similar to that demonstrated in studies in nondiabetics. Lovastatin had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation Of Lovastatin (EXCEL) Study:
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS):
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 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin were titrated to 40 mg daily when their LDL-C remained >110 mg/dL at the 20-mg starting dose.
Lovastatin reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, lovastatin 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 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 on outcomes could not be adequately assessed in this subgroup.
Atherosclerosis:
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.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA compared to diet and, in some cases, low-dose resin.
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:
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant differences between the lovastatin 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.
Non-Clinical Toxicology
Hypersensitivity to any component of this medication.Active liver disease or unexplained persistent elevations of serum transaminases (see ).
Pregnancy And Lactation
Lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.
See and CLINICAL PHARMACOLOGY, Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (>1 quart daily)
Interactions With Lipid-lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4 inhibitors, but which can cause myopathy when given alone.
See .
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥ 1 g/day)
Lovastatin may elevate creatine phosphokinase and transaminase levels (see and ). This should be considered in the differential diagnosis of chest pain in a patient on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia:
Lovastatin is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies:
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see ).
Expanded Clinical Evaluation Of Lovastatin (EXCEL) Study:
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. chest pain; acid regurgitation, dry mouth, vomiting; leg pain, shoulder pain, arthralgia; : insomnia, paresthesia; : alopecia, pruritus; : eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with lovastatin. The value for the placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS):
Concomitant Therapy:
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, g-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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