Side Effects of Mevacor (lovastatin)

洛伐他汀(lovastatin) is an HMG-CoA reductase inhibitor, (a "statin") used to reduce totalcholesterolandtriglyceridesin patients with elevatedcholesterol levels.

Statinsreduce cholesterol by inhibiting an enzyme in theliver(HMG-CoA reductase) that is necessary for the production of cholesterol. In the blood, statins lower total cholesterol, low density lipoprotein (LDL) cholesterol ("bad" cholesterol) andtriglycerides.

LDL cholesterolis believed to be an important cause ofatherosclerosisandcoronary artery disease(cardiovascular disease). LoweringLDL cholesterollevels slows and may even reversecoronary artery disease.

Statins also increase high density lipoprotein (HDL) cholesterol ("good" cholesterol). RaisingHDL cholesterollevels, like loweringLDL cholesterol, may slow coronary artery disease.

Common side effects of Mevacor include

• headache,
• nausea,
• vomiting,
• diarrhea,
• abdominal pain,
• muscle pain, and
• abnormal liver tests.

Serious side effects of Mevacor include

• hypersensitivity reactions,
• liver damage,
• muscle inflammation or breakdown (rhabdomyolysis), and
• increases in HbA1c and fasting serum glucose levels as are seen indiabetes,memory loss, forgetfulness,amnesia,confusion, and memory impairment.

Drug interactionsof Mevacor includeerythromycin,ketoconazole,itraconazole,clarithromycin,telithromycin,cyclosporine,nefazodone,boceprevir,telaprevir,voriconazole, andprotease inhibitorssuch asindinavirandritonavirbecause thesedrugsthat decrease elimination of lovastatin, which could increase the levels of lovastatin in the body and increase the risk of muscle toxicity from lovastatin.

• Large quantities of grapefruit juice (more than 1 quart daily) also will increase blood levels of lovastatin and should be avoided.
• Amiodarone,verapamil,diltiazem,danazol,niacin,colchicine, ranolazine,gemfibrozil, andfenofibratealso may increase the risk of muscle toxicity when combined with lovastatin.
• Cyclosporine or gemfibrozil should not be combined with lovastatin.
• Patients takingamiodaroneshould not exceed 40 mg daily of lovastatin.
• Patients taking verapamil, diltiazem, or danazol should start with 10 mg and should not exceed 20 mg of lovastatin daily.
• Patients taking niacin (greater than or equal to 1 g/day), fenofibrate or cyclosporine should not take more than 20 mg of lovastatin.
• Lovastatin may increase the effect ofwarfarin, a blood thinner.

Pregnantwomen should not use lovastatin because the developing fetus requires cholesterol for development, and lovastatin reduces the production of cholesterol. Lovastatin should only be administered to women of child bearing age if they are not likely to become pregnant.

Because of the risk of adverse effects to the developing infant, lovastatin should not be administered tobreastfeedingmothers.

The most common side effects of lovastatin are:

• headache,
• nausea,
• vomiting,
• diarrhea,
• abdominal pain,
• musclepain, and
• abnormalliver tests.

Hypersensitivity reactions also have been reported.

The most serious potential side effects are liver damage and muscle inflammation or breakdown.

• Lovastatin shares side effects, such as liver and muscle damage associated with all statins.
• Serious liver damage caused by statins is rare. More often, statins cause abnormalities of liver tests.
• Abnormal tests usually return to normal even if a statin is continued, but if the abnormal test value is greater than three times the upper limit of normal, the statin usually is stopped.
• Liver functiontests should be performed at the beginning of treatment and then as needed thereafter.
• Inflammation of the muscles caused by statins can lead to a serious breakdown of muscle cells calledrhabdomyolysis. Rhabdomyolysis causes the release of muscle protein (myoglobin) into the blood.
• Myoglobin can cause kidney failure and even death. When used alone, statins cause rhabdomyolysis in less than 1% of patients.
• To prevent the development of rhabdomyolysis, patients taking lovastatin should contact their healthcare provider immediately if they develop unexplained musclepain,weakness, or muscle tenderness.
• Statins have been associated with increases in HbA1c and fasting serum glucose levels as are seen indiabetes.
• There are also post-marketing reports ofmemory loss, forgetfulness, amnesia, confusion, and memory impairment.
• Symptoms may start one day to years after starting treatment and resolve within a median of three weeks after stopping the statin.

洛伐他汀is generally well tolerated; adverse reactions usually have been mild and transient.

Phase III Clinical Studies

• In Phase III controlled clinical studies involving 613 patients treated with Mevacor, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study.
• Persistent increases of serum transaminases have been noted.
• About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions.
• 的corresponding values for the control agentcholestyraminewas 9 percent.
• This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported.

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study

• 洛伐他汀was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300 mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study.
• Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥ 1% in any treatment group are shown in the table below.
• For no event was the incidence on drug and placebo statistically different.

	Placebo (N = 1663) %	洛伐他汀20 mg q.p.m. (N = 1642) %	洛伐他汀40 mg q.p.m. (N = 1645) %	洛伐他汀20 mg b.i.d. (N = 1646) %	洛伐他汀40 mg b.i.d. (N = 1649) %
Body As a Whole
Asthenia	1.4	1.7	1.4	1.5	1.2
Gastrointestinal
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
Musculoskeletal
Muscle cramps	0.5	0.6	0.8	1.1	1.0
Myalgia	1.7	2.6	1.8	2.2	3.0
Nervous System/ Psychiatric
Dizziness	0.7	0.7	1.2	0.5	0.5
Headache	2.7	2.6	2.8	2.1	3.2
Skin
Rash	0.7	0.8	1.0	1.2	1.3
Special Senses
Blurred vision	0.8	1.1	0.9	0.9	1.2

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.

• Body as a Whole:chest pain;
• Gastrointestinal:acid regurgitation,dry mouth, vomiting;
• Musculoskeletal:leg pain,shoulder pain,arthralgia;
• Nervous System/Psychiatric:insomnia, paresthesia;
• Skin:alopecia, pruritus;
• Special Senses:eye irritation.

In the EXCEL study, 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 Mevacor. The value for the placebo group was 2.5%.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

• In AFCAPS/TexCAPS involving 6,605 participants treated with 20-40 mg/day of Mevacor (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with Mevacor was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up.
• The adverse experiences reported in AFCAPS/TexCAPS were similar to those reported in EXCEL.

Concomitant Therapy

• 在受控洛伐他汀的临床研究was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed.
• The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine.
• Otherlipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies.
• Preliminary data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin alone.
• In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid).
• The combined use of lovastatin with cyclosporine or gemfibrozil should be avoided. Caution should be used when prescribing otherfibratesor lipid-lowering doses ( = 1 g/day) of niacin with lovastatin.

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.

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 extraocular 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,lupuserythematous-like syndrome,polymyalgia rheumatica,dermatomyositis,vasculitis, purpura,thrombocytopenia, leukopenia, hemolyticanemia, 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 activehepatitis, cholestaticjaundice, 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 ofcataracts(lensopacities), ophthalmoplegia.

Laboratory Abnormalities

elevated transaminases,alkaline phosphatase, γ-glutamyl transpeptidase, andbilirubin; thyroid function abnormalities.

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 Mevacor (10 to 40 mg daily) was generally similar to that of the groups treated with placebo.

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.
• Strong inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin,HIVprotease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and grapefruit juice increase the risk of myopathy by reducing the elimination of lovastatin.

与Ca的降脂药物use Myopathy When Given Alone

The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A4 inhibitors, but which can cause myopathy when given alone.

Gemfibrozil

Other fibrates

Niacin (nicotinic acid) ( ≥ 1 g/day)

Other Drug Interactions

Cyclosporine:The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine.

Danazol, Diltiazem, Dronedarone or Verapamil:The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol, diltiazem, dronedarone or verapamil particularly with higher doses of lovastatin.

Amiodarone:The risk of myopathy/rhabdomyolysis is increased when amiodarone is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor class.

CoumarinAnticoagulants: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 have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and frequently enough during early therapy to insure 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 lovastatin 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.

Ranolazine:The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine.

Propranolol:In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol.

Digoxin:In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.

OralHypoglycemicAgents:In pharmacokinetic studies of Mevacor in hypercholesterolemic noninsulin dependent diabetic patients, there was no drug interaction withglipizideor withchlorpropamide.

Endocrine Function

• Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Mevacor.
• HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production.
• Results ofclinical trialswith 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.
• In the same study, the mean testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin 40 mg daily for 16 weeks in 21 men.
• The effects of HMG-CoA reductase inhibitors on malefertilityhave not been studied in adequate numbers of male patients.
• The effects, if any, on the pituitarygonadal axis in pre-menopausal women are unknown.
• 与洛伐他汀治疗的患者中,开发临床cal 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.

CNS Toxicity

• Lovastatin producedoptic nervedegeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normaldogsin a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity).
• Vestibulocochlear Wallerian-like degeneration and retinalganglioncell chromatolysis were also seen in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60 mg/kg/day dose.
• CNS vascular lesions, characterized by perivascular hemorrhage andedema, 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 (Cmax) 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.
• Cataractswere seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at 60 mg/kg/day.