Simvastatin 80 MG Oral Tablet
Generic Name: SIMVASTATIN
Brand Name: Simvastatin
- Substance Name(s):
- SIMVASTATIN
DRUG INTERACTIONS
7 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3) * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Grapefruit juice Avoid grapefruit juice Other Lipid-lowering Medications: Use with other fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects.
Caution should be used when prescribing with simvastatin.
(5.1, 7.2, 7.4) Coumarin anticoagulants: Concomitant use with simvastatin prolongs INR.
Achieve stable INR prior to starting simvastatin.
Monitor INR frequently until stable upon initiation or alteration of simvastatin therapy.
(7.6) 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol Strong CYP3A4 Inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4.
Simvastatin 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.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin.
[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)].
If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol.
Therefore, concomitant use of these drugs is contraindicated [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)].
Other fibrates: Caution should be used when prescribing with simvastatin [see Warnings and Precautions (5.1)].
7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Table 3 in Clinical Pharmacology (12.3)].
7.4 Niacin Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products.
In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products.
Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.
[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] 7.5 Digoxin In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma.
Patients taking digoxin should be monitored appropriately when simvastatin is initiated [see Clinical Pharmacology (12.3)].
7.6 Coumarin Anticoagulants In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively.
With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly.
In such patients, prothrombin time should be determined before starting simvastatin 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 simvastatin is changed or discontinued, the same procedure should be repeated.
Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
7.7 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.
OVERDOSAGE
10 Significant lethality was observed in mice after a single oral dose of 9 g/m2.
No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively.
No specific diagnostic signs were observed in rodents.
At these doses the only signs seen in dogs were emesis and mucoid stools.
A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g.
All patients recovered without sequelae.
Supportive measures should be taken in the event of an overdose.
The dialyzability of simvastatin and its metabolites in man is not known at present.
DESCRIPTION
11 Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus.
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form.
This is 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.
Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β (2S*,4S*),-8aβ]].
The molecular formula of simvastatin is C25H38O5 and its molecular weight is 418.57.
Its structural formula is: Simvastatin USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
Tablets simvastatin for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin USP and the following inactive ingredients: ascorbic acid, lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), hydroxypropyl cellulose, hypromellose, titanium dioxide, talc, citric acid monohydrate, isopropyl alcohol, magnesium stearate and butylated hydroxyanisole.
Simvastatin 5 mg also contains ferric oxide yellow, simvastatin 10 mg and simvastatin 20 mg also contains ferric oxide red and ferric oxide yellow, simvastatin 40 mg and simvastatin 80 mg also contains ferric oxide red.
Chemical Structure
CLINICAL STUDIES
14 14.1 Clinical Studies in Adults Reductions in Risk of CHD Mortality and Cardiovascular Events In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8 mmol/L).
In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years.
Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%.
Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group).
The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths).
There was no statistically significant difference between groups in non-cardiovascular mortality.
Simvastatin significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events).
The risk of having a hospital-verified non-fatal MI was reduced by 37%.
Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients).
Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients).
Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels.
Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed.
However, simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event).
The randomization was stratified by angina alone (21% of each treatment group) or a previous MI.
Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed.
However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort.
Additionally, simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years), compared with younger patients.
The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267 on placebo).
Patients were allocated to treatment using a covariate adaptive method3 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups.
Patients had a mean age of 64 years (range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%).
At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.
The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).
————————————————— 3 D.R.
Taves, Minimization: a new method of assigning patients to treatment and control groups.
Clin.
Pharmacol.
Ther.
15 (1974), pp.
443-453 Table 4: Summary of Heart Protection Study Results Endpoint Simvastatin (N=10,269) n (%)* Placebo (N=10,267) n (%)* Risk Reduction (%) (95% CI) p-Value Primary Mortality CHD mortality 1,328 (12.9) 587 (5.7) 1,507 (14.7) 707 (6.9) 13 (6 to 19) 18 (8 to 26) p=0.0003 p=0.0005 Secondary Non-fatal MI Stroke 357 (3.5) 444 (4.3) 574 (5.6) 585 (5.7) 38 (30 to 46) 25 (15 to 34) p<0.0001 p<0.0001 Tertiary Coronary revascularization Peripheral and other non-coronary revascularization 513 (5) 450 (4.4) 725 (7.1) 532 (5.2) 30 (22 to 38) 16 (5 to 26) p<0.0001 p=0.006 * n = number of patients with indicated event Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1).
A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin had events and 1,212 patients on placebo had events).
A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with simvastatin had events and 2,585 patients on placebo had events).
Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001).
Treatment with simvastatin produced significant relative risk reductions for all components of the composite endpoints.
The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity.
Diabetics showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD.
Figure 1 The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS N = number of patients in each subgroup.
The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line.
The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population.
The vertical solid line represents a relative risk of one.
The vertical dashed line represents the point estimate of relative risk in the entire study population.
Angiographic Studies In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD.
In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo.
Angiograms were evaluated at baseline, two and four years.
The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively.
Simvastatin significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis.
In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.
Modifications of Lipid Profiles Primary Hyperlipidemia (Fredrickson type lla and llb) Simvastatin has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia.
Maximal to near maximal response is generally achieved within 4 to 6 weeks and maintained during chronic therapy.
Simvastatin significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin also decreased TG and increased HDL-C (see Table 5).
Table 5: Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks) TREATMENT N TOTAL-C LDL-C HDL-C TG* Lower Dose Comparative Study † (Mean % Change at Week 6) Simvastatin 5 mg q.p.m.
Simvastatin 10 mg q.p.m.
109 110 -19 -23 -26 -30 10 12 -12 -15 Scandinavian Simvastatin Survival Study ‡ (Mean % Change at Week 6) Placebo 2223 -1 -1 0 -2 Simvastatin 20 mg q.p.m.
2221 -28 -38 8 -19 Upper Dose Comparative Study § (Mean % Change Averaged at Weeks 18 and 24) Simvastatin 40 mg q.p.m.
Simvastatin 80 mg q.p.m.¶ 433 664 -31 -36 -41 -47 9 8 -18 -24 Multi-Center Combined Hyperlipidemia Study # (Mean % Change at Week 6) Placebo Simvastatin 40 mg q.p.m.
Simvastatin 80 mg q.p.m.
125 123 124 1 -25 -31 2 -29 -36 3 13 16 -4 -28 -33 * median percent change †mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL ‡mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL § mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL ¶ 21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively.
Patients with TG >350 mg/dL were excluded # mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
Hypertriglyceridemia (Fredrickson type IV) The results of a subgroup analysis in 74 patients with type IV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.
Table 6: Six-week, Lipid-lowering Effects of Simvastatin in Type IV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline* TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8) Simvastatin 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23) Simvastatin 80 mg/day 74 -32 (-38, -24) -37 (-46, -26) +15 (+5, +23) -34 (-45, -18) -41 (-57, -28) -38 (-49, -32) * The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.
Dysbetalipoproteinemia (Fredrickson type III) The results of a subgroup analysis in 7 patients with type III hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7.
Table 7: Six-week, Lipid-lowering Effects of Simvastatin in Type III Hyperlipidemia Median Percent Change (min, max) from Baseline* TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C + IDL Non-HDL-C Placebo 7 -8 (-24, +34) -8 (-27, +23) -2 (-21, +16) +4 (-22, +90) -4 (-28, +78) -8 (-26, -39) Simvastatin 40 mg/day 7 -50 (-66, -39) -50 (-60, -31) +7 (-8, +23) -41 (-74, -16) -58 (-90, -37) -57 (-72, -44) Simvastatin 80 mg/day 7 -52 (-55, -41) -51 (-57, -28) +7 (-5, +29) -38 (-58, +2) -60 (-72, -39) -59 (-61, -46) * The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
Homozygous Familial Hypercholesterolemia In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses.
In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40 and 80 mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively.
One patient had an increase of 15% in LDL-C.
Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80 mg dose.
Endocrine Function In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration.
Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine.
There was no effect on plasma gonadotropin levels.
In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin.
In another 24-week study, simvastatin 20 to 40 mg had no detectable effect on spermatogenesis.
In 4S, in which 4,444 patients were randomized to simvastatin 20 to 40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different.
Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant.
The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown.
Figure 1 The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS 14.2 Clinical Studies in Adolescents In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study).
Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL.
The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
In a 24-week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo.
Simvastatin significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8).
Results from the extension at 48 weeks were comparable to those observed in the base study.
Table 8: Lipid-lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline) * median percent change Dosage Duration N Total-C LDL-C HDL-C TG* Apo B Placebo 24 Weeks 67 % Change from Baseline (95% CI) 1.6 (-2.2, 5.3) 1.1 (-3.4, 5.5) 3.6 (-0.7, 8) -3.2 (-11.8, 5.4) -0.5 (-4.7, 3.6) Mean baseline, mg/dL (SD) 278.6 (51.8) 211.9 (49) 46.9 (11.9) 90 (50.7) 186.3 (38.1) Simvastatin 24 Weeks 106 % Change from Baseline (95% CI) -26.5 (-29.6, -23.3) -36.8 (-40.5, -33) 8.3 (4.6, 11.9) -7.9 (-15.8, 0) -32.4 (-35.9, -29) Mean baseline, mg/dL (SD) 270.2 (44) 203.8 (41.5) 47.7 (9) 78.3 (46) 179.9 (33.8) After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64 to 289 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128 to 334 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH.
The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
HOW SUPPLIED
16 /STORAGE AND HANDLING Simvastatin Tablets USP, 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side.
They are supplied as follows: Bottles of 30 NDC 16714-681-01 (Child Resistant Closure) Bottles of 90 NDC 16714-681-02 (Child Resistant Closure) Simvastatin Tablets USP, 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side.
They are supplied as follows: Bottles of 30 NDC 16714-682-01 (Child Resistant Closure) Bottles of 90 NDC 16714-682-02 (Child Resistant Closure) Bottles of 1,000 NDC 16714-682-03 (Non-Child Resistant Closure) Simvastatin Tablets USP, 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side.
They are supplied as follows: Bottles of 30 NDC 16714-683-01 (Child Resistant Closure) Bottles of 90 NDC 16714-683-02 (Child Resistant Closure) Bottles of 1,000 NDC 16714-683-03 (Non-Child Resistant Closure) Simvastatin Tablets USP, 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side.
They are supplied as follows: Bottles of 30 NDC 16714-684-01 (Child Resistant Closure) Bottles of 90 NDC 16714-684-02 (Child Resistant Closure) Bottles of 1,000 NDC 16714-684-03 (Non-Child Resistant Closure) Simvastatin Tablets USP, 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side.
They are supplied as follows: Bottles of 30 NDC 16714-685-01 (Child Resistant Closure) Bottles of 90 NDC 16714-685-02 (Child Resistant Closure) Bottles of 1,000 NDC 16714-685-03 (Non-Child Resistant Closure) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Contraindications (4) 02/2014 Warnings and Precautions Myopathy/Rhabdomyolysis (5.1) 02/2014
GERIATRIC USE
8.5 Geriatric Use Of the 2,423 patients who received simvastatin in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin, 363 (15%) and 5,366 (52%), respectively were ≥65 years old.
In HPS, 615 (6%) were ≥75 years old.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin should be prescribed with caution in the elderly.
[See Clinical Pharmacology (12.3).] A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age.
In 4S, 1,021 (23%) of 4,444 patients were 65 or older.
Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD.
In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older).
The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1)].
In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73.
Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75.
There were no overall differences in safety between older and younger patients in either 4S or HPS.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be prescribed with caution in the elderly.
In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age.
[See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
DOSAGE FORMS AND STRENGTHS
3 Tablets simvastatin 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side.
Tablets simvastatin 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side.
Tablets simvastatin 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side.
Tablets simvastatin 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side.
Tablets simvastatin 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side.
Tablets: 5 mg; 10 mg; 20 mg; 40 mg; 80 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration.
Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol.
In addition, simvastatin reduces VLDL and TG and increases HDL-C.
INDICATIONS AND USAGE
1 Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin tablets, USP can be started simultaneously with diet.
Simvastatin tablets, USP are an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events.
(1.1) Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
(1.2) Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbetalipoproteinemia.
(1.2) Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia.
(1.2) Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.
(1.2, 1.3) Limitations of Use Simvastatin tablets, USP have not been studied in Fredrickson Types I and V dyslipidemias.
(1.4) 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin tablets, USP are indicated to: Reduce the risk of total mortality by reducing CHD deaths.
Reduce the risk of non-fatal myocardial infarction and stroke.
Reduce the need for coronary and non-coronary revascularization procedures.
1.2 Hyperlipidemia Simvastatin tablets, USP are indicated to: Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia).
Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).
Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) Simvastatin tablets, USP are indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: 1.
LDL cholesterol remains ≥190 mg/dL; or 2.
LDL cholesterol remains ≥160 mg/dL and There is a positive family history of premature cardiovascular disease (CVD) or Two or more other CVD risk factors are present in the adolescent patient.
The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL.
The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.
1.4 Limitations of Use Simvastatin tablets, USP have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche.
Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo.
Doses greater than 40 mg have not been studied in this population.
In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.
[See Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1)].
Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.
PREGNANCY
8.1 Pregnancy Teratogenic Effects Pregnancy Category X [See Contraindications (4).
] Simvastatin is contraindicated in women who are or may become pregnant.
Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development.
Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of use with simvastatin during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero.
Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity.
Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development.
Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin may cause fetal harm when administered to a pregnant woman.
If simvastatin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
There are rare reports of congenital anomalies following intrauterine exposure to statins.
In a review2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population.
However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate.
In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area.
However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.
Women of childbearing potential, who require treatment with simvastatin for a lipid disorder, should be advised to use effective contraception.
For women trying to conceive, discontinuation of simvastatin should be considered.
If pregnancy occurs, simvastatin should be immediately discontinued.
¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ 2 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk.
Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants.
A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4)].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80 mg dose.
(5.1) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines.
Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported.
(4, 5.1, 8.5, 8.6) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness.
Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.
See Drug Interaction table.
(5.1) Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur.
Check liver enzyme tests before initiating therapy and as clinically indicated thereafter.
(5.2) 5.1 Myopathy/Rhabdomyolysis Simvastatin 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 statin activity in plasma.
Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
The risk of myopathy, including rhabdomyolysis, is dose related.
In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively.
The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses.
In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day.
The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day.
The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment.
In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin.
Therefore, the 80 mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)].
If, however, a patient who is currently tolerating the 80 mg dose of simvastatin needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction.
Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness.
If symptoms occur, treatment should be discontinued immediately.
[See Warnings and Precautions (5.2).] There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use.
IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing simvastatin.
Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.
In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued.
Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus.
Such patients merit closer monitoring.
Simvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
Simvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Drug Interactions The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma.
Simvastatin is metabolized by the cytochrome P450 isoform 3A4.
Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy.
These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice [see Clinical Pharmacology (12.3)].
Combination of these drugs with simvastatin is contraindicated.
If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
[See Contraindications (4) and Drug Interactions (7.1).] The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].
Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2)].
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7)].
The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3)] [also see Dosage and Administration, Patients with Homozygous Familial Hypercholesterolemia (2.4)] .
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products.
In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product.
Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products.
Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.
It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4)].
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3, 2.4), Drug Interactions (7), Clinical Pharmacology (12.3)].
Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors e.g.,: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol Contraindicated with simvastatin Verapamil Diltiazem Dronedarone Do not exceed 10 mg simvastatin daily Amiodarone Amlodipine Ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Grapefruit juice Avoid grapefruit juice 5.2 Liver Dysfunction Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies.
When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels.
The increases were not associated with jaundice or other clinical signs or symptoms.
There was no evidence of hypersensitivity.
In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)], the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs.
12 [0.6%]).
Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223).
Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study.
Among these 8 patients, 5 initially developed these abnormalities within the first year.
All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40 and 80 mg dose, respectively.
No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.
It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin.
If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, promptly interrupt therapy.
If an alternate etiology is not found do not restart simvastatin.
Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].
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 diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.
Moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin.
These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.
5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.
Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ].
Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin.
17.1 Muscle Pain All patients starting therapy with simvastatin should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing simvastatin.
Patients using the 80 mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80 mg dose.
The risk of myopathy, including rhabdomyolysis, occurring with use of simvastatin is increased when taking certain types of medication or consuming grapefruit juice.
Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.
17.2 Liver Enzymes It is recommended that liver function tests be performed before the initiation of simvastatin, and thereafter when clinically indicated.
All patients treated with simvastatin should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using simvastatin.
Discuss future pregnancy plans with your patients, and discuss when to stop taking simvastatin if they are trying to conceive.
Patients should be advised that if they become pregnant they should stop taking simvastatin and call their healthcare professional.
17.4 Breastfeeding Women who are breastfeeding should not use simvastatin.
Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.
_________________________________________________________________________________________________________________ Manufactured for: Northstar Rx LLC Memphis, TN 38141 Toll Free: 1-800-206-7821 Manufactured by: Aurobindo Pharma Limited Unit-VII (SEZ) Mahaboob Nagar (Dt)-509302 India M.L.No.: 22/MN/AP/2009/F/R Revised: 04/2015
DOSAGE AND ADMINISTRATION
2 Dose range is 5 to 40 mg/day.
(2.1) Recommended usual starting dose is 10 or 20 mg once a day in the evening.
(2.1) Recommended starting dose for patients at high risk of CHD is 40 mg/day.
(2.1) Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80 mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
(2.2) Patients who are currently tolerating the 80 mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.
(2.2) Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80 mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40 mg dose of simvastatin tablets should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
(2.2) Adolescents (10 to 17 years of age) with HeFH: Starting dose is 10 mg/day; maximum recommended dose is 40 mg/day.
(2.5) 2.1 Recommended Dosing The usual dosage range is 5 to 40 mg/day.
In patients with CHD or at high risk of CHD, simvastatin tablets can be started simultaneously with diet.
The recommended usual starting dose is 10 or 20 mg once a day in the evening.
For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day.
Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.
2.2 Restricted Dosing for 80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80 mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].
Patients who are currently tolerating the 80 mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.
Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80 mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40 mg dose of simvastatin tablets should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
2.3 Coadministration with Other Drugs Patients taking Verapamil, Diltiazem, or Dronedarone The dose of simvastatin tablets should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].
Patients taking Amiodarone, Amlodipine or Ranolazine The dose of simvastatin tablets should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].
2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)].
Simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of simvastatin tablets should be reduced by 50% if initiating lomitapide.
Simvastatin tablets dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken simvastatin tablets 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide.
2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia The recommended usual starting dose is 10 mg once a day in the evening.
The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day.
Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines1 and Clinical Studies (14.2) ].
Adjustments should be made at intervals of 4 weeks or more.
———————————— 1National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents.
Pediatrics.
89(3):495-501.
1992.
2.6 Patients with Renal Impairment Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment.
However, caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
2.7 Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products.
Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.
The cause of the increased risk of myopathy is not known.
It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.
[See Warnings and Precautions (5.1).]