Simvastatin 10mg 20mg & 40mg Film-coated Tablets



4.2 Posology and method of administration

Homozygous familial hypercholesterolaemia
Based on the results of a controlled clinical study, the recommended starting dosage is Ssimvastatin 40 mg/day in the evening. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

In patients taking lomitapide concomitantly with simvastatin, the dose of simvastatin must not exceed 40 mg/day (see sections 4.3, 4.4 and 4.5).

Dosage in renal insufficiencyRenal impairment
No modification of dosage should be necessary in patients with moderate renal insufficiency.
In patients with severe renal insufficiency impairment (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Use in older patientsElderly
No dosage adjustment is necessary.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Active liver disease or unexplained persistent elevations of serum transaminases
• Pregnancy and breast-feeding (see section 4.6)
• Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone and medicinal products containing cobicistat) (see sections 4.4 and 4.5)
• Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5)
• In patients with HoFH (homozygous familial hypercholesterolaemia), concomitant administration of lomitapide with doses >40 mg simvastatin (see sections 4.2, 4.4 and 4.5)

4.4 Special warnings and precautions for use

Reduced function of transport proteins
Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.
Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin acid and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (Ssee section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment (see section 4.8).

Before the treatment
All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.
Caution should be exercised in patients with pre-disposing factors of for rhabdomyolysis.
In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

• Older patientsElderly (age ≥ 65 years)
• Female gender
• Renal impairment
• Uncontrolled hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Alcohol abuse.

Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)
The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat), as well as gemfibrozil, ciclosporin, and danazol. Use of these medicinal products is contraindicated (see section 4.3).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil or diltiazem with certain doses of simvastatin (see sections 4.2 and 4.5). For patients with HoFH, this risk may be increased by concomitant administration of fusidic acid with statins (see section 4.5). For patients with HoFH, this risk may be increased by concomitant use of lomitapide with simvastatin.

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone and medicinal products containing cobicistat is contraindicated (see sections 4.3 and 4.5). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) is unavoidable, therapy with simvastatin must be suspended (and the use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

The use of simvastatin with gemfibrozil is contraindicated (see section 4.3). Due to the increased risk of myopathy and rhabdomyolysis, the dose of simvastatin should not exceed 10 mg daily in patients taking simvastatin with other fibrates, except fenofibrate (see sections 4.2 and 4.5).
Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone.

Simvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see section 4.5). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid.

In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of simvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

The combined use of simvastatin at doses higher than 20 mg daily with amiodarone, amlodipine, verapamil or diltiazem should be avoided (see sections 4.2 and 4.5). In patients with HoFH, the combined use of simvastatin at doses higher than 40 mg daily with lomitapide must be avoided (see section 4.2, 4.3 and 4.5).

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy. When co-administering simvastatin with a moderate inhibitor of CYP3A4 (agents that increase the AUC approximately 2-5 fold), a dose adjustment of simvastatin may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20 mg simvastatin is recommended (see section 4.2).

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

In a clinical trial (median follow-up 3.9 years ) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid). Therefore physicians contemplating combined therapy with simvastatin and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadminstered with modified-release nicotinic acid/laropiprant 2000 mg/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than non-Chinese patients, co-administration of simvastatin with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients.

4.5 Interaction with other medicinal products and other forms of interaction

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting agents	Prescribing recommendations
Potent CYP3A4 inhibitors: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors (e.g. nelfinavir) Boceprevir Telaprevir Nefazodone Cobicistat Ciclosporin Danazol Gemfibrozil	Contraindicated with simvastatin
Other fibrates (except fenofibrate)	Do not exceed 10 mg simvastatin daily
Fusidic acid	Is not recommended with simvastatin
Niacin (nicotinic acid) (≥ 1 g/day)	For Asian patients, not recommended with simvastatin
Amiodarone Amlodipine Verapamil Diltiazem	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 40 mg simvastatin daily
Fusidic acid	Is not recommended with simvastatin
Niacin (nicotinic acid) (≥ 1 g/day)	For Asian patients, not recommended with simvastatin
Grapefruit juice	Avoid grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interactions involving inhibitors of CYP3A4
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), and nefazodone and medicinal products containing cobicistat. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone and medicinal products containing cobicistat is contraindicated, as well as gemfibrozil, ciclosporin, and danazol (see section 4.3). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) is unavoidable, therapy with simvastatin must be suspended (and the use of an alternative statin considered) during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil or diltiazem (see sections 4.2 and 4.4).

Fusidic acid
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.

Lomitapide
The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with simvastatin (see section 4.3 and 4.4). Therefore, in patients with HoFH, the dose of simvastatin must not exceed 40 mg daily in patients receiving concomitant medication with lomitapide.

Colchicine
There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiencyimpairment.
Close clinical monitoring of such patients taking this combination is advised.

Fertility
No clinical trial data are available on the effects of simvastatin on human fertility. Simvastatin had no effect on the fertility of male and female rate (see section 5.3).

4.8 Undesirable effects

Nervous system disorders:
Rare: headache, paraesthesiaparesthesia, dizziness, peripheral neuropathy
Very rare: memory impairment

Musculoskeletal and connective tissue disorders:
Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps
Not known: tendinopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy (see section 4.4)**

* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively) (see sections 4.4 and 4.5).
** There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, during or after treatment with some statins. IMNM is clinically characterised by: persistent 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 (see section 4.4).

Paediatric population (children and adolescents 10-17 years of age)
In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with simvastatin was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment (see sections 4.2, 4.4, and 5.1).

5.1 Pharmacodynamic properties

Paediatric populationClinical Studies in Children and Adolescents (10-17 years of age)
In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo 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 and received simvastatin 40 mg or placebo.

5.2 Pharmacokinetic properties

Biotransformation and Elimination
Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of the IV dose was excreted in urine as metabolites.

Simvastatin acid is taken up actively into the hepatocytes by the transporter OATP1B1.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core
ascorbic acid
butylhydroxyanisole (E320)
citric acid monohydrate
lactose monohydrate
magnesium stearate
cellulose microcrystalline
maize starch, pregelatinised
21
talc

[10 mg]
Tablet Coat
hypromellose
lactose monohydrate
titanium dioxide (E171)
triacetin
iron oxide red (E172)

[20 mg]
Tablet Coat
hypromellose
lactose monohydrate
titanium dioxide (E171)
triacetin
iron yellow (E172)
iron oxide red (E172)

[40 mg]
Tablet Coat
hypromellose
titanium dioxide (E171)
triacetin
iron oxide yellow (E172)
iron oxide red (E172)
polydextrose (containing small amounts of glucose and sorbitol (E420)) macrogol 8000

[80 mg]
Tablet Coat
hypromellose
lactose monohydrate
titanium dioxide (E171)
triacetin
iron oxide red (E172)
Tablet Coat
hypromellose lactose monohydrate – 10mg, 20mg & 80mg only
titanium dioxide (E171)
triacetin
iron oxide red (E172) iron oxide yellow (E172) – 20mg & 40mg only polydextrose (containing small amounts of glucose and sorbitol (E420)) – 40mg only macrogol 8000 – 40mg only

 

Section 4.3      Contraindications

Hypersensitivity to

simvastatin the active substance or to any of the excipients listed in section 6.1

 

 

 

Concomitant administration of potent CYP3A4 inhibitors

(agents that increase AUCapproximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone) (see sections 4.4 and 4.5)

 

 

Section 4.4      Special warnings and precaution for use

 

 

In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing simvastatin to Asian patients and the lowest dose necessary should be employed.

Reduced function of transport

 

proteins
Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin acid and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (See section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

There have been very rare reports of an immune- mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

 

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil or diltiazem with certain doses of simvastatin (see sections 4.2 and 4.5).
The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5).

 

 

 

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended (and the use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided.

Simvastatin must not be co-administered with fusidic acid. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination (see section 4.5). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for co-administration of simvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision.

 

 

Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy. When co-administering simvastatin with a moderate inhibitor of CYP3A4 (agents that increase the AUC approximately 2-5 fold), a dose adjustment of simvastatin may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20 mg simvastatin is recommended (see section 4.2).

 

 

 

In a clinical trial (median follow-up 3.9 years ) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipidmodifying doses (≥1 g/day) of niacin (nicotinic acid). Therefore Pphysicians contemplating combined therapy with simvastatin and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

 

 

In addition, in this trial, the incidence of myopathy was approximately 0.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg compared with 1.24% for Chinese patients on simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadminstered with modified-release nicotinic acid/laropiprant 2000 mg/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence is higher in Chinese than non-Chinese patients, co-administration of simvastatin with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients. Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.

 

 

 

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) coadministered with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of simvastatin 80 mg with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or products containing niacin.
If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastatin treatment may be considered.

 

 

 

Section 4.5      Interactions with other medicinal products and other forms of interaction

 

 

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

 

 

Interacting agents:

Voriconazole
Prescribing recommendations: Contraindicated with simvastatin

 

 

 

 

Interacting agents:

Fusidic acid
Prescribing recommendations:

Fusidic acid

Patients should be closely monitored. Temporary suspension of simvastatin treatment may be consideredIs not recommended with simvastatin.

 

 

 

 

Interacting agents:

Niacin (nicotinic acid) (

Niacin (nicotinic acid) (

 

≥ 1 g/day)
Prescribing recommendations: For Asian patients, not recommended with simvastatin

 

 

 

 

Interactions involving inhibitors of CYP3A4

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), and nefazodone.

 

Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated, as well as gemfibrozil, ciclosporin, and danazol (see section 4.3). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended (and the use of an alternative statin considered) during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil or diltiazem (see sections 4.2 and 4.4).

 

 

- Ciclosporin
The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with simvastatin; therefore, use with ciclosporin is contraindicated (see sections 4.3 and 4.4). Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.

 

 

 

- 

Gemfibrozil
Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway and/or OATP1B1 (see sections 4.3 and 4.4). Concomitant administration with gemfibrozil is contraindicated.

 

 

 

- 

 

Fusidic acid
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, simvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. (See section 4.4).

 

 

 

 

Inhibitors of the Transport Protein OATP1B1

 

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of the medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see sections 4.3 and 4.4).


Section 4.8      Undesirable effects

 

Respiratory, thoracic and mediastinal disorders:

Not known: exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

Musculoskeletal and connective tissue disorders:
Not known: tendinopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy (see section 4.4)

Section 5.2      Pharmacokinetic properties

Biotransformation and Elimination

 

 

Special populations

 

 

SLOC1B1 polymorphism


Section 6.1      List of excipients

Tablet Coat
hypromellose
lactose monohydrate – 10mg, 20mg & 80mg only
titanium dioxide (E171)
triacetin
iron oxide red (E172) – 10mg & 80mg only
iron oxide yellow (E172) – 20mg & 40mg only
polydextrose (containing small amounts of glucose and sorbitol (E420)) – 40mg only
macrogol 8000 – 40mg only

 

10. DATE OF REVISION OF THE TEXT

 

August 2015




(internal ref: UK/H/0613/IB/081 PR575804, 576220, 494231)

 

Simvastatin was changed to lower case throuout section 2 to 10

3 - scoreline changed to breakline, halves changed to doses

4.2 - Paediatric population replaces 'use in children and adolescents'

4.3 - lactation changed to breast-feeding

4.4 - older pateints replaces elderly

text added -

Reduced function of transport proteins

 

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (eg ciclosporin) or in patients who are carriers of the SLCO1B1

c.521T>C genotype.

 

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin and increased risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a

15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT) (See section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping

does not exclude that myopathy can still occur.

and

The 40 mg film-coated tablets contain small amounts of glucose and sorbitol (E420) in the film-coating. Patients with rare hereditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine.

4.8 - Reporting of side effects changed to current guidelines

5.2 Text added

Simvastatin is taken up actively into the hepatocytes by the transporter OATP1B1.

 

Special populations

 

Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The mean exposure (AUC) of the main active metabolite, simvastatin acid is 120% in heterozygote carriers (CT) of the C allele and 221% in homozygote (CC) carriers relative to that of patients who have the most common genotype (TT). The C allele has a frequency of 18% in the European population. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of simvastatin, which may lead to an increased risk of rhabdomyolysis (see section 4.4).[

6.1 - (E171) added

10 - date of revision changed

section 2 - caps lock removed from Simvastatin, 'and tablet coat' deleted
section 3 - scoreline change to breakline, halves changed to doses
section 4.2 - subheading 'Posology' added, capslock removed from Simvastatin and See, elderly changed to older patients, paediatric population replaces 'use in children and adolescents', text asdded

Method of administration

 

For oral use.

section 4.3 - lactation changed to breast-feeding

secttion 4.4 - capslock removed from Simvastatin, 'elderly' changed to 'older patients', paediatric population replaces 'use in children and adolescents'

text added:

The 40 mg film-coated tablets contain small amounts of glucose and sorbitol (E420) in the film-coating. Patients with rare hereditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine.

section 4.5 -

under danazol subheading - 'with simvastatin' added

section 4.6 - capslock removed from Simvastatin

section 4.8 - caspslock removed from Simvastatin

reporting of side effects section changed to this:

Reporting of suspected adverse reactions

section 5.1 - capslock removed from Simvastatin, flow changed to 'bloodflow'

section 6.1 - (E171) added to titanium dioxide

Date of revision of text chnaged to July 2014

$04.2 Posology and method of administration$0$0$0$0$0Homozygous familial hypercholesterolaemia$0$0Remove 80mg/day dosage$0$0$0$0$0Concomitant therapy$0$0amlodipine & diltiazem  added$0$0$0$0$0$0$0$04.3 Contraindications$0$0Concomitant administration of boceprevir, telaprevir, gemfibrozil, ciclosporin, danazol added$0$0$0$0$0$0$0$04.4 Special warnings and precautions for use$0$0Added warning for risk of myopathy in patients on simvastatin 80 mg$0$080mg dose of Simvastatin should only be used in patients with severe hypercholesterolemia and at high risk for cardiovascular complications.$0$0$0$0$0Measures to reduce the risk of myopathy caused by medicinal product interactions $0$0Addition of contraindicated medicinal products: boceprevir, telaprevir, ciclosporin, amlodipine, diltiazem, gemfibrozil $0$0$0$0$0Hepatic effects$0$0rare post-marketing reports of fatal and non-fatal hepatic failure $0$0$0$0$0$0$0$04.5 Interaction with other medicinal products and other forms of interaction$0$0$0$0$0Pharmacokinetic interactions$0$0Addition Interacting agents: Boceprevir, Telaprevir$0$0$0$0$0Ciclosporin$0$0use with ciclosporin is contraindicated $0$0$0$0$0Danazol$0$0use with danazol is contraindicated$0$0$0$0$0Gemfibrozil$0$0with gemfibrozil is contraindicated$0$0$0$0$0Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin$0$0$0$0$0$0$0$04.8 Undesirable effects$0$0$0$0$0Respiratory, thoracic and mediastinal disorders:$0$0Not known: exceptional cases of interstitial lung disease, especially with long term therapy $0$0$0$0$0Hepatobiliary disorders:$0$0Very rare: fatal and non-fatal hepatic failure$0$0$0$0$0Increases in HbA1c and fasting serum glucose levels have been reported $0$0$0$0$0There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion)$0$0$0$0$0$0$0$06.1 List of Excipients$0$0$0$0$0polydextrose (containing small amounts of glucose and sorbitol (E420)) – 40mg only$0$0$0$0$0$0$0$010. DATE OF REVISION OF THE TEXT$0$0$0$0$0Date changed to June 2013$0

Section 4.4 Following text added:

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Section 4.8 Following side effects added:

Musculoskeletal and connective tissue disorders:

Not known: tendinopathy, sometimes complicated by rupture

Section 10 Date changed to:

June 2012

4.2    Posology and method of administration
The 80 mg dose is only recommended in patients with severe hypercholesterolemia and high risk for cardiovascular complications, who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see sections 4.4 and 5.1).

Concomitant therapy
In patients taking ciclosporin, danazol, gemfibrozil or other fibrates (except fenofibrate) or lipid-lowering doses ( 1g/day) of niacin concomitantly with Simvastatin, the dose of Simvastatin should not exceed 10 mg/day.  In patients taking amiodarone or verapamil concomitantly with Simvastatin, the dose of Simvastatin should not exceed 20 mg/day. In patients taking diltiazem or amlodipine concomitantly with Simvastatin, the dose of Simvastatin should not exceed 40 mg/day. (See sections 4.4 and 4.5.)

4.3     Contraindications
• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors ( e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5).

4.4     Special warnings and precautions for use
..... In a clinical trial database in which 41,413 patients were treated with Simvastatin with 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%, 0.08 % and 0.61 % at 20, 40 and 80 mg/day.....

In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1).

Before the treatment
Caution should be exercised ...... in the following situations:
• Elderly (age >65 years)
• Female gender
....

Whilst on treatment
A higher rate of myopathy has been observed in patients titrated to the 80 mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Measures to reduce the risk of myopathy ....
The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), nefazodone), as well as gemfibrozil, danazol, and ciclosporin (see section 4.2).

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, lipid-lowering doses (³ 1g/day) of niacin or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5).  There is also a slight increase in The risk is increased by concomitant use of diltiazem or amlodipine with simvastatin 80 mg (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5)

Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin ..... (see sections 4.3 and 4.5).  If treatment with itraconazole, ketoconazole, posaconazole, erythromycin.....  Moreover, caution should be exercised when combining Simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin....

The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol or gemfibrozil, or lipid-lowering doses (³1g/day) of niacin. .....  The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), niacin, danazol, or ciclosporin should be carefully weighted against the potential risks of these combinations. (See sections 4.2 and 4.5)

The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.
Physicians contemplating combined therapy with simvastatin and lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased.

In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co-administered with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of simvastatin 80 mg with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid-modifying doses (≥1 g/day) of niacin (nicotinic acid) or products containing niacin.
If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastatin treatment may be considered.

Interstitial lung disease
Exceptional cases of interstitial lung disease ......
The 40 mg film-coated tablets contain small amounts of glucose and sorbitol (E420) in the film-coating. Patients with rare hereditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine.

4.5     Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates and niacin (nicotinic acid) (³ 1g/day).
Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses ( ≥1g/day) of niacin (see section 4.4).

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Added Interacting agents:
Posaconazole
HIV protease inhibitors
(e.g. nelfinavir)
Amlodipine
Fusidic acid     Patients should be closely monitored. Temporary suspension of Simvastatin treatment may be considered

Deleted:
Niacin (1 g/day)

Interactions involving inhibitors of  CYP3A4
.... Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), and nefazodone. ....
Therefore, combination with itraconazole, ketoconazole, posaconazole,  HIV protease inhibitors (e.g. nelfinavir), erythromycin, ....  If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, ....  Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, ....

• Amiodarone and verapamil
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin (see section 4.4). In an on-going clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
An analysis of the available clinical trials showed an approximately 1% incidence of myopathy in patients receiving simvastatin 40 mg or 80 mg and verapamil.  In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4.  Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Calcium Channel Blockers

 

• Verapamil
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

• Diltiazem
An analysis of the available clinical trials showed a 1% incidence of myopathy in patients receiving simvastatin 80 mg and diltiazem.  The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4).

• Amlodipine
Patients on amlodipine treated concomitantly with simvastatin 80 mg have an increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

• Niacin (nicotinic acid)
Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses ( ≥1 g/day) of niacin (nicotinic acid). In a pharmacokinetic study, the co-administration of a single dose of nicotinic acid prolonged-release 2 g with simvastatin 20 mg resulted in a modest increase in the AUC of simvastatin and simvastatin acid and in the Cmax of simvastatin acid plasma concentrations.

• Fusidic acid
The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4)

• Colchicine
There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicines and simvastatin in patients with renal insufficiency.
Close clinical monitoring of such patients taking this combination is advised.

• Rifampicin
Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.

4.8     Undesirable effects
The frequencies of adverse events are ranked .... including isolated reports not known (cannot be estimated from the available data).

Psychiatric disorders:
Very rare: insomnia
Not known: depression

Nervous system disorders:
Very rare: memory impairment

Respiratory, thoracic and mediastinal disorders:
Not known: interstitial lung disease (see section 4.4)

Hepatobiliary disorders: 
Very rare: hepatic failure

Musculoskeletal and connective and bone tissue disorders:
Rare:  myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps

* In a clinical trial, myopathy occurred commonly in patients treated with Simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).

Reproductive system and breast disorders:
Not known: erectile dysfunction

The following additional adverse events have been reported with some statins:
• Sleep disturbances, including insomnia and nightmares
...
• Depression
• Exceptional cases of interstitial lung disease, especially with long term therapy (see section 4.4)

5.1     Pharmacodynamic properties
The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Simvastatin 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, nonfatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; Simvastatin 20 mg (n = 1553; 25.7 %) vs. Simvastatin 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Simvastatin 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.

10.      DATE OF REVISION OF THE TEXT

February 2012

 

None provided