Hypercholesterolaemia
Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to
diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.
Treatment of homozygous familial hypercholesterolaemia (HoFH) as an adjunct to diet and other lipidlowering
treatments (e.g. LDL apheresis) or if such treatments are not appropriate.
Cardiovascular prevention
Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular
disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of
other risk factors and other cardioprotective therapy (see section 5.1).

 

Posology
The dosage range is 5-80 mg/day given orally as a single dose in the evening. Adjustments of dosage, if
required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single
dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and
at 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).
Hypercholesterolaemia
The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during
treatment with Simva. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients

who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single
dose in the evening. Adjustments of dosage, if required, should be made as specified above.
Homozygous familial hypercholesterolaemia
Based on the results of a controlled clinical study, the recommended starting dosage is Simva 40 mg/day in the
evening. Simva 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 Simvad, the dose of Simva must not exceed 40 mg/day (see
sections 4.3, 4.4 and 4.5).
Cardiovascular prevention
The usual dose of Simva is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of
coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously
with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy
Simva is effective alone or in combination with bile acid sequestrants. Dosing should occur either > 2 hours
before or > 4 hours after administration of a bile acid sequestrant.
In patients taking Simva concomitantly with fibrates, other than gemfibrozil (see section 4.3) or fenofibrate,
the dose of Simva should not exceed 10 mg/day. In patients taking amiodarone, amlodipine, verapamil, or
diltiazem concomitantly with Simva, the dose of Simva should not exceed 20 mg/day. (See sections 4.4 and
4.5.)
Patients with renal impairment
No modification of dosage should be necessary in patients with moderate renal impairment.
In patients with severe renal impairment (creatinine clearance < 30 ml/min), dosages above 10 mg/day should
be carefully considered and, if deemed necessary, implemented cautiously.
Older people
No dosage adjustment is necessary.

Paediatric population
For children and adolescents (boys Tanner Stage II and above and girls who are at least one year postmenarche,
10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual
starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard
cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during
simvastatin treatment.
The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses
should be individualized according to the recommended goal of therapy as recommended by the paediatric
treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or
more.
The experience of Simva in pre-pubertal children is limited.
Method of administration
Simva is for oral administration. Simva can be administered as a single dose in the evening.

• 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 lactation (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, 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, concomitant administration of lomitapide with doses > 40 mg Simva (see sections 4.2, 4.4 and 4.5)

Myopathy/Rhabdomyolysis
Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle
pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN).
Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to
myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of
HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a
clinical trial database in which 41,413 patients were treated with Simva, 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, respectively. In these trials, patients were
carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which patients with a history of myocardial infarction were treated with Simva 80 mg/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.)
The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies
with similar LDL-C-lowering efficacy. Therefore, the 80-mg dose of Simva should only be used in patients
with severe hypercholesterolemia and at 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. In
patients taking simvastatin 80 mg for whom an interacting agent is needed, a lower dose of simvastatin or an
alternative statin-based regimen with less potential for drug-drug interactions should be used (see below
Measures to reduce the risk of myopathy caused by medicinal product interactions and sections 4.2, 4.3, and
4.5).
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.

Creatine Kinase measurement
Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible
alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly
elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.
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 for rhabdomyolysis. In order to establish a
reference baseline value, a CK level should be measured before starting a treatment in the following situations:
• Elderly (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.
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical
monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin,
treatment with a different member of the class should only be initiated with caution. If CK levels are
significantly elevated at baseline (> 5 x ULN), treatment should not be started.
Whilst on treatment
If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels
should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated
(> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even
if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any
other reason, treatment should be discontinued.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after
treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and
elevated serum creatine kinase, which persist despite discontinuation of statin treatment (see section 4.8).
If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an
alternative statin may be considered at the lowest dose and with close monitoring.
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.
Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when
any major medical or surgical condition supervenes.

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). The risk of myopathy,
including rhabdomyolysis, 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, 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 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 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.
The combined use of simvastatin at doses higher than 20 mg daily with amiodarone, amlodipine, verapamil, or
diltiazem should be avoided. In patients with HoFH, the combined use of simvastatin at doses higher than 40
mg daily with lomitapide must be avoided. (See sections 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
coadministering simvastatin with a moderate inhibitor of CYP3A4 (agents that increase 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 20mg 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 coadministered 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 in non-Chinese patients, coadministration 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.

Hepatic effects
In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult
patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the
transaminase levels usually fell slowly to pre-treatment levels.
It is recommended that liver function tests be performed before treatment begins and thereafter when clinically
indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after
titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment.
Special attention should be paid to patients who develop elevated serum transaminase levels, and in these
patients, measurements should be repeated promptly and then performed more frequently. If the transaminase
levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should
be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate
myopathy (see above Myopathy/Rhabdomyolysis).
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 hyperbilirubinaemia or jaundice
occurs during treatment with Simva, promptly interrupt therapy. If an alternate etiology is not found, do not
restart Simva.
The product should be used with caution in patients who consume substantial quantities of alcohol.
As with other lipid-lowering agents, moderate (< 3 x 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 interruption of treatment was
not required.

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 > 30 kg/m2, raised triglycerides,
hypertension) should be monitored both clinically and biochemically according to national guidelines.
Interstitial lung disease
Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with
long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and
deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed
interstitial lung disease, statin therapy should be discontinued.

Paediatric population
Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial
hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and
above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse
experience profile generally 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 detectable effect on growth
or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See
sections 4.2, 4.8, and 5.1). Adolescent females should be counselled on appropriate contraceptive methods
while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have
not been studied for treatment periods > 48 weeks' duration and long-term effects on physical, intellectual, and
sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor
in pre-pubertal children and pre-menarchal girls.
Excipient
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction studies have only been performed in adults.
Pharmacodynamic interactions
Interactions with lipid-lowering medicinal products that can cause myopathy when given alone
The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates.
Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma
levels (see below Pharmacokinetic interactions and sections 4.3 and 4.4). When simvastatin and fenofibrate
are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks
of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare
cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipidmodifying
doses (≥ 1 g/day) of niacin (see section 4.4).
Pharmacokinetic interactions
Prescribing recommendations for interacting agents are summarized in the table below (further details are
provided in the text; see also sections 4.2, 4.3, and 4.4).
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

 

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, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g.
nelfinavir), boceprevir, telaprevir, 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, 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 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).
Fluconazole
Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have
been reported (see section 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.

Danazol
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with
simvastatin; therefore, use with danazol is contraindicated. (see sections 4.3 and 4.4).
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.) .
Amiodarone
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with
simvastatin (see section 4.4). In a 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.
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.
• Diltiazem
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with
simvastatin 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem
caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4.

Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication
with diltiazem.
• Amlodipine
Patients on amlodipine treated concomitantly with simvastatin have an increased risk of myopathy. 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 20 mg daily in patients receiving
concomitant medication with amlodipine.
Lomitapide
The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with
simvastatin (see sections 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.
Moderate Inhibitors of CYP3A4
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 (see section 4.4).
Inhibitors of the Transport Protein OATP1B1
Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of 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).
Niacin (nicotinic acid)
Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipidmodifying
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.
Grapefruit juice
Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of
grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml
of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of
grapefruit juice during treatment with simvastatin should therefore be avoided.

Colchicine
There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine
and simvastatin in patients with renal impairment. 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.
Effects of simvastatin on the pharmacokinetics of other medicinal products
Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not
expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.
Oral anticoagulants
In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin
20-40 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. Very rare cases of elevated INR have been reported. In patients
taking coumarin anticoagulants, 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.

 

Pregnancy
Simva is contraindicated during pregnancy (see section 4.3).
Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been
conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMGCoA
reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively
followed pregnancies exposed during the first trimester to Simva or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general

population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in
congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Simva
or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population,
maternal treatment with Simva may reduce the foetal levels of mevalonate which is a precursor of cholesterol
biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal
products during pregnancy should have little impact on the long-term risk associated with primary
hypercholesterolaemia. For these reasons, Simva must not be used in women who are pregnant, trying to
become pregnant or suspect they are pregnant. Treatment with Simva must be suspended for the duration of
pregnancy or until it has been determined that the woman is not pregnant. (See sections 4.3 and 5.3.)

Breast-feeding
It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal
products are excreted in human milk and because of the potential for serious adverse reactions, women taking
Simva must not breast-feed their infants (see section 4.3).
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 rats (see section 5.3).

Simva has no or negligible influence on the ability to drive and use machines. However, when driving vehicles
or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing
experiences.

The frequencies of the following adverse events, which have been reported during clinical studies and/or postmarketing
use, are categorized based on an assessment of their incidence rates in large, long-term, placebocontrolled,
clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1).
For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and
CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less
than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous
report events, these adverse events are categorized as “rare”.
In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of Simva (n = 10,269) or placebo (n
= 10,267), the safety profiles were comparable between patients treated with Simva 40 mg and patients treated 

with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable
(4.8 % in patients treated with Simva 40 mg compared with 5.1 % in patients treated with placebo). The
incidence of myopathy was < 0.1 % in patients treated with Simva 40 mg. Elevated transaminases (> 3 x ULN
confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Simva 40 mg compared with
0.09 % (n = 9) of patients treated with placebo.
The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (≥
1/100, < 1/10), Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10,000, < 1/1000), Very Rare (< 1/10,000), not
known (cannot be estimated from the available data).
Blood and lymphatic system disorders:
Rare: anaemia
Psychiatric disorders:
Very rare: insomnia
Not known: depression
Nervous system disorders:
Rare: headache, paresthesia, dizziness, peripheral neuropathy
Very rare: memory impairment
Respiratory, thoracic and mediastinal disorders:
Not known: interstitial lung disease (see section 4.4)
Gastrointestinal disorders:
Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis
Hepatobiliary disorders:
Rare: hepatitis/jaundice
Very rare: fatal and non-fatal hepatic failure

Skin and subcutaneous tissue disorders:
Rare: rash, pruritus, alopecia
Musculoskeletal and connective 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 Simva 80 mg/day compared to
patients treated with 20 mg/day (1.0 % vs 0.02 %, respectively) (see sections 4.4 and 4.5).
Not known: tendinopathy, sometimes complicated by rupture; immune-mediated necrotizing myopathy
(IMNM)**
** 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 characterized 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).
Reproductive system and breast disorders:
Not known: erectile dysfunction
General disorders and administration site conditions:

Rare: asthenia
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following
features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis,
thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever,
flushing, dyspnoea and malaise.
Investigations:
Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl
transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels
(see section 4.4).
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Simva.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,
amnesia, memory impairment, confusion) associated with statin use, including simvastatin. The reports are
generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day
to years) and symptom resolution (median of 3 weeks).
The following additional adverse events have been reported with some statins:
• sleep disturbances, including nightmares
• sexual dysfunction
• Diabetes mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥
5.6 mmol/L, BMI > 30 kg/m2, raised triglycerides, history of hypertension).
Paediatric population
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 Simva 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).

To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Ext: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority.

To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients
recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic
and supportive measures should be adopted.

Pharmacotherapeutic group: HMG-CoA reductase inhibitor
ATC-Code: C10A A01
Mechanism of action
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding
active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3
methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early
and rate-limiting step in the biosynthesis of cholesterol.
Simva has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from verylow-
density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The
mechanism of the LDL-lowering effect of Simva may involve both reduction of VLDL-cholesterol (VLDL-C)
concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of
LDL-C. Apolipoprotein B also falls substantially during treatment with Simva. In addition, Simva moderately
increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDLto
HDL-C are reduced.
Clinical efficacy and safety
High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease
In the Heart Protection Study (HPS), the effects of therapy with Simva were assessed in 20,536 patients (age
40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease
or diabetes mellitus. In this study, 10,269 patients were treated with Simva 40 mg/day and 10,267 patients
were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels
below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42
%) had levels greater than 135 mg/dL.

Treatment with Simva 40 mg/day compared with placebo significantly reduced the risk of all cause mortality
(1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003),
due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk
reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Simva also
decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death)
by 27 % (p < 0.0001). Simva reduced the need for undergoing coronary revascularization procedures
(including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral
and other non-coronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively.
Simva reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p <0.0001). In addition, within the subgroup of patients with diabetes, Simva reduced the risk of developing
macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty),
lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was
similar in each subgroup of patients studied, including those without coronary disease but who had
cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry
into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l
at inclusion.
In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with Simva on total mortality was
assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this
multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial
infarction (MI) were treated with diet, standard care, and either Simva 20-40 mg/day (n = 2,221) or placebo (n
= 2,223) for a median duration of 5.4 years. Simva reduced the risk of death by 30 % (absolute risk reduction
of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Simva also
decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI)
by 34 %. Furthermore, Simva significantly reduced the risk of fatal plus nonfatal cerebrovascular events
(stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between
groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH)
evaluated the effect of treatment with Simva 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, non-fatal 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; Simva 20 mg (n = 1553;
25.7 %) vs. Simva 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDLC
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 Simva 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 %.
Primary Hypercholesterolaemia and Combined Hyperlipidaemia
In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with
hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of
patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in
triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 %
(placebo: 3 %), respectively.

Paediatric population
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 LDLC
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.
Simva significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48
weeks were comparable to those observed in the base study. After 24 weeks of treatment, the mean achieved
LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Simva 40 mg group compared to 207.8
mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.
After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week
intervals), Simva decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by
32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels
by 8.3 % (placebo: 3.6 %). The long-term benefits of Simva on cardiovascular events in children with heFH
are unknown.
The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous
familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce
morbidity and mortality in adulthood has not been established.

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a
potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in
human plasma is very slow.
The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and
adolescents are not available.
Absorption
In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the
liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The
availability of the beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found
to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately
1-2 hours after administration of simvastatin. Concomitant food intake does not affect the absorption.

The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal
product occurred after multiple dosing.
Distribution
The protein binding of simvastatin and its active metabolite is > 95 %.
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 betahydroxyacid
metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of the IV dose was excreted
in urine as inhibitors.
Simvastatin acid is taken up actively into the hepatocytes by the transporter OATP1B1.
Special Populations
SLCO1B1 polymorphism
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 acid, which may lead to an increased risk of rhabdomyolysis (see section 4.4).
 

Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and
carcinogenicity, there are no other risks for the patient than may be expected on account of the
pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, simvastatin produced
no foetal malformations, and had no effects on fertility, reproductive function or neonatal development.

1. Ludipress
2. Pregelatinised starch
3. Hydroxypropylcellulose
4. Crospovidone
5. Povidone
6. Croscarmellose sodium
7. Citric acid monohydrate
8. Microcrystalline Cellulose
9. Silicon Dioxide Colloidal
10. Magnesium Stearate
Coating material:
11. Opadry white
12. Propylene glycol
13. Talc
14. Polysorbate 80
15. Butylated Hydroxyanisole
16. Simethicone
17. Purified Water

Not applicable.

24 months.

Do not store above 30°C, Keep out of the reach of children.

Al-Foil& PVC/ACLAR Film Clear 

Outer carton 

Oatient information leaflet (PIL) 

No special requirements.