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RANZOLONT 10MG TABLETS
Active substance(s): SIMVASTATIN
NAME OF THE MEDICINAL PRODUCT
Simvastatin 10 mg Tablets or Ranzolont 10 mg Tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 10 mg simvastatin.
Excipients with known effect: Each film-coated tablet contains 70.46 mg of lactose.
For the full list of excipients, see 6.1
Peach coloured, film-coated, oval shaped tablets, debossed with ‘SST’ on one
side and ‘10’ on the other side with intact coating.
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 as an adjunct to diet
and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments
are not appropriate.
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 and method of administration
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 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).
The patient should be placed on a standard cholesterol-lowering diet, and should continue on
this diet during treatment with Simvastatin Tablets. 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
Simvastatin Tablets 40 mg/day in the evening.
Simvastatin Tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL
apheresis) in these patients or if such treatments are unavailable.
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)
The usual dose of Simvastatin Tablets 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.
Simvastatin Tablets are 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
In patients taking Simvastatin concomitantly with fibrates, other than gemfibrozil (see section
4.3) or fenofibrate, the dose of Simvastatin should not exceed 10 mg/day. In patients taking
amiodarone, amlodipine, verapamil, or diltiazem concomitantly with Simvastatin, the dose of
Simvastatin 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.
No dosage adjustment is necessary.
For children and adolescents (boys Tanner Stage II and above and girls who are at least one
year post-menarche, 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 Simvastatin in pre-pubertal children is limited.
Method of administration
For oral use.
This medicinal product is contraindicated in patients with:
Hypersensitivity to the active substance or to any of the excipients as 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
In patients with HoFH, concomitant administration of lomitapide with doses > 40 mg
Simvastatin (see sections 4.2, 4.4 and 4.5)
Special warnings and precautions for use
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 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, 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
Simvastatin 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 statinbased therapies with similar LDL-C-lowering efficacy. Therefore, the 80-mg dose of
Simvastatin 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)
Personal or familial history of hereditary muscular disorders
Previous history of muscular toxicity with a statin or fibrate
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
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).
Simvastatin must not be co-administered with systemic formulations of fusidic acid or within
7 days of stopping fusidic acid treatment. 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 tablets and
fusidic acid should only be considered on a case by case basis and under close medical
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.
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 lipidmodifying 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 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
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
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 Simvastatin, promptly interrupt
therapy. If an alternate etiology is not found, do not restart Simvastatin
The product should be used with caution in patients who consume substantial quantities of
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.
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.
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
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.
This product contains lactose. Therefore patients with rare hereditary problems of lactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Interactions with lipid-lowering medicinal products that can cause myopathy when given
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 lipid-modifying doses (≥ 1g/day) of niacin (see section
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, 4.4).
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Potent CYP3A4 inhibitors:
HIV protease inhibitors (e.g. nelfinavir)
Contraindicated with Simvastatin
Other fibrates (except fenofibrate)
Do not exceed 10 mg simvastatin daily
Do not exceed 20 mg simvastatin daily
For patients with HoFH, do not exceed 40
mg simvastatin daily
Avoid grapefruit juice when taking
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
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 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).
Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and
fluconazole have been reported (see section 4.4.).
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.
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
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.
The risk of myopathy including rhabdomyolysis may be increased by the concomitant
administration of systemic fusidic acid with statins. The mechanism of this interaction
(whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have
been reports of rhabdomyolysis (including some fatalities) in patients receiving this
If treatment with systemic fusidic acid is necessary, simvastatin treatment should be
discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4
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
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
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.
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 amlopidine.
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
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 coadministered 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 prolongedrelease 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 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.
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.
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
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.
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.
Fertility, pregnancy and lactation
Simvastatin 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 HMG-CoA reductase inhibitors have been received.
However, in an analysis of approximately 200 prospectively followed pregnancies exposed
during the first trimester to Simvastatin Tablets 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 2.5fold 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 Simvastatin Tablets or another closely related HMG-CoA reductase inhibitor
differs from that observed in the general population, maternal treatment with Simvastatin
Tablets may reduce the foetal levels of mevalonate which is a precursor of cholesterol
biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipidlowering medicinal products during pregnancy should have little impact on the long-term risk
associated with primary hypercholesterolaemia. For these reasons, Simvastatin Tablets must
not be used in women who are pregnant, trying to become pregnant or suspect they are
pregnant. Treatment with Simvastatin Tablets must be suspended for the duration of
pregnancy or until it has been determined that the woman is not pregnant. (See sections 4.3
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 Simvastatin Tablets should not breast-feed their infants (see
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).
Effects on ability to drive and use machines
Simvastatin 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 post-marketing use, are categorized based on an assessment of their incidence
rates in large, long-term, placebo-controlled, 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 Simvastatin
Tablets (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between
patients treated with Simvastatin Tablets 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 Simvastatin Tablets 40 mg compared with 5.1 % in patients treated
with placebo). The incidence of myopathy was < 0.1 % in patients treated with Simvastatin
Tablets 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21
% (n = 21) of patients treated with Simvastatin Tablets 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:
Very rare: insomnia
Not known: depression
Nervous system disorders:
Rare: headache, paraesthesia, dizziness, peripheral neuropathy
Very rare: memory impairment
Respiratory, thoracic and mediastinal disorders:
Not known: interstitial lung disease (see section 4.4)
Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting,
Very rare: Fatal and non-fatal hepatic failure
Skin and subcutaneous tissue disorders:
Rare: rash, pruritus, alopecia
Musculoskeletal. connective tissue and bone disorders:
Rare: myopathy* (including myotitis), 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 Tablets
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
** 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:
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.
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,
There have been rare post-marketing 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
The following additional adverse events have been reported with some statins:
Sleep disturbances, including nightmare
Diabetes Mellitus: Frequency will depend on the presence or absence of risk
factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides,
history of hypertension).
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.)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the Yellow
Card Scheme at: www.mhra.gov.uk/yellowcard.
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
Pharmacotherapeutic group: HMG-CoA reductase inhibitor
ATC-Code: C10A AO1
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 ratelimiting step in the biosynthesis of cholesterol.
Simvastatin Tablets have been shown to reduce both normal and elevated LDL-C
concentrations. LDL is formed from very-low-density protein (VLDL) and is
catabolised predominantly by the high affinity LDL receptor. The mechanism of the
LDL-lowering effect of Simvastatin Tablets may involve both reduction of VLDLcholesterol (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 Simvastatin Tablets. In addition, Simvastatin
Tablets moderately increases HDL-C and reduces plasma TG. As a result of these
changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.
High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease
In the Heart Protection Study (HPS), the effects of therapy with Simvastatin Tablets
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 Simvastatin Tablets 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 Simvastatin Tablets 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. Simvastatin Tablets also decreased the risk of major coronary events (a
composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001).
Simvastatin Tablets 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. Simvastatin
Tablets 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, Simvastatin Tablets 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
Simvastatin Tablets 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
Simvastatin Tablets 20-40 mg/day (n == 2,221) or placebo (n == 2,223) for a median
duration of 5.4 years. Simvastatin Tablets 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 %). Simvastatin Tablets also decreased the risk of having major
coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %.
Furthermore, Simvastatin Tablets 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 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,
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; '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 %.
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.
Clinical 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.
Simvastatin 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 Simvastatin 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), Simvastatin 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 Simvastatin 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
The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data
in children and adolescents are not available.
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 betahydroxyacid 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.
The protein binding of simvastatin and its active metabolite is >95%.
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
Simvastatin is taken up actively into the hepatocytes by the transporter OATP1B1.
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).
Preclinical safety data
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
List of excipients
Citric acid monohydrate
Film-coat: Opadry 20A 54963 Pink
Hypromellose 15cP (E464)
Titanium dioxide (E171)
Iron oxide red (E172)
Iron oxide black (E172)
Iron oxide yellow (E172)
Special precautions for storage
Do not store above 25°C. Store in the original package.
Nature and contents of container
Blister strips comprising of PVdC coated PVC clear transparent film with a backing
of hard tempered heat sealable aluminium foil coated with heat seal lacquer
containing 6, 10, 12, 20, 28, 49, 84 and 98 tablets.
Not all pack sizes may be marketed.
Special precautions for disposal
No special requirements.
MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited
5th floor, Hyde Park, Hayes 3
11 Millington Road
Hayes, UB3 4AZ
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
10/01/2004 / 07/04/2009
DATE OF REVISION OF THE TEXT
Source: Medicines and Healthcare Products Regulatory Agency
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