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RANZOLONT 40MG TABLETS
Active substance(s): SIMVASTATIN
NAME OF THE MEDICINAL PRODUCT
Simvastatin 40 mg Tablets or Ranzolont 40 mg Tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 20 mg simvastatin.
Excipients with known effect: Each film-coated tablet contains 140.92 mg of lactose.
For the full list of excipients, see 6.1
Brick red coloured, film-coated, oval shaped tablets, debossed with ‘SST’ on one side
and ‘40’ 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
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
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
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
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 cholesterollowering 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
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 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
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
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
statin-based 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
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
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 supervision.
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
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
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
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.
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
Simvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not
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.
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 discontinued.
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 this medicine.
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
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 4.4).
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.
Other fibrates (except fenofibrate)
Contraindicated with Simvastatin
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 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 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
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
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 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
If treatment with systemic fusidic acid is necessary, simvastatin treatment should be
discontinued throughout the duration of the fusidic acid treatment. Also see section
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 verapamil.
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 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 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
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
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 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.
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 2.5-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 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 lipid-lowering 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 and 5.3).
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 section 4.3).
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,
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 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:
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
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 weeks).
The following additional adverse events have been reported with some statins:
• Sleep disturbances, including nightmare
• Sexual dysfunction
• 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 inhibitors.
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 54964 Pink
Hypromellose 15cP (E464)
Titanium dioxide (E171)
Iron oxide red (E172)
Iron oxide yellow (E172)
Iron oxide black (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
07/04/2009 / 07/04/2009
DATE OF REVISION OF THE TEXT
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