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RANZOLONT 20MG TABLETS

Active substance(s): SIMVASTATIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Simvastatin 20 mg Tablets or Ranzolont 20 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 40 mg simvastatin.
Excipients with known effect: Each film-coated tablet contains 281.84 mg of lactose.
For the full list of excipients, see 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablets.
Tan coloured, film-coated, oval shaped tablets, debossed with ‘SST’ on one side and
‘20’ on the other side with intact coating.

4

CLINICAL PARTICULARS

4.1

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

4.2

Posology and method of administration
Posology
The dosage range is 5-80 mg/day given orally as a single dose in the evening.
Adjustments of dosage, if required, should be made at intervals of not less than 4
weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80 mg
dose is only recommended in patients with severe hypercholesterolaemia and high
risk for cardiovascular complications who have not achieved their treatement goals on
lower doses and when the benefits are expected to outweigh the potential risks (see
section 4.4).
Hypercholesterolaemia
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.
Cardiovascular Prevention
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.
Concomitant therapy
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 sequestrant.
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 insufficiency
No modification of dosage should be necessary in patients with moderate renal
insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30
ml/min), dosages above 10 mg/day should be carefully considered and, if deemed
necessary, implemented cautiously.
Older peopleNo dosage adjustment is necessary.

Paediatric populationFor 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.
4.3

Contraindications
This medicinal product is contraindicated in patients with:



Active liver disease or unexplained persistent elevations of serum transaminases



Pregnancy and lactation (see section 4.6)



Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole,
ketoconazole, fluconazole, posaconazole, HIV protease inhibitors (e.g.
nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin
and nefazodone) (see sections 4.4 and 4.5).



4.4

Hypersensitivity to simvastatin or to any of the excipients as listed in section 6.1.

Concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections
4.4 and 4.5).

Special warnings and precautions for use

Myopathy /Rhabdomyolysis
Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes
myopathy manifested as muscle pain, tenderness or weakness with creatine kinase
(CK) above ten times the upper limit of normal (ULN).
Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal
failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of
myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in
plasma.
As with other HMG-CoA reductase inhibitors the risk of myopathy/rhabdomyolysis is
dose related. In a clinical trial database in which 41,413 patients were treated with
simvastatin with 24,747 (approximately 60 %) treated for 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
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
4.5).
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.
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, erythromycin, clarithromycin, telithromycin, HIV
protease inhibitors(e.g. nelfinavir) , boceprevir, telaprevir, nefazodone), as well as
gemfibrozil, danazol and ciclosporin (see section 4.2). Use of these medicinal
products is contraindicated (see section 4.3).
The risk of myopathy and rhabdomyolysis is also increased by concomitant use of
other fibrates or by concomitant use of amiodarone, amlodipine, diltiazem or
verapamil with certain doses of simvastatin (see sections 4.2 and 4.5). The risk of
myopathy, including rhabdomyolysis, may be increased by concomitant
administration of fusidic acid with statins (see section 4.5.)
Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly
with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g.
nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and
nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with
itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or
telithromycin is unavoidable, therapy with simvastatin must be suspended 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.
Caution should be used when prescribing fenofibrate with simvastatin, as either agent
can cause myopathy when given alone.

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.
The combined use of simvastatin at doses higher than 20 mg daily with amiodarone
amlodipine, diltiazem or verapamil should be avoided (see sections 4.2 and 4.5).
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant
administration of HMG-CoA reductase inhibitors and lipid modifying doses (≥1
g/day) of niacin (nicotinic acid), either of which can cause myopathy when given
alone.
Physicians contemplating combined therapy with simvastatin and lipid modifying
doses (≥1 g/day) of niacin (nicotinic acid) or products containing niacin should
carefully weigh the potential benefits and risks and should carefully monitor patients
for any signs and symptoms of muscle pain, tenderness, or weakness, particularly
during the initial months of therapy and when the dose of either medicinal product is
increased.
In an interim analysis of an ongoing clinical outcomes study, an independent safety
monitoring committee identified a higher than expected incidence of myopathy in
Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40
mg. Therefore, caution should be used when treating Chinese patients with
simvastatin (particularly doses of 40 mg or higher) co administered with
lipid modifying doses (≥1 g/day) of niacin (nicotinic acid) or products containing
niacin. Because the risk of myopathy with statins is dose-related, the use of
simvastatin 80 mg with lipid modifying doses (≥1 g/day) of niacin (nicotinic acid) or
products containing niacin is not recommended in Chinese patients. It is unknown
whether there is an increased risk of myopathy in other Asian patients treated with
simvastatin co-administered with lipid modifying doses (≥1 g/day) of niacin
(nicotinic acid) or products containing niacin.
If the combination proves necessary, patients on fusidic acid and simvastatin should
be closely monitored (see section 4.5). Temporary suspension of simvastatin
treatment may be considered.
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.
Reduced function of transport proteins
Reduced function of hepatic OATP transport proteins can increase the systemic
exposure of simvastatin and increase the risk of myopathy and rhabdomyolysis.
Reduced function can occur as the result of inhibition by interacting medicines (eg
ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active
OATP1B1 protein have an increased systemic exposure of simvastatin and increased
risk of myopathy. The risk of high dose (80 mg) simvastatin related myopathy is
about 1 % in general, without genetic testing. Based on the results of the SEARCH
trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15%
risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT)
is 1.5%. The corresponding risk is 0.3% in patients having the most common
genotype (TT) (See section 5.2). Where available, genotyping for the presence of the
C allele should be considered as part of the benefit-risk assessment prior to
prescribing 80 mg simvastatin for individual patients and high doses avoided in those
found to carry the CC genotype. However, absence of this gene upon genotyping does
not exclude that myopathy can still occur.
Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some
patients, at high risk of future diabetes, may produce a level of hyperglycaemia where
formal diabetes care is appropriate. This risk, however, is outweighed by the reduction
in vascular risk with statins and therefore should not be a reason for stopping statin
treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m2, raised
triglycerides, hypertension) should be monitored both clinically and biochemically
according to national guidelines.
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some statins,
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.
Hepatic effects
In clinical studies, persistent increases (to> 3 x ULN) in serum transaminases have
occurred in a few adult patients who received simvastatin. When simvastatin was
interrupted or discontinued in these patients, the transaminase levels usually fell
slowly to pre-treatment levels.
It is recommended that liver function tests be performed before treatment begins and
thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive
an additional test prior to titration, 3 months after titration to the 80mg 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 post-marketing 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 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.
Use in children and adolescents (10-17 years of age)
Safety and effectiveness of simvastatin in patients 10-17 years of age with
heterozygous familial hypercholesterolaemia have been evaluated in a controlled
clinical trial in adolescent boys Tanner Stage II and above and in girls who were at
least one year post-menarche. Patients treated with simvastatin had an adverse
experience profile generally similar to that of patients treated with placebo. Doses
greater than 40 mg have not been studied in this population. In this limited controlled
study, there was no detectable effect on growth or sexual maturation in the adolescent
boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8,
and 5.1.) Adolescent females should be counselled on appropriate contraceptive
methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18
years, efficacy and safety have not been studied for treatment periods > 48 weeks'
duration and long-term effects on physical, intellectual, and sexual maturation are
unknown. Simvastatin has not been studied in patients younger than 10 years of age,
nor in pre-pubertal children and pre-menarchal girls.
Excipient
This product contains lactose. 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.
Pharmacodynamic interactions
Interactions with lipid-lowering medicinal products that can cause myopathy when
given alone.
The risk of myopathy, including rhabdomyolysis, is increased during concomitant
administration with fibrates. Additionally, there is a pharmacokinetic interaction with
gemfibrozil resulting in increased simvastatin plasma levels (see below
Pharmacokinetic interactions and sections 4.2 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).



4.5

Pharmacokinetic interactions
Prescribing recommendations for interacting agents are summarized in the table
below (further details are provided in the text; see also sections 4.2, 4.3, 4.4).
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting agents
Prescribing recommendations
Potent CYP3A4 inhibitors:
Itraconazole
Ketoconazole
Posaconazole,
Erythromycin
Clarithromycin
Telithromycin
Contraindicated with Simvastatin
HIV protease inhibitors (e.g. nelfinavir)
Boceprivir
Telaprevir
Nefazodone
Gemfibrozil
Ciclosporin
Danazol
Other fibrates (except fenofibrate)
Amiodarone
Verapamil
Diltiazem
Amlodipine
Fusidic acid
Grapefruit juice

Do not exceed 10 mg Simvastatin daily

Do not exceed 20 mg Simvastatin daily
Patients should be closely monitored.
Temporary suspension of simvastatin
treatment may be considered.
Avoid grapefruit juice when taking
Simvastatin

Effects of other medicinal products on simvastatin
Interactions involving inhibitors of CYP3A4
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome
P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the
concentration of HMG-CoA reductase inhibitory activity in plasma during
simvastatin therapy. Such inhibitors include itraconazole, ketoconazole,
posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors
(e.g. nelfinavir), boceprevir, telaprevir, and nefazodone. 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, HIV protease inhibitors
(e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin
and nefazodone is contraindicated as well as gemfibrozil, ciclosporin, and danazol
(see section 4.3). If treatment with itraconazole, ketoconazole, posaconazole,
erythromycin, clarithromycin or telithromycin is unavoidable, therapy with
simvastatin must be suspended during the course of treatment. Caution should be
exercised when combining simvastatin with certain other less potent CYP3A4
inhibitors: fluconazole,verapamil, or diltiazem (see sections 4.2 and 4.4).

Fluconazole
Rare cases of rhabdomyolysis associated with concomitant administration of
simvastatin and fluconazole have been reported (see section 4.4.).
Ciclosporin
The risk of myopathy/rhabdomyolysis is increased by concomitant administration of
ciclosporin with simvastatin; therefore, use with Ciclosporin is contraindicated (see
sections 4.3 and 4.4) Although the mechanism is not fully understood, ciclosporin has
been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in
AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
Danazol
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of danazol with simvastatin therefore, use with danazol is contraindicated (see
sections 4.3 and 4.4)
Gemfibrozil
Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to
inhibition of the glucuronidation pathway (see sections 4.3 and 4.4). Concomitant
administration with gemfibrozil is contraindicated.
Amiodarone
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of amiodarone with simvastatin (see section 4.4). In an ongoing clinical trial,
myopathy has been reported in 6 % of patients receiving simvastatin 80 mg and
amiodarone.
Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving
concomitant medication with amiodarone.
Calcium Channel Blockers
Verapamil
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic
study, concomitant administration with verapamil resulted in a 2.3 fold increase in
exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4.
Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving
concomitant medication with verapamil.
Amlodipine
Patients on amlodipine treated concomitantly with simvastatin have an increased risk
of myopathy. In a pharmacokinetic study, concomitant administration of amlodipine
caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of
simvastatin should not exceed 20 mg daily in patients receiving concomitant
medication with amlopidine.
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.
Diltiazem
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of diltiazem with simvastatin 80 mg (see section 4.4). In a pharmacokinetic study,

concomitant administration of diltiazem caused a 2.7 -fold increase in exposure of
simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of
simvastatin should not exceed 20 mg daily in patients receiving concomitant
medication with diltiazem.
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
concentrations.



Fusidic acid
The risk of myopathy may be increased by concomitant administration of fusidic acid
with statins, including simvastatin. Isolated cases of rhabdomyolysis have been
reported with simvastatin. Temporary suspension of simvastatin treatment may be
considered. If it proves necessary, patients on fusidic acid and simvastatin should be
closely monitored (see section 4.4).
Grapefruit juice
Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large
quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold
increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the
morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of
grapefruit juice during treatment with simvastatin should therefore be avoided.
Colchicine
There have been reports of myopathy and rhabdomyolysis with the concomitant
administration of colchicine and simvastatin, in patients with renal insufficiency.
Close clinical monitoring of such patients taking this combination is advised.
Rifampicin
Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term
rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of
simvastatin. In a pharmacokinetic study in normal volunteers, the area under the
plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with
concomitant administration of rifampicin.
Effects of simvastatin on the pharmacokinetics of other medicinal products
Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore,
simvastatin is not expected to affect plasma concentrations of substances metabolised
via cytochrome P450 3A4.
Oral anticoagulants
In two clinical studies, one in normal volunteers and the other in
hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the
effect of coumarin anticoagulants: the prothrombin time, reported as International
Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in
the volunteer and patient studies, respectively. Very rare cases of elevated INR have
been reported. In patients taking coumarin anticoagulants, prothrombin time should
be determined before starting simvastatin and frequently enough during early therapy
to ensure that no significant alteration of prothrombin time occurs. Once a stable
prothrombin time has been documented, prothrombin times can be monitored at the
intervals usually recommended for patients on coumarin anticoagulants. If the dose of

simvastatin is changed or discontinued, the same procedure should be repeated.
Simvastatin therapy has not been associated with bleeding or with changes in
prothrombin time in patients not taking anticoagulants.

4.6

Fertility, pregnancy and lactation
Pregnancy
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 section 4.3.)
Breastfeeding
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).

4.7

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.

4.8

Undesirable effects

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:
Rare: anaemia
Psychiatric 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)
Gastrointestinal disorders:
Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea,
vomiting, pancreatitis
Hepato-biliary disorders:
Rare: hepatitis/jaundice
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).
Not known: tendinopathy, sometimes complicated by rupture, Immune-mediated
necrotizing myopathy (see section 4.4)
Reproductive system and breast disorders:
Not known: erectile dysfunction
General disorders and administration site conditions:
Rare: asthenia
An apparent hypersensitivity syndrome has been reported rarely which has included
some of the following features: angioedema, lupus-like syndrome, polymyalgia
rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR
increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea
and malaise.
Investigations:
Rare: increases in serum transaminases (alanine aminotransferase, aspartate
aminotransferase, γ-glutamyl transpeptidase) (see section 4.4 Hepatic effects),
elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).
Increases in HbA1c and fasting serum glucose levels have been reported with statins,
including Simvastatin.
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 non serious, and reversible upon
statin discontinuation, with variable times to symptom onset (1 day to years) and
symptom resolution (median of 3 weeks).
The following 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).

Children and adolescents (10-17 years of age)
In a 48-week study involving children and adolescents (boys Tanner Stage II and
above and girls who were at least one year post-menarche) 10-17 years of age with

heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability
profile of the group treated with Simvastatin was generally similar to that of the group
treated with placebo. The long-term effects on physical, intellectual, and sexual
maturation are unknown. No sufficient data are currently available after one year of
treatment. (See sections 4.2, 4.4, and 5.1.)
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.
4.9

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

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
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.

5.2

Pharmacokinetic properties

Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the
corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase.
Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is
very slow.
The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data
in children and adolescents are not available.
Absorption
In man simvastatin is well absorbed and undergoes extensive hepatic first-pass
extraction. The extraction in the liver is dependent on the hepatic blood flow. The

liver is the primary site of action of the active form. The availability of the 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.
Distribution
The protein binding of simvastatin and its active metabolite is > 95 %.
Elimination
Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major
metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four
additional active metabolites. Following an oral dose of radioactive simvastatin to
man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within
96 hours. The amount recovered in the faeces represents absorbed medicinal product
equivalents excreted in bile as well as unabsorbed medicinal product. Following an
intravenous injection of the 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.
Special populations
Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The
mean exposure (AUC) of the main active metabolite, simvastatin acid is 120% in
heterozygote carriers (CT) of the C allele and 221% in homozygote (CC) carriers
relative to that of patients who have the most common genotype (TT). The C allele
has a frequency of 18% in the European population. In patients with SLCO1B1
polymorphism there is a risk of increased exposure of simvastatin, which may lead to
an increased risk of rhabdomyolysis (see section 4.4).
5.3

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
development.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core tablet:
Lactose monohydrate

Pregelatinised starch
Ascorbic acid
Citric acid monohydrate
Microcrystalline cellulose
Butylhydroxyanisole (E320)
Magnesium stearate
Film-coat: Opadry 20A 56532 Brown
Hydroxypropylcellulose (E463)
Hypromellose 15cP (E464)
Titanium dioxide (E171)
Talc
Iron oxide yellow (E172)
Iron oxide red (E172)
Iron oxide black (E172)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 25°C. Store in the original package.

6.5

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.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited
Building 4, Chiswick Park
566 Chiswick High Road
London, W4 5YE
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 14894/0149

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/01/2004 / 19/03/2009

10

DATE OF REVISION OF THE TEXT
23/03/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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