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SIMVASTATIN VALE PHARMACEUTICALS 20MG/5ML ORAL SUSPENSION

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Simvastatin Vale Pharmaceuticals 20mg/5ml Oral Suspension

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml contains 4mg of Simvastatin (20mg/5ml)
Excipients: 1 ml contains methyl parahydroxybenzoate (E218) 1.8mg, ethyl
parahydroxybenzoate (E214) 0.4mg and propyl parahydroxybenzoate (E216) 0.16mg,
Propylene glycol (E1520) 17.2mg/ml
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Oral Suspension
A white to off-white suspension with strawberry flavour and odour.

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
The dosage range is 5 - 80mg/day (1.25 – 20ml) 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 80mg/day (20ml) given as a single dose in the
evening. The 80mg (20ml) 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 section 4.4 and 5.1).
This product strength is the most suitable presentation when doses of 20mg or below
are required. For higher doses use the 40mg/5ml strength product.
Hypercholesterolaemia
The patient should be placed on a standard cholesterol-lowering diet, and should
continue on this diet during treatment with simvastatin. The usual starting dose is 10 20 mg/day (2.5 – 5ml) 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 (5 –
10ml) 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 dosage is
simvastatin 40mg/day (10ml) in the evening. Simvastatin Oral Suspension 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 Oral Suspension is 20 to 40mg/day (5 – 10ml) 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 Oral Suspension is effective alone or in combination with bile acid
sequestrants. Dosing should occur either >2 hours before or >4 hours after
administration of a bile acid sequestrant.

In patients taking Simvastatin Oral Suspension concomitantly with fibrates other than
gemfibrozil (see section 4.3) or fenofibrate, the dose of Simvastatin Oral Suspension
should not exceed 10mg/day (2.5ml). In patients taking amiodarone, amlodipine,
verapamil, or diltiazem concomitantly with Simvastatin Oral Suspension, the dose of
Simvastatin Oral Suspension should not exceed 20mg/day. (See sections 4.4 and 4.5.)
Dosage in renal insufficiency
No modification of dosage should be necessary in patients with moderate renal
insufficiency.
In patients with severe renal insufficiency (creatinine clearance <30ml/min), dosages
above 10mg/day (2.5ml) should be carefully considered and, if deemed necessary,
implemented cautiously.
Use in the elderly
No dosage adjustment is necessary.
Use in children and adolescents (10-17 years of age)
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 10mg (2.5ml) 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 (2.5ml to 10ml); the maximum
recommended dose is 40mg/day (10ml). 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.

4.3

Contraindications
Hypersensitivity to simvastatin or to any of the excipients
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, posaconazole, HIV protease inhibitors (e.g. nelfinavir),
erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.4
and 4.5).

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

4.4

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 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 80mg/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 80mg/day (mean follow-up 6.7 years), the incidence of
myopathy was approximately 1.0% compared with 0.02% for patients on 20mg/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
(20ml) 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 (20ml) 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), nefazodone), as well as gemfibrozil, ciclosporin

and danazol (see section 4.2). The use of these medicinal products is contraindicated
(see section 4.3).
The risk of myopathy and rhabdomyolysis is also increased by concomitant use of
amiodarone, amlodipine, verapamil, or diltiazem with certain doses of simvastatin
(see sections 4.2 and 4.5.)., The risk of myopathy, including rhabdomyolysis, may be
increased by concomitant administration of fusidic acid with statins (see section 4.5).
Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly
with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g.
nelfinavir), 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, ciclosporin, verapamil,
diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and
simvastatin should be avoided.
The use of simvastatin with gemfibrozil is contraindicated (see section 4.3). Due to
the increased risk of myopathy and rhabdomyolysis, the dose of simvastatin should
not exceed 10 mg daily in patients taking simvastatin with other fibrates, except
fenofibrate. (See sections 4.2 and 4.5.)Caution should be used when prescribing
fenofibrate with simvastatin, as either agent can cause myopathy when given alone.
The combined use of simvastatin at doses higher than 20 mg daily with amiodarone,
amlodipine, verapamil, or diltiazem should be avoided (see sections 4.2 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.
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant
administration of HMG-CoA reductase inhibitors and lipid-modifying doses (
1g/day) of niacin (nicotinic acid), either of which can cause myopathy when given
alone.



Physicians contemplating combined therapy with simvastatin and lipid-modifying
doses ( 1g/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 40mg and nicotinic acid/laropiprant
2000mg/40mg. Therefore, caution should be used when treating Chinese patients with
simvastatin (particularly doses of 40mg or higher) co-administered with lipidmodifying doses ( 1g/day) of niacin (nicotinic acid) or products containing niacin.
Because the risk of myopathy with statins is dose-related, the use of simvastatin 80mg
with lipid-modifying doses ( 1g/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 ( 1g/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.
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 80mg 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)
The product should be used with caution in patients who consume substantial
quantities of alcohol.
As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum
transaminases have been reported following therapy with simvastatin. These changes
appeared soon after initiation of therapy with simvastatin, were often transient, were
not accompanied by any symptoms and interruption of treatment was not required.
Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some
patients, at high risk of future diabetes, may produce a level of hyperglycaemia where
formal diabetes care is appropriate. This risk, however, is outweighed by the
reduction in vascular risk with statins and therefore should not be a reason for
stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L,
BMI>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.

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 40mg 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.
Excipients
This product contains methyl parahydroxybenzoate (E218), ethyl
parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216). These may cause
allergic reactions (possibly delayed).

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 summarised in the table
below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).

Drug Interactions Associated with Increased Risk of

Myopathy/Rhabdomyolysis
Interacting agents

Prescribing recommendations

Potent CYP3A4 inhibitors:

Contraindicated with simvastatin

Itraconazole
Ketoconazole
Posaconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors(e.g. nelfinavir)
Nefazodone
Ciclosporin
Danazol
Gemfibrozil
Other fibrates (except fenofibrate)

Do not exceed 10mg simvastatin
daily

Amiodarone

Do not exceed 20mg simvastatin
daily

Amlodipine
Verapamil
Diltazem

Fusidic acid

Patients should be closely
monitored. Temporary suspension
of simvastatin treatment may be
considered

Grapefruit juice

Avoid grapefruit juice when taking
simvastatin

Effects of other medicinal products on simvastatin
Interactions involving inhibitors of CYP3A4
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome
P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the
concentration of HMG-CoA reductase inhibitory activity in plasma during
simvastatin therapy. Such inhibitors include itraconazole, ketoconazole,
posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors
(e.g. nelfinavir), and nefazodone. Concomitant administration of itraconazole resulted
in a more than 10-fold increase in exposure to simvastatin acid (the active betahydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to
simvastatin acid.
Combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors
(e.g. nelfinavir), 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,
ciclosporin, verapamil, 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 particularly with higher doses of simvastatin; therefore, use with
ciclosporin is contraindicated (see sections 4.3 and 4.4). Therefore, the dose of
simvastatin should not exceed 10mg daily in patients receiving concomitant
medication with ciclosporin. 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 higher doses of 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 4.3and 4.4). Concomitant
administration with gemfibrozil is contraindicated.
Amiodarone
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial,
myopathy was reported in 6% of patients receiving simvastatin 80mg and
amiodarone. Therefore the dose of simvastatin should not exceed 20 mg daily in
patients receiving concomitant medication with amiodarone.
Calcium Channel Blockers
Verapamil
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic
study, concomitant administration with verapamil resulted in a 2.3-fold increase in
exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4.

Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving
concomitant medication with verapamil..
Diltiazem
The risk of myopathy and rhabdomyolysis is increased by concomitant administration
of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients
taking simvastatin 40 mg was not increased by concomitant diltiazem (see section
4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a
2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of
CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients
receiving concomitant medication with diltiazem.
Amlodipine
Patients on amlodipine treated concomitantly with simvastatin have an increased risk
of myopathy.. In a pharmacokinetic study, concomitant administration of amlodipine
caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of
simvastatin should not exceed 20 mg daily in patients receiving concomitant
medication with amlodipine.
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 increased risk of myopathy.
Niacin (nicotinic acid)
Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin coadministered with lipid-modifying doses ( 1g/day) of niacin (nicotinic acid). In a
pharmacokinetic study, the co-administration of a single dose of nicotinic acid
prolonged-release 2g with simvastatin 20mg 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 240ml 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 efficiacy 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 - 40mg/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 Oral Suspension 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 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 or another closely related HMG-CoA reductase
inhibitor differs from that observed in the general population, maternal treatment with
simvastatin 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 Oral Suspension must not be used in women who are
pregnant, trying to become pregnant or suspect they are pregnant. Treatment with
Simvastatin Oral Suspension 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).
Lactation
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 Oral Suspension
should not breast-feed their infants (see section 4.3).
Fertility
At maximally tolerated doses in both the rat and the rabbit, simvastatin had no effects
on fertility (see section 5.3).

4.7

Effects on ability to drive and use machines
Simvastatin Oral Suspension 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 40mg/day of
simvastatin (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable
between patients treated with simvastatin 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 compared with 5.1% in patients treated
with placebo). The incidence of myopathy was < 0.1% in patients treated with
simvastatin 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test)
occurred in 0.21% (n = 21) of patients treated with simvastatin compared with 0.09%
(n = 9) of patients treated with placebo.
The frequencies of adverse events are ranked according to the following: Very
common (> 1/10), Common ( 1/100, < 1/10), Uncommon ( 1/1000, < 1/100), Rare
( 1/10,000, < 1/1000), Very Rare (< 1/10,000), not known (cannot be estimated from
the available data).







Blood and lymphatic system disorders:
Rare: anaemia
Psychiatric disorders:
Very rare: insomnia
Not Known: depression
Nervous system disorders:
Rare: headache, paresthesia, dizziness, peripheral neuropathy
Very rare: memory impairment
Respiratory, thoracic and mediastinal disorders:
Not known: interstitial lung disease (see section 4.4)
Gastrointestinal disorders:
Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea,
vomiting, pancreatitis
Hepato-biliary disorders:
Rare: hepatitis/jaundice
Very rare: hepatic failure

Skin and subcutaneous tissue disorders:
Rare: rash, pruritus, alopecia
Musculoskeletal and connective tissue disorders:
Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal
faliure (see section 4.4), myalgia, muscle cramps
*In a clinical trial, myopathy occurred commonly in patients treated with simvastatin
80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%,
respectively). (see sections 4.4 and 4.5)
Not Known: tendinopathy, sometimes complicated by rupture
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, -glutamyl transpeptidase) (see section 4.4 Hepatic effects),
elevated alkaline phosphatase; increase in serum CK levels (see section 4.4).

γ

The following additional adverse events have been reported with some statins:
• sleep disturbances, including nightmares
• memory loss
• 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 the 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).

4.9

Overdose
To date, a few cases of overdosage have been reported; the maximum dose taken was
3.6g. 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 A01
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 has 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 may involve both reduction of VLDL-cholesterol
(VLDL-C) concentration and induction of the LDL receptor, leading to reduced
production and increased catabolism of LDL-C. Apolipoprotein B also falls
substantially during treatment with simvastatin. In addition, simvastatin 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 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 40mg/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 116mg/dL; 5,063 patients (25%) had levels
between 116mg/dL and 135mg/dL; and 8,680 patients (42%) had levels greater than
135mg/dL.

Treatment with simvastatin 40mg/day compared with placebo significantly reduced
the risk of all cause mortality (1328 [12.9%] for simvastatin-treated patients versus
1507 [14.7%] for patients given placebo; p = 0.0003), due to an 18% reduction in
coronary death rate (587 [5.7%] versus 707 [6.9%]; p = 0.0005; absolute risk
reduction of 1.2%). The reduction in non-vascular deaths did not reach statistical
significance. Simvastatin 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 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 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
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 3.0mmol/l at inclusion.
In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with
simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline
total cholesterol 212 - 309mg/dL (5.5 - 8.0mmol/L). In this multicentre, randomised,
double-blind, placebo-controlled study, patients with angina or a previous myocardial
infarction (MI) were treated with diet, standard care, and either simvastatin 20 40mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years.
Simvastatin 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 also decreased the risk of having major coronary events (CHD death plus
hospital-verified and silent nonfatal MI) by 34%. Furthermore, simvastatin
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 80mg 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 40mg and 80mg, 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 400mg/dL and at least one
parent with an LDL-C level >189mg/dL. The dosage of simvastatin (once daily in the
evening) was 10mg for the first 8 weeks, 20mg for the second 8 weeks and 40mg
thereafter. In a 24-week extension, 144 patients elected to continue therapy and
received simvastatin 40mg or placebo.
Simvastatin significantly decreased plasma levels of LDL-C, TG and ApoB. 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 124.9mg/dL (range:
64.0-289.0mg/dL) in the simvastatin 40mg group compared to 207.8mg/dL (range:
128.0 – 334.0mg/dL) in the placebo group.
After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up
to 40mg 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 40mg 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.

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 (12.5 mg/kg b.i.d.) 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
Methyl parahydroxybenzoate (E218)

Ethyl parahydroxybenzoate (E214)
Propyl parahydroxybenzoate (E216)
Propylene glycol (E1520)
Aluminium magnesium silicate
Carmellose sodium (E466)
Simeticone emulsion
Citric acid monohydrate (E330)
Di-sodium hydrogen phosphate anhydrous (E339)
Sodium laurilsulfate (E470a)
Acesulfame potassium (E950)
Strawberry flavour (contains propylene glycol (E1520))
Butylhydroxyanisole (BHA)
Purified water

6.2

Incompatibilities
Not applicable

6.3

Shelf life
18 months
After first opening: 1 month

6.4

Special precautions for storage
Do not store above 25°C

6.5

Nature and contents of container
Amber (Type III) glass bottles
Closures: HDPE, EPE wadded, tamper evident, child resistant closure
Dosing Device: 1.25ml, 2.5ml and 5ml single ended polystyrene spoon.
Pack Size: 150ml

6.6

Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Rosemont Pharmaceuticals Ltd.,
Yorkdale Industrial Park,
Braithwaite Street,
Leeds,
LS11 9XE,
UK.

8

MARKETING AUTHORISATION NUMBER(S)
PL 00427/00230

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/06/2013

10

DATE OF REVISION OF THE TEXT
11/09/2013

Expand Transcript

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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