Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g.
CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.


Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.

Interaction studies have only been performed in adults.

Pharmacodynamic interactions
Interactions with lipid-lowering medicinal products that can cause myopathy when given alone

The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates.

Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.3 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent.

Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (see section 4.4).

Pharmacokinetic interactions
Prescribing recommendations for interacting agents are summarized in the table below (further details are provided in the text; see also sections 4.2, 4.3 and 4.4).
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting agents                             Prescribing recommendations Potent CYP3A4 inhibitors, e.g.,                Contraindicated with simvastatin Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors (e.g., nelfinavir)
Boceprevir
Telaprevir
Nefazodone
Cobicistat
Ciclosporin
Danazol
Gemfibrozil


Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting agents                      Prescribing recommendations Other fibrates (except fenofibrate)     Do not exceed 10 mg simvastatin daily 
Fusidic acid                                  Is not recommended with simvastatin 
Niacin (nicotinic acid) (≥ 1 g/day)           For Asian patients, not recommended with simvastatin
Amiodarone                                    Do not exceed 20 mg simvastatin daily Amlodipine
Elbasvir
Grazoprevir

Verapamil                                     Do not exceed 10 mg simvastatin daily Diltiazem
Lomitapide                                    For patients with HoFH, do not exceed 40 mg simvastatin daily
Daptomycin                                    It should be considered to temporarily suspend simvastatin in patients using daptomycin unless the benefits of concomitant administration outweigh the risk (see section 4.4)

Ticagrelor                                    Doses greater than 40 mg simvastatin daily are not recommended
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, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g.
nelfinavir), boceprevir, telaprevir, nefazodone and medicinal products containing cobicistat. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite).
Telithromycin caused an 11-fold increase in exposure to simvastatin acid.

Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin , nefazodone and medicinal products containing cobicistat is contraindicated, as well as gemfibrozil, ciclosporin, and danazol (see section 4.3). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) is unavoidable, therapy with simvastatin must be suspended (and use of an alternative statin considered) during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil or diltiazem (see sections 4.2 and 4.4).


Fluconazole
Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported (see section 4.4).

Ciclosporin
The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with simvastatin; therefore, use with ciclosporin is contraindicated (see sections 4.3 and 4.4). Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.

Danazol
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with simvastatin; therefore, use with danazol is contraindicated (see sections 4.3 and 4.4).

Gemfibrozil
Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway and/or OATP1B1 (see sections 4.3 and 4.4).
Concomitant administration with gemfibrozil is contraindicated.

Fusidic acid
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, simvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.

Amiodarone
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone.

Calcium Channel Blockers
• Verapamil
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4.
Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving 
concomitant medication with verapamil.

• Diltiazem
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with diltiazem.

• Amlodipine
Patients on amlodipine treated concomitantly with simvastatin have an increased risk of myopathy. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amlodipine.

• Lomitapide
The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with simvastatin (see sections 4.3 and 4.4). Therefore, in patients with HoFH, the dose of simvastatin must not exceed 40 mg daily in patients receiving concomitant medication with lomitapide.

• Moderate Inhibitors of CYP3A4
Patients taking other medicines labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy (see section 4.4).

• Inhibitors of the Transport Protein OATP1B1
Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see sections 4.3 and 4.4).

Inhibitors of Breast Cancer Resistant Protein (BCRP)
Concomitant administration of medicinal products that are inhibitors of BCRP, including products containing elbasvir or grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy (see section 4.2 and 4.4).

Niacin (nicotinic acid)
Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co- administered 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.


Ticagrelor
Co-administration of ticagrelor with simvastatin increased simvastatin Cmax by 81 % and AUC by 56% and increased simvastatin acid Cmax by 64 % and AUC by 52 % with some individual increases equal to 2-to 3-fold. Co-administration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause adverse reactions of simvastatin and should be weighed against potential benefits. There was no effect of simvastatin on ticagrelor plasma levels. The concomitant use of ticagrelor with doses of simvastatin greater than 40 mg is not recommended.

Grapefruit juice
Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 liter daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided.

Colchicine
There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal impairment. Close clinical monitoring of such patients taking this combination is advised.

Daptomycin
The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. simvastatin) and daptomycin (see section 4.4).

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.