Lipid-lowering drugs

Drug interaction
  1. Bile acid sequestrants (resins): Cholestyramine, Colesevelam, Colestipol
  2. Ezetimibe
  3. Fibrates: Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozil
  4. Omega-3-fatty-acids (ethyl esters)
  5. PCSK9 inhibitors: Alirocumab, Evolocumab
  6. Statins: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin
  7. Microsomal triglyceride transfer protein (MTP) inhibitors: Lomitapide
  8. Mipomersen: Antisense oligonucleotide anti-apo B100

1. Bile acid sequestrants

Cholestyramine, Colesevelam, Colestipol

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antidiabetic drugs:
- Glibencamide, Glimepiride, Glipizide
- Metformin
Colesevelam increases the exposure of metforminMonitor glucose plasma levels
Bile-acid sequestrants reduce the absorption of:
- Digoxin
- Glibencamide, Glipizide, Glyburide, Glimepiride
- Levothyroxine
- Olmesartan
- Oral contraceptives containing ethinyl estradiol and norethindrone
- Propranolol
- Statins
- Tetracyclines
- Thiazide diuretics
- Warfarin
Sequestrants can delay or reduce the absorption of these drugs Concurrent drugs should be taken either at least 1 h before or 4–6 h after cholestyramine
CiclosporinDecrease the exposure of ciclosporinMonitor ciclosporin plasma levels and adjust the doses if combined with cholestyramine
Fat-soluble vitamins (vitamin K) and folic acidCholestyramine may interfere with their absorptionPatients may require supplementation with Vitamins A, D and K and folic acid
WarfarinReduce the absorption of vitamin KMonitor the INR

Colesevelam have no significant effect on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid and pioglitazone.

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2. Ezetimibe

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Bile-acid sequestrantsCholestyramine decreases the expected reduction in LDL-CCholestyramine decreases the absorption and decreases the exposure of ezetimibeAdminister ezetimibe either ≥ 2 hours before or ≥ 4 hours after the bile acid sequestrant
CiclosporinEzetimibe markedly increases the plasma concentrations of ciclosporin possibly due to P-gp inhibitionMonitor ciclosporin plasma levels
Fibrates:
- Fenofibrate
- Gemfibrozil
Possible risk of cholelithiasis and gallbladder diseaseEzetimibe increases the plasma concentrations of fenofibrate and gemfibrozil (unspecified mechanism)
WarfarinPost-marketing reports of increased INRMonitor the INR as appropriate

No interactions with cimetidine, dapsone, dextromethorphan, digoxin, fibrates, glipizide, HIV-protease inhibitors, midazolam, mipomersen, nicotinic acid, oral contraceptives (ethinyl estradiol and levonorgestrel), rifampicin, sirolimus, statins or tolbutamide.

Ezetimibe does not affect the absorption of vitamin A, C and D.

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3. Fibrates

Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozil

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
α-blockersPotential for hypotension and tachycardia
AnticoagulantsFibrates may potentiate effects of oral anticoagulantsReduce the dose of anticoagulants
Antidiabetics:
- Insulin
- Oral hypoglycemic drugs
Concomitant use can result in hypoglycemic reactions Fibrates can displace some oral antiadiabetics from plasma proteins and increase their free plasma levelsMonitor plasma glucose levels is recommended
BexaroteneGemfibrozil increases the plasma levels of bexaroteneAvoid the combination
Bile-acid sequestrantsPotentiate the lipid lowering effects of fibratesThey may reduce their oral bioavailability of fibratesFibrates should be taken at least 1 h before or 4–6 h after resins
ColchicineCase reports of neuromyopathy or rhabdomyolysisMonitor the patient, particularly the elderly and patients with renal impairment. Avoid the combination
CYP2C9 substrates:
- Celecoxib
- Glimepiride
- S-warfarin
Fenofibrate may inhibit the metabolism of drugs substrate of CYP2C9Adjust the dose of these drugs
FibratesThe combination increases the risk gallstonesFenofibrate and gemfibrozil slightly increase the exposure to ezetimibe Avoid the combination if gallstones or gall bladder disease is suspected
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Isolated cases of reversible impairment of renal functionAvoid the combination
Monitor renal function in organ transplant patients
MAOIsWhen combined with bezafibrate there is an increased risk of hepatotoxicityWith caution. All patients should be told to report muscle pain or weakness
Nicotinic acidIncrease the risk of myopathyWith caution. All patients should be told to report muscle pain or weakness
Phenytoin Fibrates can displace phenytoin from plasma proteins and increase their free plasma levelsDoses of these drugs should be reduced as needed
RosiglitazoneEnhances the risk of hypoglycemiaGemfibrozil increases the exposure to rosiglitazoneCareful with the combination
Statins:
- Atorvastatin
- Lovastatin
- Pravastatin
- Simvastatin
- Rosuvastatin
Increased risk of severe myopathy, rhabdomyolysis and acute renal failureGemfibrozil interferes with OATP1B1-mediated transport of these statins into the hepatocyte which increases their plasma levelsCKD, and it varies with different fibrates.
Avoid the combination of gemfibrozil with statins
ThyroxinFibrates can displace thyroxin from plasma proteins and increase their free plasma levelsDoses of these drugs should be reduced as needed
WarfarinFibrates may increase the effects of warfarin and prolong the PT/INRThe dose of warfarin should be reduced (30-50%) and the INR should be monitorized

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3.1 Gemfibrozil

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Aluminium-containing antiacids They may decrease gemfibrozil exposureAvoid the combination
BexaroteneGemfibrozil increases the exposure of bexaroteneAvoid the combination
CilostazolGemfibrozil increases the exposure to cilostazol by affecting CYP2C19 metabolismReduce the dose of cilostazol by 50% or avoid the combination
Dabrafenib Dabrafenib is a substrate of CYP2C8. Gemfibrozil and its metabolite (gemfibrozil 1-O-β-glucuronide) are potent inhibitors of CYP2C8, inhibit the metabolism and increase the plasma levels of dabrafenibMonitor patients closely for adverse reactions
DasafubirIncreased dasafubir exposure may increase the risk of QT prolongationCoadministration of gemfibrozil with dasafubir increases dasafubir plasma concentrations due to CYP2C8 inhibitionAvoid the combination
CYP2C8 substrates:
- Dabrafenib
- Dasabuvir
- Enzalutamide
- Loperamide
- Montelukast
- Paclitaxel
- Pioglitazone
- Repaglinide
- Selexipag
Increased dasafubir exposure may increase the risk of QT prolongationGemfibrozil inhibits CYP2C8 and increases the exposure to these drugs (and of their active metabolites if any)Reduce the dose of drugs that are mainly metabolized by CYP2C8 when gemfibrozil is used concomitantly.
Co-administration of gemfibrozil with repaglinide, dasabuvir or selexipag is contraindicated
HIV-protease inhibitors:
- Dasabuvir
- Ombitasv
- Paritaprevir
- Ritonavir
Decrease gemfibrozil exposureGemfibrozil increases the exposure and effects of these drugs Monitor the response to gemfibrozil
Sulfonylureas:
- Glimepiride
- Glipizide
- Glyburide
Enhances the risk of hypoglycemiaGemfibrozil displaces sulfonylureas fromm their plasma protein binding sites and increases their plasma protein. Gemfibrocil also inhibits CYP2C9-mediated metabolism of sulfonylureasMonitor plasma glucose levels. Avoid the combination or use alternative drug or adjust the dose of sylfonylureas
ValsartanGemfibrozil will increase the level or effect of valsartanMonitor the effects of valsartan

Gemfibrocil inhibits CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1, and UGTA3, resulting in an increased exposure of many medicinal products

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4. Omega-3-fatty-acids (ethyl esters)

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Anticoagulants High doses (4 g/daily) of omega-3 prolong the bleeding time and increase the risk of bleedingPatients receiving anticoagulant therapy should be monitored periodically
WarfarinMonitor the INR

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5. PCSK9 inhibitors

Alirocumab, Evolocumab

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Drugs that increase the production of PCSK9:
- Ezetimibe
- Fenofibrate
- Statins
Statins increase the clearance and reduce systemic exposure of alirocumab or evolocumab.
Increase (20%) the clearance of evolocumab when co-administered with statins
The role of this possible interaction is uncertain

Since alirocumab is a human IgG1 monoclonal antibody and evolocumab is a human IgG2 monoclonal antibody (both produced in Chinese Hamster Ovary cells by recombinant DNA technology), no pharmacokinetic effects of alirocumab or evolocumab on other medicinal products and no effect on cytochrome P450 enzymes are anticipated.

No formal drug-drug interaction studies have been conducted for with evolocumab. No studies on pharmacokinetic and pharmacodynamics interaction between evolocumab and lipid-lowering drugs other than statins and ezetimibe have been conducted.

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6. Statins (3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors)

Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Aluminium/Magnesium hydroxyde-containing antiacids Modest reduction in the bioavailability of atorvastatin, pravastatin and rosuvastatinClinical relevance is uncertain
Amiodarone Amiodarone inhibits CYP3A4 and 2C9Reduce the maximum daily dose of statins biotransformed via CYP3A4 and/or 2C9. Amiodarone does not interact with pravastatin
AntiarrhythmicsAmiodarone and verapamil increases the risk of myopathyAmiodarone inhibits CYP3A4 and 2C9Reduce the dose when given in patients taking amiodarone or verapamil
Azole antifungalsMyopathy and isolated cases of rhabdomyolysis the combination of atorvastatin, lovastatin and simvastatin and an azole antifungalItraconazole, ketoconazole, posaconazole and voriconazole are potent inhibitors of CYP3A4.
Fluconazole increases fluvastatin and pravastatin exposure
Itraconazole increases lovastatin and simvastatin exposure; moderate increase in atorvastatin exposure.
Posoconazole markedly increases simvastatin exposure
Monitor for signs of myopathy.
The combination of lovastatin and simvastatin with azole antifungals is contraindicated.
Avoid the combination of simvastatin and voriconazole
Avoid atorvastatin doses greater than 20-40 mg daily with itraconazole
No clinically relevant interactions with pravastatin
BexaroteneBexarotene induces CYP3A4 and reduces exposure to atorvastatin, lovastatin and simvastatinIt may be necessary to increase the dose of the statin
Bile-acid sequestrants:
- Cholestiramine
- Cholestipol
The lowering effects on total and LDL cholesterol increases when combined with statins They reduce the absorption of statinsStatins should be given either 1 h before or at least 4 h after the resin to avoid the interaction
Calcium channel blockers:
- Diltiazem
- Verapamil
They inhibit CYP3A9 and increase exposure to atorvastatin, lovastatin and simvastatinThe benefit/risk ratio of this combination should be evaluated. Other statins can be used
ColchicineIncreases the risk of myopathy, including rhabdomyolysisWith caution. All patients should be told to reports muscle pain or weakness
EzetimibeIncrease risk of myopathy. The combination with statins increases the risk of muscle related events, including rhabdomyolysisAll patients should be told to report muscle pain or weakness
FibratesIncrease the risk for myopathy/rhabdomyolysis. This risk is highest for gemfibrozil. This interaction is not expected with fenofibrateThe combination of gemfibrozil with statins is contraindicated.
Avoid the combination with lovastatin, pravastatin and simvastatin. Combination with atorvastatin, pitavastatin and rosuvastatin is accepted if indicated and fenofibrate is not an option. If coadministered, clinical monitoring of these patients is recommended
Fusidic acidIncreases the risk of myopathy including rhabdomyolysis Statins should be discontinued if treatment with systemic fusidic acid is necessary
Grapefruit juiceInhibits CYP3A4Avoid the combination with atorvastatin, lovastatin and simvastatin
Hepatitis C virus (HCV)-protease inhibitors:
- Boceprevir
- Simeprevir
- Telaprevir
They inhibit CYP3A4Boceprevir: avoid the combination with lovastatin and simvastatin.
Telaprevir: avoid the combination with atorvastatin, lovastatin and simvastatin.
For fluvastatin, pitavastatin, pravastatin, and rosuvastatin, caution is warranted and clinical monitoring recommended
HIV-protease inhibitors:
- Darunavir
- Fosamprenavir
- Lopinavir
- Ritonavir
- Saquinavir
- Selfinavir
- Tipranavir
Cases of myopathy or rhabdomyolysisInhibits CYP3A4 and markedly increases atorvastatin, lovastatin and simvastatin exposure.
- Pravastatin exposure is only slightly increased
Patients should be told to report any signs of myopathy or weakness. If myopathy occur, statin should be stopped immediately
ImatinibIncreases the exposure to atorvastatin, lovastatin and simvastatin exposureThese statins should be used at the lowest possible dose
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Ciclosporin increases the exposure to atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin; statins do not alter ciclosporin exposureMaximum daily doses of atorvastatin, pravastatin and rosuvastatin 10 mg, 10-20 and 40 mg, respectively.
Avoid the combination with lovastatin, pitavastatin or simvastatin
LenalidomideIncreased risk of rhabdomyolysis when statins are combined to lenalidomideClose monitoring of the patient is required
Moderate CYP3A4 inhibitors:
- Amiodarone
- Diltiazem
- Erythromycin
- Fluconazole
- Verapamil
Increase the risk of myopathyThey increase the plasma concentration of atorvastatin, lovastatin and simvastatin A lower maximum dose of these statins should be used and appropriate clinical monitoring of the patient is recommended
Nicotinic acid (> or equal to 1 g/day)Increase the risk of myopathy With caution when coadministered with lovastatin, rosuvastatin and simvastatin. All patients should be told to reports muscle pain or weakness
Non-nucleoside reverse transcriptase inhibitors:
- Delavirdine
- Efavirenz
- Etravirine
- Nevirapine
Cases of myopathyDelavirdine increases the exposure to atorvastatin, fluvastatin, lovastatin and simvastatin.
Efavirenz and nevirapine induce CYP3A4 activity and reduce the exposure to atorvastatin, pravastatin and simvastatin.
Etravirine increases fluvastatin exposure
Monitor the clinical response of the patient
Potent CYP3A4 inducers:
- Carbamazepin
- Efavirenz
- Griseofulvin
- Phenytoin
- Rifampin
- St. John's Wort
Reduce plasma levels of atorvastatin, lovastatin and simvastatinMonitor the clinical response of the patient
Potent CYP3A4 inhibitors:
- Azole antifungals: Itraconazole, Ketoconazole, Posiconazole, Voriconazole
- Ciclosporin
- Delavirdine
- Fibrates: gemfibrozil
- HIV-protease inhibitors: Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Ritonavir, Saquinavir
- Hepatitis C antivirals: Elbasvir/Grazoprevir
- Macrolides: Clarithromycin, Erythromycin, Roxithromycin, Telithromycin
- Nefazodone
- Nicotinic acid (≥ 1 g/day)
- Stiripentol
- Telithromycin
Increase the risk of myopathy and other adverse effectsThey markedly increase the plasma concentration of atorvastatin, lovastatin and simvastatin Avoid the combination if possible. If not, both starting and maximum doses should be reduced and appropriate clinical monitoring of the patient is recommended.
Macrolides are contraindicated with lovastatin and simvastatin
WarfarinIn patients treated with VKA, initiation of treatment or dosage up-titration of statins doses may result in an increase in INRThe INR should be monitored following the initiation of a statin or a change in statin dose. The impact on the INR appears lowest for fluvastatin, pitavastatin and rosuvastatin

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6.1 Atorvastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antiviral drugs:
- Nelfinavir
- Boceprevir
- Telaprevir
Plasma concentrations of atorvastatin are markedly increased when co-administered with telaprevirAvoid concomitant administration of telaprevir and atorvastatin
ColchicineCases of myopathy, including rhabdomyolysis, when atorvastatin is co-administered with colchicineAvoid the combination
DiltiazemAppropriate clinical monitoring of the patient is recommended
DigoxinAtorvastatin (10 mg) increase the plasma levels of digoxinMonitor the patient, including SDC
Fusidic acidIncreases the risk of myopathy including rhabdomyolysis Atorvastatin should be discontinued during the treatment with systemic fusidic acid
HCV-protease inhibitors:
- Boceprevir
The maximum dose of atorvastatin should be limited to 40 mg
Hepatitis C virus (HCV) NS3/4A protease inhibitor:
- Telaprevir
It inhibits CYP3A4Avoid the combination. If atorvastatin is necessary, do not exceed 10 mg daily
HIV-protease inhibitors:
- Fosamprenevir
- Lopinavir
- Ritonavir
- Tripanavir
Increases the risk of myopathy including rhabdomyolysisAt atorvastatin doses <20 mg daily, clinical monitoring of thepatients is recommended
Darunavir, Fosamprenevir, Ritonavir, Saquinavir: at doses of atorvastatin >40 mg daily clinical monitoring of these patients is recommended
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Increases the systemic exposure of atorvastatinCaution when the dose of atorvastatin exceeds 10 mg daily
ItraconazoleAt doses of atorvastatin >40 mg daily clinical monitoring of these patients is recommended.
Patients should be told to report any signs of myopathy or weakness
Macrolide antibiotics:
- Clarithromycin
- Erythromycin
- Telithromycin
Increase the plasma concentration of atorvastatin, lovastatin and simvastatin
Caution when the dose of atorvastatin exceeds 20 mg. Patients should be told to report any signs of myopathy or weakness.
Azithromycin would not be expected to interact
Oral contraceptives (norethindrone and ethinyl estradiol)Atorvastatin increases blood levels of the norethindrone and ethinyl estradiol
Potent CYP450 inhibitorsMarkedly increase exposure to atorvastatin
WarfarinCases of changes in PT have been described, but no bleeding PT be determined in patients treated with VKA before starting atorvastatin to ensure that no significant alteration during the treatment

Atorvastatin is metabolised by CYP3A4 and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter.

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6.2 Fluvastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsPharmacokinetic interactions
CYP2C9 inhibitors:
- Amiodarone
- Cimetidine
- Fluconazole
- Fluoxetine
- Fluvoxamine
- Isoniazide
- Itraconazol
- Metronidazol
- Ticlopidine
- Zafirlukast
Reduce the biotransformation of fluvastatinReduce the dose of fluvastatin. Co-administer with caution
- With fluconazole limit the dose of fluvastatin to 40 mg daily
Histamine H2-receptor antagonists:
- Cimetidine
- Ranitidine
Reduce fluvastatin clearance and increase fluvastatin plasma levelsWith caution
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Contradictory results on fluvastatin exposureLimit the dose of fluvastatin to 40 mg daily
OmeprazoleReduces fluvastatin clearance and increases its plasma levelsWith caution
Oral antidiabetic agents
- Glibenclamide
- Tolbutamide
Increase fluvastatin exposureMonitor the response when the fluvastatin dose is increased to 80 mg daily
RifampicinReduces the bioavailability of fluvastatin by about 50%.Adjustment of fluvastatin dosage may be required
St John´s wortReduces the efficacy of simvastatinInduces CYP3A4 and decreases the exposure to atorvastatinStop St John´s wort or increase the dose of atorvastatin. No interaction with pravastatin
WarfarinRare cases bleeding episodes and/or increased PT have been reportedIncreases the plasma levels of S-warfarinMonitor the PT when fluvastatin treatment is initiated, discontinued or the dosage changes

No interactions withamlodipine, clopidogrel, digoxin, losartan, propranaolol or grapefruit juice.

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6.3 Lovastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Amiodarone Increases the risk of myopathy/rhabdomyolysisThe dose of lovastatin should not exceed 40 mg daily
AmlodipineLimit the dose of lovastatin to 20 mg daily
ConivaptanAvoid the combination
DronedaroneIncreases the risk of myopathyLimit the dose of lovastatin to 20 mg daily
ErythromycinIncrease the risk of myopathyAvoid the combination
GemfibrozilAvoid the combination
HIV protease inhibitors:
- Boceprevir
- Telaprevir
Increase the risk of myopathyAvoid the combination
Immunosuppressants:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Avoid the combination
Moderate CYP3A4 inhibitors:
- Diltiazem
- Verapamil
Increases the risk of myopathy/rhabdomyolysisThe dose of lovastatin should not exceed 20 mg daily. Patients should be told to report any signs of myopathy or weakness
NefazodoneAvoid the combination
Potent CYP3A4 inducersIncrease the risk of myopathyAvoid the combination
Potent CYP3A4 inhibitorsIncrease the risk of myopathyIncrease the exposure of lovastatinThe dose of lovastatin should not exceed 20 mg daily. Avoid the combination if possible
Ranolazine Increase the risk of myopathyIncrease the exposure of lovastatinWith caution and dose adjustment of lovastatin may be necessary.
TicagrelorLimit the dose of lovastatin to 40 mg daily
WarfarinMonitor the INR

No interactions with propranolol, glipizide or digoxin.

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6.4 Pitavastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
ErythromycinThe maximal dose of pitavastatin should be 1 mg daily
GemfibrozilMetabolism of pitavastatin via CYP2C9 is unaffected by gemfibrozil
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Avoid the combination
RifampicinThe maximal dose of pitavastatin should be 2 mg daily

Pitavastatin is not a substrate for CYP3A4; thus it is unlikely to interact with CYP3A4 inhibitors/inducers

It does not interact with antiretrovirals

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6.5 Pravastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Markedly increases pravastatin exposureLimit the dose of lovastatin to 40 mg daily. Clinical and biochemical monitoring of patients is recommended
Macrolides:
- Clarithromycin
- Erythromycin
- Roxithromycin
Increases the risk of myopathiesMacrolides can increase statin exposure when used in combinationLimit the dose of lovastatin to 40 mg daily
RifampicinMarkedly increases pravastatin exposureNo interaction is expected if their dosing is made at least 2 h apart

Pravastatin is not metabolised to a clinically significant extent by the cytochrome P450 system (CYP3A4 or CYP2C9).

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6.6 Rosuvastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Antiacids (aluminium/magnesium)Reduces rosuvastatin plasma levels (50%)Administer the antiacid 2 h after rosuvastatin. The clinical relevance is uncertain
ErythromycinDecreases (20-30%) rosuvastatin exposure due to an increase in gut motility
GemfibrozilIncreases the risk of myopathy/rhabdomyolysisIncreases rosuvastatin exposureLimit the dose of rosuvastatin to 5-10 mg daily (only if needed). Patients should be told to report any signs of myopathy or weakness
HIV-protease inhibitors:
- Atazanavir/ritonavir
- Lopinavir/ritonavir
- Simeprevir
Increase rosuvastatin exposure up to 5-foldIn HIV patients receiving protease inhibitors rosuvastatin is not recommended. Limit the dose of rosuvastatin to 10 mg daily with atazanavir, with or without ritonavir, or lopinavir with ritonavir
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Decreases the clearance of rosuvastatin and markedly increases rosuvastatin exposure. No changes in ciclosporin plasma levelsAvoid the combination. Limit the dose of rosuvastatin to 5 mg daily
Oral contraceptivesRosuvastatin increases the AUC of ethinyl estradiol and norgestrel
WarfarinIncreases the INRMonitor the INR

No interaction with digoxin, fluconazole, ketoconazole

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6.7 Simvastatin

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneIncreases the risk of myopathyIncreases simvastain expoosureLimit the dose of simvastatin to 20 mg daily. Patients should be told to report any signs of myopathy or weakness
AmlodipineIncreases the risk of myopathyLimit the dose of simvastatin to 20 mg daily
ConivaptanIncreases the risk of myopathyAvoid the combination
DanazolIncreases the risk of myopathyAvoid the combination
DigoxinMonitor for potential digoxin toxicity
DiltiazemIncreases the risk of myopathyLimit the dose of simvastatin to 10 mg daily
DronedaroneIncreases the risk of myopathyLimit the dose of simvastatin to 10 mg daily
Fibrates (except fenofibrate)Increases the risk of myopathy/rhabdomyolysisLimit the dose of simvastatin to 10 mg daily. Avoid the combination with gemfibrozil
Immunosuppressant drugs:
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Increases the risk of myopathyAvoid the combination
Macrolide antibioticsIncreases the risk of myopathyAvoid the combination
NefazodoneIncreases the risk of myopathyAvoid the combination
Potent CYP3A4 inhibitorsIncrease the risk of myopathy/rhabdomyolysisAvoid the combination
RanolazineRanolazine inhibits CYP3A4 and increases the exposure to simvastatinThe maximum daily dose of simvastatin is 20 mg daily. Patients should be told to report any signs of myopathy or weakness
St John´s wortReduces the efficacy of simvastatinInduces CYP3A4 and decreases the exposure to simvastatin.Stop St John´s wort or increase the dose of simvastatin. No interaction with pravastatin
TicagrelorIncreases the exposure to simvastatinLimit the dose of simvastatin to 40 mg daily
VerapamilIncreases the risk of myopathyLimit the dose of simvastatin to 10 mg daily

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7. Microsomal triglyceride transfer protein (MTP) inhibitors

Lomitapide

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Bile Acid Sequestrants Bile acid sequestrants can interfere with the absorption of oral lomitapideAdministration of lomitapide and bile acid sequestrants should be separated by at least 4 h
Grapefruit juiceAvoid while taking lomitapide
Moderate CYP3A4 inhibitors:
- Aprepitant
- Ciprofloxacin
- Crizotinib
- Calcium channels blockers: Diltiazem, Verpamail
- HIV-protease inhibitors: Amprenavir, Atazanavir, Darunavir/ritonavir, Fosamprenavir
- Diltiazem
- Erythromycin
- Fluconazole
- Imatinib
The possible interaction has not been studies but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly
P-glycoprotein (P-gp) substrates:
- Aliskiren
- Ambrisentan
- Colchicine
- Dabigatran
- Digoxin
- Everolimus
- Fexofenadine
- Maraviroc
- Posaconazole
- Ranolazine
- Saxagliptin
- Sirolimu
- Sitagliptin
- Tyrosine kinase inhibitors: Imatinib, Lapatinib, Nilotinib,
- Tolvaptan
- Topotecan
Lomitapide inhibits P-glycoprotein (P-gp) and may increase the absorption of P-gp substratesDose reduction of the P-gp substrate should be considered when used concomitantly with lomitapide.
Statins:
- Simvastatin
Lomitapide approximately doubles the exposure of simvastatinLimit simvastatin dosage to 20 mg daily.
Reduce the dose of simvastatin by 50% when initiating the treatment with lomitapide
Strong CYP3A4 Inhibitors:
- Azole antifungals: Itraconazole, Ketoconazole, Posaconazole, Voriconazole
- Boceprevir
- Conivaptan
- HIV-protease inhibitors: Indinavir, Lopinavir/ritonavir, Nelfinavir, Ritonavir, Saquinavir, Telaprevir,
- Macrolides: Clarithromycin, telithromycin
- Nefazodone
Markedly increase lomitapide exposureAvoid the combination
Weak CYP3A4 inhibitors:
- Alprazolam
- Amiodarone
- Amlodipine
- Atorvastatin,
- Bicalutamide
- Cilostazol
- Cimetidine,
- Ciclosporin
- Fluoxetine
- Fluvoxamine
- Isoniazid
- Lapatinib
- Nilotinib
- Oral contraceptives
- Pazopanib
- Ranitidine
- Ranolazine
- Tipranavir/ritonavir
- Ticagrelor
- Zileuton
They increase lomitapide exposure approximately 2-foldLomitapide dosage should not exceed 30 mg daily when it is used concomitantly with weak CYP3A4 inhibitors
WarfarinLomitapide increases the INRLomitapide increases (30%) plasma concentrations of both R(+)- warfarin and S(-)-warfarinMonitor the INR, INR, particularly after any changes in lomitapide dosage

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8. Mipomersen

Antisense oligonucleotide anti apo-B100

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Hepatotoxic Drugs:
- Acetaminophen
- Alcohol
- Allopurinol
- Amiodarone
- Azole antifungals: Itraconazole, Ketoconazole
- Clopidogrel
- Enalapril
- Erythromycin
- Ibuprofen
- Isotretinoin
- Losartan
- Metotrexate
- NSAIDs
- Sulfonylureas: Glimepiride, Glipizide, Glyburide
- Tamoxifen
- Tetracyclines
Mipomersen increases hepatic fat (steatosis) with or without concomitant increases in transaminases. Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicityUse concomitantly with caution. Monitoring of LFTs may be warranted. Advise patients to promptly report symptoms of possible liver injury

There are no clinical interactions between mipomersen and ezetimibe, simvastatin or warfarin

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Abbreviations

AUC: area under the plasma drug concentration-time curv
CKD: chronic kidney disease
CYP: cytochrome P450 superfamily
ECG: electrocardiogram
HCV: Hepatitis C virus
HIV: human immunodeficiency virus
IgG: immunoglobulin G
INR: International Normalised Ratio
LDL-C: low density cholesterol
LFT: liver function test
MAOls: monoamino-oxidase (MAO) inhibitors
NSAIDs: nonsteroidal anti-inflammatory drugs
OATP: organic-anion-transporting polypeptide
PT: prothrombin time
SDC; serum digoxin concentrations
UGTA: uridine 5′-diphospho-glucuronosyltransferase
VKA: vitamin K antagonists.