chapter
Lipid-lowering drugs
Pages 10

Give the NSAID 1 hour before or 4-6 hours after colestyramine; however, meloxicam, piroxicam, sulindac and tenoxicam should not be given with colestyramine

ANION EXCHANGE RESINS PARACETAMOL Colestyramine ↓ paracetamol by 60% when they are given together

Colestyramine binds paracetamol in the intestine

Give colestyramine and paracetamol at least 1 hour apart

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CARDIOVASCULAR DRUGS LIPID-LOWERING DRUGS Anion exchange resins

Colestyramine binds amiodarone, reducing its absorption and interrupting its enterohepatic circulation

Avoid co-administration

ANION EXCHANGE RESINS ANTIBIOTICS

ANION EXCHANGE RESINS TETRACYCLINE ↓ levels of tetracycline and possible therapeutic failure

Tetracycline binds with colestipol and colestyramine in the gut therefore reducing its absorption

Dosing should be as separate as possible

ANION EXCHANGE RESINS VANCOMYCIN (ORAL) ↓ vancomycin levels Inhibition of absorption Separate doses as much as possible ANION EXCHANGE RESINS ANTICANCER AND IMMUNOMODULATING DRUGS

ANION EXCHANGE RESINS METHOTREXATE Parenteral methotrexate levels may be ↓ by colestyramine

Colestyramine interrupts the enterohepatic circulation of methotrexate

Avoid co-administration

ANION EXCHANGE RESINS MYCOPHENOLATE ↓ plasma concentrations of mycophenolate by approximately 40%. Risk of therapeutic failure

Due to interruption of enterohepatic circulation because of binding of recirculating mycophenolate with cholestyramine in the intestine

Avoid co-administration

ANION EXCHANGE RESINS LEFLUNOMIDE ↓ levels of leflunomide ↓ absorption Avoid co-administration ANION EXCHANGE RESINS ANTICOAGULANTS – ORAL ↓ anticoagulant effect with

colestyramine ↓ absorption of warfarin Give warfarin 1 hour before or

4-6 hours after colestyramine

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acarbose

Uncertain Monitor blood glucose during and co-administration and after discontinuation of concurrent therapy

ANION EXCHANGE RESINS SULPHONYLUREAS – GLIPIZIDE

Glipizide absorption may be ↓ by colestyramine

Colestyramine interrupts the enterohepatic circulation of glipizide

Avoid co-administration

ANION EXCHANGE RESINS CALCIUM CHANNEL BLOCKERS

Colestipol ↓ diltiazem levels Colestipol binds diltiazem in the intestine

Monitor for poor response to diltiazem. Separating doses of diltiazem and colestipol does not seem to ↓ this interaction

ANION EXCHANGE RESINS CARDIAC GLYCOSIDES Colestipol and colestyramine may ↓ digoxin and digitoxin levels

Both colestipol and colestyramine are ion exchange resins that bind bile sodiums and prevent reabsorption in the intestine; this breaks the enterohepatic cycle of digoxin and digitoxin

Colestipol and colestyramine should be given at least 1.5 hours after digoxin and digitoxin

ANION EXCHANGE RESINS DIURETICS Both colestipol and colestyramine markedly ↓ levels of loop diuretics and thiazides

Colestipol and colestyramine bind diuretics in the intestine

Give the anion exchange resin 3 hours after furosemide and 4 hours after thiazides (although the effect of hydrochlorothiazide may still be ↓ by colestyramine)

ANION EXCHANGE RESINS IRON – ORAL ↓ iron levels when iron is given orally with cholestyramine

↓ absorption Separate doses as much as possible – monitor FBC closely

ANION EXCHANGE RESINS LIPID-LOWERING DRUGS – STATINS

Anion-binding resins ↓ the absorption of statins, but the overall lipid-lowering effect is not altered

Anion-binding resins bind statins in the intestine

Giving the statin 1 hour before or 3-6 hours after the anion exchange resin should minimize this effect

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CARDIOVASCULAR DRUGS LIPID-LOWERING DRUGS Fibrates

Colestyramine interrupts the enterohepatic circulation of raloxifene

Avoid co-administration

ANION EXCHANGE RESINS THYROID HORMONES ↓ efficacy of thyroid hormones ↓ absorption Separate doses by at least 4-6 hours. Monitor TFTs

EZETIMIBE

EZETIMIBE ANTICANCER AND IMMUNOMODULATING DRUGS – CICLOSPORIN

≠ levels of both drugs when ezetimibe is co-administered with ciclosporin

Uncertain Watch for signs of ciclosporin toxicity

EZETIMIBE LIPID-LOWERING DRUGS Risk of gallstones with fibrates Uncertain Stop co-administration if symptoms develop

FIBRATES

FIBRATES ANTACIDS Gemfibrozil levels may be ↓ by antacids

Uncertain Give gemfibrozil 1-2 hours before the antacid

FIBRATES ANTIBIOTICS – DAPTOMYCIN

Risk of myopathy Additive effect Avoid co-administration

FIBRATES ANTICANCER AND IMMUNOMODULATING DRUGS

GEMFIBROZIL CYTOTOXICS – BEXAROTENE

Gemfibrozil may ≠ bexarotene levels

Uncertain at present Avoid co-administration

FIBRATES IMMUNOMODULATING DRUGS – CICLOSPORIN

≠ risk with renal failure Uncertain at present Monitor renal function closely

FIBRATES ANTICOAGULANTS – ORAL ≠ efficacy of warfarin and phenindione

Uncertain; postulated that fibrates displace anticoagulants from their binding sites

Monitor INR closely

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TOLBUTAMIDE

sulphonylureas

Uncertain; postulated that fibrates displace sulphonylureas from plasma proteins and ↓ their hepatic metabolism. In addition, fenofibrate may inhibit CYP2C9mediated metabolism of tolbutamide

Monitor blood glucose levels closely

GEMFIBROZIL REPAGLINIDE Nearly eightfold ≠ in repaglinide levels, with risk of severe hypoglycaemia. Risk of severe and prolonged hypoglycaemia

Hepatic metabolism inhibited The European Agency for the Evaluation of Medicinal Products contraindicated concurrent use in 2003. Bezafibrate and fenofibrate are suitable alternatives if a fibric acid derivative is required

GEMFIBROZIL ROSIGLITAZONE ≠ in blood levels of rosiglitazone – often doubled

Gemfibrozil is a relatively selective inhibitor of CYP2C8

Watch for hypoglycaemic events and ↓ the dose of rosiglitazone after repeated blood sugar measurements. Warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

FIBRATES ANTIEPILEPTICS Gemfibrozil may≠ carbamazepine levels

Uncertain at present Watch for features of carbamazepine toxicity

FIBRATES LIPID-LOWERING DRUGS

FIBRATES EZETIMIBE Risk of gallstones with fibrates Uncertain Stop co-administration if symptoms develop

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CARDIOVASCULAR DRUGS LIPID-LOWERING DRUGS Statins

Uncertain Avoid co-administration of simvastatin and gemfibrozil. When using other statins, warn patients to watch for the features of myopathy

STATINS

SIMVASTATIN ANTIARRHYTHMICS – AMIODARONE

≠ risk of myopathy with high doses (40 mg) of simvastatin coadministered with amiodarone

Uncertain; amiodarone inhibits intestinal P-gp, which may ≠ the bioavailability of statins

Avoid20 mg doses of simvastatin in patients taking amiodarone; if higher doses are required, switch to an alternative statin

STATINS ANTIBIOTICS

FIBRATES ANTIBIOTICS – DAPTOMYCIN Risk of myopathy Additive effect Avoid co-administration

STATINS FUSIDIC ACID Cases of rhabdomyolysis reported when fusidic acid was co-administered with atorvastatin or simvastatin

Uncertain at present Monitor LFTs and CK closely; warn patients to report any features of rhabdomyolysis

ATORVASTATIN, SIMVASTATIN

MACROLIDES Macrolides may ≠ levels of atorvastatin and simvastatin; the risk of myopathy ≠ over 10-fold when erythromycin is co-administered with a statin

Macrolides inhibit CYP3A4mediated metabolism of atorvastatin and simvastatin. Also, erythromycin and clarithromycin inhibit intestinal P-gp, which may ≠ the bioavailability of statins

Avoid co-administration of macrolides with atorvastatin or simvastatin (temporarily stop the statin if the patient needs macrolide therapy). Manufacturers also recommend that patients be warned to look for the early signs of rhabdomyolysis when other statins are co-ingested with macrolides

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Uncertain Avoid chronic co-administration

STATINS RIFAMPICIN Rifampicin may lower fluvastatin and simvastatin levels

Uncertain Monitor lipid profile closely; look for poor response to fluvastatin and simvastatin

STATINS ANTICANCER AND IMMUNOMODULATING DRUGS

SIMVASTATIN DASATINIB Possible ↓ simvastatin levels ≠ metabolism of simvastatin Monitor lipid profile closely and adjust simvastatin dose accordingly when starting and stopping co-administration

ATORVASTATIN, SIMVASTATIN

IMATINIB Imatinib may ≠ atorvastatin and simvastatin levels

Imatinib inhibits CYP3A4mediated metabolism of simvastatin

Monitor LFTs, U&Es and CK closely

STATINS – ATORVASTATIN, LOVASTATIN, ROSUVASTATIN, SIMVASTATIN

CICLOSPORIN ≠ plasma concentrations of these statins, with risk of myopathy and rhabdomyolysis

Ciclosporin is a moderate inhibitor of CYP3A4, which metabolizes these statins

↓ statins to lowest possible dose (do not give simvastatin in doses 10 mg). Monitor LFTs and CK closely; warn patients to report any features of rhabdomyolysis. This interaction does not occur with pravastatin

STATINS TACROLIMUS Single case report of rhabdomyolysis when was simvastatin added to tacrolimus

Uncertain at present Monitor LFTs and CK closely; warn patients to report any features of rhabdomyolysis

STATINS ANTICOAGULANTS – ORAL Possible ≠ anticoagulant effect with fluvastatin and simvastatin

Uncertain; possibly due to inhibition of CYP2C9-mediated metabolism of warfarin

Monitor INR closely

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CARDIOVASCULAR DRUGS LIPID-LOWERING DRUGS Statins

Uncertain at present Monitor lipid profile closely; look for poor response to simvastatin

STATINS NATEGLINIDE, REPAGLINIDE

≠ incidence of adverse effects such as myalgia. There was an ≠ in maximum concentration of repaglinide by 25% with high variability

Uncertain. Statins are also substrates for CYP3A4, and competition for metabolism by the enzyme system may be a factor

Clinical significance is uncertain, but it is necessary to be aware of this. Warn patients about the adverse effects of statins and repaglinide

EZETIMIBE, SIMVASTATIN REPAGLINIDE ≠ repaglinide levels, risk of hypoglycaemia

Hepatic metabolism is inhibited Watch for and warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

STATINS ANTIFUNGALS Azoles markedly ≠ atorvastatin, simvastatin (both with cases of myopathy reported) and possibly pravastatin. These effects are less likely with fluvastatin and rosuvastatin, although fluconazole may cause moderate rises in their levels

Itraconazole and ketoconazole inhibit CYP3A4-mediated metabolism of these statins; they also inhibit intestinal P-gp, which ≠ the bioavailability of statins; itraconazole may block the transport of atorvastatin due to inhibition of the OATP1B1 enzyme system. Some manufacturers suggest that the small ≠ in plasma levels of pravastatin may be due to ≠ absorption. Voriconazole is an inhibitor of CYP2C9. Fluconazole inhibits CYP2C9 and CYP3A4

Avoid co-administration of simvastatin and atorvastatin with azole antifungals. Care should be taken with co-administration of other statins and azoles. Although fluvastatin and rosuvastatin may be considered as alternatives, consider reducing the dose of statin and warn patients to report any features of rhabdomyolysis. Check LFTs and CK regularly

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ANTIHYPERTENSIVES

Uncertain; bosentan moderately inhibits CYP3A4

Monitor lipid profile closely; look for poor response to simvastatin

STATINS ANTIPLATELET AGENTS – CLOPIDOGREL

Atorvastatin and possibly simvastatin ↓ the antiplatelet effect of clopidogrel in a dosedependent manner

Atorvastatin and simvastatin inhibit CYP3A4-mediated activation of clopidogrel

Use these statins at the lowest possible dose; otherwise consider using an alternative statin

STATINS ANTIVIRALS

STATINS NNRTIs ↓ levels of atorvastatin, pravastatin and simvastatin with efavirenz

Uncertain; efavirenz is known to induce intestinal P-gp, which may ↓ the bioavailability of some statins (including atorvastatin)

Monitor lipid profile closely

ATORVASTATIN PROTEASE INHIBITORS ≠ efficacy and ≠ risk of adverse effects of atorvastatin

Inhibition of CYP3A4-mediated metabolism of atorvastatin

Use with caution: monitor for atorvastatin toxicity; monitor CK. Inform patient and ↓ dose if necessary or start with 10 mg once daily. Use the lowest dose possible to attain target low-density lipoprotein reduction. Alternatives are pravastatin or fluvastatin

LOVASTATIN, SIMVASTATIN

PROTEASE INHIBITORS ≠ risk of adverse effects Inhibition of CYP3A4-mediated metabolism of simvastatin

Avoid co-administration

STATINS CALCIUM CHANNEL BLOCKERS

≠ plasma levels of atorvastatin, lovastatin and simvastatin; case reports of myopathy when atorvastatin and simvastatin are co-administered with diltiazem or verapamil

Uncertain, but postulated to be due to inhibition of CYP3A4mediated metabolism of statins in the intestinal wall. Also, diltiazem and verapamil inhibit intestinal P-gp, which may ≠ the bioavailability of statins

Watch for side-effects of statins. It has been suggested that the dose of simvastatin should not exceed 20 mg when given with verapamil, and 40 mg when given with diltiazem

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CARDIOVASCULAR DRUGS LIPID-LOWERING DRUGS Statins

Atorvastatin inhibits intestinal P-gp, which ≠ digoxin absorption

Watch for digoxin toxicity

MODAFINIL

concentrations of fluvastatin if CYP2C9 is the predominant metabolic pathway and the alternative pathways are either genetically deficient or affected

Modafinil is a moderate inhibitor of CYP2C9

Be aware

STATINS GRAPEFRUIT JUICE ≠ levels with simvastatin; slight rise with atorvastatin. ≠ risk of adverse effects such as myopathy

Constituent of grapefruit juice inhibits CYP3A4-mediated metabolism of simvastatin

Patients taking simvastatin and atorvastatin should avoid grapefruit juice

STATINS LIPID-LOWERING DRUGS

STATINS ANION EXCHANGE RESINS Anion-binding resins ↓ the absorption of statins, but the overall lipid-lowering effect is not altered

Anion-binding resins bind statins in the intestine

Giving the statin 1 hour before or 3-6 hours after the anion exchange resin should minimize this effect

STATINS FIBRATES Gemfibrozil may ≠ atorvastatin, rosuvastatin and simvastatin levels, with risk of myopathy with simvastatin

Uncertain Avoid co-administration of simvastatin and fibrates. When using other statins, warn patients to watch for the features of myopathy

STATINS NICOTINIC ACID Slight risk of rhabdomyolysis Uncertain at present Monitor LFTs and CK closely; warn patients to report any features of rhabdomyolysis

STATINS PROTON PUMP INHIBITORS Possible ≠ efficacy and adverse effects of atorvastatin

Inhibition of P-gp, reducing firstpass clearance

Monitor closely