ABSTRACT
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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Mechanism Precautions
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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Mechanism Precautions
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
