ISCHEMIC STROKE / PREVENTION

Statins and their interactions

David Goldemund M.D.
Updated on 11/07/2024, published on 19/10/2023

statins are competitive HMG-CoA reductase inhibitors that are effective in stroke prevention
interactions of statins with other drugs affect their metabolism and can be clinically serious; they may be responsible for up to nearly 60% of statin-related myopathy/rhabdomyolysis cases

Classification of drug interactions

interactions are, in general, divided into:
- pharmacodynamic (usually the interaction at the target receptor site)
  - less likely mechanism in statins because HMG-CoA reductase is a highly selective enzyme. There are no other known receptors for this enzyme, and statins inhibit this enzyme very selectively
- pharmacokinetic (the reaction between drugs during their pathway to the target site of action and elimination)
  - the vast majority of statin interactions are pharmacokinetic interactions at the level of metabolism (because statins are substrates of cytochrome P450 isoenzymes)

Pharmacokinetic interactions of statins

drugs that may interact with statins at the level of metabolism are either inhibitors or inducers of CYP450 enzymes
- statins are predominantly metabolized by two different P450 isoforms, CYP3A4 and CYP2C9
  - lipophilic statins lovastatin, simvastatin, and atorvastatin – isoenzyme 3A4
  - fluvastatin and partially rosuvastatin (10%) – isoenzyme 2C9
- pravastatin and rosuvastatin are mainly excreted unchanged in feces and urine
the pharmacokinetic interactions of statins may also involve interactions at the level of glucuronidation and membrane transporters
- OATP1B1*5, OATP2B1 – organic anion transporting polypeptide
- MDR1 – multidrug resistance protein 1
- P-glycoprotein
- MRP2 – multidrug resistance-associated protein 2

	CYP2C9	CYP3A4	Pgp	OATP1B1	OATP1B3
atorvastatin		+	+	+
fluvastatin	+				+
lovastatin		+	+
pravastatin				+	+
rosuvastatin	+			+	+
simvastatin		+	+	+
OATP – organic anion-transporting polypeptide, Pgp – P-glycoprotein

The potency of P450 inhibitors taking part in statin metabolism

3A4 (3A5,3A7)

2C9

2C8

indinavir, nelfinavir, ritonavir, saquinavir

clarithromycin, erythromycin

cetoconasole, itraconasole

cyclosporin

erythromycin

fluconazole

verapamil

diltiazem

amiodaron

fluconazole

amiodaron

fenofibrate

fluvoxamine

sertraline

sulfamethoxazole

gemfibrozil

trimethoprim

strong inhibitor ~ 5-fold increase in plasma AUC or > 80% decrease in clearance
moderate inhibitor ~ 2-fold increase in plasma AUC or 50-80% decrease in clearance

Rosuvastatin

CYP2C9 Inhibitors (e.g., fluconazole, ketoconazole) – ↑ rosuvastatin plasma levels (⇒ myopathy)
fibrates (e.g., fenofibrate) – elevated risk of myopathy or rhabdomyolysis; avoid gemfibrozil
anticoagulants (e.g., warfarin) – increased bleeding risk
cyclosporine – avoid (↑ rosuvastatin plasma levels and risk of myopathy)
niacin – increased risk of myopathy
HIV protease inhibitors – altered rosuvastatin pharmacokinetics with increased risk of myopathy; max 10 mg or avoid
digoxin – increased digoxin levels
oral contraceptives – co-administration may increase ethinyl estradiol and norgestrel levels
alcohol – additive hepatotoxicity risk
macrolides – no significant interaction

Atorvastatin

CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) – ↑ atorvastatin plasma levels (⇒ myopathy) – avoid (or dose < 40mg)
CYP3A4 inducers (e.g., rifampin) – ↓ atorvastatin efficacy due to decreased plasma levels
anticoagulants (e.g., warfarin) – increased bleeding risk
fibrates (e.g., fenofibrate) – elevated risk of myopathy or rhabdomyolysis; avoid gemfibrozil
digoxin – elevated digoxin plasma levels when co-administered
calcium channel blockers (e.g., amlodipine) – potential for increased atorvastatin levels (⇒ myopathy), but may be used
amiodarone – ↑ atorvastatin levels (⇒ myopathy), low risk
HIV protease inhibitors – increased atorvastatin levels (⇒ myopathy); max 10 mg
macrolides – interaction with clarithromycin/erythromycin/telithromycin; atorvastatin is not contraindicated but should be used with caution

Simvastatin

CYP3A4 Inhibitors (e.g., itraconazole, ketoconazole, grapefruit juice) – ↑ simvastatin plasma levels (⇒ myopathy/rhabdomyolysis) – avoid
CYP3A4 Inducers (e.g., rifampin) – ↓ simvastatin efficacy due to decreased simvastatin levels
fibrates (e.g., gemfibrozil, fenofibrate) – ↑ risk of myopathy/rhabdomyolysis; avoid gemfibrozil
anticoagulants (e.g., warfarin) – ↑ bleeding risk
amiodarone – ↑ simvastatin plasma levels (⇒ myopathy/rhabdomyolysis); max dose 10 mg
calcium channel blockers (e.g., verapamil, amlodipine) – ↑ simvastatin levels (⇒ myopathy/rhabdomyolysis); max dose 10 mg or switch to atorvastatin
digoxin – slight elevation of digoxin plasma levels
HIV protease inhibitors – ↑ simvastatin plasma levels (⇒ myopathy/rhabdomyolysis) – contraindicated
alcohol – ↑ hepatotoxicity risk,
macrolides – significant interaction with clarithromycin/erythromycin/telithromycin ⇒ avoid

Statins and macrolide antibiotics

probably the most common statin interaction
the most serious interactions are with simvastatin/lovastatin + clarithromycin/erythromycin/telithromycin ⇒ avoid
- interaction with roxithromycin is less significant
the combination of atorvastatin+clarithromycin/erythromycin is not contraindicated; increased caution is advised; the interaction with azithromycin is clinically unlikely to be serious
drug interactions between macrolides and fluvastatin, rosuvastatin and pravastatin are not expected; patients should be monitored for symptoms of myopathy
a physician prescribing a macrolide antibiotic should actively seek to determine whether the patient is taking a statin
if the patient is taking simvastatin/lovastatin:
- prescribe a macrolide other than clarithromycin (azithromycin)
- indicate a completely different antibiotic
- replace or temporarily discontinue statin

Statins and calcium blockers

calcium blockers like diltiazem and verapamil inhibit CYP3A4 and P-glycoprotein, which can increase the availability of statins
- simvastatin and lovastatin can have their AUC increased by 3-8 fold
verapamil or diltiazem: maximal dose of simvastatin 10 mg or switch to fluvastatin, rosuvastatin, or atorvastatin
amlodipine: maximal dose of simvastatin 20 mg or switch to a statin with lower interaction potential
when combining atorvastatin with diltiazem, close monitoring for signs of rhabdomyolysis is advised

Statins and HIV protease inhibitors

HIV protease inhibitors (such as saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir) are potent inhibitors of CYP3A4
- a 30-fold increase in simvastatin AUC has been demonstrated with ritonavir potentiated by saquinavir
fluvastatin and pravastatin (except in combination with darunavir) can be used without dose changes
atorvastatin can be given only in low doses (≤ 10 mg); careful monitoring and appropriate patient education are required
rosuvastatin therapy should start with low doses while monitoring the patient; some manufacturers recommend taking no more than 10 mg of rosuvastatin in combination with protease inhibitors
simvastatin and lovastatin are contraindicated when protease inhibitors are used

Statins and azole antifungal drugs

azole antifungal drugs (ketoconazole, itraconazole, fluconazole) are potent inhibitors of CYP3A4, increasing plasmatic levels of statins
avoid a combination of simvastatin/lovastatin/atorvastatin together with ketoconazole or itraconazole; their levels increase up to 20-fold); avoid such combination
- some manufacturers allow the use of atorvastatin ≤ 40 mg
fluvastatin, pravastatin, and rosuvastatin levels are not affected, or very little (up to 1.5-fold) ⇒ no clinical intervention is required

Statins and cyclosporine

interactions may increase statin levels (↑ risk of myalgia) and reduce the effect of cyclosporine
- these interactions are likely to occur through several mechanisms – inhibition of CYP3A4 (intestinal and hepatic), P-glycoprotein, and membrane transporters (OATP1B1, OATP2B1, MRP2)
cyclosporine increases up to 7-fold the AUC of rosuvastatin ⇒ co-administration of rosuvastatin and cyclosporine should be avoided
cyclosporine also increases plasma levels of other statins; concomitant use should be well-monitored
- simvastatin max 10 mg (or avoid according to some experts)
- atorvastatin/lovastatin/pravastin max 10 mg
simvastatin and atorvastatin decrease affect cyclosporine plasma levels (no effect on levels was observed with fluvastatin, lovastatin, and pravastatin)
closer monitoring of cyclosporine levels is recommended for statins

Statins and amiodarone

amiodarone is an inhibitor of both CYP3A4 and the CYP2C9 form and, therefore, interacts with statins metabolized by these cytochrome P450 isoforms
the most clinically relevant interactions with amiodarone are with simvastatin/lovastatin
- a maximum of 10 mg simvastatin and 40 mg lovastatin is recommended
when higher doses are indicated, it is recommended to switch to a “safer” statin (rosuvastatin, fluvastatin, pravastatin)
interaction with atorvastatin is not clinically significant

Statins and warfarin

statins can interact with warfarin via
- competition for metabolism on CYP3A4 (simvastatin)
- inhibition of S-warfarin metabolism on CYP2C9 (fluvastatin)
- unknown mechanism (rosuvastatin)
this interaction (not very serious) may result in an increase in INR as well as an increased risk of myopathy
it is recommended that INR, creatine kinase (CK), and myopathy symptoms be carefully monitored when starting, stopping, or changing any treatment with warfarin + simvastatin (or other statins)

Statins and other hypolipidemics

fibrates are increasingly used in combination with statins
this combination increases the risk of myopathy, which has mostly been observed in the first 12 weeks of co-administration; interactions with gemfibrozil are the most frequent and serious
multiple mechanisms are probably involved (pharmacodynamic and pharmacokinetic
cases of rhabdomyolysis have also been described with the use of bezafibrate, clofibrate, and fenofibrate alone

Statins and grapefruit

grapefruit and grapefruit juice are potent inhibitors of CYP3A4
one glass (200 ml) of juice and/or one-half of grapefruit is sufficient to reduce CYP3A4 activity by half (and increase simvastatin AUC 3-4 times)
the effect persists for at least 24 hours
patients taking simvastatin, lovastatin, or atorvastatin, which are preferentially metabolized by CYP3A4, should avoid consuming grapefruit, pomelo, or their juices (and replace it with orange juice)
patients may switch to fluvastatin, rosuvastatin, pitavastatin, pravastatin

Enzyme inducers and statins

enzyme inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort, barbiturates) may decrease the AUC of statins; the highest reductions were observed with simvastatin, lovastatin, and atorvastatin
if statins and enzyme inducers are used together, it is recommended to monitor the efficacy of statins and increase their dose if necessary
therapeutic options can also be considered to avoid the use of an inducer

Contraindicated and harmful combinations

Contraindicated combinations
simvastatin, lovastatin	ketoconazole, itraconazole, HIV protease inhibitors, clarithromycin (cyclosporine)
atorvastatin	HIV protease inhibitors
rosuvastatin	(cyclosporine)
Potentially harmful combinations
simvastatin, lovastatin	cyclosporine, erythromycin, roxithromycin, diltiazem, verapamil, fluconazole, voriconazole, amiodarone, fibrates (except for gemfibrozil), grapefruit
rosuvastatin	fluconazole, ciclosporine, fibrates, HIV protease inhibitors
atorvastatin	cyclosporine, fibrates, grapefruit
fluvastatin	fibrates (except for gemfibrozil)