Warfarin with Simvastatin Interaction Details

Brand Names Associated with Warfarin

Brand Names Associated with Simvastatin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 10, 2023

Interaction Effect

Increased risk of bleeding and an increased risk of rhabdomyolysis

Interaction Summary

Concomitant administration of simvastatin and warfarin resulted in increases in INR, and was associated with rhabdomyolysis and acute renal failure as described in a case report . In a cohort study, addition of simvastatin to a previously stable dose regimen of warfarin produced clinically significant increases in INR values that required warfarin dose adjustments to maintain target INR . In patients taking coumarin anticoagulants, obtain an INR before starting simvastatin and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concurrent use of simvastatin and coumarin anticoagulants may increase INR. In patients taking coumarin anticoagulants, obtain an INR before starting simvastatin and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.

Mechanism Of Interaction

Competition for CYP3A4-mediated metabolism

Literature Reports

A) Coadministration of simvastatin with warfarin provoked substantial increases in the international normalized ratio (INR) values of patients previously receiving stable doses of warfarin. In a cohort study, patients (n=29) having stable warfarin dose requirements for at least 3 prior clinic visits (time frame unspecified) were evaluated for changes in INR after beginning concomitant treatment with simvastatin. INR values were recorded just prior to beginning simvastatin therapy, at the clinic visit immediately following initiation of simvastatin, and the daily warfarin dose requirement was monitored until a stable dose requirement was achieved over the extent of 3 consecutive clinic visits. After the start of simvastatin therapy, mean INR values (baseline of 2.5) increased by 27% (to 3.15) and the mean required warfarin dose was reduced by 9% (from 4.2 milligrams (mg) to 3.8. mg daily) .

B) A 61-year-old male on warfarin therapy for five years was started on simvastatin for hypercholesterolemia. Four months later, he experienced a minimal head trauma and two weeks later complained of a severe headache and a stiff neck. An MRI revealed bilateral subdural hematoma. The hematoma was attributed to the increased anticoagulatory effect of warfarin caused by simvastatin .

C) An 82-year-old male patient was admitted to the hospital with complaints of bilateral lower extremity myalgia and weakness with a duration of seven days. He was stabilized on furosemide, digoxin, potassium, and simvastatin 20 mg daily for the past 18 months. One week before admission, warfarin 5 mg daily was initiated for deep venous thrombosis. Laboratory results on admission revealed acute renal failure (serum creatinine 3.4 mg/dL [301 mcmol/L]), hyperkalemia (8.2 mEq/L [8.2 mmol/L]), an elevated international normalized ratio (4.3), and a serum creatine phosphokinase of 785 U/L. Simvastatin was discontinued while his renal failure and hyperkalemia were appropriately managed, and laboratory abnormalities and symptoms resolved within five days. Because this patient's symptoms disappeared upon the discontinuation of simvastatin, the acute renal failure and rhabdomyolysis were attributed to an interaction between warfarin and simvastatin, possibly because of competition for cytochrome P450 3A4-mediated metabolism .

D) In 2 clinical studies, 1 in hypercholesterolemic patients and the other in healthy volunteers, simvastatin 20 to 40 mg daily increased the effect of coumarin anticoagulants; 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 .

E) A case report detailed a significant increase in INR 4 weeks after switching from oral atorvastatin 10 mg once daily to oral simvastatin 10 mg once daily in an 82-year-old Caucasian female. The patient had been stable on 2.5 mg of oral warfarin for 2 years prior to incident (therapeutic INR range, 2.0 – 3.5) and had been taking warfarin for 30 years because of several episodes of deep venous thrombosis and one episode of lung embolism. A routine anticoagulant follow-up visit 4 weeks after she started simvastatin found her INR to be above the detection range of the equipment (greater than 8). The patient denied taking any additional medications and reported being compliant with her warfarin regimen. Comorbidities included polycythemia, intermittent claudication, migraines, gout, glaucoma, and hypertension. Her hypertension was untreated due to a history of syncope while on antihypertensives. Her only other medication was oral aspirin 75 mg/day for 9 years due to an episode of transient ischemic attack and a cerebral infarction. Her reported blood pressure (BP) at presentation was 198/118 millimeters of Mercury (mmHg). She was given 5 mg of oral vitamin K and placed on bed rest. A few hours later the patient suffered a left cerebral hemorrhage with a reported systolic BP of 220 mg Hg and died shortly thereafter. The Naranjo probability scale indicated that the reaction was probably caused by a warfarin-simvastatin interaction. Among possible mechanisms, simvastatin adversely affecting the metabolism of warfarin was suggested as well as the unique sensitivity of this patient to changes in warfarin metabolism (as evidenced by her very low dose of warfarin) .

Warfarin Overview

• Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

Simvastatin Overview

• Simvastatin is used together with diet, weight-loss, and exercise to reduce the risk of heart attack and stroke and to decrease the chance that heart surgery will be needed in people who have heart disease or who are at risk of developing heart disease. Simvastatin is also used to decrease the amount of fatty substances such as low-density lipoprotein (LDL) cholesterol (''bad cholesterol'') and triglycerides in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol (''good cholesterol'') in the blood. Simvastatin may also be used to decrease the amount of cholesterol and other fatty substances in the blood in children and teenagers 10 to 17 years of age who have familial heterozygous hypercholesterolemia (an inherited condition in which cholesterol cannot be removed from the body normally). Simvastatin is in a class of medications called HMG-CoA reductase inhibitors (statins). It works by slowing the production of cholesterol in the body to decrease the amount of cholesterol that may build up on the walls of the arteries and block blood flow to the heart, brain, and other parts of the body.

• Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats with simvastatin has been shown to prevent heart disease, angina (chest pain), strokes, and heart attacks.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.