Alexandra Darrow
Coumadin (warfarin sodium)
Boxed warning: There is a warning for bleeding risk as Coumadin (warfarin sodium) has the potential to cause major or even fatal bleeding. In order to prevent this from happening, regular monitoring of INR (international normalized ratio) should be performed. INR’s are used to measure how long it takes blood to clot. In addition to this, physicians should notify patients as to how they should prevent the risk of bleeding and importance of notifying them if they have any symptoms.
Indications and Usage: warfarin is used to prevent and treat:
1. Venous thrombosis (blood clot that develops in a vein) and following this, pulmonary embolism (blood clot that blocks a lung artery)
2. Migrated blood clots that are associated with atrial fibrillation and/or cardiac valve replacement
Contraindications: warfarin is contraindicated in the following cases:
1. warfarin is contraindicated for women who are pregnant. This does not include women who are pregnant and have mechanical heart valves. When taking warfarin while pregnant, the mother can experience miscarriage and fatal mortality. The fetus can also be harmed and this can result in fetal deformations.
2. Patients who are unlikely to follow dosage directions and will not take their medicine as prescribed
3. Hypersensitivity to warfarin
4. Bleeding tendencies
Warnings and Precautions:
1. Hemorrhage: It’s important to monitor patients INR’s frequently because major or even fatal bleeding can be caused by warfarin. There are certain risk factors that make patients more likely to experience this, such as an INR>4.0 or the patient being over 65. It is also important to take frequent INRs because dietary changes can affect the patients INR results. Bleeding is most likely to occur in the first month so this is a critical time to monitor the patient.
2. Tissue Necrosis: While this is unlikely (<0.1%), it is possible that the patient could experience tissue necrosis or gangrene. If this occurs, the patient should stop using the drug immediately because there isn’t a known treatment for necrosis.
3. Use in Pregnant Women with Mechanical Heart Valves: While it is not recommended that women who are pregnant use warfarin, it is possible that the benefits outweigh the risks for women who are pregnant and have mechanical heart valves. warfarin has the potential to cause major congenital malformations and it is more likely that the mother will have a miscarriage. Doctor’s should discuss all of the possible risks with the mother to make sure she understands before beginning use of warfarin.
4. Endogenous Factors Affecting INR: There are certain factors that can affect INR results. These are listed below.
a. Increased INR results: Vitamin K deficiency, poor nutrition, diarrhea
b. Decreased INR results: Increased vitamin K intake
Drug Interactions:
1. CYP450 Interactions: The CYP450 enzymes that affect the metabolism of warfarin include: CYP2C9, CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4. Inhibitors and inducers of CYP2C9, CYP1A2, and/or CYP3A4 can either increase (inducer) or decrease (inhibitor) the effects of warfarin. Some examples of inhibitors and inducers CYP2C9, CYP1A2, and CYP3A4 are below.
a. Enzyme:
i. CYP2C9
1. Inhibitors: amiodarone, cotrimoxazole, etravirine, fluconazole, fluvastatin
2. Inducers: aprepitant, bosentan, carbamazepine, rifampin
ii. CYP1A2
1. Inhibitors: caffeine, ciprofloxacin, disulfiram, oral contraceptives, terbinafine
2. Inducers: moricizine, phenytoin, cigarette smoking
iii. CYP3A4
1. Inhibitors: amiodarone, atazanavir, ciprofloxacin, fluoxetine, nelfinavir, ritonavir
2. Inducers: aprepitant, modafinil, rifampin, fuinamide
2. Drugs that Increase Bleeding Risk: Examples of drugs that have the potential to increase bleeding risk in patients taking warfarin are listed below.
a. Drug class:
i. Anticoagulants: argatroban, desirudin, heparin
ii. Antiplatelet Agents: aspirin, cilostazol, dipyridamole, ticlopidine
iii. Nonsteroidal Anti-Inflammatory Agents: ibuprofen, ketoprofen, naproxen, oxaprozin
iv. Serotonin Reuptake Inhibitors: citalopram, fluvoxamine, paroxetine, vilazodone
3. Antibiotics and Antifungals: While clinical pharmacokinetic studies have not been able to provide concrete evidence that antibiotics and antifungals affect the plasma concentrations of warfarin, it is important to monitor the patients INR frequently while starting or stopping antibiotic or antifungal drug usage.
4. Botanical (Herbal Products and Foods): Due to the fact that herbal supplement companies can essentially regulate themselves, the amount of an active ingredient in a specific supplement can vary from brand to brand. Because of this, care should be taken when trying these due to the possibility of increased bleeding risk. Garlic and Ginkgo biloba can cause bleeding when taken by themselves so these should not be taken with warfarin. This is because they both have anticoagulant effects that could cause major bleeding. In addition to this, co-enzyme Q10, and St. John’s Wort ginseng can decrease the effects of warfarin. Just like with antibiotics and antifungal use, INR’s should be monitored when starting or stopping botanical usage.
Use in Specific Populations:
1. Pregnancy: warfarin is a Pregnancy Category D for women who have mechanical heart valves (due to the fact that benefits can outweigh risks), and it’s a Pregnancy Category X for other pregnant women. It is not recommended for use in pregnant women due to the possible risks to the fetus.
2. Geriatric Use: INR responses for patients 60 years and older were higher than expected so the drug is contraindicated in patients who are senile and unsupervised. Patients with higher risk of hemorrhage should also be closely monitored.
3. Hepatic Impairment: If a patient has liver impairment, caution should be taken when taking warfarin. This is because liver impairment can lower the metabolism of the drug and impair the creation of clotting factors.
4. Females of Reproductive Potential: Due to the fact that warfarin can cause spontaneous abortion, fetal death, and birth defects, doctors should warn women of the potential risks of becoming pregnant while taking warfarin.
Clinical Pharmacology:
1. Mechanism of Action: warfarin essentially works against vitamin K to try to ensure that blood clots at a slower rate than it normally would. It does this by inhibiting the production of clotting factors that are vitamin K dependent, and it does this in the liver. Vitamin K acts to aid blood in clotting, and this is usually advantageous because then reduced amounts of blood are lost.
2. Pharmacodynamics: The anticoagulant effects of warfarin usually occur within 24 hours after taking the medication but these effects can also occur 72-96 hours after administration. This is most likely where they decided that patients who forget a dose should take it as soon as possible once they remember but they shouldn’t take two doses in one day.
3. Pharmacodynamics:
a. Absorption: The peak concentration of warfarin occurs about 4 hours after a patient takes their dose.
b. Metabolism: warfarin is metabolized by CYP450. This is probably where researchers found drug interactions since the drug is metabolized by CYP450 enzymes
c. Excretion: Up to 92% of the dosage that a patient took is excreted in the urine
d. Geriatric patients: Geriatric patients have been found to be more sensitive to the anticoagulant effects of warfarin. This could be caused by multiple factors, such as pharmacokinetics and pharmacodynamics. This affects patients over 60 years old and can cause them to have an increased INR response
Nonclinical Toxicology: There have not been any studies on carcinogenicity, mutagenicity, or fertility studies for warfarin.
Clinical Studies:
1. Atrial Fibrillation: warfarin greatly reduced the chances of systemic thromboembolism in five, randomized clinical trials which included 3711 patients. These patients had non-rheumatic atrial fibrillation. The risk was reduced 60-86%.
2. Mechanical and Bioprosthetic Heart Valves: In randomized studies on about 200 patients, patients who were given high intensity INR (INR 9.0), major bleeding events were more common than a lower intensity group (INR 2.65).
3. Myocardial Infarction: In studies of patients who were hospitalized for acute myocardial infarction, it was found that major bleeding events were four times more likely in patients taking warfarin that solely aspirin.
These clinical studies help to show where the risk of major bleeding comes from and the information on mechanical heart valves.