Prescription Drug Information: Warfarin Sodium (Page 4 of 6)

8.3 Females and Males of Reproductive Potential

Pregnancy Testing
Warfarin sodium can cause fetal harm [see Use in Specific Populations (8.1)].
Verify the pregnancy status of females of reproductive potential prior to initiating warfarin sodium therapy.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment, and for at least 1 month after the final dose of warfarin sodium.

8.4 Pediatric Use

Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin sodium should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

8.5 Geriatric Use

Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology ( 12.3)]. Warfarin sodium tablets are contraindicated in any unsupervised patient with senility. Observe caution with administration of warfarin sodium to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of warfarin sodium in elderly patients [see Dosage and Administration ( 2.2, 2.3)].

8.6 Renal Impairment

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment.

8.7 Hepatic Impairment

Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using warfarin sodium in these patients.

10 OVERDOSAGE

10.1 Signs and Symptoms

Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.

10.2 Treatment

The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of warfarin sodium anticoagulation may be obtained by discontinuing warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K 1 .

The use of vitamin K 1 reduces response to subsequent warfarin sodium therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of warfarin sodium administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of warfarin sodium is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.

11 DESCRIPTION

Warfarin sodium, USP is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α- acetonylbenzyl)-4-hydroxycoumarin sodium salt, and is a racemic mixture of the R — and S -enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its molecular formula is C 19 H 15 NaO 4 , and its structural formula is represented by the following:

warfarin-structure
(click image for full-size original)

Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether.

Each warfarin sodium tablet, USP intended for oral administration contains warfarin sodium clathrates equivalent to 1 mg or 2 mg or 2.5 mg or 3 mg or 4 mg or 5 mg or 6 mg or 7.5 mg or 10 mg of warfarin sodium. In addition each tablet contains the inactive ingredients lactose monohydrate, starch, pregelatinised starch, hydroxypropyl cellulose, starlac and magnesium stearate. Additionally each

1 mg tablet contains: D&C Red #30 aluminum lake

2 mg tablet contains: FD&C Red #40 aluminum lake and FD&C Blue#2

2.5 mg tablet contains: D&C Yellow # 10 aluminum lake and FD&C Blue#2

3 mg tablet contains: FD&C Yellow # 6 aluminum lake, FD&C Blue#2 and FD&C R ed # 40 aluminum lake

4 mg tablet contains: FD&C Blue#2

5 mg tablet contains: FD&C Yellow # 6 aluminum lake

6 mg tablet contains: FD&C Yellow # 6 aluminum lake and FD&C Blue #2

7.5 mg tablet contains: D&C Yellow # 10 aluminum lake and FD&C Yellow # 6 aluminum lake

10 mg tablet is dye free .

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ -carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Clinical Pharmacology ( 12.5)].

12.2 Pharmacodynamics

An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of warfarin sodium may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin K-dependent clotting factors and anticoagulation proteins: Factor II — 60 hours, VII — 4 to 6 hours, IX — 24 hours, X — 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.

12.3 Pharmacokinetics

Warfarin sodium is a racemic mixture of the R — and S -enantiomers of warfarin. The S -enantiomer exhibits 2 to 5 times more anticoagulant activity than the R -enantiomer in humans, but generally has a more rapid clearance.

Absorption

Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first four hours.

Distribution

Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4’-, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance [see Clinical Pharmacology( 12.5)].

Excretion

The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radio labeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Geriatric Patients

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation [see Dosage and Administration ( 2.3, 2.4) ].

Asian Patients

Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age.

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