Warfarin Sodium (Page 5 of 10)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D for women with mechanical heart valves [see Warnings and Precautions (5.5)] and Pregnancy Category X for other pregnant populations [see Contraindications (4)].

Warfarin is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin may outweigh the risks. Warfarin can cause fetal harm when administered to a pregnant woman. Warfarin exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of warfarin have not been evaluated in animals. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4) and Warnings and Precautions (5.6)].

8.3 Nursing Mothers

Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, six nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other nine nursing infants. Monitor breast-feeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when warfarin is administered to a nursing woman.

8.4 Pediatric Use

Adequate and well controlled studies with warfarin have not been conducted in any pediatric population, and the optimum dosing, safety and efficacy in pediatric patients is unknown. Pediatric use of warfarin is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin 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, 1,885 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 is contraindicated in any unsupervised patient with senility. Observe caution with administration of warfarin 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 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 in these patients.

8.8 Females of Reproductive Potential

Warfarin exposure during pregnancy can cause spontaneous abortion, birth defects or fetal death. Females of reproductive potential who are candidates for warfarin therapy should be counseled regarding the benefits of therapy and potential reproductive risks. Discuss pregnancy planning with females of reproductive potential who are on warfarin therapy. If the patient becomes pregnant while taking warfarin, she should be apprised of the potential risks to the fetus.

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 anticoagulation may be obtained by discontinuing warfarin therapy and, if necessary, by administration of oral or parenteral vitamin K1 .

The use of vitamin K1 reduces response to subsequent warfarin therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of warfarin 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 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 overdosage.

11 DESCRIPTION

Warfarin sodium (crystalline) is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S- enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its molecular formula is C19 H15 NaO4 , and its structural formula is represented by the following:

Warfarin Structural Formula

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.

Warfarin sodium tablets, USP for oral administration contain either 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg or 10 mg warfarin sodium, USP. In addition they also contain the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, stearic acid and,

1 mg tablets: FD&C Red No. 40 Aluminum Lake

2 mg tablets: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake

2.5 mg tablets: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake

3 mg tablets: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake

4 mg tablets: FD&C Blue No. 1 Aluminum Lake

5 mg tablets: FD&C Yellow No. 6 Aluminum Lake

6 mg tablets: FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake

7.5 mg tablets: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake

10 mg tablets: Dye Free

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