Melphalan

Class: Antineoplastic Agents
VA Class: AN100
CAS Number: 148-82-3
Brands: Alkeran

• Experience of Supervising Clinician


• 
  

  For administration only by individuals experienced in the administration of chemotherapeutic agents.^{b c}

  
  
  • Hematologic Toxicity
  
  
  • 
    

    Risk of severe bone marrow suppression (e.g., thrombocytopenia, leukopenia), resulting in bleeding and infection.^{b c} (See Hematologic Effects under Cautions.)

    
    
  
  
  • Mutagenicity and Carcinogenicity
  
  
  • 
    

    Known carcinogen.^{b c} (See Mutagenicity and Carcinogenicity under Cautions.)

    
    
  
  
  • 
    

    Produces chromosomal aberrations in vitro and in vivo; considered potentially mutagenic in humans.^{b c} (See Mutagenicity and Carcinogenicity under Cautions.)

    
    
  
  
  • Hypersensitivity Reactions
  
  
  • 
    

    Hypersensitivity reactions, including anaphylaxis, reported.^c

    
    
  
  

Introduction

Antineoplastic agent; nitrogen mustard derivative; alkylating agent.^{a b c}

Uses for Melphalan

Multiple Myeloma

Used alone and as a component of various chemotherapeutic regimens in the palliative treatment of multiple myeloma.^{a b c}

As effective as cyclophosphamide; combination of either agent with prednisone is considered treatment of choice.^{a d}

Ovarian Cancer

Palliative treatment of nonresectable epithelial ovarian cancer.^{113 122 b}

Has been administered intraperitoneally† for treatment of advanced ovarian cancer confined to the peritoneal cavity and/or associated with malignant ascites.¹⁰¹

Breast Cancer

Has been used alone or as a component of various chemotherapeutic regimens as an adjunct to surgery in the treatment of breast cancer†.^{134 135 136 138 139 a}

Melanoma

Has been used alone and in combination regimens in isolated limb perfusion† for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma† of the extremities.^{144 145 146 148}

Amyloidosis

Has been used with prednisone in the treatment of amyloidosis†.¹⁴¹

Melphalan Dosage and Administration

General

• 
  

  Adjust dosage carefully according to clinical and hematologic response, based on weekly blood counts, and tolerance of the patient to obtain optimum therapeutic results with minimum adverse effects.^{a b}

  
  


• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{106 b c}

  
  

Administration

Administer orally or by IV infusion.^{b c}

Has been administered by regional isolation perfusion† (e.g., for melanoma†)^{144 145 146 148 149} and intraperitoneally† (e.g., for advanced ovarian cancer).¹⁰¹

Usually administered orally;^{113 123 124 125 126 127 b} however, can also be administered IV in the palliative treatment of multiple myeloma^{106 114 115 116 117 118 120} in patients in whom oral therapy is not feasible.^{106 118 120 c}

Oral Administration

Administer orally on an empty stomach.¹⁰⁸

Administer continuously (as single daily doses) or intermittently (e.g., daily for 7 days every 4–6 weeks).^{a b}

IV Administration

For drug compatibility information, see Compatibility under Stability.

Administer IV only by individuals experienced in the administration of the drug.^{a c}

Administer diluted solution slowly into a freely running IV infusion via an injection port or into a central venous line.^c

Avoid extravasation; do not administer by direct injection into a peripheral vein.^c (See Local Effects under Cautions.)

Handle cautiously (e.g., use protective gloves);^c avoid exposure during handling and preparation of IV solution.^c If skin or mucosal contact occurs, immediately wash skin or mucosa with soap and water and flush with water.^c

Reconstitution

Reconstitute vial containing 50 mg of melphalan by rapidly adding 10 mL of the diluent provided by the manufacturer with a 20-gauge or larger needle to provide a solution containing 5 mg/mL.^{106 118 119 c}

Shake vigorously until a clear solution is obtained.^{106 118 119 c} Must be diluted (immediately after reconstitution) prior to IV infusion.^a

Dilution

Immediately dilute reconstituted solution with 0.9% sodium chloride injection to a concentration not >0.45 mg/mL.^{106 118 119 c}

Rate of Administration

Administer by IV infusion over >15 minutes.^{106 119 120 c} Administration should be completed within 60 minutes of reconstitution.^{106 119 c}

Dosage

Available as melphalan and melphalan hydrochloride; dosage expressed in terms of melphalan.^{106 b c}

Consult published protocols for the dosage of melphalan and other chemotherapeutic agents and the method and sequence of administration.^a

Consider dosage adjustments based on the blood cell nadir and blood counts taken on the day of therapy.^{106 113 119} Generally, maintain leukocyte count between 3000–3500/mm³.^b

Therapeutic response may occur gradually over several months.^b 3–12 months of repeated courses or continuous therapy may be required to evaluate drug response and obtain maximum benefit from the drug.^{a b}

Adults

Multiple Myeloma

Oral

Usual initial and maintenance dosage regimen: 6 mg daily for 2–3 weeks.^{a b} Withhold therapy until leukocyte and platelet counts increase (i.e., up to 4 weeks) and then initiate maintenance therapy of 2 mg daily.^{a b} Adjust dosage, as required, to maintain a degree of bone marrow depression.^{a b}

Alternatively, 10 mg daily for 7–10 days.¹¹³ Withhold therapy until platelet and leukocyte counts exceed 100,000/mm³ and 4000/mm³, respectively, and then initiate maintenance therapy of 2 mg daily.¹¹³ Adjust dosage, as required, to between 1–3 mg daily, depending on hematologic response.¹¹³

Alternatively, 0.15 mg/kg daily for 7 days.^{a b} Withhold therapy until platelet and leukocyte counts increase (i.e., 2–6 weeks), and then initiate maintenance therapy of ≤0.05 mg/kg daily.^b Adjust dosage, as required, depending on hematologic response.^b

Alternatively, 0.25 mg/kg daily for 4 days or 0.2 mg/kg daily for 5 days, with prednisone; administer at 4–6 week-intervals, if granulocyte and platelet counts are normal.^b

IV

Usual dosage: 16 mg/m² at 2-week intervals for 4 doses.^{106 118 119 120} After satisfactory recovery from toxicity, initiate maintenance therapy of 16 mg/m² at 4-week intervals.^{106 118 119 120}

Ovarian Cancer

Oral

Usual dosage: 0.2 mg/kg daily for 5 successive days; administer at intervals of 4–5 weeks.^{113 b}

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^{b c}

Renal Impairment

Oral

In patients with moderate to severe renal impairment, consider reducing initial dosage; however, no specific dosage recommendations at this time.^b

IV

In patients with renal impairment (BUN ≥30 mg/dL), reduce dosage by 50%. ^{106 118 120 c}

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.^{b c}

Cautions for Melphalan

Contraindications

• 
  

  Prior resistance to melphalan therapy.^{a b c}

  
  


• 
  

  Known hypersensitivity to melphalan or any ingredient in the formulation.^{a b c}

  
  

Warnings/Precautions

Warnings

Adequate Patient Evaluation and Monitoring

Administer only under constant supervision by clinicians experienced in therapy with cytotoxic agents.^{a b c}

Hematologic Effects

Risk of dose-limiting myelosuppression, manifested principally by leukopenia and thrombocytopenia; anemia also may occur.^{a b c d}

Severe myelosuppression more common with IV melphalan than with oral melphalan.^c

Leukocyte and platelet nadirs generally occur 2–3 weeks after treatment; recovery usually occurs 4–5 weeks after treatment.^{a c} Irreversible bone marrow depression has been reported.^{106 113 119 c}

Careful hematologic monitoring required.^a Perform CBCs (leukocyte count with differential, platelet count, hemoglobin) prior to and at periodic intervals during therapy (i.e., prior to each subsequent course of oral melphalan and prior to each subsequent dose of IV melphalan).^{106 b c} Withhold therapy until leukocyte count is >3000/mm³ and platelet count is >100,000/mm³.^b

Monitor closely for symptoms of bone marrow suppression (e.g., severe infections, bleeding, symptomatic anemia).^{b c}

Use with caution in patients with compromised bone marrow reserve (i.e., prior radiation therapy or prior therapy with other cytotoxic agents).^{b c}

Positive direct Coombs’ test results and concurrent hemolytic anemia have been reported.^a

Mutagenicity and Carcinogenicity

Possible leukemia or secondary malignancies; assess risk/benefits of therapy.^{106 113 b c d}

Causes chromatid or chromosome damage in humans.^{106 113 b c}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.^{106 113 b c} Avoid pregnancy during therapy.^{b c} If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.^{106 113 b c}

Fertility

Reversible and irreversible testicular suppression reported.^{b c d}

Ovarian suppression and amenorrhea reported in premenopausal females.^{106 113 b c d}

Local Effects

Extravasation may produce severe local tissue necrosis.^c

Administration by regional isolation perfusion may cause erythema and/or edema of perfused area, thrombophlebitis, necrotizing fasciitis, and varying degrees of vesiculation and tissue necrosis; amputation sometimes has been necessary.^{147 148}

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, urticaria, pruritus, edema, rashes, tachycardia, bronchospasm, dyspnea, and hypotension reported in 2% of patients receiving IV melphalan and rarely in patients receiving oral melphalan.^{a b c}

If hypersensitivity reaction occurs, discontinue immediately and initiate appropriate therapy as indicated (e.g., plasma volume expanders, vasopressors, corticosteroids, antihistamines).^{106 b c}

Cross-Sensitivity

Potential for cross-sensitivity (rash) between melphalan and other alkylating agents.^a

General Precautions

Immunization.

Avoid administration of live vaccines to immunocompromised patients.^{b c}

Pulmonary Toxicity

Pulmonary embolism, sometimes fatal,¹⁴⁸ and fibrosis have been reported.^{106 113 148 d}

Specific Populations

Pregnancy

Category D.^{b c} (See Fetal/Neonatal Morbidity and Mortality and also Fertility, under Cautions.)

Lactation

Not known whether melphalan is distributed into milk;^{106 113 b c} discontinue nursing or the drug.^{106 113 b c}

Pediatric Use

Safety and efficacy not established.^{106 113}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.^{b c}

Renal Impairment

Increased bone marrow suppression and risk of severe leukopenia in patients with renal impairment receiving IV melphalan; dosage reduction should be considered.^c Closely monitor patients with azotemia receiving oral melphalan; oral dosage reductions may be required.^{106 118 b} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Bone marrow suppression, mild nausea.^b

Interactions for Melphalan

Specific Drugs

Drug	Interaction	Comments
Carmustine	Possible reduced threshold for carmustine-induced pulmonary toxicity with IV melphalan106 119 c
Cimetidine	Possible reduced serum melphalan concentrations secondary to cimetidine-induced inhibition of GI absorption of melphalan 109	Monitor for decreased melphalan activity109
Cisplatin	Possible decreased clearance of melphalan secondary to cisplatin-induced renal impairment106 119 c
Cyclosporine	Possible increased risk of cyclosporine-induced nephrotoxicity107 112 c	Monitor renal function107 112 c Consider reducing cyclosporine dosage in patients receiving high-dose melphalan112
Interferon alfa	Interferon alfa-induced fever may increase plasma elimination of melphalan110 111
Nalidixic acid	Possible increased incidence of severe hemorrhagic necrotic enterocolitis in pediatric patients106 119 c

Melphalan Pharmacokinetics

Absorption

Bioavailability

Absorption from the GI tract is incomplete and extremely variable.^{a b}

Food

Food decreases bioavailability by about 35%.¹⁰⁸

Distribution

Extent

Rapidly distributed throughout total body water;^a distributes into CSF in low concentrations.^{106 113 119 b c}

Not known whether melphalan crosses the placenta or is distributed into milk.^{a b c}

Plasma Protein Binding

About 60–90% (30% irreversibly); mainly albumin and to a lesser extent α₁-acid glycoprotein.^{106 113 119 b c}

Elimination

Metabolism

Undergoes spontaneous hydrolysis in plasma to monohydroxymelphalan and dihydroxymelphalan.^{a b c}

Elimination Route

20–35% of oral dose excreted in urine within 24 hours; 20–50% excreted in feces within 6 days.^a

Not removed by hemodialysis.^{106 113}

Half-life

Following oral administration, terminal half-life of unchanged drug is 1.5 hours;^a terminal half-lives of monohydroxymelphalan and dihydroxymelphalan are 2–3 times longer.^a

Following IV administration, terminal half-life is about 75 minutes.^{106 c}

Stability

Storage

Oral

Tablets

2–8°C.^b

Parenteral

Powder for Injection

15–30°C; protect unopened vials from light.^c

Reconstituted and diluted solutions are unstable; following reconstitution, 1% of label strength hydrolyzed every 10 minutes.^c Use within 60 minutes of reconstitution.^c

Following reconstitution, do not refrigerate; refrigeration of reconstituted solution may cause precipitation.^c

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

¹ Incompatible by standard definition; recommended for dilution with use in shorter periods of time.

Incompatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%1

Drug Compatibility

Y-Site CompatibilityHID

Compatible

Acyclovir sodium

Amikacin sulfate

Aminophylline

Ampicillin sodium

Aztreonam

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Cefazolin sodium

Cefepime HCl

Cefotaxime sodium

Cefotetan disodium

Ceftazidime

Ceftizoxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Cimetidine HCl

Cisplatin

Clindamycin phosphate

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dacarbazine

Dactinomycin

Daunorubicin HCl

Dexamethasone sodium phosphate

Diphenhydramine HCl

Doxorubicin HCl

Doxycycline hyclate

Droperidol

Enalaprilat

Etoposide

Famotidine

Filgrastim

Floxuridine

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Gallium nitrate

Ganciclovir sodium

Gentamicin sulfate

Granisetron HCl

Haloperidol lactate

Heparin sodium

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl

Hydroxyzine HCl

Idarubicin HCl

Ifosfamide

Imipenem–cilastatin sodium

Lorazepam

Mannitol

Mechlorethamine HCl

Meperidine HCl

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Mitomycin

Mitoxantrone HCl

Morphine sulfate

Nalbuphine HCl

Ondansetron HCl

Pentostatin

Potassium chloride

Prochlorperazine edisylate

Promethazine HCl

Ranitidine HCl

Sodium bicarbonate

Streptozocin

Teniposide

Thiotepa

Ticarcillin disodium–clavulanate potassium

Tobramycin sulfate

Vancomycin HCl

Vinblastine sulfate

Vincristine sulfate

Vinorelbine tartrate

Zidovudine

Incompatible

Amphotericin B

Chlorpromazine HCl

ActionsActions

• 
  

  Interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function.^a

  
  


• 
  

  Active against both resting and rapidly dividing tumor cells.^{b c}

  
  


• 
  

  Possesses some immunosuppressive activity.^a

  
  

Advice to Patients

• 
  

  Risk of bone marrow suppression, hypersensitivity reactions, infertility, pulmonary toxicities, and secondary malignancies.^{106 113 b c d}

  
  


• 
  

  Advise patients that oral melphalan should be taken on an empty stomach.¹⁰⁸

  
  


• 
  

  Importance of close medical supervision of patients receiving melphalan.^{a b c}

  
  


• 
  

  Importance of informing clinicians if rash, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps or masses occur.^{b c}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.^{b c}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{b c}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^b (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Melphalan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	2 mg	Alkeran (with povidone; scored)	Celgene

Melphalan Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection	50 mg (of melphalan)	Alkeran (with povidone and with diluent containing alcohol 0.52 mL, propylene glycol, and sodium citrate)	Celgene

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Alkeran 2MG Tablets (CELGENE CORP): 50/$245.98 or 150/$719.94

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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100. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983; 2:822-4. [IDIS 176847] [PubMed 6137651]

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102. Greene MH, Harris EL, Gershenson DM et al. Melphalan may be a more potent leukemogen than cyclophosphamide. Ann Intern Med. 1986; 105:360-7. [IDIS 220340] [PubMed 3740675]

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105. Wadler S, Yeap B, Vogl S et al. Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results—Eastern Cooperative Oncology Group Study E2878. Cancer. 1996; 77:733-42. [IDIS 363630] [PubMed 8616766]

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128. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 1995 Dec 12.

129. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet. 1992; 339:1-15,71-85. [IDIS 290641] [PubMed 1345950]

130. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976; 294:405-10. [PubMed 1246307]

131. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995; 332:901-6. [IDIS 344958] [PubMed 7877646]

132. Wood WC, Budman DR, Korzun AH et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994; 330:1253-9. [IDIS 329429] [PubMed 8080512]

133. Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995; 273:542-7. [IDIS 342272] [PubMed 7837388]

134. Fisher B, Redmond C, Wickerman DL et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989; 7:572-82. [PubMed 2651576]

135. Fisher B, Glass A, Redmond C et al. l-Phenylalanine mustard (l-PAM) in the management of breast cancer: an update of earlier findings and a comparison with those utilizing l-PAM plus fluorouracil (5-FU). Cancer. 1977; 39(Suppl):2883-903. [PubMed 194679]

136. Fisher ER, Redmond C, Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Cancer Project. VIII. Relationship of chemotherapeutic responsiveness to tumor differentiation. Cancer. 1983; 51:181-91. [IDIS 165062] [PubMed 6821810]

137. Fisher B, Redmond C, Brown A et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986; 4:459-71. [PubMed 2856857]

138. Rivkin SE, Green S, Metch B et al. Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study. J Clin Oncol. 1989; 7:1229-38. [PubMed 2671283]

139. Fisher B, Redmond C, Brown A et al. Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast disease. J Clin Oncol. 1983; 1:227-41. [PubMed 6366135]

140. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

141. Kyle RA, Gertz MA, Greipp PR et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997; 336:1202-7. [IDIS 383378] [PubMed 9110907]

142. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997; 337:898-909. [IDIS 391785] [PubMed 9302305]

143. Skinner M, Anderson JJ, Simms R et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. 1996; 100:290-8. [IDIS 362735] [PubMed 8629674]

144. Melanoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2000 Aug.

145. Duran Garcia E, Santolaya R, Requena T. Treatment of malignant melanoma. Ann Pharmacother. 1999; 33:730-8. [IDIS 428254] [PubMed 10410188]

146. Houghton A, Coit D, Bloomer W et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology (Huntingt). 1998; 12:153-77.

147. Koops HS, Vaglini M, Suciu S et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol. 1998; 16:2906-12. [IDIS 414236] [PubMed 9738557]

148. Hafstrom L, Rudenstam CM, Blomquist E et al. Regional hyperthermic perfusion with melphalan after surgery for recurrent malignant melanoma of the extremities. Swedish Melanoma Study Group. J Clin Oncol. 1991; 9:2091-4. [PubMed 1960549]

149. Fraker DL, Alexander HR, Andrich M et al. Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol. 1996; 14:479-89. [IDIS 362040] [PubMed 8636761]

a. AHFS drug information 2007. McEvoy GK, ed. Melphalan. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1125-8.

b. Glaxo Wellcome. Alkeran (melphalan hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2004 Nov.

c. Glaxo Wellcome. Alkeran (melphalan hydrochloride) for injection prescribing information. Research Triangle Park, NC; 2007 Mar.

d. Treatment Guidelines from the Medical Letter Drugs of Choice for Cancer. Abramowicz M, ed. New Rochelle, NY: The Medical Letter, Inc.; 2003 Mar: 94.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1046-53.

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Warfarin

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

WARNING: BLEEDING RISK

• Warfarin sodium can cause major or fatal bleeding [see Warnings and Precautions (5.1)].


• Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1)].


• Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin sodium therapy [see Drug Interactions (7)].


• Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)].

1. INDICATIONS AND USAGE

Warfarin sodium tablets,USP are indicated for:

• Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).


• Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.


• Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Limitations of Use

Warfarin sodium tablets, USP have no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.

2. DOSAGE AND ADMINISTRATION

Individualized Dosing

The dosage and administration of Warfarin sodium must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with Warfarin sodium [see References (15)].

Recommended Target INR Ranges and Durations for Individual Indications

An INR of greater than 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

Venous Thromboembolism (including deep venous thrombosis [DVT] and PE)

Adjust the Warfarin dose to maintain a target INR of 2.5 (INR range, 2 to 3) for all treatment durations. The duration of treatment is based on the indication as follows:

• For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with Warfarin for 3 months is recommended.


• For patients with an unprovoked DVT or PE, treatment with Warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.


• For patients with two episodes of unprovoked DVT or PE, long-term treatment with Warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

Atrial Fibrillation

In patients with non-valvular AF, anticoagulate with Warfarin to target INR of 2.5 (range, 2 to 3).

• In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with Warfarin is recommended.


• In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with Warfarin is recommended.


• For patients with AF and mitral stenosis, long-term anticoagulation with Warfarin is recommended.


• For patients with AF and prosthetic heart valves, long-term anticoagulation with Warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

Mechanical and Bioprosthetic Heart Valves

• For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with Warfarin to a target INR of 2.5 (range, 2 to 3) is recommended.


• For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with Warfarin to a target INR of 3 (range, 2.5 to3.5) is recommended.


• For patients with caged ball or caged disk valves, therapy with Warfarin to a target INR of 3 (range, 2.5 to3.5) is recommended.


• For patients with a bioprosthetic valve in the mitral position, therapy with Warfarin to a target INR of 2.5 (range, 2 to 3) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2 to 3) is recommended.

Post-Myocardial Infarction

• For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2 to 3) Warfarin plus low-dose aspirin (≤ 100 mg/day) for at least 3 months after the MI is recommended.

Recurrent Systemic Embolism and Other Indications

Oral anticoagulation therapy with Warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2 to3) may be used for these patients.

Initial and Maintenance Dosing

The appropriate initial dosing of Warfarin sodium varies widely for different patients. Not all factors responsible for Warfarin dose variability are known, and the initial dose is influenced by:

• Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities


• Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5)]

Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2)].

Dosing Recommendations without Consideration of Genotype

If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of Warfarin sodium is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance Warfarin sodium doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5)]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (> 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

Table 1Three Ranges of Expected Maintenance Warfarin Sodium Daily Doses Based on CYP2C9 and VKORC1 Genotypes†

†Ranges are derived from multiple published clinical studies. VKORC1 −1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of Warfarin dose.
			CYP2C9
VKORC1	*1/*1	*1/*2	*1/*3	*2/*2	*2/*3	*3/*3
GG	5 to7 mg	5 to 7 mg	3 to 4 mg	3 to 4 mg	3 to 4 mg	0.5 to 2 mg
AG	5 to 7 mg	3 to 4 mg	3 to 4 mg	3 to 4 mg	0.5 to 2 mg	0.5 to 2 mg
AA	3 to 4 mg	3 to 4 mg	0.5 to 2 mg	0.5 to 2 mg	0.5 to 2 mg	0.5 to 2 mg

Monitoring to Achieve Optimal Anticoagulation

Warfarin sodium is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during Warfarin sodium therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other Warfarin products are interchanged with Warfarin sodium, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7)].

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of Warfarin sodium therapy.

Missed Dose

The anticoagulant effect of Warfarin sodium persists beyond 24 hours. If a patient misses a dose of Warfarin sodium at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.

Treatment During Dentistry and Surgery

Some dental or surgical procedures may necessitate the interruption or change in the dose of Warfarin sodium therapy. Consider the benefits and risks when discontinuing Warfarin sodium even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of Warfarin sodium to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

Conversion From Other Anticoagulants

Heparin

Since the full anticoagulant effect of Warfarin sodium is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with Warfarin sodium, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to Warfarin sodium may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap Warfarin sodium therapy with heparin for 4 to 5 days and until Warfarin sodium has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

As heparin may affect the INR, patients receiving both heparin and Warfarin sodium should have INR monitoring at least:

• 5 hours after the last intravenous bolus dose of heparin, or


• 4 hours after cessation of a continuous intravenous infusion of heparin, or


• 24 hours after the last subcutaneous heparin injection.

Warfarin sodium may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (> 50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

Other Anticoagulants

Consult the labeling of other anticoagulants for instructions on conversion to Warfarin sodium.

3. DOSAGE FORMS AND STRENGTHS

• 1 mg are pink, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘1’ and bisect on one side and plain on other side.


• 2 mg are lavender, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘2’ and bisect on one side and plain on other side.


• 2.5 mg are green, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘2½’ and bisect on one side and plain on other side.


• 3 mg are tan, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘3’ and bisect on one side and plain on other side.


• 4 mg are blue, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘4’ and bisect on one side and plain on other side.


• 5 mg are peach, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘5’ and bisect on one side and plain on other side.


• 6 mg are teal, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘6’ and bisect on one side and plain on other side.


• 7.5 mg are yellow, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘7½’ and bisect on one side and plain on other side.


• 10 mg are white to off white, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘10’ and bisect on one side and plain on other side.

4. CONTRAINDICATIONS

• Pregnancy

Warfarin sodium tablets are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. Warfarin sodium tablets can cause fetal harm when administered to a pregnant woman. Warfarin sodium tablets exposure during pregnancy causes a recognized pattern of major congenital malformations (Warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If Warfarin sodium tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)].

• Hemorrhagic tendencies or blood dyscrasias


• Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions (5.7)]


• Bleeding tendencies associated with:

           − Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract

           − Central nervous system hemorrhage

           − Cerebral aneurysms, dissecting aorta

           − Pericarditis and pericardial effusions

           − Bacterial endocarditis

• Threatened abortion, eclampsia, and preeclampsia


• Unsupervised patients with conditions associated with potential high level of non-compliance


• Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding


• Hypersensitivity to Warfarin or to any other components of this product (e.g., anaphylaxis) [see Adverse Reactions (6)]


• Major regional or lumbar block anesthesia


• Malignant hypertension

5. WARNINGS AND PRECAUTIONS

Hemorrhage

Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR > 4), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5)], certain concomitant drugs [see Drug Interactions (7)], and long duration of Warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin sodium therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7)].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)].

Tissue Necrosis

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (< 0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of Warfarin sodium therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue Warfarin sodium therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with Warfarin sodium may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as "purple toes syndrome." Discontinue Warfarin sodium therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

Heparin-Induced Thrombocytopenia

Do not use Warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and Warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with Warfarin sodium may be considered after the platelet count has normalized.

Use in Pregnant Women with Mechanical Heart Valves

Warfarin sodium can cause fetal harm when administered to a pregnant woman. While Warfarin sodium is contraindicated during pregnancy, the potential benefits of using Warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue Warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (Warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. 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 a fetus [see Use in Specific Populations (8.1)].

Females of Reproductive Potential

Warfarin sodium exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on Warfarin sodium therapy [see Contraindications (4) and Use in Specific Populations (8.8)].

Other Clinical Settings with Increased Risks

In the following clinical settings, the risks of Warfarin sodium therapy may be increased:

• Moderate to severe hepatic impairment


• Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)


• Use of an indwelling catheter


• Severe to moderate hypertension


• Deficiency in protein C-mediated anticoagulant response: Warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following Warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with Warfarin sodium may minimize the incidence of tissue necrosis in these patients.


• Eye surgery: In cataract surgery, Warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As Warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue Warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.


• Polycythemia vera


• Vasculitis


• Diabetes mellitus

Endogenous Factors Affecting INR

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary Warfarin resistance.

6. ADVERSE REACTIONS

The following serious adverse reactions to Warfarin sodium are discussed in greater detail in other sections of the labeling:

• Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10)]


• Necrosis of skin and other tissues [see Warnings and Precautions (5.2)]


• Systemic atheroemboli and cholesterol microemboli [see Warnings and Precautions (5.3)]


• Other adverse reactions to Warfarin sodium include:


• Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)


• Vascular disorders: vasculitis


• Hepatobiliary disorders: hepatitis elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of Warfarin sodium and ticlopidine.


• Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating


• Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia


• Respiratory disorders: tracheal or tracheobronchial calcification  


• General disorders: chills

7. DRUG INTERACTIONS

Drugs may interact with Warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with Warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with Warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning].

Consult the labeling of all concurrently used drugs to obtain further information about interactions with Warfarin sodium or adverse reactions pertaining to bleeding.

CYP450 Interactions

CYP450 isozymes involved in the metabolism of Warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent Warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

• Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of Warfarin by increasing the exposure of Warfarin.


• Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of Warfarin by decreasing the exposure of Warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant mediations. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

Table 2 Examples of CYP450 Interactions with Warfarin

Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir / ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir / ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with Warfarin, closely monitor patients receiving any such drug with Warfarin.

Table 3Drugs that Can Increase the Risk of Bleeding

Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Antibiotics and Antifungals

There have been reports of changes in INR in patients taking Warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of Warfarin.

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking Warfarin.

Botanical (Herbal) Products and Foods

Exercise caution when botanical (herbal) products are taken concomitantly with Warfarin sodium. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and Warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of Warfarin sodium. Conversely, some botanicals may decrease the effects of Warfarin sodium (e.g., co-enzyme Q10, St. John’s wort ginseng). Some botanicals and foods can interact with Warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

Monitor the patient’s response with additional INR determinations when initiating or discontinuing any botanicals.

8. USE IN SPECIFIC POPULATIONS

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 sodium tablets are 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 sodium may outweigh the risks. Warfarin sodium can cause fetal harm when administered to a pregnant woman. Warfarin sodium 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 sodium 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)].

Nursing Mothers

Based on published data in 15 nursing mothers, Warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Monitor breastfeeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when Warfarin sodium is administered to a nursing woman.

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.

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)].

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.

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.

Females of Reproductive Potential

Warfarin sodium exposure during pregnancy can cause spontaneous abortion, birth defects, or fetal death. Females of reproductive potential who are candidates for Warfarin sodium 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 sodium therapy. If the patient becomes pregnant while taking Warfarin sodium, she should be apprised of the potential risks to the fetus.

10. OVERDOSAGE

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.

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 K1.

The use of vitamin K1 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 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 C19H15NaO4, and its structural formula is represented by the following:

Warfarin sodium, USP is a white crystalline powder. It is very soluble in water.

Each Warfarin sodium tablet 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 hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and pregelatinized starch. Additionally each 1 mg tablet contains D&C red no. 6 barium lake, 2 mg tablet contains FD&C blue no. 2 aluminum lake and FD&C red no. 40 aluminum lake, 2.5 mg tablet contains D&C yellow no. 10 aluminum lake and FD&C blue no. 1 aluminum lake, 3 mg tablet contains FD&C yellow no. 6 aluminum lake, FD&C blue no. 2 aluminum lake and FD&C red no. 40 aluminum lake, 4 mg tablet contains FD&C blue no. 1 aluminum lake, 5 mg tablet contains FD&C yellow no. 6 aluminum lake, 6 mg tablet contains FD&C yellow no. 6 aluminum lake and FD&C blue no. 1 aluminum lake, 7.5 mg tablet contains D&C yellow no. 10 aluminum lake and FD&C yellow no.6 aluminum lake and 10 mg tablet is dye free.

12. CLINICAL PHARMACOLOGY

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)].

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.

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 4 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 po