CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`_
`RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`
`09-218/S097
`09-218/S097
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1056
`
`

`

`FEB 1 7 ?nn
`FEB 1 7 rinin
`
`NDA 09-218/S-097
`NDA 09L218/S-097
`
`DuPont Pharmaceuticals Company
`DuPont Pharmaceuticals Company
`Attention: James L. Gaskill, R.Ph.
`Attention: James L: Gaskill, R.Ph.
`Chestnut Run Plaza, MR2146
`Chestnut Run Plaza, MR2146
`974 Centre Road
`974 Centre Road
`Wilmington, DE 19805
`Wilmington, DE 19805
`
`Dear Mr. Gaskill:
`Dear Mr. Gaskill:
`
`Please refer to your supplemental new drug application dated November 12,1999, received
`Please refer to your supplemental new drug application dated November 12, 1999, received
`November 17,1999, submitted under section 505(b) of the FederaWFeod, Drug, and Cosmetic
`November 17, 1999, submitted under section 505(b) of the Federal-Food, Drug, and Cosmetic
`Act for Coumadin® (Warfarin Sodium Tablets, USP) Tablets and Coumadin® (Warfarin
`Act for Coumadin® (Warfarin Sodium Tablets, USP) Tablets and Coumadin® (Warfarin
`Sodium for Injection, USP) for Injection.
`Sodium for Injection, USP) for Injection.
`
`"This "Changes Being Effected in 30 days" supplemental new drug application provides for the —
`--This "Changes Being Effected in 30 days" supplemental new drug application provides for the
`following: m the PRECAUTIONS section, the "EXOGENOUS FACTORS" .subsection
`following: in the PRECAUTIONS section, the "EXOGENOUS FACTORS" subsection
`(factors that may be responsible for INCREASED PT/INR response), the^Specific Drugs
`(factors that may be responsible for INCREASED PT/INR response), the'Specific Drugs
`Reported** table, the addition of the drug names "celecoxib", "rofecoxib", and "capecitabine".
`Reported" table, the addition of the drug names "celecoxib", "rofecokib", and "capecitabine".
`Your submission stated January 4,2000 as the implementation date for the changes.
`Your submission stated January 4, 2000 as the implementation date for the changes.
`
`We have completed the review of this supplemental application and have concluded that
`We have completed the review of this supplemental application and have concluded that
`adequate information has been presented to demonstrate that the drug product is safe and
`adequate information has been presented to demonstrate that the drug product is safe and
`effective for use as recommended in the submitted final printed labeling submitted —
`effective for use as recommended in the submitted final printed labeling submitted
`November 12,1999. Accordingly, the supplemental application is approved effective on the date
`- November 12, 1999. Accordingly, the supplemental application is approved effective on the date
`of this letter.
`of this letter.
`
`If a letter communicating important information about this drug product (i.e., a "Dear Health
`If a letter communicating important information about this drug product (i.e., a "Dear Health
`Care Practitioner" letter) is issued to physicians and others responsible for patient care, we
`Care Practitioner" letter) is issued to physicians and others responsible for patient care, we
`request that you submit a copy of the letter to this NDA and a copy to the following address:
`request that you submit a copy of the letter to this NDA and a copy to the following address:
`
`MEBWATCH, HF-2
`ME13-WATCH, HF-2
`FDA
`FDA
`5600 Fishers Lane
`5600 Fishers Lane
`Rockville, MD 20857
`Rockville, MD 20857
`
`APPEARS THIS WAY
`APPEARS THIS WAY
`ON ORIGINAL _
`ON ORIGINAL _
`
`0002
`
`0002
`
`

`

`NDA 09-218/S-097
`NDA 09-218/S-097
`"Page 2
`Page 2
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`under 21 CFR 314.80 and 314.81.
`
`If you have any questions, contact Karen Oliver, Regulatory Health Project Manager,
`If you have any questions, contact Karen Oliver, Regulatory Health Project Manager,
`at (301) 827-7457.
`at (301) 827-7457.
`
`Sincerely,
`Sincerely,
`
`-
`
`1 -i7-oo
`0 /7- co
`
`Lilia Talarico, MJX-
`Lilia Talarico, M.D._
`Director
`Director
`Division of Gastrointestinal and Coagulation Drug
`Division of Gastrointestinal and Coagulation Drug
`Products
`*
`-
`Products
`-
`-
`Office of Drug Evaluation III
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`Center for Drug Evaluation and Research
`
`APPEARS THIS WAY
`APPEARS THIS WAY
`- ON ORIGINAL
`- ON ORIGINAL
`
`0003
`
`0003
`
`

`

`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`
`09-218/S097
`09-218/5097
`
`APPROVABLE LETTER
`APPROVABLE LETTER
`
`0004
`
`0004
`
`

`

`NDA9-218/S-097
`NDA 9-218/S-097
`
`DuPont Pharmaceuticals Company
`DuPont Pharmaceuticals Company
`Attention: JamesL". Gaskill, R.Ph.
`Attention: James L. Gaskill, R.Ph.
`Chestnut Run Plaza, MR2146
`Chestnut Run Plaza, MR2146
`974 Centre Road
`974 Centre Road
`Wilmington, Delaware 19805
`Wilmington, Delaware 19805
`
`Dear Mr. Gaskill:
`Dear Mr. Gaskill:
`
`NOV 2 9
`NOV 29
`
`We have received your supplemental application submitted under section 505(b) of the Federal Food,
`We have received your supplemental application submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act for the following:
`Drug, and Cosmetic Act for the following:
`
`Name of Drug Product: Coumadin® (Warfarin Sodium Tablets) Tablets
`-
`Name of Drug Product: Coumadin® (Warfarin Sodium Tablets) Tablets
`Coumadin® (Warfarin Sodium" for Injection) for Injection
`Coumadin® (Warfarin Sodium for Injection) for Injection
`_
`_ _
`_
`NDA Number: 9-218 —
`NDA Number: 9-218 _
`
`Supplement Number: S-097
`Supplement Number: S-097
`
`Date of Supplement: November 12,1999
`Date of Supplement: November 12, 1999
`
`Date of Receipt: November 17,1999
`Date of Receipt: November 17, 1999
`
`This supplemental application, submitted as "Supplement - Changes Being Effected" proposes the
`This supplemental application, submitted as "Supplement — Changes Being Effected" proposes the
`following change: in the PRECAUTIONS section, the "EXOGENOUSE FACTORS'1 (factors that
`following change: in the PRECAUTIONS section, the "EXOGENOUSE FACTORS" (factors that
`may be responsible for INCREASED PT/INR response), the "Specific Drugs Reported" table, the
`may be responsible for INCREASED PT/INR response), the "Specific Drugs Reported" table, the
`following drug names have been added: celecoxib, rofecoxib, and capecitabine. In your submission —
`following drug names have been added: celecoxib, rofecoxib, and capecitabine. In your submission --
`- you state that the change to the package insert will be implemented January 4,2000.
`you state that the change to the package insert will be implemented January 4, 2000.
`
`Unless we notify you within 60-days of our receipt date that the application is not sufficiently
`Unless we notify you within 60-days of our receipt date that the application is not sufficiently
`complete to" permit a substantive review, this application will be filed under section 505(b) of the Act
`complete to permit a substantive review, this application will be filed under section 505(b) of the Act
`on January 16,2000 in accordance with 21 CFR314.101(a).
`on January 16, 2000 in accordance with 21 CFR 314.101(a).
`
`All communications concerning this supplemental application should be addressed as follows:
`All communications concerning this supplemental application should be addressed as follows:
`
`U.S. Postal/Courier/Ovemrght Mail:
`U.S. Postal/Courier/Overnight Mail:
`
`Food and Drug Administration
`Food and Drug Administration
`Center for Drug Evaluation and Research
`—
`Center for Drug Evaluation and Research
`Division of Gastrointestingtiand Coagulation Drug Products^HFD-180
`Division of Gastrointestinal-and Coagulation Drug Products,-HED-180
`Attention: Division Document Room, Rm. 6B-24
`Attention: Division Document Room, Rm. 6B-24
`5600 Fishers Lane
`5600 Fishers Lane
`Rockville. Maryland 20857
`Rockville Maryland 20857
`
`(
`
`APPEARS THIS WAY
`APPEARS THIS WAY
`ON ORIGINAL
`ON ORIGINAL
`
`0005
`
`0005
`
`

`

`If you have any questions, contact me at (301) 827-7310.
`If you have any questions, contact me at (301) 827-7310.
`
`Sirfcerely,
`Sincerely,
`
`NDA 9-218/S-097
`NDA 9-218/S-097
`Page 2
`Page 2
`
`Karen Oliver, RN, MSN"
`Karen Oliver, RN, MSN
`Regulatory Health Project Manager
`Regulatory Health Project Manager
`Division of Gastrointestinal and
`Division of Gastrointestinal and
`CoaguJarion Drug Products
`Coagulation Drug Products
`Office of Drug Evaluation III
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`Center for Drug Evaluition and Research
`
`/ 2- y,yg 5
`
`cc:
`--
`cc:
`Archival NDA 9-218/S-097
`Archival NDA 9-218/S-097
`HFD-180/Div. Files
`HFD-180/Div. Files
`HFD-180/K.Oliver
`HFD-180/K.Oliver
`HFD-180/Reviewers and Team Leaders
`HFD-180/Reviewers and Team Leaders
`DISTRICT OFFICE
`•
`DISTRICT OFFICE
`•
`
`Drafted by: mk 11/23/99
`Drafted by: mk 11/23/99
`Initialed by: K. Oliver 11/29/99
`Initialed by: K. Oliver 11/29/99
`final: M. Kidwell 11/29/99
`final: M. Kidwell 11/29/99
`filename:
`filename.
`
`
`".(3 S. -o j StIPPLEMENT ACKNOWLEDGEMENT (AC)
`
`5 a
`
`SUPPLEMENT ACKNOWLEDGEMENT (AC)
`
`APPEARS THIS WAY
`APPEARS THIS WAY
`ON ORIGINAL
`ON ORIGINAL
`
`0006
`
`0006
`
`

`

`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`_
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`
`09-218/S097
`09-218/S097
`
`FINAL PRINTED LABELING
`FINAL PRINTED LABELING
`
`0007
`
`0007
`
`

`

`6466-03/Rev. October, 1999
`6466-03/Rev. October, 1999
`
`Ant/coagufant
`Anticoagulant
`
`COUMADIN®TABLETS
`COUMADIN®TABLETS
`(Warfarin Sodium Tablets, USP) Crystalline
`(Warfarin Sodium Tablets, USP) Crystalline
`COUMADIN® FOR INJECTION
`COUMADIN® FOR INJECTION
`(Warfarin Sodium for Injection, USP)
`(Warfarin Sodium for Injection, USP)
`
`RjoJ 7
`
`ordy
`
`-
`— -
`DESCRIPTION
`DESCRIPTION
`COUMADIN (crystalline warfarin sodium), is an anticoagulant which acts by Inhibiting vitamin K-dependent coagulation factors.
`COUMADIN (crystalline warfarin sodium), is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors.
`Chemically, it Is 3-(a-acetonyIbenzylH-hydroxycournarin and Is a racemia mixture of the R and S enantiomers. Crystalline warfarin
`Chemically, it is 3-(aacetonyibenzyff-4-hydroxycournarin and Is a racemic mixture of the R and S enantiorners. Crystalline warfarin
`sodium Is an isopropanoJ clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous
`sodium Is an isopropand clathrate. The crystallization of warfarin sodium virtually eliminates trace Impurities present in amorphous
`warfarin. Its empirical formula is C^H^NaO* and its structural formula may be represented by the following:
`warfarin. Its empirical formula is Ci9HisNa04 and its structural formula may be represented by the following:
`"V
`
`H
`I
`
`APPROVED
`APPROVED
`
`ora
`eti,coeib
`(Ucoctfe
`ONa
`Crystalline warfare sodium occurs as a white, odorless, crystalline powder, is discolored by Bght and is veiy soluble in water; "freely
`Crystalline warfarin sodium occurs as a white, odorless, crystallite poirder, is discolored by light and is very soluble in water; freely
`soluble in alcohol; vety s&ghtty soluble in chJofefotm and in ether.
`soluble in alcohol; very sightly soluble in chloroform and in ether.
`I T 2000
`FEB
`• FEB 1 7 2000
`COUMADIN Tablets for oral use also contain:
`COUMADIN Tablets for oral use also contaLactose, in:
`
`- -Lactose, starch and magnesium stearate
`All strengths:
`
`starch and magnesium stearate
`All strengtha
`D&C Red No. 6 Barium Late
`""
`'
`"
`1 mg:
`' — D&C Red No. 6 Barium Lake
`1 mg:
`FD&C Blue No. 2 Aluminum Lake and FD&C Red-No^40 Aluminum Lake
`FD&C Blue No. 2 Aluminum Lake and FD&C Red Nn 40 Aluminum Lake
`2mg:
`2 mg:
`D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake
`D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake
`2-1/2 mg:
`2-1/2 mg:
`FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake
`FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake
`3mg:
`3 mg:
`and FD&C Red No. 40 Aluminum Lake
`and FD&C Red No. 40 Aluminum Lake
`FD&C Blue No. 1 Aluminum Lake
`4mg:
`FD&C Blue No. 1 Aluminum Lake
`4 mg:
`FD&C Yellow No. 6 Aluminum Lake
`S.mg:
`FD&C Yellow No. 6 Aluminum Lake
`1mg:
`FD&C Yelow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake
`FD&C YellOW No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake
`6mg:
`D&C YellowTJo. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake
`D&C Yellow-No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake
`7-1/2 mg:
`7-1/2 mg:
`Dye Free
`TOmg:
`Dye Free
`- —TO mg:
`COUMADIN for Injection is supplied as a sterile, lyophiiized powder, which, after reconstitution with 2.7 ml sterile Water for Injection,
`COUMADIN for Injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mLsterile Water for Injection,
`• -
`- -
`contains:
`contains:
`2mg/mL
`Warfarin Sodium
`2 mg/mL
`Warfarin Sedum
`4.98 mg/mL
`Sodium Phosphate, Dibasic, Heptahydrate
`4.98 mg/mL
`Sodium Phosphate, Dibasic, Heptahydrate
`0.194 mg/mL
`Sodium Phosphate, Monobasic, Monohydrate
`0.194 mg/mL
`Sodium Phosphate, Monobasic, Monohydrate
`0.1 mg/mL _
`Sodium Chloride
`0.1 mg/mL _
`Sodium Chloride
`38.0 mg/mL -
`-
`Mannftol
`38.0 mg/ml. -
`Mannitol
`8.1 to 6.3
`Sodium Hydroxide, as needed for pH adjustment to
`8.1 to 8.3
`Sodium Hydroxide, as needed for pH adjustment to
`CLINICAL PHARMACOLOGY
`CLINICAL PHARMACOLOGY
`thesis of vitamin K dependent clotting factors, which include
`COUMADIN and other coumarin anticoagulants act by inhibiting the
`Factors ii, Vii, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II • 60 hours,
`Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours,
`VU - 4-6 hours, IX - 24 hours, and X - 48*72 hours. The haiMives of proteins C and S are approximately 8 hours and-SO hours,
`VII - 4-6 hours, IX - 24 hours, and X - 48-72 hours. The half-lives of proteins C and S are approximately 8 hours and-30 hours,
`respectively. The resultant in vivo effect is a sequential depression of Factors Vii, IX, X and il activities. Vitamin K is an essential
`respectively. The resultant in *o effect Is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential
`cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors.-The vitamin promotes the biosynthesis of
`cofactor for the post ribosomal synthesis of the vitamin I< dependent clotting factors.-The vitamin promotes the biosynthesis of
`Y-caiboxyglutamic acid residues in the proteins which are essentia! for biological activity. Warfarin Is thought to interfere with clotting
`"carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin Is thought to interfere with clotting
`factor synthesis by inhibition ofthe regeneration of vitamin K, epoxide. The degree of depression is dependent upon the dosage
`factor synthesis by- inhibition of-the regeneration of vitamin Ki epoxide. The degree of depression is dependent upon the dosage
`administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent dotting factor
`administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent dotting factor
`-
`made by the fiver by approxlmateiy 30%_to 50%.
`made by the liver by approximately 30% to 50%.
`An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be
`An anticoagulatlon effect generally occurs within 24 hours after drug 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 COUMADIN may
`delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may
`become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established
`become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established
`thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment
`thrombus, nor do they reverse lschemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment
`is to prevent further extension of the formed dot and prevent secondary thromboembolic complications which may result in serious and
`is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and
`possibly fatal sequelae.
`possibly fatal sequoias.
`Pharmacokinetics: COUMADIN is a racemic mixture of the R' and S-enantiomers. The S-enantiomer exhibits 2-5 times more
`Pharmacokineties: COUMADIN is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more
`_
`anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
`anticoagulant activity than the R-enandomer in humans, but generally has a more rapid clearance.
`Absorption: COUMADIN Is essentially completely absorbed after oral administration with peak concentration generally attained within
`Absorption: COUMADIN is essentially completely absorbed after oral administration with peak concentration generally attained within
`-­
`thefirst 4 hours.
`the-first 4 hours.
`Distribution: There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses
`Distribution: There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses
`of warfarin solution. Warfarin distributes into a relatively email apparent volume of distribution of about 0.14 liter/kg. A distribution
`of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution
`phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one
`phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous ablution. Using a one
`compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R* and S-warfarin are similar to
`compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to
`been found
`each other and to that of the racemate. Concentrations in fetal plasma approach-the maternal values, but warfarin has
`each other and to that of the racemate. Concentrations in fetal plasma approach-the maternal values, but warfarin has rti been found
`in human milk (see WARNINGS • lactation). Approximately 99% of the drug is bound to plasma proteins.
`in human milk (see WARNINGS -Lactation). Approximately 99% of the drug is bound to plasma proteins.--
`
`65
`
`0008
`
`0008
`
`

`

`Metabolism: The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectiveiy metabolized by hepatic
`Metabolism: The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic
`microsomal enzymes (cytochrome P-450) to inactive hydroxyiated metaboStes predominant route) and by reductases to reduced
`microsomal enzymes (cytochrome P450) to 1nm:the hydroxylated nietabrffitels (p(redominaM route) and by reductases to reduced
`metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are prindpally excreted into
`metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into
`the urine; and to a lesser extent into the bile. The metabolites of warfarm that have been identified include dehydrowarfarin, two
`the urine; and to a lesser extent into the bile. The metabolites of warfann that have been Identified include dehydrowarfarin, two
`dlastereoisomer alcohols, 4'-, 6-, 7% 8- and 10-hydroxywarfarin. The Cytochrome P-450 isozymes involved in the metabolism of
`diastemoisomer alcohols, 41-, 6-, 7-, 8- and 10-hydroxywarfarin. The Cytochrorne P-450 isozymes involved in the metabolism of
`warfarin include 2C9,2C19,2C8,2C18,1A2, and 3M. 2C9 is Gkely to be the principal form of human fiver P-450 which modulates the
`warfarin include 2C9, 2019, 2C8, 2C18, 1A.2. and 3A4.2C9 Is likely to be the principal form of human liver P450 which modulates the
`in vivo anticoagulant activity of warfarin.
`in vivo anticoagulant activity of warfarin.
`- — Excretion: The terminal half-life of warfarirrafter a single dose Is approximately (me week; however, the effective half-life ranges from 20
`Excretion: The terminal hall-life of warladnafter 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
`to 60 hours, with a mean of about 40 hours. The clearance of Ft-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
`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 radiolabeled drug have demonstrated that up to 92% of the orally
`hours, while that of 9-warfarin ranges from 21 to 43 hours. Studies with radiolabeled 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.
`administered dose is recovered In urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.
`Elderly: Patients 60 years or older appear to exhibit greater than expected PT/1NR response to the anticoagulant effects of warfarin.
`Elderly: Patients 60 years or older appear to exhibit greater than expected PTIINR response to the anticoagulant effects of warfarin.
`The cause of the increased sensilivity to the anticoagulant effects of warfarin in this age group is unknown. This increased
`The cause of the Increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This Increased
`anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin
`anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and phannacodynamic factors. Racemic warfarin
`clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of
`clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference In the clearance of
`S-warfarin in the elderly versus young subjects. However, mere may be a slight decrease in the clearance of R-warfarin in the elderly
`9-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warlarin 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
`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.
`level of anticoagulation.
`Renal Dysfunction: Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage
`Renal Dysfunction: Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage
`adjustment is necessary for patients with renal failure.
`adjustment Is necessary for patients with renal failure.
`Hepatic Dysfunction: Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and
`Hepatic Dysfunction: Hepatic dysfunction can potentiate the response to warfarin through Impaired synthesis of cloning factors and
`decreased metabolism of warfarin.
`decreased metabolism of warfarin.
`--
`The administration of COUMADIN via the intravenous (i.V.) route should provide the patient with the same concentration of an equal
`The administration of COUMADIN via the Intravenous (I.V.) route should provide the patient with the same concentration of an equal
`oral dose, but maxiffHmi plasma concentration will be reached earlier. However, the full anticoagulant effect of adose of warfarin may
`oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect Ora dose of warfarin may
`not be achieved until 72-96 hours after dosing, indicating that the administration of I.V. COUMADIN should not provide any increased-
`not be achieved until 72-96 hours after dosing, indicating that the administration of I.V. COUMADIN should not provide any increaser
`biological effect or.earfier onset of action.
`~
`_
`.
`•
`biologital effect olithWer onset of action.
`Clinical Trials
`-
`Clinical Trials
`Atrial Fibrillation (AF): In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin
`Atrial Fibrillation (AF): In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin
`significantly reduced theiisk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86%
`significantly reduced the-risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86%
`m ail except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of
`in all except one trial (CAFk. 45%) which stopped early due to published positive results from two of these trials. The incidence of
`majorbleeding in these Mais ranged from 0.6 to 2.7% (See Table 1). Meta-analysis findings of these studies revealed that the effects
`major bleeding in these trials ranged from 0.6 to 2.7% (See Table 1). Meta-analysis findings ofthese studies revealed that the effects
`of warfarin in reducing thromboembolicevents including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0).
`of warfarin in reducing thromboembolicevents including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.44.0).
`There was a significant reduction in minor bleeds at the low INR Similar data from clinical studies in valvular atrial fibrillation patients
`There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients
`are not available.
`are not available.
`
`~
`
`0009
`
`0009
`
`

`

`TABLET
`TABLE1
`CLINICAL STUDIES OF WARFARIN IN NON-RHEUMATIC AF PATIENTS*
`CLINICAL SIVDffiS OF WARPARIN IN NON-MBUMAtlC AF PATIENTS*
`
`Study
`Study
`
`N
`N
`
`Control
`Control
`Patients
`Patients
`
`Warfarin-
`Warfarin-
`Treated
`Treated
`Patents
`Patients
`
`PT Ratio
`PT Ratio
`
`INR
`INR
`
`%M4or Bleeding
`Thromboembolism
`% Major Bleeding
`Thromboembolism
`Watfarin- Control
`%HisK
`%Risk
`fl ak* Warfartn- Control
`Reduction
`Treated *~ Patents
`Reduction
`Treated --- Patients
`Patients
`Patients
`
`AFASAK
`AFASAK
`SPAF
`SPAF
`0AATAF
`BAATAF
`CAFA
`CAFA
`SPINAF
`SPINAF
`
`335
`335
`210
`210
`212
`212
`187
`187
`260
`280
`
`336
`336
`211
`211
`208
`208
`191
`191
`265
`265
`
`1.5-&0
`1.5-2.0
`15-1^
`1.3-1.8
`1^-1^
`1.2-1.5
`1^-1^
`1.3-1.6
`1^-15
`1.2-1.5
`
`Z8-42
`2.84.2
`2.045
`2.0-4.5
`1.5-2.7
`1.5-2.7
`2.0-3.0
`2.0-3.0
`1.4-2A-
`1.4-2.8_
`
`60
`60
`67
`67
`86
`86
`45
`45
`79
`79
`
`0.027
`0.027
`0.01
`0.01
`<0.05
`<0.05
`0.25
`0.25
`0.001
`0.001
`*Aii study results of warfarin vs. control are based on inten&orrto-treal analysis, and include ischemic stroke and systemic
`*A11 study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic
`thromboembolism, excfudfng hemorrhage and transient Ischemic attacks.
`thromboembolism, excluding hemorrhage and transient IschernIc attacks.
`Myocardial Infarction: WARtS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks
`Myocardial Infarction: WARIS (The Warfarin Re-Infarction Study) was a double-bOnd, randomized study of 1214 patients 2 to 4 weeks
`postinfarction treated with warfarin to a target INR of 2.8 to 4.6. [But note that a tower INR was achieved and increased bleeding was
`post-Infarction treated with warfarin to a target INR of 2.8 to 4.8. (But note that a lower INR was achieved and Increased bleeding was
`associated with INR's above 4-.0; (see DOSAGE AND ADMINISTRATION)). The primary endpoint was a combination of total mortality --
`associated with INR's above 4;0; (see DOSAGE AND ADMINISTRATION)). The primary endpoint was a combination of total mortality
`and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-tjp of the patients was 37
`and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37
`months. The results for each endpoint separately/including an analysis of vascular death, are provided m the fofowing table:
`months. The results for each endpoint separately, including an analysis of vascular death, are providedin the following table:
`TABLE 2 -
`TABLE 2-
`
`0.6
`0.6
`1.9
`1.9
`03
`0.9
`2.7
`2.7
`2.3
`2.3
`
`0.0
`0.0
`1.9
`1.9
`0.5
`0.5
`0.5 —
`0.5 -
`15
`1.5
`
`Event
`Event
`
`Warfarin
`Warfarin
`(Ns607)
`(N307)
`
`Placebo
`Placebo
`(N&607)
`(N--607)
`
`RR(95%C|)
`RR (95%C0
`
`%fVsk
`%Risk
`Reduction
`Reduction
`(p-vaiue)
`(p-value)
`
`Total Patient Years of Follow-up
`Total Patient Years of Follow-up
`
`2018
`2018
`
`1944
`1944
`
`Total Mortality
`Total Mortality -
`
`Vascular Death
`Vascular Death
`
`94 (4.7/100 py) 123 (6.3/100 py) 0.76(0.60,0.97)
`123 (6.3/100 py)
`0.76 (0.60, 0.97)
`94 (4.7/100 py)
`
`24(tte0.030)_
`24 (or-0.030)__
`
`62 (4.1/100 py) 105 (5.4/100 py) 0.78 <0.60,1-02)
`82 (4.1/100 py)
`105 (5.4/100 py)
`0.78 (0.60,1.02)
`
`22(p=0.068)
`22 (0=0.068)
`
`Recurrent Ml
`Recurrent MI
`
`82 (4.1/100 py) 124 (6.4/100 py) 0.66(051,0^5)
`82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85)
`
`34(p*0.001)
`34 (c=0.001)
`
`Cerebrovascular Event
`Cerebrovascular Event
`
`20 (1.0/100 py)
`20 (1.0/100 py)
`
`44 (2.3/100 py) 0.46(0J28.0.75)
`44 (2.3/100 py) 0.46 (0.28, 0.75)
`
`S4(p^.002)
`54 (p=0.002)
`
`RRsReiaUve risk; Risk reductions(t - RR); CisConAdence interval; M]=Myocardiai infarction; pyspafient years
`RF1=Relative risk; Risk reduction4 - RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years
`
`0010
`
`0010
`
`

`

`Mechanical and Bloprosthetic Heart Valves: In a prospective, randomized, open label, positive-controlled study (Molt et al, 1985) in
`254 patients, the thromboembollc-free interval was found to be significantly greater In gents with mechanical prosthetic heart valves
`treated with warfarin alone compared with dipyridamoie-aspirin {p<Q.Q05) and pentoxrfytline-aspirtn (p<0^5) treated paterts. Bates o(
`treated with warfarin atone compared with dipyridamole-aspirin (p4.0.005) and pento ?atiine-aspirin (pc0.05) treated patients. Rates of
`thromboembolic events {n these groups were 22,8.6, and 7.9/100 patient years, respectively. Major bleeding rates were ZS, 0.0, and
`thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5. 0.0, and
`0.9/100 patient years, respectively.
`0.9/100 patient years, respectively.
`In a prospective, open label, clinical trial (Saour et a!, 1990) comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin
`In a prospective, open label, clinical trial (Saour et at, 1990) comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin
`therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency i