DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville MD 20857
`
`NDA 20-785/S-012, S-014
`
`Celgene Corporation
`Attention: Steve Thomas, Ph.D.
`Vice President, Regulatory Affairs and Project Management
`7 Powder Horn Drive
`Warren, NJ 07059
`
`Dear Dr. Thomas:
`
`Please refer to your supplemental new drug applications dated January 18, 2000 and May 17, 2000,
`received January 19, 2000 and May 18, 2000, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act for THALOMID® (thalidomide) Tablets, 50 mg.
`
`We acknowledge receipt ofyour submissions dated June 8, 2000, December 12, 2000, July 6, 2001 and
`August 22, 200 1.
`
`These supplemental new drug applications provide for the following changes to the THALOMID®
`label. The deleted text is noted by strikethrough and the added text is noted by double underline as
`follows:
`
`1. The words "one month" were changed to "4 weeks" throughout the label.
`
`2. PRESCRlHERS Box
`• The following sentence was revised as follows:
`
`"Two reliable forms of contraception must be used simultaneously unless continuous
`abstinence from reproductive heterosexual sexual intercourse contact is the chosen method."
`
`• A sentence for male patients was added after the "Before starting treatment" paragraph to read:
`
`"Male Patients: Because thalidomide is present in the semen of patients receiving the drug.
`males receiving thalidomide must always use a latex condom during any sexual contact with
`women of childbearing potential."
`
`3. In the FEMALE PATIENTS box, the first sentence in the fourth bullet was revised as follows:
`
`"she has received both oral and written warnings of the risk of possible contraception failure
`and of the need to use two reliable forms of contraception simultaneously (see
`CONTRAINDICATIONS), unless continuous abstinence from reproductive heterosexual
`sexual contact is the chosen method."
`
`
`
`Page 1 of 8
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`CELGENE EXHIBIT 2009
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01103
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`

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`NDA 20-785/S-012, S-014
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`2
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`4. In the MALE PATIENTS box, the fourth and fifth bullets have been revised as follows:
`
`• he has received both oral and written warnings ofthe risk of possible contraception failure and
`of the need to use barrier contraception when having sexual intercourse with women of
`childbearing potential, even if he has undergone successful vasectomy.presence of thalidomide
`in semen. He has been instructed that he must always use barrier contraception Clatex condom)
`during any sexual contact with women of childbearing potential. even if he has undergone
`successful vasectomy.
`• he acknowledges, in writing, his understanding of these warnings and of the need for using
`barrier contraception (latex condom) even if he has undergone successful vasectomy, during
`any sexual contact with women of childbearing potential. even if he has undergone successful
`vasectomy. Sexually mature women who have not undergone a hysterectomy or who have not
`been post-menopausal for at least 24 consecutive months (i.e., who have had menses at any
`time in the preceding 24 consecutive months) are considered to be women of childbearing
`potential..
`
`5. CLINICAL PHARMACOLOGY
`•
`In the Pharmacokinetics and Drug Metabolism subsection, the Distribution subsection was revised
`to read:
`
`It is not knmvn 'tvhether thalidomide is present in the ejaculate of males.
`
`The extent of plasma protein binding ofthalidomide is unknown.
`
`In human blood plasma. the geometric mean plasma protein binding was 55% and 66%.
`respectively. for (+)-CR)- and (-)-(S)-thalidomide. 8 In a pharmacokinetic study of thalidomide in
`HIV-seropositive adult male subjects receiving thalidomide 100 mg/day. thalidomide was
`detectable in the semen.
`
`6. CONTRAINDICATIONS
`• The word "intercourse" was changed to "contact" in the first paragraph under Pregnancy: Category
`X
`
`• A paragraph was added and is now the next-to-the-last paragraph in this section as follows:
`
`Because thalidomide is present in the semen of patients receiving the drug. males receiving
`thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
`
`7. WARNINGS
`• The third sentence in the first paragraph concerning Birth defects was changed from:
`
`Because it is not knovm 'tvhether or not thalidomide is present in the ejaculate of males
`receiving the drug, males receiving thalidomide must always use a latex condom when
`engaging in sexual activity with women of childbearing potential.
`
`
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`Page 2 of 8
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`

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`NDA 20-785/S-012, S-014
`
`to:
`
`3
`
`Because thalidomide is present in the semen of patients receiving the drug. males receiving
`thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
`
`8. PRECAUTIONS
`• The Stevens-Johnson Syndrome subsection was revised as follows:
`
`Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:
`Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal
`necrolysis, which may be fatal, have been reported. THALOMID® (thalidomide) should be
`discontinued if a skin rash occurs and only resumed following appropriate clinical evaluation.
`If the rash is exfoliative, purpuric, or bullous or if Stevens-Johnson syndrome or toxic
`epidermal necrolysis is suspected, use of THALOMID® (thalidomide) should not be resumed.
`
`• A subsection concerning Seizures was added after the Stevens-Johnson Syndrome and Toxic
`Epidermal Necrolysis subsection to read:
`
`Seizures:
`Although not reported from pre-marketing controlled clinical trials. seizures. including grand
`mal convulsions. have been reported during post-approval use of THALOMID® (thalidomide)
`in clinical practice. Because these events are reported voluntarily from a population of
`unknown size. estimates of frequency cannot be made. Most patients had disorders that may
`have predisposed them to seizure activity. and it is not currently known whether thalidomide
`has any epileptogenic influence. During therapy with thalidomide. patients with a historv of
`seizures or with other risk factors for the development of seizures should be monitored closely
`for clinical changes that could precipitate acute seizure activity.
`
`•
`
`In the Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal
`Contraceptives subsection, the last sentence was revised as follows:
`
`Therefore, women requiring treatment with one or more of these drugs must use two OTHER
`effective or highly effective methods of contraception or abstain from reproductive
`heterosexual sexual intercourse contact.
`
`• The Pregnancy subsection was revised as follows:
`
`Pregnancy Category X: See BOXED WARNING and CONTRAINDICATIONS.
`Because of the known human teratogenicity of thalidomide, thalidomide is contraindicated in
`women who are or may become pregnant and who are not using the two required types of birth
`control or who are not continually abstaining from reproductive heterosexual sexual intercourse
`contact. If thalidomide is taken during pregnancy, it can cause severe birth defects or death to
`an unborn baby. Thalidomide should never be used by women who are pregnant or who could
`become pregnant while taking the drug. Even a single dose [1 capsule (50 mg)] taken by a
`
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`NDA 20-785/S-012, S-014
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`4
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`pregnant woman can cause birth defects. If pregnancy does occur during treatment, the drug
`should be immediately discontinued. Under these conditions, the patient should be referred to
`an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and
`counselling counseling. Any suspected fetal exposure to THALOMID@ (thalidomide) must be
`reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene
`Corporation.
`Because thalidomide is present in the semen of patients receiving the drug. males receiving
`thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
`Animal studies to characterize the effects of thalidomide on late stage pregnancy have not been
`conducted.
`
`9. ADVERSE REACTIONS
`• The following sentence has been added after the first paragraph to read:
`
`Because thalidomide is present in the semen of patients receiving the drug. males receiving
`thalidomide must always use a latex condom during any sexual contact with women of
`childbearing potential.
`
`10. STORAGE AND DISPENSING
`• The first paragraph of the PHARMACISTS NOTE was revised as follows:
`
`DRUG MUST ONLY BE DISPENSED IN NO MORE THAN A l MONTH SUPPLY AND
`ONLY ON PRESENTATION OF A NEW PRESCRIPTION WRITTEN WITHIN THE
`PREVIOUS 7 Df.YS. SPECIFIC INFORMED CONSENT (copy attached as part of this
`package insert) f"ND COMPLIANCE \VITH THE Mf"NDf"TORY Pf"TIENT REGISTRY
`AND SURVEY ARB REQUIRED FOR ALL PATIENTS (MALE AND FEMALE) PR10R TO
`DISPENSING BY THE PHAR~4ACIST.
`
`BEFORE DISPENSING THALOMID@ (thalidomide). YOU MUST ACTIVATE THE
`AUTHORIZATION NUMBER ON EVERY PRESCRIPTION BY CALLING THE CELGENE
`CUSTOMER CARE CENTER AT 1-888-4-CELGENE CL-888-423-5436) AND OBTAINING
`A CONFIRMATION NUMBER YOU MUST ALSO WRITE THE CONFIRMATION
`NUMBER ON THE PRESCRIPTION. YOU SHOULD ACCEPT A PRESCRIPTION ONLY
`IF IT HAS BEEN ISSUED WITHIN THE PREVIOUS 7 DAYS (TELEPHONE
`PRESCRIPTIONS ARE NOT PERMITTED): DISPENSE NO MORE THAN A 4-WEEK (28-
`DAY) SUPPLY. WITH NO AUTOMATIC REFILLS: DISPENSE BLISTER PACKS INTACT
`(CAPSULES CANNOT BE REPACKAGED):
`DISPENSE SUBSEQUENT PRESCRIPTIONS ONLY IF FEWER THAN 7 DAYS OF
`THERAPY REMAIN ON THE PREVIOUS PRESCRIPTION: AND EDUCATE ALL STAFF
`PHARMACISTS ABOUT THE DISPENSING PROCEDURE FOR THALOMID@
`(thalidomide).
`
`
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`Page 4 of 8
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`NDA 20-785/S-012, S-014
`
`5
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`11. Important Information and Warnings for All Patients Taking THALOMID!jg (thalidomide)
`• The first line in the WARNING box has been revised to read:
`
`WARNING: SERIOUS SEVERE. LIFE-THREATENINGHUMANBIRTHDEFECTS.
`
`• The CONSENT FOR WOMEN and the CONSENT FOR MEN have been completely revised to
`read:
`
`All Patients
`• The patient understands that severe birth defects can occur with the use of THALOMID®
`(thalidomide).
`• The patient has been warned by his/her doctor that an unborn baby will almost certainly
`have serious birth defects and can even die, if a woman is pregnant or becomes pregnant
`while taking THALOMID® (thalidomide).
`• THALOMID® (thalidomide) will be prescribed ONLY for the patient and must NOT be
`shared with ANYONE, even someone who has similar symptoms.
`• THALOMID® (thalidomide) must be kept out of the reach of children and should NEVER
`be given to women who are able to have children.
`• The patient cannot donate blood while taking THALOMID@ (thalidomide).
`• The patient has read the THALOMID® (thalidomide) patient brochure and/or viewed the
`videotape, "Important Information for Men and Women Taking THALOMID®
`(thalidomide)" and understands the contents, including other possible health problems
`from THALOMID@ (thalidomide), "side effects."
`• The patient's doctor has answered any questions the patient has asked.
`• The patient must participate in a telephone survey and patient registry, while taking
`THALOMID® (thalidomide).
`
`•
`
`Female Patients of Childbearing Potential
`• The patient must not take THALOMID® (thalidomide) if she is pregnant, breast-feeding a
`baby, or able to get pregnant and not using the required two methods of birth control.
`• The patient confirms that she is not now pregnant, nor will she try to become pregnant
`during THALOMID@ (thalidomide) therapy and for at least 4 weeks after she has
`completely finished taking THALOMID@ (thalidomide).
`If the patient is able to become pregnant, she must use at least one highly effective method
`and one additional effective method of birth control (contraception) AT THE SAME
`TIME:
`At least one highly effective method
`One additional effective method
`Latex condom
`IUD
`Hormonal (birth control pills, injections, or implants) Diaphragm
`Tubal ligation
`Cervical cap
`Partner's vasectomy
`• These birth control methods must be used for at least 4 weeks before starting
`THALOMID® (thalidomide) therapy, all during THALOMID® (thalidomide) therapy, and
`for at least 4 weeks after THALOMID® (thalidomide) therapy has stopped.
`• The patient must use these birth control methods unless she comoletelv abstains from
`
`AND
`
`
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`Page 5 of 8
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`NDA 20-785/S-012, S-014
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`6
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`•
`
`heterosexual sexual contact.
`If a hormonal method (birth control pills, injections, or implants) or IUD is not medically
`possible for the patient, she may use another highly effective method or two barrier
`methods AT THE SAME TIME.
`• The patient must have a pregnancy test done by her doctor within the 24 hours prior to
`starting THALOMID<ID (thalidomide) therapy, then every week during the first 4 weeks of
`THALOMID<ID(thalidomide) therapy.
`• Thereafter, the patient must have a pregnancy test every 4 weeks if she has regular
`menstrual cycles, or every 2 weeks if her cycles are irregular while she is taking
`THALOMID<ID (thalidomide).
`• The patient must immediately stop taking THALOMID~TP (thalidomide) and inform her
`doctor:
`
`If she becomes pregnant while taking the drug
`If she misses her menstrual period, or experiences unusual menstrual bleeding
`If she stops using birth control
`If she thinks FOR ANY REASON that she may be pregnant
`The patient understands that if her doctor is not available, she can call l-888-668-2528
`for information on emergency contraception.
`
`Female Patients Not of Childbearing Potential
`• The patient certifies that she is not now pregnant, nor of childbearing potential as she has
`been postmenopausal for at least 24 months (been through the change of life); or she has
`had a hysterectomy.
`• The patient or guardian certifies that a prepubertal female child is not now pregnant, nor is of
`childbearing potential as menstruation has not yet begun, and/or the child will not be engaging
`in heterosexual sexual contact for at least 4 weeks before THALOMID@ (thalidomide) therapy,
`during THALOMID@ (thalidomide) therapy, or for at least 4 weeks after stopping therapy.
`
`Male Patients
`• The patient has been told by his doctor that he must NEVER have unprotected sexual
`contact with a woman who can become pregnant.
`• Because THALOMID<ID (thalidomide) is present in semen, his doctor has explained that he
`must either completely abstain from sexual contact with women who are pregnant or able
`to become pregnant, or he must use a latex condom EVERY TIME he engages in any
`sexual contact with women who are pregnant or may become pregnant while he is taking
`THALOMID@ (thalidomide) and for 4 weeks after he stops taking the drug, even if he has
`had a successful vasectomy.
`• The patient must inform his doctor:
`If he has had unprotected sexual contact with a woman who can become pregnant.
`If he thinks FOR ANY REASON, that his sexual partner may be pregnant
`The patient understands that if his doctor is not available, he can call 1-888-668-2528 for
`information on emergency contraception.
`• The patient cannot donate semen while taking THALOMID<ID (thalidomide).
`
`
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`Page 6 of 8
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`NDA 20-785/S-012, S-014
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`7
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`Authorization:
`This information has been read aloud to me in the language of my choice. I understand that if I
`do not follow all of my doctor's instructions, I will not be able to receive THALOMID®
`(thalidomide
`I now authorize my doctor to begin my treatment with THALOMID® (thalidomide).
`Date ________ _
`Patient Signature
`I have fully explained to the patient the nature, purpose, and risks of the treatment described
`above, especially the risks to women of childbearing potential. I have asked the patient if
`he/she has any questions regarding his/her treatment with THALOMID@ (thalidomide) and
`have answered those questions to the best of my ability. I will comply with all of my
`obligations and responsibilities as a prescriber registered under the S. TE.P.S.rM restricted
`distribution program.
`Prescriber Name (please type): ______________________ _
`
`DEA Number: ________ Social Security Number if PA or NP:
`
`Street Address:
`
`City: _____________ State: __ ______ _ Zip:
`
`Prescriber Signature
`
`12. REFERENCES
`•The following reference has been added and is now number 8 in the section to read:
`
`"8.
`
`Eriksson T, Bjorkman S, Roth B, et al. 1998. Chirality. 10(3): 223-228."
`
`We have completed the review of these supplemental applications, as amended, and have concluded
`that adequate information has been presented to demonstrate that the drug product is safe and effective
`for use as recommended in the agreed upon labeling text. Accordingly, the supplemental application is
`approved efiective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the submitted draft labeling (package insert
`submitted August 22, 2001).
`
`Please submit the copies of final printed labeling (FPL) electronically to each application according to
`the guidance for industry titled Providing Regulatoty Submissions in Electronic Format- NDA
`(January 1999). Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but
`no more than 30 days after it is printed. Please individually mount ten of the copies on heavy-weight
`paper or similar material. For administrative purposes, these submissions should be designated "FPL
`for approved supplements NDA 20-785/S-012, S-014." Approval ofthese submissions by FDA is not
`required before the labeling is used.
`
`
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`NDA 20-785/S-012, S-014
`
`8
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`If a letter communicating important information about this drug product (i.e., a "Dear Health Care
`Professional" 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:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, call Robin Anderson, Labeling Reviewer, at (301) 827-2127.
`
`Sincerely,
`
`electronic
`
`Mark J. Goldberger, M.D., M.P.H.
`Director
`Division of Special Pathogen and Immunologic Drug
`Products
`Oftice of Drug Evaluation IV
`Center for Drug Evaluation and Research
`
`
`
`Page 8 of 8