IIIGIILIGIITS OF PRESCRIBING INFORNIATTON
`These highlights do not include all the information nctded to use
`ZOLADEX safely and effectively. Set: full prescribing information for
`ZOLADEX.
`
`ZOLADEXI (goserelin acetate implant) 3.6 mg
`Initial U.S. Appcwni: 1989
`
`A INDICATIONS AND USAGEA
`ZOI.ADF.X is a Gonadotropin Releasing Hormone (GHRI-I) agonist indicated
`for:
`I
`
`Use in combination with flutamide for the management of locally
`confined carcinoma of the prostate (Q)
`Palliative treatment of advanced carcinoma of the prostate Lg)
`‘lhe management of endometriosis fl._3_)
`Use as an endomehial-thinning agent prior to endometrial ablation for
`dysfimctional uterine blcediw {(131
`Use in the palliative treatment 01'advanced breast cancer in pre- and
`pcrimenopausal women {Q1
`
`I
`I
`I
`
`I
`
`--A IIIOSAGE AND ADMINISTRATKIN
`I
`7.()I.AI)lé2X 3.6 mg should be administered subcutaneously every 28
`days (A. 2_.T)
`For the management of cndornetriosis. the recommended duration of
`administration is 6 months for women 1 8 years of age and older (24)
`
`o
`
`A DOSAGE FORMS AND STRENGTHS
`Implant 3.6 mg (_3_)
`
`I
`I
`
`I
`
`I
`
`I
`
`CONTRAINDICATIONS
`llypersensitivily (4.1 1
`Pregnancy unless used for treatment of advanced breast cancer 14.21
`
`WARNINGS AND PRECAUTIONS
`Women ofChildbearing Potential and Pregnancy: Pregnancy must be
`excluded for use in benign gynecological conditions. Women should
`avoid pregnancy [E]
`Tumor Flare Phenomenon: Transient worsening of tumor symptoins
`may occur during the first few weeks oftreatment with ZOLADEX.
`which may include ureteral obstruction and spinal cord compression.
`Monitor patients at risk for complications oftumor flare (Q. Q)
`Hyperglycemia and Diabetes: I-lyperglyecmia and an increased risk of
`developing diabetes have been reported in men receiving GnRH analogs.
`Monitor blood glucose level and manage according to current clinical
`practice (Si)
`
`FULL PRESCRIBING INFORMATION: CONTENTS:
`
`1 INDICATIONS AND USAGE
`1.1 Stage B2—C Proslatit: Carcinonia
`1.2 Prnstatic Carcinoma
`1.3 Endomclriosis
`1.4 E-ndcvmelrial Thinning
`1.5 Advanced Breast Cancer
`2 DOSAGE AND ADMIN IS’l'RATION
`2.1 Stage B2-C Prostalit: Carcinoma
`2.2 Prostatic Carcinoma
`2.3 Endomelriosis
`2.4 Endomelrial Thinning
`2.5 Breast Cancer
`2.6 Renal or Hepatic Impairment
`2.7 Administration Technique
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`4.1 Hypersensitivity
`4.2 Pregnancy
`5 WARNINGS AND PRECAUTIONS
`5.1 Women of Childbearing Potential and Pregnancy
`5.2 Turnor Flare Phenomenon
`5.3 Hypcrglyccrnin and Diabetes
`5.4 Cardiovascular Diseases
`5.5 Hypcrealceinia
`5.6 Hypersensitivity
`5.7 Cervical Resistance
`5.8 I-ltfect on Q'l‘fQ'I‘c Interval
`5.9 injection Site Injury
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
`Cardiovascular Diseases: Increased risk of myocardial infarctioii. sudden
`cardiac death and stroke has been reported in association with use of
`GnR.I'I analogs in men. Monitor for cardiovascular disease and manage
`according to current clinical practice {$1
`llypercalcemia: Hypcrcalcemia has been reported in patients with bone
`metastases treated with ZOLADIZX. Monitor and manage appropriately
`EA)
`Ilypersensilivity: Systemic hypersensitivity has been reported in patients
`receiving goscrelinll/.OI.ADI-‘X implants L, E)
`Cervical Resistance: Increase in cervical resistance may occur. Caution
`is recommended when dilating the cervix for cndometrial ablation LS1]
`Effect on QT/QT: Interval: Androgen deprivation therapy may prolong
`the QT interval. Consider risks and benefits gig
`Injection Site Injury: Injection site injury and vascular injury have been
`reported during administration of ZOLADEX L53)
`
`A ADVERSE REACTIONS
`The most common. clinically significant adverse reactions occurring in >1 0%
`of men: hot flashes. sexual dysfunction. decreased encctions and lower urinary
`tract symptoms [Q
`
`'1he adverse event profile was similar for women treated for breast cancer,
`dysfunctional uterine bleeding or endomclriosis and included (>20%): hot
`flushes, headache, sweating, acne, emotional lability, depression, decreased
`libido. vaginilis, brrnst atrophy. seborrhea, and peripheral edema Q3)
`Tumor flare can occur on the initiation of 201 .ADl-ZX for both men and
`women being treated for cancer L9)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Astrnleneca
`at 1-800-236-9933 or FDA at I-D01!-FDA-1088 or wvi1v.t'da.govfmedwatch.
`
`I
`
`I
`
`None
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`Nursing mothers: Discontinue drug or nursing taking into account the
`importance of drug to the mother LSA)
`No information available for use in Pediatric patients
`Geriatric (Q1
`Renal and Hepatic Impairment: No dose adjustment is necessary (2_.£_i.
`
`See IT for PATIENT‘ (‘.0(TNSELING INFORMATION
`
`Revised:
`
`I<”ebI'i.IaI'y 2016
`
`6 ADVERSE REACTIONS
`6.1 Stage B2-C Prostatic Carcinoma
`6.2 Proslatic Carcinoma
`6.3 Females
`6.4 Endornetriosis
`6.5 Endon1e'lrialThinni.ng
`6.6 Breast Cancer
`6.7 Hormone Replacement Therapy
`6.8 Changes in Bone Mineral Density
`6.9 Changes in Laboratory Values During Treatment
`6.10 Poslmarkeling Experience
`7 DRUG INTERACTIONS
`7.1 Drug/laboratory Test Interactions
`8 USE IN SPECIFIC POPITLATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`3.5 Geriatric Use
`8.6 Renal Insufficiency
`8.7 Hepatic insufficiency
`ll] OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`l2.1 Mechanism OIAIEIIUII
`12.2 Phormacodynamics
`12.3 Pharmacokinctics
`13 NONCIJNICAI. TOICICOIJIGY
`l3.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`Astrazeneca Ex. 2048 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01324
`
`

`
`14.! Stage B2-C Prostatie Carcinoma
`14.2 Proslalie Caieinorna
`14.3 I-jndomctriosis
`14.4 Endometrial Thinning
`145 Breast Cancer
`
`16 HOW SLIPFLIEDISTORAGE AND HANDLING
`17 l’AT].EN'l' COUNSELING LVFORMATION
`17.1 Males
`17.2 Females
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`1.1 Stage B2-C Prostatie Carcinoma
`
`ZOLADEX is indicated for use in combination with flutamidc for the management of locally confined Stage T2b-T4
`
`(Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamidc should start 8 weeks prior to initiating
`
`radiation therapy and continue during radiation therapy [see Dosage and Administration (2.1) and Clinical Studies
`[I4.i'._|I.
`
`1.2 Prostatic Carcinoma
`
`ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate [see Dosage and Administt‘atian
`(2.2; and Clinical Studies (14. 21].
`
`1.3 Endometriosis
`
`ZOLADEX is indicated for the management of cndornetriosis, including pain relief and reduction ofendometriotic lesions
`
`for the duration of therapy. Experience with ZOLADEX for the management of endometriosis has been limited to women
`
`18 years of age and older treated for 6 months [see Dosage and Administration (2.31 and Ciinicai Studies (14.3;/.
`
`1.4 Endomctrial Thinning
`
`ZOLADEX is indicated for use as an endometrial-thinning agent prior to endornetrial ablation for dysfiinctional uterine
`
`bleeding [see Dosage and Administration (2.41 and Clinical Studies tr’ 4.4 2].
`
`1.5 Advanced Breast Cancer
`
`ZOLADEX is indicated for use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women.
`
`The estrogen and progesterone receptor values may help to predict whether ZOLADEX therapy is likely to be beneficial
`/see Dosage and Administration (2.6; Clinical PharmacriioggiI (12.12, and Ciinica! Studies (I451/.
`
`The automatic safety feature of the syringe aids in the prevention of ncedlestick injury.
`
`2 DOSAGE AND ADMINISTRATION
`
`ZOLAJDEX, at a dose of 3.6 mg, should be administered subcutaneously every 28 days into the anterior abdominal wall
`
`below the navel line using an aseptic technique under the supervision of a physician [see Dosage and Administration
`{Jil-
`
`While a delay of a few days is permissible, every effort should be made to adhere to the 28-day schedule.
`
`2.1 Stage B2—C Prostatie Carcinoma
`
`When ZOLADEX is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C)
`
`prostatie carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during
`
`radiation therapy. A treatment regimen using a ZULADEX 3.6 mg depot 8 weeks before radiotherapy, followed in 28
`days by the ZOLADEX 10.8 mg depot, can be administered. Alternatively, four injections of3.6 mg depot can be
`
`administered at 28-day intervals, two depots preceding and two during radiotherapy.
`
`Astrazeneca Ex. 2048 p. 2
`
`

`
`2.2 Prostatic Carcinoma
`
`For the management of advanced prostate cancer, ZOLADEX is intended for long-term administration unless clinically
`inappropriate.
`
`2.3 Endometriosis
`
`For the management of endometriosis, the recommended duration of administration is 6 months.
`
`Currently, there are no clinical data on the effect of treatment of benign gynecological conditions with ZOLADEX for
`
`periods in excess of 6 months.
`
`Retreatment cannot be recommended for the management of endometriosis since safety data for retreatrnent are not
`
`available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with ZOLADEX is
`
`contemplated, consideration should be given to monitoring bone mineral density. Clinical studies suggest the addition of
`
`Hormone Replacement Therapy (estrogcns and/or progestins) to ZOLADEX is effective in reducing the bone mineral loss
`
`which occurs with ZOLADEX alone without compromising the efiicacy of ZOLADEX in relieving the symptoms of
`
`endometriosis. The addition of Honnone Replacement Therapy may also reduce the occurrence of vasomotor symptoms
`
`and vaginal dryness associated with hypoestrogenism. The optimal drugs, dose and duration of treatment has not been
`established.
`
`2.4 Endometrial Thinning
`
`For use as an endometrial-thinning agent prior to endometrial ablation, the dosing recommendation is one or two depots
`
`(with each depot given four weeks apart). When one depot is administered, surgery should be performed at four weeks.
`When two depots are administered, surgery should be performed within two to four weeks following administration of the
`
`second depot.
`
`2.5 Breast Cancer
`
`For the management of advanced breast cancer, ZOLADEX is intended for long-tenn administration unless clinically
`
`inappropriate.
`
`2.6 Renal or Hepatic Impairment
`
`No dosage adjustment is necessary for patients with renal or hepatic impairment.
`
`2.7 Administration Technique
`
`The proper method of administration of ZOLADEX is described in the instructions that follow.
`
`1. Put the patient in a comfortable position with the upper part of the body slightly raised. Prepare an area of the anterior
`abdominal wall below the navel line with an alcohol swab.
`
`NOTE: Caution should be taken while injecting ZOLADEX into the anterior abdominal wall due to the proximity of
`
`underlying inferior epigastric artery and its branches.
`
`2. Examine the foil pouch and syringe for damage. Remove the syringe from the opened foil pouch and hold the syringe
`
`at a slight angle to the light. Check that at least part of the ZOLADEX implant is visible.
`
`3. Grasp the red plastic safety tab and pull away from the syringe, and discard. Remove needle cover. Unlike liquid
`
`injections, there is no need to remove air bubbles as attempts to do so may displace the ZOLADEX implant.
`
`Astrazeneca Ex. 2048 p. 3
`
`

`
`4. Holding the syringe around the protective sleeve, using an aseptic technique, pinch the skin of the patient’s anterior
`abdominal wall below the navel line. With the bevel of the needle facing up, insert the needle at a 30 to 45 degree
`
`angle to the skin in one continuous deliberate motion until the protective sleeve touches the patient’s skin.
`
`NOTE." the ZOLADEX syringe cannot be usedfor aspiration. If the h_}p0d€t'tflfC needle penetrates a large vessel,
`
`blood will be seen instantly in the syringe chamber. lfa vessel is penetrated, withdraw the needle and inject with in
`
`new syringe elsewhere. Monitor patients for signs or symptoms ofabdominal hemorrhage. Use extra care when
`
`administering ZOLADEX to patients with a law BMI and/or to patients receivingfiill dose anticoagulatian [see
`
`Warnings and Precautions (5.9i_|l.
`
`5. Do not penetrate into muscle or peritoneum.
`
`6. To administer the ZOLADEX implant and to activate the protective sleeve, grasp the barrel at the finger grip and
`
`depress the plunger until you cannot depress it any further. If the plunger is not depressed fully, the protective sleeve
`will NOT activate. When the protective sleeve ‘clicks’, the protective sleeve will automatically begin to slide to cover
`the needle.
`
`NOTE: The needle does not retract.
`
`7. Withdraw the needle and allow protective sleeve to slide and cover needle. Dispose of the syringe in an approved
`
`sharps collector.
`
`NOTE:
`
`In the unlikely event of the need to surgically remove ZOLADEX, it may be localized by ultrasound.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`ZOLADEX is supplied as a sterile and totally biodegradable D,L—lactic and glycolic acids copolymer (1 3.3—l4.3 mg/dose)
`
`impregnated with goserelin acetate equivalent to 3.6 mg of goserelin in a disposable syringe device fitted with a 16-gauge
`
`x 36 +/- 0.5 mm siliconized hypodennic needle with protective needle sleeve [SafeSystem’”" Syringe] (NDC 0310-0950-
`36).
`
`4 CONTRAINDICATIONS
`
`4.1 Hypersensitivity
`
`Anaphylactic reactions to ZOLADEX have been reported in the medical literature. ZOLADEX is contraindicated in those
`
`patients who have a known hypersensitivity to GnRH, GnRH agonist analogues or any of the components in ZOLADEX
`
`[see Warnings and Precautions [5.62].
`
`4.2 Pregnancy
`
`ZOLADEX is contraindicated during pregnancy unless ZOLADEX is being used for palliative treatment of advanced
`
`breast cancer. ZOLADEX can cause fetal harm when administered to a pregnant woman. If this drug is used during
`
`pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss
`due to expected hormone changes that occur with ZOLADEX treatment [see Use in S eci Ic Po ulatians 8.1 _
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Women of Childbearing Potential and Pregnancy
`
`Before starting treatment with ZOLADEX, pregnancy must be excluded for women using ZOLADEX for benign
`
`gynecological conditions. Women of childbearing potential should be advised to avoid becoming pregnant.
`
`Astrazeneca Ex. 2048 p. 4
`
`

`
`Effective nonhormonal contraception must be used by all premenopausal women during ZOLADEX therapy and for 12
`weeks following discontinuation of therapy. When used every 28 days, ZOLADEX usually inhibits ovulation and stops
`
`menstruation; however, pregnancy prevention is not ensured. Effects on reproductive function are expected to occur with
`chronic administration as a result of the anti—gonadotrophic properties of the drug.
`
`Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, ZOLADEX can
`
`cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy for the palliative
`
`treatment of breast cancer, then the patient should be apprised of the potential hazard to the fetus [see Use in SQ£’.C.itIC'
`Populations (8.1 1].
`
`5.2 Tumor Flare Phenomenon
`
`Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of testosterone in men with
`
`prostate cancer, and estrogen in women with breast cancer. Transient worsening of symptoms, or the occurrence of
`
`additional signs and symptoms of prostate or breast cancer, may occasionally develop during the first few weeks of
`
`ZOLADEX treatment. A small number of patients may experience a temporary increase in bone pain, which can be
`managed symptomatically.
`
`As with other GnRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed in
`
`patients with prostate cancer. If spinal cord compression or renal impairment secondaiy to ureteral obstruction develops,
`standard treatment of these complications should be instituted. For extreme cases in prostate cancer patients, an immediate
`
`orchiectomy should be considered.
`
`5.3 Hyperglycemia and Diabetes
`
`Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists.
`
`Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with
`diabetes. Monitor blood glucose and/or glycosylated hemoglobin (l-IbAlc) periodically in patients receiving a GnRH
`
`agonist and manage with current practice for treatment of hyperglycemia or diabetes [see Patient C'rmnseIr'ng Information
`[I7.1lJ.
`
`5.4 Cardiovascular Diseases
`
`Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with
`
`use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully
`
`along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a
`
`GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be
`
`managed according to current clinical practice [see Patient (Y:-unseling Information [1 7. 131'.
`
`5.5 I-Iypercalcemia
`
`As with other GnRH agonists or hormonal therapies (antiestrogcns, estrogcns, etc.), hypercaleemia has been reported in
`
`some prostate and breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalcemia
`
`does occur, appropriate treatment measures should be initiated.
`
`5.6 Hypersensitivity
`
`Hypersensitivity, antibody formation and acute anaphylactie reactions have been reported with GnRH agonist analogues
`[see Contmino'1'ecrri0nS (4. I 1.7.
`
`Of 115 women worldwide treated with ZDLADEX and tested for development of binding to goserelin following
`
`treatment with ZOLADEX, one patient showed low—titer binding to goserelin. On further testing of this patient's plasma
`obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman
`
`immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation.
`
`Astrazeneca Ex. 2048 p. 5
`
`

`
`5.7 Cervical Resistance
`
`The pharmacologic action of ZOLADEX on the uterus and cervix may cause an increase in cervical resistance. Therefore,
`
`care should be taken when dilating the cervix for cndomctrial ablation.
`
`5.8 Effect on QT/QTc Interval
`
`Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of
`
`androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart
`
`failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte
`
`abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
`
`5.9 Injection Site Injury
`
`Injection site injury and vascular injury including pain, hematoma, hemorrhage and hemorrhagic shock, requiring blood
`
`transfusions and surgical intervention, have been reported with ZOLADEX. Extra care should be taken when
`
`administering ZOLADEX to patients with a low BMI and/or to patients receiving full dose anticoagulation [see Dosage
`aridAdmim1s‘frati0n (2. 7i and Patient F()un.reiing Iiifirrmation (17.1 and 17.21/.
`
`6 ADVERSE REACTIONS
`
`6.1 Stage B2-C Prostatic Carcinoma
`
`Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone. The
`following adverse experiences were reported during a multieeriter clinical trial comparing ZOLADEX + flutamide +
`
`radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below:
`
`Table 1 ADVERSE EVENTS DURING ACUTE RADIATION THERAPY (within first 90 days of radiation
`therapy)
`
`(n=23 1)
`flutamide +
`ZOLADEX +
`
`(n:235)
`Radiation
`
`% All
`
`80
`
`Rectum/Larc Bowel
`
`Table 2 ADVERSE EVENTS DURING LATE RADIATION PHASE (after 90 days of radiation therapy)
`
`flutamide +
`ZDLAEDEX +
`
`(112235)
`Radiation
`
`Radiation
`
`Only
`
`nu
`
`Diarrhea
`
`Cystitis
`Rectal Bleedin
`
`Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal
`
`treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of
`
`Astrazeneca Ex. 2048 p. 6
`
`

`
`patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash
`(8%).
`
`6.2 Prostatic Carcinoma
`
`ZOLAIDEX has been found to be generally well tolerated in clinical trials. Adverse reactions. reported in these trials were
`
`rarely severe enough to result in the patients‘ withdrawal from ZOLADEX treatment. As seen with other hormonal
`
`therapies, the most commonly observed adverse events during ZOLADEX therapy were due to the expected physiological
`
`effects from decreased testosterone levels. These included hot flashes, sexual dysfimetion and decreased erections.
`
`Tumor F{are Phenomenon: Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels of
`
`testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms, usually
`
`manifested by an increase in cancer—related pain which was managed symptomatically. Isolated cases of exacerbation of
`disease symptoms, either ureteral obstruction or spinal cord compression, occurred at similar rates in controlled clinical
`
`trials with both ZOLADEX and orchicctomy. The relationship of these events to therapy is uncertain [see Warnings and
`Preccmrions (5.233.
`
`In the controlled clinical trials of ZOLADEX versus orchiectomy, the following events were reported as adverse reactions
`
`in greater than 5% of the patients.
`
`Table 3 TREATMENT RECEIVED
`
`n=242
`
`n=254
`
`62
`
`unuit.-iLnLn:3\a\-J-.1oc
`
`53
`_- U1
`n=v 5%
`
`'—‘-§'—‘UJl‘-F-§'—‘l“-JDCUJ-li-GO
`
`Hot Flashes
`
`Sexual Dysfunction
`Decreased Erections
`
`Lower Urinary Tract Symptoms
`Lethar
`
`Edema
`U o I er Res to irato
`Rash
`
`Infection
`
`Sweating
`Anorexia
`Chronic Obstructive Pulmona
`
`Conestive Heart Failure
`Dizziness
`Insomnia
`Nausea
`
`Corn lications of Sure
`Complications related to surgery were reported in 18% of the orchiectomy patients. while only 3% of ZOLADEX patients
`reported adverse reactions at the injection site. The surgical complications included scrotal infection (5.9%), groin pain
`(4.7%), wound seepage (3. l%), scrotal hematoma (2.8%), incisional discomfort (1.6%) and skin necrosis (1.2%).
`
`Ln
`6
`
`IN)
`»—~ 00
`
`The following additional adverse reactions were reported in greater than 1% but less than 5% of the patients treated with
`ZOLADEX: CARDIOVASCULAR - arrhythmia, cerebrovascular accident, hypertension, myocardial infarction,
`
`peripheral vascular disorder, chest pain; CENTRAL NERVOUS SYSTEM - anxiety, depression, headache;
`
`GASTROINTESTINAL - constipation, diarrhea, ulcer, Vomiting; HEMATOLOGIC - anemia;
`METABOLIC/NUTRITIONAL - gout, hyperglycemia, weight increase; MISCELLANEOUS - chills, fever;
`
`UROGENITAL - renal insufficiency, urinary obstruction, urinary tract infection, breast swelling and tenderness.
`
`Astrazeneca Ex. 2048 p. 7
`
`

`
`6.3 Females
`
`As would be expected with a drug that results in hypoestrogenism, the most frequently reported adverse reactions were
`those related to this effect.
`
`6.4 Endometriosis
`
`In controlled clinical trials comparing ZOLADEX every 28 days and danazol daily for the treatment of endometriosis, the
`
`following events were reported at a frequency of 5% or greater:
`
`Table 4 TREATMENT RECEIVED
`
`ZOLADEX DANAZOL
`n=4 I 1
`n=2lI7
`%
`%
`96
`67
`"-JU1
`Lo)
`
`4 6
`
`U1
`44
`
`30
`48
`U1 U]
`
`»—- DJ
`
`O\U\‘~J-‘GU:
`
`14
`12
`1 3
`
`ADVERSE EVENT
`Hot Flushes
`
`Va initis
`Headache
`Emotional Labili
`Libido Decreased
`
`Sweatin
`De ression
`Acne
`Breast Atro o h
`Scborrhea
`Peri heral Edema
`
`Breast Enlargement
`Pelvic S mtoms
`Pain
`
`Dywareunia
`Libido Increased
`Infection
`Asthenia
`Nausea
`
`Hirsutisrn
`Insomnia
`Breast Pain
`Abdominal Pain
`Back Pain
`
`Flu Syndrome
`Dizziness
`
`Application Site Reaction
`
`-—m-33U14:[U '—‘I\JU-I-.l-L»)
`
`Leg Cramps
`Increased Appetite
`Pruritus
`
`Hypertonia
`
`Astrazeneca Ex. 2048 p. 8
`
`

`
`The following adverse events not already listed above were reported at a frequency of 1% or greater, regardless of
`causality, in ZOLADEX-treated women from all clinical trials: WHOLE BODY - allergic reaction, chest pain, fever,
`
`malaise; CARDIOVASCULAR — hemorrhage, hypernension, migraine, palpitations, tachycardia; DIGESTIVE — anorexia,
`
`constipation, diarrhea, dry mouth, dyspepsia, flatulence; HEMATOLOGIC — ecchymosis; METABOLIC AND
`
`NUTRITIONAL — edema; MUSCULOSKELETAL — arthralgia, joint disorder; CNS — anxiety, paresthesia, somnolence,
`
`thinking abnormal; RESPIRATORY - bronchitis, cough increased, epistaxis, rhinitis, sinusitis; SKIN - alopecia, dry skin,
`
`rash, skin discoloration; SPECIAL SENSES - amblyopia, dry eyes; UROGENITAL - dysmenorrhea, urinary frequency,
`
`urinary tract infection, vaginal hemorrhage.
`
`6.5 Endometrial Thinning
`
`The following adverse events were reported at a frequency of 5% or greater in premenopausal women presenting with
`
`dysfunctional uterine bleeding in Trial 0022 for endometrial thinning. These results indicate that headache, hot flushes
`
`and sweating were more common in the ZOLADEX group than in the placebo group.
`
`Table 5 ADVERSE EVENTS REPORTED AT A FREQUENCY OF 5% OR GREATER IN ZOLADEX AND
`PLACEBO TREATMENT GROUPS OF TRIAL D022
`
`ZOLADEX Placebo
`
`3.6 mg
`(n=180)
`%
`
`(n=l 7'7)
`
`%
`
`ADVERSE EVENT
`
`Whole Bad -2
`Headache
`32
`22
`Abdominal Pain
`1 l
`10
`Pelvic Pain
`9
`6
`Back Pain
`4
`7
`Cardiovascular
`
`Ill
`7
`4
`Migraine
`H ertension
`
`6
`
`2
`
`Digestive
`
`Nervous
`
`Res irator
`
`Sinusitis
`
`3
`
`6
`
`Skin and a endaes
`-1
`-2
`
`Vulvovainitis
`
`Menorrhagia
`Vaginitis
`
`5
`
`4
`1
`
`1
`
`5
`6
`
`6.6 Breast Cancer
`
`The adverse event profile for women with advanced breast cancer treated with ZOLADEX is consistent with the profile
`described above for women treated with ZOLADEX for endomctriosis. In a controlled clinical trial (SWOG—8692)
`
`Astrazeneca Ex. 2048 p. 9
`
`

`
`comparing ZOLADEX with oophoreetomy in premenopausal and perimenopausal women with advanced breast cancer,
`the following events were reported at a frequency of 5% or greater in either treatment group regardless of causality.
`
`Table 6 TREATMENT RECEIVED
`
`ADVERSE JEVENT
`Hot Flashes—
`
`ZOLADEX OOPHORECTOMY
`
`(n=57)
`% of Pts.
`
`(n=55)
`% of Pts.
`
`Nausea
`Edema
`
`Malaise/Fatigue/Lethargy Vomitin ;
`
`In the Phase II clinical trial program in 333 pre- and perimenopauisal women with advanced breast cancer, hot flashes
`were reported in 75.9% of patients and decreased libido was noted in 47.7% of patients. These two adverse events reflect
`
`the pharmacological actions of ZOLADEX.
`
`Injection site reactions were reported in less than 1% of patients.
`
`6.7 Hormone Replacement Therapy
`
`Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to ZOLADEX may
`
`decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypocstrogenism without
`
`compromising the efficacy of ZOLADEX in relieving pelvic symptoms. The optimal drugs, dose and duration of
`treatment has not been established.
`
`6.8 Changes in Bone Mineral Density
`
`After 6 months of ZOLADEX treatment, 109 female patients treated with ZOLADEX showed an average 4.3% decrease
`
`of vertebral trabecular bone mineral density (BMD) as compared to pretreatment values. BMD was measured by dual-
`
`photon absorptiometry or dual energy x—ray absorptiometry. Sixty-six of these patients were assessed for BMD loss 6
`
`months after the completion (posttherapy) of the 6-month therapy period. Data from these patients showed an average
`
`2.4% BMD less compared to pretreatment values. Twenty-eight of the 109 patients were assessed for BMD at 12 months
`
`postthcrapy. Data from these patients showed an average decrease of 2.5% in BMD compared to pretreatment values.
`These data suggest a possibility of partial reversibility. Clinical studies suggest the addition of Hormone Replacement
`
`Therapy [estrogens andlor progestins) to ZOLADEX is effective in reducing the bone mineral loss which occurs with
`ZOLADEX alone without compromising the efficacy of ZOLADEX in relieving the symptoms of endometriosis. The
`
`optimal drugs, dose and duration of treatment has not been established [see Patient C’oimr.seZing Irjormation (1 7.2)].
`
`6.9 Changes in Laboratory Values During Treatment
`
`Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to ZOLADEX
`
`(representing less than 1% of all patients).
`
`Lipids.‘ In a controlled trial, ZOLADEX therapy resulted in a minor, but statistically significant effect on scnun lipids. In
`
`patients treated for endometriosis at 6 months following initiation of therapy, danazol treatment resulted in a mean
`
`increase in LDL cholesterol of 33.3 mg/dL and a decrease in HDL cholesterol of 21.3 mg/dL compared to increases of
`
`21.3 and 2.7 mg/dL in LDL cholesterol and HDL cholesterol, respectively, for ZOLADEX—treated patients. Triglycerides
`
`increased by 8.0 mg/dL in ZOLADEX-treated patients compared to a decrease of 8.9 mg/dL in danazol-treated patients.
`
`AstraZeneea Ex. 2048 p. 10
`
`

`
`In patients treated for endometriosis, ZOLADEX increased total cholesterol and LDL cholesterol during 6 months of
`
`treatment. However, ZOLADEX therapy resulted in HDL cholesterol levels which were significantly higher relative to
`
`danazol therapy. At the end of 6 months of treatment, HDL cholesterol fractions (HDL; and HDL3) were decreased by
`13.5 and 7.7 mg/dL, respectively, for danazol-treated patients compared to treatment increases of I .9 and 0.8 mgldls,
`
`respectively, for ZOLADEX-treated patients.
`
`6.10 Postrnarketing Experience
`
`The following adverse reactions have been identified during post-approval use ofZOLADEX. Because these reactions are
`reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
`
`establish a causal relationship to drug exposure.
`
`Bone Mineral l)ensizy.' Osteoporosis, decreased bone mineral density and bone fracture in men [see Patient (10unsez’ing
`Information ('1 7.1‘! and (I 7.2!].
`
`Cara'iovasc'uIar.' Deep vein thrombosis, pulmonary embolism, myocardial infarction. stroke. and transient ischemic attack
`
`have been observed in women treated with GnRH agonists. Although a temporal relationship was reported in some cases,
`most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association
`
`between the use of GnRH analogs and these events.
`
`Ovarian ("ysts Ovarian cyst fonnation and, in combination with gonadotropins. ovarian hyperstimulation syndrome
`(OH SS).
`
`Changes in Blood Pressure: Hypotension and hypertension have been reported. These changes are usually transient,
`
`resolving either during continued therapy or after cessation of therapy.
`
`PinmaryApopIexy and Tumors: Pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland)
`
`and pituitary adenoma have been diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first
`
`dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache,
`vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate
`
`medical attention has been required. Pituitary tumors have been reported.
`
`Acne: Usually within one month of starting treatment.
`
`Other Adverse Reactions.‘ Psychotic disorders, convulsions and mood swings.
`
`7 DRUG INTERACTIONS
`
`No fonnal drug-drug interaction studies have been perfonned. No confirmed interactions have been reported between
`ZOLADEX and other drugs.
`
`7.1 Drug/Laboratory Test Interactions
`
`Administration of ZOLADEX in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this
`
`suppression, diagnostic tests of pituitary—gonadotropic and gonadal functions conducted during treatment and until the
`resumption of menses may show results which are misleading. Normal function is usually restored within 12 weeks after
`treatment is discontinued.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category D in patients with advanced breast cancer.
`
`Pregnancy Category X in patients with endomctriosis and cndornctrial thinning.
`
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`
`

`
`ZOLADEX is contraindicated during pregnancy unless ZOLADEX is being used for palliative treatment of advanced
`
`breast cancer. There are no adequate and well-controlled studies in pregnant women using ZOLADEX. Based on
`
`mechanism of action in humans and findings of increased pregnancy loss in animal studies, ZOLADEX can cause fetal
`
`hann when administered to a pregnant woman. If this drug is used during pregnancy, the patient should be apprised of the
`
`potential hazard to