I-IIGHLIGI-ITS OF PRE.S(.‘RlB[NG INFORMATION
`These highlights do not include all the information needed to use
`ZOLADEX safely and effectively. See full prescribing information for
`ZOLADEX.
`
`ZOLADEX” (goscrelin acetate implant} 3.6 mg
`Initial ILS. Approval: I989
`
`INDICATIONS AND USAGE
`ZOLADEX is a Gonadotropin Releasing Ilonrtone (CmRl I) agonist indicated
`for:
`0
`
`Use in combination with Iltttamide for the management of locally
`confined carcinoma of the prostate gm)
`Palliative treatment of advanced carcinoma of the prostate (_Q)
`The management ofendoinetriosis Lg;
`Use as an endometrial-tliinning agent prior to endometrial ablation for
`dysfunctional uterine bleeding j__l_.i[
`Use in the palliative treatment ol'advanced breast cancer in pre— and
`pcrimenopausal women t 1.5.1
`
`0
`Is
`I
`
`-
`
`-A DOSAGE AND ADMINISTRATION
`-
`ZOLADI-LX 3.6 mg should be administered subcutaneously every 28
`days t2._t. 2+?)
`For the management ofendometriosis, the recommended duration of
`administration is 6 months for women 18 years of age and older (E)
`
`-
`
`-———-—-—-—-— DOSAGE FORMS AND STRENGTHS
`Implant 3.6 mg 1;)
`
`CONTRAINDICATIONS
`Hypersensitivity 14.1 1
`Pregnancy unless used for treatment of advanced breast cancer [42]
`
`0
`-
`
`—-—-—-—-——-——- WARNINGS AND PRECAUTIONS
`
`-
`
`I
`
`-
`
`Women of Childbearing Potential and Pregnancy: Pregnancy must be
`excluded for use in benign gynecological conditions. Women should
`avoid pregnancy
`Tumor I-‘lare Phenomenon: Transient worsening of tumor symptoms
`may occur during the tirst Few weeks of treatment with ZDLADEX.
`which may include uretcral obstruction and spinal cord compression.
`Monitor patients at risk for complications of tumor flare (Q, Q‘)
`Hyperglycemia and Diabetes: Hyperglycemia and an increased risk of
`developing diabetes have been reported in men receiving Gnl-{H analogs.
`Monitor blood glucose level and manage according to current clinical
`practice 1531
`
`FULL PRESCRIBING INFORMATION: CONTENTS:
`
`I INDICATIONS AND IISAGE.
`|.i Stage B2413 Prostatie Carcinoma
`l.2 Prostatic Carcinoma
`L3 Endometriosis
`l.4 Endometrial Thinning
`l.5 Advanced Breast Cancer
`2 DOSAGE AND ADMINISTRATION
`2.1 Stage B2~C Prostatic Carcinoma
`2.2 Prostatic Carcinoma
`2.3 Endometriosis
`2.4 Endomctrial Thinning
`2.5 Breast Canccr
`2.6 Renal or Hepatic lmpainnent
`2.7 Administration Technique
`3 DOSAGE FORMS AND STRENGTHS
`4 (‘0N’I‘RAlNDICA"I‘lONS
`4.1 llypersensitivity
`4.2 Pregnancy
`5 WARNINGS AND PRE(.‘AliTIONS
`5.1 Women ot‘Childbearing Potential and Pregnancy
`5.2. Tumor Flare Phenomenon
`5.3 Hyperglycemia and Diabetes
`5.4 Cardiovascular Diseases
`5.5 Hypercalcemia
`5.6 Hypersensitivity
`5.7 Cervical Resistance
`5.8 Effect on QT/QTc Interval
`5.9 Injection Site Injury
`
`I
`
`0
`
`0
`
`-
`
`-
`
`I
`
`‘Cardiovascular Diseases: Increased risk of myocardial infarction, sudden
`cardiac death and stroke has been reported in association with use of
`GnRIl analogs in men. Monitor for cardiovascular disease and manage
`according to current clinical practice
`Hypcrcalcemia: Hypercalccrnia has been reported in patients with bone
`metastases treated with ZOLADEX. Monitor and manage appropriately
`
`Hypersensitivity: Systemic hypersensitivity has been reported in patients
`receiving goserelin/ZOLADIEX impiants (Q, E
`Cervical Resistance: Increase in cervical resistance may occur. Caution
`is recommended when dilating the cervix for endometrial ablation
`Effect on QT.fQ~Tc Interval: Androgen deprivation therapy may prolong
`the QT interval. Consider risks and bcnctits mg
`Injection Site Injury: Injection site injury and vascular injury have been
`reported during administration of Z0l.AD[-IX l_5._9)
`
`ADVERSE REACTIONS
`The most common, clinically significant adverse reactions occurring in >-10%
`of men: hot flashes, sexual dysfunction, decreased erections and lower urinary
`tract symptoms [Q]
`
`The adverse event profile was similar For women treated for breast cancer.
`dysfunctional uterine bleeding or endometriosis and included (>20%): hot
`Flushes, headache. sweating, acne. emotional lubility, depression, decrerused
`libido. vaginitis. breast atrophy. scborrhea. and peripheral edema L511
`Tumor flare can occur on the initiation of ZOLADEX for both men and
`women being treated for cancer Lg]
`
`To report SIISPECTED ADVERSE REACTIONS. contact Astraleneea
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.Ida.gow'medwatch.
`
`-I
`
`a
`
`t
`
`None
`
`DRUG INTERACTIONS
`
`US]: IN SPE(.‘Il~‘lC POPULATIONS
`Nursing mothers: Discontinue drug or nursing taking into account the
`importance ofdrug to the mother IQ}
`No infonnation available for use in Pediatric patients {fit
`Geriatric 58.51
`Renal and Hepatic impairment: No dose adjustment is necessary (as.
`fi. El
`
`See I? for PATIENT COUNSELING INFORMATION
`
`Revised: February 2016
`
`6 ADVERSE REACTIONS
`6.] Stage B2-C Prostatic Carcinoma
`6.2 Prostatic Carcinoma
`6,3 Females
`6.4 Endomctriosis
`6.5 Endonietrial Thinning
`6.6 Breast Cancer
`6.7 Hormone Rcplaccmcrtt Therapy
`6.3 Changes in Bone Mineral Density
`6.9 Changes in Laboratory Values During Treatment
`6.10 Postmarketing Experience
`7 DRUG INTERACTIONS
`?.l Drug/Laboratory Test Interactions
`8 USE IN SPECIFIC POPIILATIONS
`3.] Pregnancy
`8.3 Nursing Mothers
`3.4 Pediatric Use
`85 Geriatric Use
`8.6 Renal lnsufficiency
`8.7 Hepatic Insufficiency
`I0 OVERDOSAGE
`II DESCRIPTION
`[2 CLINICAL PIIARIVIACOLOGY
`!2.l Mechanism of Action
`l2.2 Pliainiacodynainics
`l2.3 Pharmaeokinetics
`I3 NON(.‘.LINl(.‘.AL 'I‘0Xl(.?0LOGY
`l3.| Carcinogenesis, Mutagcnesis. Impairment of Fertility
`I4 (.‘I.INICAI. STUDIES
`
`Astrazeneca Ex. 2048 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR20l6-01325
`
`

`
`|4.l Stage B2-C Prostatic Carcinoma
`14.2 Proslutic (‘arcinorrra
`l4.3 Endometriosis
`|4.4 Endnmctrial Thinning
`I45 Breast Cancer
`
`I6 IIOW S[lPPLIEDi'S'l'ORAGI£ AND IIANDLING
`IT PATIENT (IUIINSELING INFORMATION
`1‘i'.| Males
`17.2 Females
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`1.1 Stage B2-C Prostatic Carcinoma
`
`ZOLADEX is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4
`
`(Stage B2-C) carcinoma of the prostate. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating
`
`radiation therapy and continue during radiation therapy [see Dosage c:r1dAdmim's!rarior1 (2.1) and Ciinicai Studies
`
`1.341;],
`
`1.2 Prostatic Carcinoma
`
`ZOLADEX is indicated in the palliative treatment of advanced carcinoma of the prostate [see Dosage cmdAdinir?isi‘ra!iorr
`12.21arm'C'i'i:rfcaiSIttdies 14.2 .
`
`1.3 Endometriosis
`
`ZOLADEX is indicated for the management of endometriosis, including pain relief and reduction of endometriotic 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 Admintstmiion (2._3J and Cliriiccn’ .S'tud:'es (14..i_)_].
`
`1.4 Endometrial Thinning
`
`ZOLADEX is indicated for use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine
`
`bleeding [see Dosage and Adrriim’s'(rati()n (2.41 and CIinii:'aI' S'Iudie.s' (14.42/.
`
`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 Adrnfnf.s'!ran'on (2.6; C'i'infcaI Pharrricrcolaggi ([2. I1, and C‘/im'cm' Smdies [14.5.
`
`The automatic safety feature of the syringe aids in the prevention of needlestick injury.
`
`2 DOSAGE AND ADMINISTRATION
`
`ZOLADEX, 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 ana'Adminisira1:'w1
`
`@727-
`
`While a delay ofa few days is permissibie, every effort should be made to adhere to the 28-day schedule.
`
`2.1 Stage B2-C Prostatic Carcinoma
`
`When ZOLADEX is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C)
`
`prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during
`
`radiation therapy. A treatment regimen using a ZOLADEX 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 of 3.6 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 ofadministration is 6 months.
`
`Currently, there are no clinical data on the effect of treatment of benign gynecological conditions with ZOLADEX for
`
`periods in excess of6 months.
`
`Retreatment cannot be recommended for the management of endometriosis since safety data for retreatment 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 (estrogens and/or 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 addition of Hormone 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-term 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 ofthe body slightly raised. Prepare an area ofthe 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 ofthe 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 aspiralion. ifrlre lg/poderniic needle penetrates a large vessel.
`
`blood will be seen imtanlly in the syringe clramber. Ifa vessel is penetrated, williclraw the needle and injec! with a
`
`new .s_vringe elsewhere. Monitor patients for signs or symptoms Qf'abclorm'nal liemorrlrage. Use extra care when
`
`admim'ster:'r7g ZOLADEX to patients with a low BM! and/or to paliems receivingfirll dose amicoagulation [see
`
`Warmings and Pr'ecam‘."on.s' [19]].
`
`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 ofthe 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 (13.3-l4.3 mg/dose)
`
`impregnated with goserelin acetate equivalent to 3.6 mg of gnserelin in a disposable syringe device fitted with a 16-gauge
`
`x 36 +l- 0.5 mm siliconized hypodermic 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 GHRH, GnRH agonist analogues or any ofthe components in ZOLADEX
`
`[see Warnings and Precautions [$7.61].
`
`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. lfthis 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 Sgecltrc Populations (8.12/.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Women of Childbearing Potential and Pregnancy
`
`Before starting treatment with ZOLA DEX, pregnancy must be excluded for women using Z0l,..ADE.X 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 premcnopausal women during ZOLADEX therapy and for l2
`
`weeks following discontinuation oftherapy. 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. Ifthis 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 Sgecifirc
`
`Pr)gJuIa!1'ons (8. I j I.
`
`5.2 Tumor Flare Phenomenon
`
`Initially, ZOLADEX, like other GnRH agonists, causes transient increases in serum levels oftestosterone 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 secondary to ureteral obstruction develops,
`
`standard treatment ofthese 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 ofglycemic control in patients with
`
`diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA l c) periodically in patients receiving a GnRH
`
`agonist and manage with current practice for treatment of hyperglycemia or diabetes [see Patient Counseling Imformatiorr
`
`117.13}.
`
`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 Patten! Cazmseling Information {I 7.1)].
`
`5.5 Hypercalcemia
`
`As with other GnRH agonists or hormonal therapies (antiestrogens, estrogens, etc.), hypercalcemia has been reported in
`
`some prostate and breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalccmia
`
`does occur, appropriate treatment measures should be initiated.
`
`5.6 Hypersensitivity
`
`Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues
`
`[see Contraindic-aliens (4.1 J J.
`
`Of] 15 women worldwide treated with ZOLADEX 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 ofantibody formation.
`
`AstraZeneca Ex. 2048 p. 5
`
`

`
`5.7 Cervical Resistance
`
`The pharrnacologic 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 endometrial ablation.
`
`5.8 Effect on QT/QTc Interval
`
`Androgen deprivation therapy may prolong the QTKQTC 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
`
`and Adrnirifstrmion (2. 71 and Pmierr! (.'o1.mSel'ing irgfbrrrrcrtiori (I 7.1 and I 7. 2}] .
`
`6 ADVERSE REACTIONS
`
`6.1 Stage B2-C Prostatic Carcinoma
`
`Treatment with ZOLADEX and flutarnide did not add substantially to the toxicity of radiation treatment alone. The
`
`following adverse experiences were reported during a multicenter 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=231)
`(n=235)
`flutamide +
`Radiation
`ZOLADEX +
`
` Radiation Onl
`% All
`% All
`
`Rectum/Large Bowel
`Bladder
`Skin
`
`80
`S8
`37
`
`76
`60
`3?
`
`Table 2 ADVERSE EVENTS DURING LATE RADIATION PHASE (after 90 days of radiation therapy)
`
`(n=231)
`flutamide +
`ZOLADEX +
`
`(n=235)
`Radiation
`
`Hematuria
`
`Radiation
`% All
`
`Only
`% All
`
`Diarrhea
`
`Cystitis
`Rectal Bleeding
`Proctitis
`
`Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal
`
`treatment and hormonal treatment plus radiation phases ofthe 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
`
`ZOLADEX 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 honnonal
`
`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 dysfunction and decreased erections.
`
`Tmnor Flare PIl?e'H()fl7€f?0f?.'
`
`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 orchiectomy. The relationship of these events to therapy is uncertain [rec Wurmngs aria’
`
`Precautions (5.213.
`
`In the controlled clinical trials ofZOLADEX versus orchiectomy, the following events were reported as adverse reactions
`
`in greater than 5% of the patients.
`
`Table 3 TREATMENT RECEIVED
`
`ADVERSE EVENT
`Hot Flashes
`
`Sexual D sfunction
`Decreased Erections
`
`Lower Urinary Tract Symptoms
`Lethargy
`Pain (worsened in the first 30 days)
`Edema
`U - er Rcsirator
`Rash
`
`Infection
`
`Sweating
`Anorexia
`Chronic Obstructive Pulmonary Disease
`Con estive Heart Failure
`
`Insomnia
`
`ZOLADEX ORCHIECTOMY
`
`(n=242)
`%
`62
`
`(n=254)
`%
`53
`
`21
`I8
`
`I3
`8
`8
`7
`7
`6
`
`6
`5
`5
`5
`
`5
`
`IS
`I6
`
`8
`4
`3
`8
`2
`I
`
`4
`2
`3
`1
`
`I
`
`I
`
`2
`5
`Nausea
`I
`18’
`0
`Complications of Surgery
`"
`Complications related to surgery were reported in 18% of the orchiectorny patients, while only 3% ofZOLADEX patients
`reported adverse reactions at the injection site. The surgical complications included scrotal infection (5.9%), groin pain
`(4.7°/all wound seepage (3.1%), scrotal hematoma (2.8%), incisional discomfort (I .6%} and skin necrosis (1.2%).
`
`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, urinaly 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 clanazol daily for the treatment of endonietriosis, the
`
`following events were reported at a frequency of 5% or greater:
`
`Table 4 TREATMENT RECEIVED
`
`ADVERSE EVENT
`
`K Hot lflushes
`Vainitis
`Headache
`
`Emotional Lability
`Libido Decreased
`
`Sweating
`Depression
`Acne
`
`Breast Atrophy
`Seborrhea
`
`Peripheral Edema
`Breast Enlargement
`Pelvic S rntoms
`Pain
`
`Dyspareunia
`Libido Increased
`Infection
`
`Asthenia
`
` ZOLADEX DANAZOL
`(n=207)
`"/0
`
`6‘?
`43
`63
`
`56
`44
`
`30
`48
`55
`
`42
`52
`
`34
`I5
`23
`16
`
`5
`I9
`I
`I
`
`13
`
`*
`
`Nausea n 14
`Hirsutism
`7
`I5
`
`I
`I
`7
`
`4
`Insomnia
`4
`Breast Pain
`7
`Abdominal Pain
`13
`Back Pain
`5
`Flu S ndrome
`Dizziness n 4
`A lication Site Reactionn -
`Voice Alterations
`8
`Pha nitis
`2
`Hair Disorders
`1 I
`M alia
`11
`Nervousness
`5
`Weiht Gain
`23
`Le Crams
`6
`Increased A - etite
`5
`Pruritus
`6
`Hypertonia
`10
`
`l
`
`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, hypertension, 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 cormnon 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 0022
`
`ZOLADEX Placebo
`
`3.6 mg
`n=180
`
`(n=l7'I')
`
`ADVERSE EVENT
`whole Bod jj
`Headache
`
`Abdominal Pain
`
`Pelvic Pain
`
`Back Pain
`Cardiovascular
`Vasodilatation E
`Miraine
`Hypertension
`Digestive
`Nausea
`Nervous
`Nervousness
`
`6
`
`5
`
`2
`
`6
`
`Depression
`Respiratory
`Pharyngitis
`Sinusitis
`
`3
`
`6
`3
`
`7"
`
`9
`6
`
`Skin and a endaes -2
`5
`Sweating
`I6
`Urogenital
`Dysmenorrhea
`Uterine Hemorrhage
`Vulvovainitis
`
`9
`4
`I
`
`7
`6
`5
`
`Menorrhagia
`Vaginitis
`
`4
`l
`
`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 endometriosis. In a controlled clinical trial (SWOG—8692)
`
`AstraZeneca Ex. 2048 p. 9
`
`

`
`comparing ZOLADEX with oophorectomy in premenopausal and perimenopausal women with advanced breast cancer,
`
`the following events were reported at a frequency of5% or greater in either treatment group regardless of causality.
`
`Table 6 TREATMENT RECEIVED
`
`ZOLADEX OOPHORECTOMY
`
`% of Pts.
`47
`
`4
`7’
`
`0 2 7
`
`ADVERSE EVENT
`Hot Flashes
`
`Tumor Flare
`Nausea
`Edema
`
`Vomitin
`
`Malaise/FatiuefLethar
`
`In the Phase ll clinical trial program in 333 pre- and perimenopausal women with advanced breast cancer, hot flashes
`
`were reported in 75.9% ofpatients and decreased libido was noted in 47.7% ofpatients. These two adverse events reflect
`
`the pharmacological actions ofZOLADEX.
`
`Injection site reactions were reported in less than l% of patients.
`
`6.7 Hormone Replacement Therapy
`
`Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens andfor progestins) to ZOLADEX may
`
`decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism 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 {BM D) as compared to pretreatment values. BMD was measured by dual-
`
`photon absorptiometry or dual energy x-ray absorptiometry. Sixty-six ofthese 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 loss compared to pretreatment values. Twenty-eight of the 109 patients were assessed for BMD at 12 months
`
`posttherapy. 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 I Iormone Replacement
`
`Therapy (estrogens and/or 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 Perrier?! C'ormseir'ng Irrfbrnzuriun {I221}.
`
`6.9 Changes in Laboratory Values During Treatment
`
`PI’as.ma Enzymes.‘ Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to ZOLADEX
`
`(representing less than 1% of all patients).
`
`Lr'pr'ds:
`
`In a controlled trial, ZOLADEX therapy resulted in a minor, but statistically significant effect on serum lipids. In
`
`patients treated for endometriosis at 6 months following initiation oftherapy, danazol treatment resulted in a mean
`
`increase in LDL cholesterol of33.3 mg/dL and a decrease in HDL cholesterol of2l .3 mg/dL compared to increases of
`
`2l.3 and 2.7 mg/dL in LDL cholesterol and HDL cholesterol, respectively, for ZOLADEX-treated patients. Triglycerides
`
`increased by 8.0 mgi’dL in ZOLADEX-treated patients compared to a decrease of 8.9 mgx’dL in danazol-treated patients.
`
`Astrazeneca 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 1.9 and 0.8 mg/dL,
`
`respectively, for ZOLADEX-treated patients.
`
`6.10 Postmarketing Experience
`
`The following adverse reactions have been identified during post-approval use of ZOLADEX. 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 Der1.sfty.' Osteoporosis, decreased bone mineral density and bone fracture in men [see Patient C'(Jun.s‘e[irrg
`
`Information (17. E3 and [1 7.22].
`
`Cardr‘ovascz.r!ar.' 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 ifthere is a causal association
`
`between the use of GnRH analogs and these events.
`
`Ovarian Cyst‘: Ovarian cyst formation and, in combination with gonadotropins, ovarian hyperstimulation syndrome
`
`(OHSS).
`
`Charrges in Blood Pressure: Hypotension and hypertension have been reported. These changes are usually transient,
`
`resolving either during continued therapy or after cessation of therapy.
`
`Pituitary Apopfexy 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, aitered 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.
`
`()!hcr Adverse Reactiorr.r.' Psychotic disorders, convulsions and mood swings.
`
`7 DRUG INTERACTIONS
`
`No formal drug-drug interaction studies have been performed. 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 ofrnenses may show results which are misleading. Normal function is usually restored within 12 weeks after
`treatment is discontinued.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.! Pregnancy
`
`Pregnancy Category D in patients with advanced breast cancer.
`
`Pregnancy Category X in patients with endometriosis and endometrial thinning.
`
`Astrazeneca Ex. 2048 p. 11
`
`

`
`ZOLADEX is contraindicated d