NOVARTIS EXHIBIT 2022
`Noven v. Novartis and LTS Lohmann
`IPR2014-00549
`Page 1 of 96
`
`

`
`NOVARTIS EXHIBIT 2022
`Noven v. Novartis and LTS Lohmann
`IPR2014-00549
`Page 2 of 96
`
`

`
`486/PHYSICIANS' DESK REFERENCE®
`
`Alza-Cont.
`
`PRECAUTIONS
`GENERAL
`Patients should be adequately hydrated prior to the infusion
`and blood pressure should be monitored during the infusion.
`ETHYOL should be administered as a IS-minute infusion
`(See DOSAGE and ADMINISTRATION).
`The safety of ETHYOL administration has not been estab(cid:173)
`lished in elderly patients, or patients with preexisting cardi(cid:173)
`ovasCular or cerebrovascular conditions such as ischemic
`heart disease, arrhythmias, congestive heart failure, or his(cid:173)
`tory of stroke or transient ischemic attacks. ETHYO~ should
`be used with particular care in these and other patients 10
`whom the common ETHYOL adverse effects of nausea/vom·
`iting and hypotension may be more likely to have serious
`consequences.
`Drug Interactions
`There are no known drug interactions with ETHYOL. How(cid:173)
`ever special consideration should be given to the administra(cid:173)
`tion ~fETHYOL in patients receiving antihypertensive med(cid:173)
`ications or other drugs that could potentiate hypotension.
`Carcinogenesis, Mutagenesis and Impairment of Fertility
`No long term animal studies have been performed to evalu(cid:173)
`ate the carcinogenic potential of ETHYOL." ETHYOL was
`negative in the Ames test and in the mouse mi~~onl;lcleus
`test. The free thiol metabolite, however, was posItive 10 the
`Ames test with S9 microsomal fraction in the TA1535 Salmo(cid:173)
`nella typhimurium strain and at the TK locus in the mouse
`L5178Y cell assay. The metabolite was negative in the mouse
`micronucleus test and negative for clastogenicity in human
`lymphocytes.
`Pregnancy
`Pregnancy Category C. ETHYOL (amifostine) has been
`shown to be embryotoxic in rabbits at doses of 50 mg/kg,
`approximately sixty percent of the recommended dose 10
`humans on a body surface area basis. There are no adequate
`and well-controlled studies in pregnant women. ETHYOL
`should be used during pregnancy only ifthe potential benefit
`justifies the potential risk to the fetus.
`Nursing Mothers
`No information is available on the excretion of ETHYOL or
`its metabolites into human milk. Because many drugs are
`excreted in human milk and because ofthe potential for ad(cid:173)
`verse reactions in nursing infants. it is recommended that
`breast feeding be discontinued if the mother is treated with
`ETHYOL.
`
`ADVERSE REACTIONS
`ETHYOL produced a transient reduction in blood pressure
`in 62% of patients treated. The mean time of onset was 14
`minutes into the IS-minute period ofETHYOL infusion, and
`the mean duration was 6 minutes. In some cases, the infusion
`had to be prematurely terminated due to a more pronounced
`drop in systolic blood pressure. In general, the blood pressure
`returned to normal within 5-15 minutes. Fewer than 3% of
`patients discontinued ETHYOL due to blood pressure reduc(cid:173)
`tions. Short term, reversible loss of consciousness has been
`reported rarely. Blood pressure reductions during ETHYOL
`administration have not been reported to cause long~term
`CNS, cardiovascular or renal sequelae, but clinical studies
`performed to date have not evaluated the safety of ETHYOL
`in elderly patients or patients with pre-existing cardiovascu(cid:173)
`lar or cerebrovascular conditions.
`Hypotension that requires interruption of the ETHYOL
`Infusion should be treated with fluid infusion and postural
`management of the patient (supine or Trendelenburg posi(cid:173)
`tion). If the blood pressure returns to normal within 5 min(cid:173)
`utes and the patient is asymptomatic, the infusion may be
`restarted, so that the full dose of ETHYOL can be adminis(cid:173)
`tered.
`Nausea and/or vomiting occur frequently after amifostine
`infusion and may be severe. In the ovarian cancer random~
`ized study, the incidence of severe nausea/vomiting on day. 1
`of cyclophosphamide-dsplatin chemotherapy was 10':0 10
`patients who did not receive ETHYOL, and 19% In patients
`who did receive ETHYOL. Other effects which have been
`described during or following ETHYOL infusion are flush(cid:173)
`ing/feeling of warmth, chills/feeling of coldness, dizziness,
`somnolence, hiccupa and sneezing. These effects have not
`generally precluded the completion of chemotherapy.
`Decrease in serum calcium concentrations is a known phar(cid:173)
`macological effect of ETHYOL. At the recommended doses,
`clinically significant hypocalcemia has occurred rarely
`«1%).
`Allergic reactions, ranging from mild skin rashes to rigors,
`have occurred rarely « 1 %). There has been no reported
`occurrence of anaphylaxis with ETHYOL.
`
`OVERDOSAGE
`In clinical trials, the maximum single dose of ETHYOL was
`1300 mg/m2. No information is available on single doses
`higher than this in adults. In the setting of a clinical trial,
`
`.. children have received single ETHYOL doses of up to 2700
`mg/m2 with no unexpected effects. Multiple infusions (up to
`three) of 740-910 mg/m2 doses of ETHYOL have i>e<1n ae!'
`ministered within a 24·hour period under study conditioru.
`without unexpected effects. Administration of ETHYOL at
`2 and 4 hours after the initial dose has not led to increased or
`cumulative side effects, such as increased nausea and vomi~
`ing or hypotension. The most likely symptom of overdosage
`is hypotension, which should be managed by infusion of nor(cid:173)
`mal saline and other supportive measures, as clinically indi,
`cated.
`DOSAGE AND ADMINISTRATION
`In adults, the recommended starting dose of ETHYOL is
`910 mg/m2 administered once daily as a IS-minute i.v. infu(cid:173)
`sion, starting 30 minutes prior to chemotherapy.
`The IS-minute infusion is better tolerated than more ex(cid:173)
`tended infusions. Further reductions in infusion times have
`not been systematically investigated.
`The infusion of ETHYOL should be interrupted if the sys(cid:173)
`tolic blood pressure det:reases significaritly from the baseline
`value as listed in the guideline below:
`
`Guideline for Interrupting ETHYOL Infusion Due to
`Decrease in Systolic Blood Pressure
`
`Baseline Systolic Blood Pressure (mm Hg)
`
`< 100
`
`100-119 120-139 140-179 ~ 180
`
`Decrease in
`systolic blood
`pressure during 20
`infusion of
`ETHYOL (mm Hg)
`
`25
`
`30
`
`40
`
`50
`
`If the blood pressure returns to normal within 5 minutes and
`the patient is asymptomatic, the infusion may be restarted
`so that the full dose of ETHYOL may be administered. If the
`full dose of ETHYOL cannot be administered, the dose of
`ETHYOL for subsequent cycles should be 740 mg/m2.
`Only limited experience is available for the usage of
`ETHYOL in children or elderly patients (more than 70 years
`ofage).
`It is recommended that antiemetic medication, including
`dexamethasone 20 mg i.v. and a serotonin 5HT3 receptor
`antagonist, be administered prior to and in conjunction with
`ETHYOL. Additional antiemetics may be required based on
`the chemotherapy drugs administered.
`.
`Reconstitution
`ETHYOL (amifostine) for Injection is supplied as a sterile
`lyophilized powder mixture requiring reconstitution for in(cid:173)
`travenous infusion. Each single-use vial contains 500 mg of
`amifostine (anhydrous basis) and 500 mg of ",annito!.
`Prior to intravenous injection, ETHYOL for Injection is re-
`. constituted with 9.5 mL of sterile Sodium Chloride Injection,
`USP 0.9%. The reconstituted solution (500 mg amifostine/
`10 mL) is chemically stable for up to 5 hours at room temper- .
`ature (approximately 25"<;) or up to 24 hours under refrigera(cid:173)
`tion(2'C to IrC).
`ETHYOL prepared in polyvinylchloride (PVc) bags at con(cid:173)
`centrations ranging from 5mg/ mL to 40 mgt mL is chemi(cid:173)
`cally stable for up to 5 hours when stored at room tempera(cid:173)
`ture (25'C) or up to 24 hours when stored under refrigeration
`(2'C to S'C).
`CAUTION: Parenteral products should be inspected visu(cid:173)
`ally for particulate matter and discoloration prior to admin(cid:173)
`istration whenever solution and container permit. Do not
`use if cloudiness or precipitate is observed.
`Incompatibilities
`The compatibility of amifostine with solutions other than
`0.9% Sodium Chloride for Injection, or Sodium Chloride
`solutions with other additives, has not been examined. The
`use of other solutions is not recommended.
`HOW SUPPLIED
`ETHYOL (amifostine) for Injection is supplied as a sterile
`lyophilized powder in 10 mL single-use vials (NDC 17314,
`3123-1). Each single-use vial contains 500 mg of amifostine
`(anhydrous basis) and 500 mg of mannitol. The vials are
`available packaged as 3 vials per carton as follows:
`3 pack-3 vials per carton (NDC 17314,3123-3)
`Store the lyophilized dosage form in a refrigerator (2'C to
`S'C).
`CAUTION: Federal (U.S.A.) law prohibits dispensing with-
`out prescription.
`.
`Manufactured by:
`Ben Venue, Inc.
`Bedford,
`Ohio 44146
`Marketed by:
`Alza Pharmaceuticals
`A division of Alza Corporation
`Palo Alto,
`California 94303
`
`Information will be superseded by supplements and subsequent editions
`
`· And:
`U.s. Bioscience, Inc.
`West' Conshohocken,
`Pennsylvania 19428
`1-80Q.506.4959
`©1995, U.S. Bioscience, Inc.
`LB2005 PB
`Revision Date 3/96
`Shown in Product Identification Guide, page 304
`'
`
`TESTODERM®
`[Tes-UHierm I
`(Testosterone Transdermal System)
`CONTROLLED DELIVERY FOR ONCE·DAIL Y
`APPLICATION
`
`@
`
`DESCRIPTION
`The Testoderm ® Testosterone TranOOermal System is d~
`signed to release controlled amounts of testosterone;. ih.
`primary circulating endogenous androgen, continuously
`upon application to scrotal skin.
`Two sises are available to provide nominal in vivo transder,
`mal delivery of 4 or 6 mg testosterone for one day (patieIiij
`vary in their ability to absorb testosterone transdel1lI'!lG;
`see Clinical Studies); they have a contact surface area 0(40'
`or 60 cm2 and contain 10 or 15 mg testosterone USP, respec(cid:173)
`tively. The composition of the two sises per uriit area:.jB
`identical. Testosterone USP is a white or creamy-whit.
`· crystalline powder or crystals chemically described·~,
`· 17 -betahydroxyandrost~n-:H>ne.
`
`C,.H 280 2m.w.2BB.43
`Testoderm® system is composed of two layers. Proceeding
`from the outer surface to the film in contact with the skin;
`these layers are a soft flexible backing of polyethylene tere.,
`phthalate and. a testosterone-containing film of ethylen~
`vinyl acetate copolymer that contacts.the skin surface and
`modulates the availability of the steroid. A protective lin.r
`of fluorocarbon diacrylate or silicone-coated polyester covera
`the drug fIlm and mUst be removed before the system can ~
`used.·
`.
`
`The active compolient of-the system is testosterone. The re:'
`maining components of the system are pharmacologically
`inactive.
`. .
`CLINICAL pHARMACOLOGY
`restoderm® releases teStosterone, the priinary endogenoUs
`androgenic hormone. Epdogenous androgens, including te&:
`tosterone and dihydrotestosterone (DHT), are responsible for.,
`the normal growth and development of the male·sex org8ll!',
`and for maintenance of secondary. sex characteristics .. Th~.
`effects include th.e growth and maturation of prostate, se",,::
`nal vesicles; penis, and scrotum; the development of malo,
`· hair distriilution, such as facial, pubic, chest, and axillary,
`· Iiair; laryngeal enlargement, vocal chord thickening, alter:
`ations in hQdy musculature, and fat distnbution .. DHT .ilI
`necessary for the normal development!,f secondary sex char:
`acteristics.
`Drugs in this class also cause retention of nitrogen, sodium,
`potassium, phoSphorus, and decreased urinary excretion of;
`calcium. Androgens have been reported to increase protein,
`anabolism and decrease protein catabolism. Nitrogen bal-,
`ance is improved only when there is sufficient intake of cal'"
`. ries and protein.
`Androgens are responsible for the growth spurt of OOoles(cid:173)
`cence and for the eventual termination of linear growth
`brought about by fusion of the epiphyseal growth centers. In,
`children, exogenous androgens accelerate linear growtH'
`rates but may cause a disproportionate advancement in bone'
`maturation. Use over long periods may result in fusion ofth._
`epiphyseal growth centers and termination of the growth'
`process. Androgens havebeen reported to stimulate the pro-.
`duction of red blood cells by enhancing the production of
`erythropoietin.
`. ,
`During exogenous administration of androgens, endogeno~
`testosterone release may be inhibited through feedback inhi-,
`bition of pituitary luteinizing hormone (LH). At large doses' .
`of exogenous androgens, spermatogenesis may also be sup(cid:173)
`pressed through feedback inhibition of pituitary follicle(cid:173)
`stimulating hormone (FSH).
`There is a lack of substantial evidence that androgens
`effective in fractu~) surgery, or convalescence.
`
`~ Endogenous tot
`
`mal mal"" foll~'
`have slightly dl
`of Testoderm ®
`tern of serum t<
`ment ofTestod,
`concentration r
`towardbaselin<
`removal. SeruI
`Hypogonadal n
`serum testoste•
`peak levels. T
`toderm® thera
`Olen (see also C
`with nominal t
`toderm® is shl
`times more per
`Testoderm® w
`concentration i
`800
`
`~ 700 /
`c
`0
`~ 600
`~
`8 500 r1
`~
`0;
`en 4000
`
`Figure A. BOh
`rwrmal young (
`1983)
`
`'Ao
`
`Figure B.. Sen
`while wearing
`Sysu,ms were aj
`There is consic
`rone as· reportt
`minutes.
`Circulating tesl
`hormone-bindil
`min-bound fral
`albumin and is
`tosterone boun
`tive. The amou,
`terone' level wil
`llonbioactive a
`prepubertal chi
`and increases ;:
`Testosterone is
`olite dihydrote
`About 90 perce
`larly is excrete
`conjugates of t
`cent of a dose i!
`gated form. In!
`the liver. Testo
`roids through t
`metabolites ar
`Norma] COncen
`dL. DHT conee
`ng/dL. DHT hi
`testosterone.lr
`lized to 3-alph.
`In many tissUE
`pend on reduc
`cYtosol recepto
`transported to
`and cellular c~
`Clinical Studi",
`After at least ~
`state is obtaine
`systems for 22
`testosterone co:
`applicstion. Sil
`maximal testo
`mean 24-hour •
`Was 9132 ngh
`
`NOVARTIS EXHIBIT 2022
`Noven v. Novartis and LTS Lohmann
`IPR2014-00549
`Page 3 of 96
`
`

`
`Pharmacokinetics
`Endogenous total testosterone serum concentrations in nor(cid:173)
`mal malo. follow a diurnal pattern. Young men and old men
`have slightly different patterns (Figure A). Dai4yapplication
`of Testoderm® approximates the natural endogenous pat(cid:173)
`tern of serum testosterone of normal males. Following place(cid:173)
`ment ofTestoderm ® on scrotal skin, the serum testosterone
`concentration rises to a maximum at 2 to 4 hours and returns
`toward baseline within approximately 2 hours after system
`removal. Serum levels reach a plateau at 3 to 4 weeks.
`Hypogonadal men using Testoderm ® therapy have trough
`serum testosterone concentrations that are about 15% of
`peak levels. The testosterone levels achieved with Tes(cid:173)
`toderm® therapy generally'are within the range for normal
`men (see also Clinical Studies). The typical pattern achieved
`with nominal testosterone delivery of 6 mg/day from Tes(cid:173)
`toderm ® is shown in Figure B. Scrotal skin is at least five
`times more permeable to testosterone than other skin sites.
`Testoderm® will not produce adequate serum testosterone
`concentration if it is applied to nongenital skin.
`I SE
`eoo
`
`c
`o
`"§
`~
`8 500
`§
`;;;
`'" 400 O~-04~oo"--0"'e~00--'~20"'0-''''6~00'-''''200''-0-2-:-'400
`
`Figure A. Hourly serum testosterone levels (meon ± SE) in
`normal young (n=17) and old (n=12) men. (From Bremner,
`19831
`I SD (n.301
`
`800
`
`j
`
`0
`
`20
`
`24
`
`16
`
`12
`Time (h)
`Figure B.- Serum concentration of testosterone (mean ± sm
`while wearing a Testoderm® system or placebo (n=301.
`Systems were applied at 0 hours and removed at 22 hours.
`There is considerable variation in the half-life of testoste(cid:173)
`rone as reported in the literature, ranging from 10 to 100
`minutes.
`Circulating teatosterone is chiefly bound in the serum to sex
`hormone-binding globulin (SHBG) and albumin. The albu(cid:173)
`min-bound fraction of testosterone easily dissociates from
`albumin and is presumed to be bioactive. The portion of tes(cid:173)
`tosterone bound to SHBG is not considered biologically ac(cid:173)
`tive. The amount of SHBG in the serum and the total,testos(cid:173)
`terone' level will determine the distribution of bioactive and
`nonbioactive androgen. SHBG-binding capacity is high in
`prepubertal children, declines during puberty and adulthood
`and increases again during the later decades of life.
`Testosterone is a substrate for conversion to an active metat>.:
`olite dihydrotestosterone (DHT>.
`Abo,ut 90 percent of a dose of testosterone given intramuscu(cid:173)
`larly is excreted in the urine as glucuronic and sulfuric acid
`conjugates of testosterone and its metabolites; about 6 per(cid:173)
`cent of a dose is excreted in the feces, mostly in theiinconju'(cid:173)
`gated form. Inactivation of testosterone occurS primarily in
`the liver. TestOsterone is metsbolized to various 17-keto ste(cid:173)
`roids through two different pathways, and the major actiye
`metabolites are estradiol and dihydrotestosterone (DHT).
`Normal concentrations of estradiol in men are 0.8 to 3.5 ng/
`dL. DHT concentrations in normal male serum are 30 to 85
`ng/dL. DHT binds with greater affinity to SHBG than does,
`~tosterone. In reproductive tissues, DHT is further metabo(cid:173)
`lized to 3-alpha and 3-beta androstenediol.
`In many tissues the activity of testosterone appears to de(cid:173)
`pend on reduction to dihydrotestosterone, which binds to
`cytosol receptor proteins. The steroid-receptor complex is
`transported to the nucleus where it initiates transcription
`and cellular changes related to androgen action.
`'
`Clinical Studies
`After at least 3 weeks of Testoderm® therapy when steady
`state is obtained, 30 hypogonadal men treated with 6 mg/d
`systems for 22 hours daily achieved mean maximum serum
`tes~terone concentrations of 593 ng/ dL at 2 to 4 hours post(cid:173)
`appl!cation. Sixty percent of the patients achieved individual
`lllaXlmal 'testosterone concentrations > 500 ng/ dL. The
`mean 24-hour steady-state A UC (area under the curve) value
`was 9132, ng/ dL. The mean DHT serum concentrations
`
`ranged from 134 to 162 ng/dL. Normal levels of testosterone
`have been maintained in patients who have worn the sys(cid:173)
`tems for up to six years. DHT levels also remain stable. The
`increase in serum testosterone concentration is proportional
`to the size of the system.
`The variability of total testosterone concentrations among
`patients receiving Testoderm® treatment had a coefficient
`of variation from 35% to 49%. The coefficient of variation of
`totsl testosterone concentrati9ns within individual patients
`was 30% to 41%. This variability is comparable to the values
`reported in the literatUre for both normal and hypogonadal
`men.
`In two 12-week clinical studies in 72 hypogonadal men,
`Testoderm® therapy produced positive effects on mood and
`sexual behavior: By 5 weeks, 45 patients not previously
`treated with Testoderm® showed statistically significant
`increases in sexual activity. Compared to baseline. mean
`sexual events per week increased for sexual intercourse (0.3
`to 0.8), orgasm (0.4 to 1.21, waking erections (1.0 to 3.5), and
`spontaneous erections <0.4 to 2.8).
`Changes in 'nonfasting serum lipid concentrations were ob(cid:173)
`served during Testoderm® therapy. By three months total
`cholesterol and high-density lipoprotein cholesterol de(cid:173)
`creased an average of 8% and 13%, respectively. High-den(cid:173)
`sity lipoprotein cholesterol remained stable thereafter. Total
`cholesterol continued to decrease through two years. At the
`end of two years, the total cholesterollhigh-density lipopro(cid:173)
`tein cholesterol ratio was not different from pretreatment
`values.
`Composite results of all studies show elevated dihydrotestos(cid:173)
`terone concentrations and a change in the ratio of testoste(cid:173)
`rone to dihydrotestosterone (T/DHT) during treatment. The
`range in this ratio was 0.7-12.5, as compared with a ratio of
`3.6-15.2 in normal untreated men. The long-term effects of
`the change in this ratio are not known.
`Estradiol levels increased to the normal range with treat(cid:173)
`ment. Sporadic elevations of estradiol above the normal
`range for men were observed in 3 of 72 patients and these
`were not associated with feminizing side effects.
`INDICATIONS AND USAGE
`Testoderm® is indicated for replacement therapy in males
`for conditions associated with a deficiency or absence of en(cid:173)
`dogenous testosterone:
`1. Primary hypogonadism (congenital or acquired)-testicu(cid:173)
`lar failure due to cryptorchidism, bilateral torsion, orchi(cid:173)
`tis, vanishing testis syndrome, orchidectomy, Klinefelter's
`syndrome, chemotherapy, or toxic damage from alcohol or
`heavy metals. These men usually have low serum testoste(cid:173)
`rone levels and gonadotropins (FSH, LH) above the nor(cid:173)
`mal range.
`2. Hypogonadotropic hypogonadism (congenital or acquired)
`-idiopathic gonadotropin or LHRH deficiency or pitui(cid:173)
`tary-hypothalamic injury from tumors, trauma, or radia_
`tion. These men have low testosterone serum levels but
`have gonadotropins in the normal or low range.
`Testoderm® therapy has not been evaluated clinitally in
`males under 18 years of age.
`CONTRAINDICATIONS
`Androgens are contraindicated. in men with carcinoma of the
`breast or known or suspected carcinoma of the prostate.
`Testoderm® therapy has not been evaluated in women and
`must not be used in women. Testosterone may cause fetal
`harm.
`Testoderm® systems should not be used in patients with
`known hypersensitivity to any components of the system.
`WARNINGS
`Prolonged use of high doses of orally active 17-alpha-alkyl
`androgens (eg, methyltestosterone) has been associated with
`serious hepatic adverse effects (peliosis hepatitis, hepatic
`neoplasms, cholestatic hepatitis, and jaundice). Long-term
`therapy with testosterone enanthate, which elevates blood
`levels for prolonged periods, has produced mUltiple hepatic
`adenomas. Testosterone is not known to produce these
`adverse effects.
`Geriatric patients treated with androgens may be at an in(cid:173)
`creased risk for the development of prostatic hyperplasia
`and prostatic carcinoma (see PRECAUTIONS: Carcinogene(cid:173)
`sis, Mutagenesis, lmpairnlent of Fertility).
`Edema with Or without congestive heart failure may be a
`serious complication in patients with preexisting cardiac,
`renal, or hepatic disease. In addition to discontinuation of
`the drug, diuretic therapy may be required.
`Gynecomastia frequently develops and occasionally persists
`in patients being treated for hypogonadism.
`PRECAUTIONS
`Information for the Patient
`A booklet containing instructions for use of the Testoderm ®
`system is available.
`'
`The physician should instruct patients to report any of the
`following side effects of androgens:
`• Too frequent or persistent erections of the penis.
`• Any nausea, vomiting, changes in skin color or ankle
`swelling.
`
`PRODUCT INFORMATION/487
`
`Virilization of female partners has been reported with use of
`a topical testosterone solution. Percutaneous creams leave
`as much as 90 mg residual testosterone on the skin. The re(cid:173)
`sults from one study indicated that, after removal of a Tes(cid:173)
`toderm® system, the potential for transfer of testosterone to
`a sexual partner was 6 ~, 1I45th the daily endogenous tes(cid:173)
`tosterone production by the female body. Changes in body
`hair distribution or significant increase in acne of the female
`partner should be brought to the attention of a physician.
`Laboratory ·Tests
`1. Hemoglobin and hematocrit levels should be checked peri(cid:173)
`odically (to detect polycythemia) in patients on long-term
`androgen therapy.
`2. Liver function, prostatic acid phosphatase, prostatic spe(cid:173)
`cific antigen, cholesterol, and high-density lipoproteins
`should be checked periodically.
`Drug Interactions
`1. Anticoagulants. C-17 substituted derivatives of testoste(cid:173)
`rone, such as methandrostenolone, have been reported to
`decrease the anticoagulant requirements of patients re~
`ceiving oral anticoagulants. Patients receiving oral antico(cid:173)
`agulant therapy require close monitoring, especially when
`androgens are started or stopped,
`'
`2. Oxyphenbutazone. Concurrent administration of oxy(cid:173)
`phenbutawne and androgens may result in elevated
`serum levels of oxyphenbutazone.
`3. Insulin. In diabetic patients the metabolic effects of andro(cid:173)
`gens may decrease blood glucose and, therefore, insulin
`requirements.
`.
`Drug/laboratory Test Interactions
`Androgens may decrease levels of thyroxin-binding globulin,
`resulting in decreased total T. serum levels and increased
`resin uptake of Ta and T •. Free thyroid hormone levels re(cid:173)
`main unchanged, however, and there is no clinical evidence
`of thyroid dysfunction.
`Carcinogenesis. Mutagenesis. Impairment of Fertility
`Animal Data. Testosterone has been tested by subeutane(cid:173)
`ous injection and implantation in mice and rats. In mice, the
`implant induced cervical-uterine tumors, which metasta(cid:173)
`sized in some cases. There is suggestive evidence that injec(cid:173)
`tion of testosterone into some strains of female mice in~
`creases their susceptibility to hepatoma. Testosterone is also'
`known to increase the number of tumors and decrease the
`degree of differentiation of chemically induced carcinomas
`of the liver in rats,
`Human Data. There are rare reports of hepatocellular car(cid:173)
`cinoma in patients receiving long-term therapy with andro(cid:173)
`gens in high doses. Withdrawal of the drugs did not lead to
`regression of the tumors. in all cases.
`Geriatric Use. Geriatric patients treated with androgens
`may be at an increased risk for the development of prostatic
`hyperplasia and prostatic carcinoma.
`Pregnancy Category X (See Contra indications).
`Teratogenic Effects. Testoderm ® therapy must not be used
`in women.
`Nursing Mothers. Testoderm® therapy must not be used
`in women.
`Pediatric Use. Testoderm® therapy has not been evalu(cid:173)
`ated clinically in males under 18 years of age.
`ADVERSE REACTIONS
`Adverse Reactions with the Testoderm® system
`In clinical
`studies of 104 patients
`treated with
`Testoderm® the most commOn adverse effects reported
`were local effects. In US clinical trials, most of the 72 pa-,
`tients filling out a daily questionnaire reported scrotal itch(cid:173)
`ing, discomfort, or irritation at some time during therapy. Of
`all the daily questionnaire responses, 7% reported itching,
`4% discomfort, and 2% irritation. All topical reactions de(cid:173)
`creased with duration of use.
`The following adverse effects were reported in association
`with Testoderm® therapy in 104 patients using the product
`for up to three years; a causal relationship to Testoderm®
`treatment was not always determined. These effects are
`listed in decreasing order of occurrence with the number of
`patients reporting the effect in parentheses: Gynecomastia
`(5), acne (4), prostatitis/urinary tract infection (4), breast
`tenderness (3), stroke (2), memory loss (I), pupillary dilation
`(1), abnormal liver enzymes (1), scrotal cellulitis (1), deep
`vein phlebitis (1), benign prostatic hyperplasia (1), rectal
`mucosal lesion over prostate (1), hematuria/bladder cancer
`(II, papilloma on scrotum (1), and congestive heart failure (1).
`See CLINICAL PHARMACOLOGY, Clinical Studies subsec(cid:173)
`tion, regarding effects on serum lipids.
`Adverse Reactions with Injection or Oral Androgen Therapy.
`Skin and Appendages. Hirsutism, male pattern of baldness,
`seborrhea, and acne.
`Endocrine and Urogenital. Gynecomastia and excessive fre(cid:173)
`quency and duration of penile erections. Oligospermia may
`occur at high dosages (see CLINICAL PHARMACOLOGY).
`Fluid and Electrolyte Disturbances. Retention of sodium;'
`chloride, water, potassium, calcium, and inorganic phos(cid:173)
`phates .
`
`Consult 1997 supplements and future editions for revision~
`
`Continued on next page
`
`LB2005 PB
`ge304
`
`@,
`
`'stem is de(cid:173)
`terone, ,th~
`mtinuously
`
`70 transder.
`ly (patients
`tsdermally,
`! area of 40
`rsp, respec(cid:173)
`nit area is
`!IUIly-white
`!SCribed as
`
`Proceeding
`h the skin,
`Lylene tere(cid:173)
`fethylene(cid:173)
`urface and
`~ctive liner
`:stercovers
`tern can b.e
`
`ne. The re(cid:173)
`cologically
`
`ndogenous
`luding tes(cid:173)
`oonsiblefor
`sex organ~
`tics. These
`;tate, seIl.li~.
`at of male
`,d axillary
`ling" alter(cid:173)
`n. DHT is
`J$xchar-
`
`n, sodium,
`{cretion of·
`LSeProtein
`rogen bal(cid:173)
`Ikeof calo-
`
`of adoles(cid:173)
`ar growth
`:enters. In
`if growth
`mtinbone
`sionofthe
`ne growth"
`te the pro-,
`duction' of
`
`,dogenous
`!backinhi(cid:173)
`lrgedoses
`so,be sup(cid:173)
`'Y follicle-
`
`-ogens are
`
`NOVARTIS EXHIBIT 2022
`Noven v. Novartis and LTS Lohmann
`IPR2014-00549
`Page 4 of 96
`
`

`
`488/PHYSICIANS' DESK REFERENCE®
`
`Alza-Cont.
`
`Gastrointestinal. Nausea, cholestatic jaundice, alterations
`in liver function tests. Rare instances of hepatocellular n"",
`plasms and peliosis hepatitis have occurred (see WARN(cid:173)
`INGS).
`Hematologic. Suppression of clotting factors II, V, VII, and
`X, bleeding in patients on concomitant anticoagulant ther(cid:173)
`apy, and polycythemia.
`Nervous System. Increased or decreaSed libido, headache,
`anxiety, depression, and generalized paresthesia.
`Metabolic. Increased serum cholesterol.
`Miscellaneous. Rarely, anaphylactoid reactions.
`DRUG ABUSE AND DEPENDENCE
`Testoderm® is a Schedule III controlled substance under
`the Anabolic Steroids Control Act.
`With oral administration, it is not possible to achieve clini(cid:173)
`cally significant serum testosterone concentrations in the
`target organs using the testosterone in Testoderm ® due to
`extensive first-pass metabolism. The half-life of an 1M injec(cid:173)
`tion of testosterone is about 10 minutes.
`Because scrotal skin is at least five times more permeable to
`testosterone than other skin sites, Testoderm ® will not pro(cid:173)
`duce adequate serum testosterone concentrations if it is ap(cid:173)
`plied to nongenital skin.
`OVERDOSAGE
`There is one report of acute overdosage with testosterone
`enanthate: testosterone levels of up to 11,400 ng/dL were
`implicated in a cerebrovascular accident.
`DOSAGE AND ADMINISTRATION
`Patients should start therapy with a 6 mg/d system applied
`daily; if scrotal area is inadequate, a 4 mg/d system should be
`used. Testoderm® should be placed on clean, dry, scrotal
`skin. Scrotal hair should be dry-shaved for optimal skin con(cid:173)
`tact. Chemical depilatories should not be used (see Patient
`Information). Testoderm® should be worn 22-24 hours.
`After 3-4 weeks of daily system use, blood should be drawn
`2-4 hours after system application for determination of
`serum total testosterone. Because of variability in analytical
`values among diagnostic
`laboratories,
`this
`laboratory
`work and later analyses for assessing the effect of the
`Testoderm ® therapy should be performed at the same
`laboratory.
`If patients have not achieved desired results by the end of
`6-{l weeks of therapy with Testodeim®, another form of
`testosterone replacement therapy should be considered.
`HOWSUPPUED
`Testoderm ® testosterone transdermal system is a Schedule
`III controlled substance under the Anabolic Steroids Control
`Act.
`Testoderm® systems are supplied as individually pouched
`systems, 30 per carton.
`Testoderm® 4 mg/d (testosterone transdermal system)
`---€ach 40 cm2 system contains 10 mg testosterone USP for
`nominal delivery of 4 mg for one day.'
`Carton of 30 systems ............................ NDC 17314-4608-3
`Testoderm® 6 mg/d (testosterone transdermal system>(cid:173)
`---€ach 60 cm2 system contains 15 mg testosterone USP for
`nominal delivery of 6 mg for one day_'
`Carton of 30 systems ............................ NDC 17314-4609-3
`Store at room temperature 15-30"C
`REFERENCE
`Bremner WJ, Vitiello MV, Prinz PN. Lass of Circadian
`Rhythmicity in Blood Testosterone Levels with Aging in Nor(cid:173)
`mal Men. J Clin Endocrin Metab (1983) 56 (6): 1278-1281.
`Caution: Federal law prohibits dispensing without pre(cid:173)
`scription.
`Manufactured by ALZA Corporation, Palo Alto, California
`94304, USA
`'See Clinical Studies
`Edition: 6/94
`
`PROGESTASERT EDUCATIONAL MATERIAL
`
`All progestasert educational materials are complimentary.
`B~klets-Brochures
`A: Patient Information Leaflet
`.
`(English and Spanish)
`B. ,Clinical EvideIice Brochure
`C.' De