EDITION
`
`PDR®
`45
`1991
`PI (cid:9) lYSICA\S
`DES
`REFER._ NCR
`
`NOVARTIS EXHIBIT 2106
`Par v Novartis, IPR 2016-00084
`Page 1 of 6
`
`

`
`EDITION
`
`1991
`
`PDR® 45
`91 (cid:9) IYSICIA\S
`D SK
`?FF.? (cid:9) \CE®
`
`Publisher • EDWARD R. BARNHART
`
`Marketing and Circulation Director
`ROBIN B. BARTLETT
`Assistant Circulation Director
`ANNETTE G. VERNON
`
`Fulfillment Manager
`ANITA H. MOORE
`
`Director of Production
`MARJORIE A. DUFFY
`Production Manager
`CARRIE WILLIAMS
`Manager of Production Services
`ELIZABETH H. CARUSO
`Format Editor
`MILDRED M. SCHUMACHER
`Index Editor
`ADELE L. DOWD
`Medical Consultant
`LOUIS V. NAPOLITANO , MD
`Art Associate
`JOAN AKERLIND
`Editorial Assistants
`CATHLEEN BUNNELL
`CHRISTINE PATRICK
`Director, PDR Development
`DAVID W. SIFTON
`Database Manager
`MUKESH MEHTA, R. Ph.
`Database Coordinator
`BEVERLY A. PFOHL
`Administrative Assistants
`Senior Research Analyst
`SONIA C. RYAN
`PATRICIA DeSIMONE
`HELENE WATTMAN
`Lay. Copyright -1991 and published by Medical Economics Data, a division of Medical Economics Company Inc. at Oradell, N.J. 07649. All rights reserved. None of the content of
`111 this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, or otherwise) without the
`prior written permission of the publisher. PHYSICIANS' DESK REFERENCE-, PDR'. PDR For Ophthalmology-, PDR For Nonprescription Drugs PDR Drug Interactions and Side
`Effects- and PDR Indications Index'" are trademarks of Medical Economics Company Inc., registered in the United States Patent and Trademark Office.
`
`Professional Relations Manager
`ANNA E. BARBAGALLO
`
`Marketing Administrator
`DAWN TERRANOVA
`
`Customer Support Coordinator
`ANNEMARIE LUTOSTANSKI
`
`Circulation Coordinator
`MARY J. CADLEY
`
`National Sales Manager
`KEVIN D. MILLER
`
`Account Managers
`CHAD E. ALCORN
`CHARLIE J. MEITNER
`JOANNE C. TERZIDES
`
`Officers of Medical Economics Data, a division of Medical Economics Company Inc.: President and Chief Executive Officer: Norman R. Snesil; Senior Vice President and Chief
`Financial Officer: Joseph T. Deithorn; Senior Vice President and Group Publisher: Edward R. Barnhart.
`
`ISBN 0-87489-716-5
`
`NOVARTIS EXHIBIT 2106
`Par v Novartis, IPR 2016-00084
`Page 2 of 6
`
`

`
`Consult PDR® Supplements for revisions
`Consult PDS (7) Supplements for revisions
`
`Product Information
`Product Information
`
`1691
`1691
`
`LIPPES LOOP
`LIPPES LOOP
`Size
`Size
`A
`A
`B
`B
`C
`C
`D
`D
`
`Number
`Number
`Woman/Months
`Woman/Months
`13,453
`13,463
`12,463
`12,463
`50,775
`50,775
`121,666
`121,566
`
`TABLE I
`TABLE I
`
`Woman/Months
`Woman/Months
`of Use
`of Use
`1st Year
`lit Year
`After Insertion
`After Insertion
`8,751
`8,761
`9,660
`9,660
`31,032
`31,032
`72,046
`72,046
`
`Woman/Months
`Woman/Months
`' of Use
`of Use
`2nd Year
`2nd Year
`After Insertion
`After Insertion
`4,702
`4,702
`2,803
`2,803
`' 19,743
`• 19,743
`49,520
`49,520
`
`of distribution (10-16 L) were calculated. The pharmacoki-
`of distribution (10-16 L) were calculated. The pharmacoki-
`netics of GnRH in normal subjects and in hypogonadotropic
`netics of GnRH in normal subjects and in hypogonadotropic
`patients were similar. GnRH was rapidly metabolized to
`patients were similar. GnRH was rapidly metabolized to
`various biologically inactive peptide fragments which are
`various biologically inactive peptide fragments which are
`readily excreted in urine. Renal failure, but not hepatic dis-
`readily excreted in urine. Renal failure, but not hepatic dis-
`ease, prolonged the half-life and reduced the clearance of
`ease, prolonged the half-life and reduced the clearance of
`GnRH.
`GnRH.
`INDICATIONS AND USAGE
`INDICATIONS AND USAGE
`LUTREPULSE (gonadorelin acetate) for Injection is
`LUTREPULSE (gonadorelin acetate) for Injection is
`indicated in the treatment of primary hypothalamic
`indicated in the treatment of primary hypothalamic
`amenorrhea.
`amenorrhea.
`DIFFERENTIAL DIAGNOSIS: Proper diagnosis is critical
`DIFFERENTIAL DIAGNOSIS: Proper diagnosis is critical
`for successful treatment with LUTREPULSE for Injection.
`for successful treatment with LUTREPULSE for Injection.
`It must be established that hypothalamic amenorrhea or
`It must be established that hypothalamic amenorrhea or
`hypogamadism is, in fact, due to a deficiency in quantity or
`hypogamadism is, in fact, due to a deficiency in quantity or
`pulsing of endogenous GnRH. The diagnosis of hypothalamic
`pulsing of endogenous GnRH. The diagnosis of hypothalamic
`amenorrhea or hypogonadism is based on the exclusion of
`amenorrhea or hypogonadism is based on the exclusion of
`other causes of the dysfunction, since there is currently no
`other causes of the dysfunction, since there is currently no
`practical technique to directly assess hypothalamic function.
`practical technique to directly assess hypothalamic function.
`Prior to initiation of therapy with LUTREPULSE (gonad-
`Prior to initiation of therapy with LUTREPULSE (gonad-
`orelin acetate) for injection, the physician should rule out
`orelin acetate) for injection, the physician should rule out
`disorders of general health, reproductive organs, anterior
`disorders of general health, reproductive organs, anterior
`pituitary, and central nervous system, other than abnormal-
`pituitary, and central nervous Bystem, other than abnormal-
`ities of GnRH secretion.
`ities of GnRH secretion.
`CONTRAINDICATIONS
`CONTRAINDICATIONS
`LUTREPULSE for Injection is contraindicated in women
`LUTREPULSE for Injection is contraindicated in women
`with any condition that could be exacerbated by pregnancy.
`with any condition that could be exacerbated by pregnancy.
`For example, pituitary prolactinoma should be considered
`For example, pituitary prolactinoma should be considered
`one such condition. Additionally, any history of sensitivity to
`one such condition. Additionally, any history of sensitivity to
`gonadorelin acetate, gonadorelin hydrochloride or any com-
`gonadorelin acetate, gonadorelin hydrochloride or any com-
`ponent of LUTREPULSE for Injection is a contraindication.
`ponent of LUTREPULSE for Injection is a contraindication.
`Patients who have ovarian cysts or causes of anovulation
`Patients who have ovarian cysts or causes of anovulation
`other than those of hypothalamic origin should not receive
`other than those of hypothalamic origin should not receive
`LUTREPULSE for Injection.
`LUTREPULSE for Injection.
`LUTREPULSE for Injection is intended to initiate events
`LUTREPULSE for Injection is intended to initiate events
`including the production of reproductive hormones (e.g. es-
`including the production of reproductive hormones (e.g. es-
`trogens and progestins). Therefore, any condition that may
`trogens and progestins). Therefore, any condition that may
`be worsened by reproductive hormones, such as hormonally-
`be worsened by reproductive hormones, such as hormonally-
`dependent tumor, is a contraindication to the use of
`dependent tumor, is a contraindication to the use of
`LUTREPULSE for Injection.
`LUTREPULSE for Injection.
`WARNINGS
`WARNINGS
`Therapy with LUTREPULSE (gonadorelin acetate) for In-
`Therapy with LUTREPULSE (gonadorelin acetate) for In-
`jection should be conducted by physicians familiar with pul-
`jection should be conducted by physicians familiar with pul-
`satile GnRH delivery and the clinical ramifications of ovula-
`satile GnRH delivery and the clinical ramifications of ovula-
`tion induction While there have been few cases of hyper-
`tion induction While there have been few cases of hyper-
`stimulation( <1%) this possibility must be considered. If
`stimulationt < 1%) this possibility must be considered. If
`hyperstimulation should occur, therapy should be discontin-
`hyperstimulation should occur, therapy should be discontin-
`ued and spontaneous resolution can be expected. The preser-
`ued and spontaneous resolution can be expected. The preser-
`vation of the endogenous feedback mechanisms makes se
`vation of the endogenous feedback mechanisms makes se-
`vere hyperstimulation (with ascites and pleural effusion)
`vere hyperstimulation (with ascites and pleural effusion)
`rare. However, the physician shoud be aware of the possibil-
`rare. However, the physician shoud be aware of the possibil-
`ity and be alert for any evidence of ascites, pleural effusion,
`ity and be alert for any evidence of ascites, pleural effusion,
`hemoconcentration, rupture of a cyst, fluid or electrolyte
`hemoconcentration, rupture of a cyst, fluid or electrolyte
`imbalance, or sepsis.
`imbalance, or sepsis.
`Multiple pregnancy is a possibility that can be minimized by
`Multiple pregnancy is a possibility that can be minimized by
`careful attention to the recommended doses and ultrasono-
`careful attention to the recommended doses and ultrasonc-
`graphic monitoring of the ovarian response to therapy.
`graphic monitoring of the ovarian response to therapy.
`Following a baseline pelvic ultrasound, follow-up studies
`Following a baseline pelvic ultrasound, follow-up studies
`should be conducted at a minimum on day 7 and day 14 of
`should be conducted at a minimum on day 7 and day 14 of
`therapy.
`therapy.
`As with any intravenous medication, scrupulous attention to
`As with any intravenous medication, scrupulous attention to
`asepsis is important. The infusion area must be monitored as
`asepsis is important. The infusion area must be monitored as
`with all indwelling parenteral approaches. The cannula and
`with all indwelling parenteral approaches. The cannula and
`IV site should be changed at 48-hour intervals.
`IV site should be changed at 48-hour intervals.
`PRECAUTIONS
`PRECAUTIONS
`GENERAL: Ovarian hyperstimulation has been reported.
`GENERAL: Ovarian hyperstimulation has been reported.
`This may be related to pulse dosage or concomitant use of
`This may be related to pulse dosage or concomitant use of
`other ovulation stimulators. Hyperstimulation may be a
`other ovulation stimulators. Hyperstimulation may be a
`greater risk in patients where spontaneous variations in
`greater risk in patients where spontaneous variations in
`endogenous GnRH secretion occur. Multiple follicle develop-
`endogenous GnRH secretion occur. Multiple follicle develop-
`ment, multiple pregnancy, and spontaneous termination of
`ment, multiple pregnancy, and spontaneous termination of
`pregnancy have been reported. Multiple pregnancy can be
`pregnancy have been reported. Multiple pregnancy can be
`minimized by appropriate monitoring of follicle formation;
`minimized by appropriate monitoring of follicle formation;
`nonetheless, the patient and her partner should be advised of
`nonetheless, the patient and her partner should be advised of
`the frequency (12%) and potential risks of multiple preg-
`the frequency (12%) and potential risks of multiple preg-
`nancy before starting treatment.
`nancy before starting treatment.
`Ovarian hyperstimulation, a syndrome of sudden ovarian
`Ovarian hyperstimulation, a syndrome of sudden ovarian
`enlargement, ascites with or without pain, and/or pleural
`enlargement, ascites with or without pain, and/or pleural
`effusion, is rare with pulsatile GnRH therapy. Among 268
`effusion, is rare with pulsatile GnRH therapy. Among 268
`patients participating in clinical trials, one case of moderate
`patients participating in clinical trials, one case of moderate
`hyperstimulation has been reported, but this cycle included
`hyperstimulation has been reported, but this cycle included
`the concomitant use of clomiphene citrate.
`the concomitant use of clomiphene citrate.
`LUTREPUISE (gonadorelin acetate) for Injection should be
`LUTREPULSE (gonadorelin acetate) for Injection should be
`administered only with the LUTREPULSE PUMP. The
`administered only with the LUTREPULSE PUMP. The
`patient should be provided with detailed oral and written
`patient should be provided with detailed oral and written
`instructions regarding infusion pump usage and potential
`instructions regarding infusion pump usage and potential
`sepsis in order to minimize the frequency of infusion pump
`sepsis in order to minimize the frequency of infusion pump
`malfunction and inflammation, infection, mild phlebitis, or
`malfunction and inflammation, infection, mild phlebitis, or
`hematoma at the catheter site.
`hematoma at the catheter site.
`LABORATORY TESTS: Following a diagnosis of primary
`LABORATORY TESTS: Following a diagnosis of primary
`hypothalamic amenorrhea, initiation of LUTREPULSE
`hypothalamic amenorrhea, initiation of LUTREPULSE
`Continued on next page
`Continued on next page
`
`Council with the LIPPES LOOP, use effectiveness was deter-
`Council with the LIPPES LOOP, use effectiveness was deter-
`mined as follows for women, as tabulated by the life table
`mined as follows for women, as tabulated by the life table
`method. (Rates are expressed as events per 100 women
`method. (Rates are expressed as events per 100 women
`through 12 and 24 months of use). This experience is based
`through 12 and 24 months of use). This experience is based
`on 198,257 woman/months of use, including 121,489 wo-
`on 198,257 Woman/months of use, including 121,489 wo-
`man/months of use in first year after insertion, and 76,768
`man/months of use in first year after insertion, and 76,768
`woman/months of use in second year after insertion.
`woman/months of use in second year after insertion.
`LIPPES LOOP Intrauterine Double-S devices are manufac-
`LIPPES LOOP Intrauterine Double-S devices are manufac-
`tured in four different sizes, and the figures giyen above rep-
`tured in four different sizes, and the figures given above rep-
`resent the totals for the four sizes. The following table pre-
`resent the totals for the four sizes. The following table pre-
`sents these figures individually for each size LOOP:
`sents these figures individually for each size LOOP:
`[See table above.]
`[See table above.]
`
`LUTREPULSE® for Injection
`LUTREPULSE® for Injection
`lgonadorelin acetate)
`(Qonadorelin acetate)
`Synthetic Gonadotropin-Releasing Hormone (GnRH) •
`Synthetic Qonadotropln-Releaslng Hormone (GnRH) -
`For Pulsatile Intravenous Injection
`For Pulsatile Intravenous Injection
`
`DESCRIPTION
`DESCRIPTION
`LUTREPULSE (gonadorelin acetate) for Injection is used for
`LUTREPULSE (gonadorelin acetate) for Injection is used for
`the induction of ovulation in women with primary hypothal-
`the induction of ovulation in women with primary hypothal-
`amic amenorrhea. Gonadorelin acetate is a synthetic deca-
`amic amenorrhea. Gonadorelin acetate is a synthetic deca-
`peptide that is identical in amino acid sequence to endoge-
`peptide that is identical in amino acid sequence to endoge-
`nous gonadotropin-releasing hormone (GnRH) synthesized
`nous gonadotropin-releasing hormone (GnRH) synthesized
`in the human hypothalamus and in various neurons termi-
`in the human hypothalamus and in various neurons termi-
`nating in the hypothalamus. The molecular formula of
`nating in the hypothalamus. The molecular formula of
`gonadorelin acetate is:
`gonadorelin acetate is:
`CasilzsNizOts-xe-211402•yH20
`CssHTsNiAs-xCyWyHsO
`Its molecular weight is 1182.3 + x60 + y18, where x and y
`Its molecular weight is 1182.3 + x60 + yl8, where x and y
`represent a non-etoichiometric ratio of acetate and water
`represent a non-etoichiometric ratio of acetate and water
`associated with the peptide, and x ranges from 1-2 and y
`associated with the peptide, and x ranges from 1-2 and y
`ranges from 2-3. The amino acid sequence of GnRH is:
`ranges from 2-3. The amino acid sequence of GnRH is:
`5-oxoPro-His-Trp-Ser-Ty'r•-Gly-Leu-Arg-Pro-Gly-NH2
`5«xoPro-His-Tn>Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
`LUTREPULSE for injection is a sterile, lyophilized powder
`LUTREPULSE for injection is a sterile, lyophilized powder
`intended for intravenous pulsatile injection after reconstitu-
`intended for intravenous pulsatile injection after reconstitu-
`tion. It is white and very soluble in water. Vials are available
`tion. It is white and very soluble in water. Vials are available
`containing 0.8 mg or 3.2 mg gonadorelin acetate (expressed
`containing 0.8 mg or 32 mg gonadorelin acetate (expressed
`as the diacetate) and 10.0 mg mannitol as a carrier. After
`as the diacetate) and 10.0 mg mannitol as a carrier. After
`reconstituting with 8 mL of diluent (sterile 0.9% Sodium
`reconstituting with 8 mL of diluent (sterile 0.9% Sodium
`Chloride Solution and hydrochloric acid to adjust the pH) for
`Chloride Solution and hydrochloric acid to adjust the pH) for
`LUTREPULSE for Injection, the concentration of gonadore-
`LUTREPULSE for Injection, the concentration of gonadore-
`lin acetate is 5 ieg per 50 pi in each vial containing 0.8 mg
`lin acetate is 5 ug per 50 u.1 in each vial containing 0.8 mg
`lyophilized hormone, and 20 14 per 50 p.l in each vial con-
`lyophilized hormone, and 20 ug per 50 ul in each vial con-
`taining 3.2 mg lyophilized hormone. LUTREPULSE (gonad-
`taining 3.2 mg lyophilized hormone. LUTREPULSE (gonad-
`orelin acetate) for Injection is intended for use with the LU-
`orelin acetate) for Injection is intended for use with the LU-
`TREPULSE for Injection KITS. The volumes and concentra-
`TREPULSE for Injection KITS. The volumes and concentra-
`tions are specific for use with the LUTREPULSE PUMP for
`tions are specific for use with the LUTREPULSE PUMP for
`appropriate dosing.
`appropriate dosing.
`CLINICAL PHARMACOLOGY
`CLINICAL PHARMACOLOGY
`Under physiologic conditions, gonadotropin-releasing hor-
`Under physiologic conditions, gonadotropin-releasing hor-
`mone (GnRH) is released by the hypothalamus in a pulsatile
`mone (GnRH) is released by the hypothalamus in a pulsatile
`fashion. The priMary effect of GnRH is the synthesis and
`fashion. The primary effect of GnRH is the synthesis and
`release of luteinizing hormone (LH) in the anterior pituitary
`release of luteinizing hormone (LH) in the anterior pituitary
`gland. GnRH also stimulates the synthesis and release of
`gland. GnRH also stimulates the synthesis and release of
`follicle stimulating hormone (FSH), but this effect is less
`follicle stimulating hormone (FSH), but this effect is less
`pronounced. LH and FSH subsequently stimulate the gonads
`pronounced. LH and FSH subsequently stimulate the gonads
`to produce steroids which are instrumental in regulating
`to produce steroids which are instrumental in regulating
`reproductive hormonal status. Unlike human menopausal
`reproductive hormonal status. Unlike human menopausal
`gonadotropin (hMG) which supplies pituitary hormones,
`gonadotropin (hMG) which supplies pituitary hormones,
`pulsatile administration of LUTREPUISE for Injection
`pulsatile administration of LUTREPULSE for Injection
`replaces defective hypothalamic secretion of GnRH. The
`replaces defective hypothalamic secretion of GnRH. The
`pulsatile administration of LUTREPULSE for Injection
`pulsatile administration of LUTREPULSE for Injection
`approximates the natural hormonal secretory pattern, caus-
`approximates the natural hormonal secretory pattern, caus-
`ing pulsatile release of pituitary gonadotropins. Accordingly,
`ing pulsatile release of pituitary gonadotropins. Accordingly,
`LUTREPULSE for Injection is useful in treating conditions
`LUTREPULSE for Injection is useful in treating conditions
`of infertility caused by defective GnRH stimulation from the
`of infertility caused by defective GnRH stimulation from the
`hypothalamus (See INDICATIONS AND USAGE). The
`hypothalamus (See INDICATIONS AND USAGE). The
`following information summarizes clinical efficacy of gonad-
`following information summarizes clinical efficacy of gonad-
`orelin acetate administered by pulsatile intravenous injec-
`orelin acetate administered by pulsatile intravenous injec-
`tion to patients with primary hypothalamic amenorrhea.
`tion to patients with primary hypothalamic amenorrhea.
`44 patients with primary hypothalamic amenorrhea (HA)
`44 patients with primary hypothalamic amenorrhea (HA)
`93% (41/44) patients ovulatory with gonadorelin acetate
`93% (41/44) patients ovulatory with gonadorelin acetate
`therapy
`therapy
`•
`62% (24/39)' patients pregnant (cid:9)
`62% (24/39)' patients pregnant
`100% (7/7) of those failing past attempts at ovulation in-
`100% (7/7) of those failing past attempts at ovulation in-
`duction by other methods were ovulatory on gonadorelin
`duction by other methods were ovulatory on gonadorelin
`acetate.
`acetate.
`• Five patients did not desire pregnancy.
`'Five patients did not desire pregnancy.
`Following intravenous injection of GnRH into normal sub-
`Following intravenous injection of GnRH into normal sub-
`jects and/or hypogonadotropic patients, plasma GnRH con-
`jects and/or hypogonadotropic patients, plasma GnRH con-
`centrations rapidly decline with initial and terminal half-
`centrations rapidly decline with initial and terminal half-
`lives of 2-10 min. and 10-40 min., respectively. In these stud-
`lives of 2-10 min. and 10-40 min., respectively. In these stud-
`ies, high clearance values (500-1500 L/day) and low volumes
`ies, high clearance values (500-1500 L/day) and low volumes
`
`Pregnancy
`Pregnancy (cid:9)
`Expulsion (cid:9)
`Expulsion
`Medical Removal (cid:9)
`Medical Removal
`Continuation Rate
`Continuation Rate
`
`Tables II-V below give the pregnancy, expulsion, medical re-
`Tables II-V below give the pregnancy, expulsion, medical re-
`moval and continuation rates for each individual size LOOP:
`moval and continuation rates for each individual size LOOP:
`TABLE II
`TABLE II
`LOOP A
`LOOP A
`(Annual Rates Per 100 Users)
`(Annual Rates Per 100 Users)
`24 Months
`24 Months
`(cumulative)
`12 Months (cid:9)
`12 Months (cumulative)
`5.3
`9.7
`5.3 (cid:9)
`9.7
`23.9 (cid:9)
`27.7
`23.9
`27.7
`12.2 (cid:9)
`20.0
`12.2
`20.0
`75.2 (cid:9)
`63.6
`63.6
`75.2
`TABLE Ill
`TABLE III
`LOOP B
`LOOPB
`(Annual Rates Per 100 Users)
`(Annual Rates Per 100 Users)
`24 Months
`24 Months
`(cumulative)
`(cumulative)
`6.3
`6.3
`24.9
`24.9
`23,8
`23.8
`69.2
`59.2
`
`Pregnancy (cid:9)
`Pregnancy
`Expulsion (cid:9)
`Expulsion
`Medical Removal (cid:9)
`Medical Removal
`Continuation Rate (cid:9)
`Continuation Rate
`
`12 Months
`12 Months
`3.4
`3.4
`18.9
`18.9
`16.1
`16.1
`74.6
`74.6
`TABLE IV
`TABLE IV
`LOOP C
`LOOPC
`(Annual Rates Per 100 Users)
`(Annual Rates Per 100 Users)
`24 Months
`24 Months
`(cumulative)
`(cumulative!
`4.8
`4.8
`24.6
`24.6
`22.1
`22.1
`62.8
`62.8
`
`Pregnancy
`Pregnancy
`Expulsion
`Expulsion
`Medical Removal
`Medical Removal
`Continuation Rate
`Continuation Rate
`
`12 Months (cid:9)
`12 Months
`3.0
`3.0 (cid:9)
`19.1 (cid:9)
`19.1
`14.3 (cid:9)
`14.3
`76.5 (cid:9)
`76.6
`TABLE V
`TABLE V
`LOOP D
`LOOPD
`(Annual Rates Per 100 Users)
`(Annual Rates Per 100 Users)
`24 Months
`24 Months
`(cumulative)
`12 Months (cid:9)
`(cumulative)
`12 Months
`2.7
`2.7 (cid:9)
`Pregnancy
`4.2
`Pregnancy
`4.2
`Expulsion
`16.0
`12.7 (cid:9)
`12.7
`Expulsion
`16.0
`15.2 (cid:9)
`Medical Removal
`23.3
`Medical Removal
`23.3
`15.2
`77.4 (cid:9)
`65.6
`Continuation Rate
`Continuation Rate
`77.4
`65.6
`the bulbous tip and the inserter flange are in a horizontal
`the bulbous tip and the inserter flange are in a horizontal
`plane.
`plane.
`Do this not more than one minute before insertion.
`Do this not more than one minute before insertion.
`2. How to insert LIPPES LOOP Intrauteririe Double-S.
`2. How to insert LIPPES LOOP Intrauterine Double-S.
`Insert the loaded inserter gently through the endocervical
`Insert the loaded inserter gently through the endocervical
`canal, with the flange in a horizontal plane. DO NOT FORCE
`canal, with the flange in a horizontal plane. DO NOT FORCE
`THE INSERTION. If resistance is encountered, do not pro-
`THE INSERTION. If resistance is encountered, do not pro-
`ceed; perforation of the uterus may occur. If the flange
`ceed; perforation of the uterus may occur. If the flange
`makes contact with the cervix WITHOUT the inserter touch-
`makes contact with the cervix WITHOUT the inserter touch-
`ing the fundal wall, withdraw 14 inch before pressing the
`ing the fundal wall, withdraw % inch before pressing the
`push rod to release the device in utero. Should the inserter
`push rod to release the device in utero. Should the inserter
`touch the fundal wall BEFORE the flange makes contact,
`touch the fundal wall BEFORE the flange makes contact,
`withdraw 1/2 inch prior to pressing the push rod to release
`withdraw % inch prior to pressing the push rod to release
`the device in utero. With the inserter now in place, proceed,
`the device in utero. With the inserter now in place, proceed,
`and WITHOUT UNDUE PRESSURE, push the rod slowly as
`and WITHOUT UNDUE PRESSURE, push the rod slowly as
`far as it will go. LIPPES LOOP Intrauterine Double-S should
`far as it will go. LIPPES LOOP Intrauterine Double-S should
`now be in place. Withdraw the inserter tube and push rod
`now be in place. Withdraw the inserter tube and push rod
`from the cervical ce until the tail is visible. Cut the tail leav-
`from the cervical os until the tail is visible. Cut the tail leav-
`ing it as long as possible.
`ing it as long as possible.
`Time of Insertion
`Tim* of Insertion
`LIPPES LOOP Intrauterine Double-S should be inserted
`LIPPES LOOP Intrauterine Double-S should be inserted
`preferably the last one or two days of a normal menstrual
`preferably the last one or two days of a normal menstrual
`period or the two days following the last day.
`period or the two days following the last day.
`The expulsion and perforation rate may be increased when
`The expulsion and perforation rate may be increased when
`insertions are made before normal uterine involution occurs
`insertions are made before normal uterine involution occurs
`(usually four to six weeks postpartum or postabortion).
`(usually four to six weeks postpartum or postabortion).
`To Remove
`To Remove
`To remove LIPPES LOOP Intrauterine Double-S, pull gently
`To remove LIPPES LOOP Intrauterine Double-S, pull gently
`on the exposed tail. On those rare occasions that the tail is
`on the exposed tail. On those rare occasions that the tail is
`not available, the device should be carefully removed.
`not available, the device should be carefully removed.
`•
`CLINICAL STUDIES (cid:9)
`CLINICAL STUDIES
`Different event rates have been recorded with the use of dif-
`Different event rates have been recorded with the use of dif-
`ferent IUD's. Inasmuch as these rates•are usually derived
`ferent lUD's. Inasmuch as these rates are usually derived
`from separate studies conducted by different investigators in
`from separate studies conducted by different investigators in
`several population groups, they cannot be compared with
`several population groups, they cannot be compared with
`precision. Furthermore, event rates tend to be lower as clini-
`precision. Furthermore, event rates tend to be lower as clini-
`cal experience is expanded, possibly due to retention in the
`cal experience is expanded, possibly due to retention in the
`clinical study of those patients who accept the treatment
`clinical study of those patients who accept the treatment
`regimen and do not discontinue due to adverse reactions or
`regimen and do not discontinue due to adverse reactions or
`pregnancy. In clinical trials conducted by the Population
`pregnancy. In clinical trials conducted by the Population
`
`NOVARTIS EXHIBIT 2106
`Par v Novartis, IPR 2016-00084
`Page 3 of 6
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`1592
`1592 (cid:9)
`
`Ortho Pharm.—Cont.
`Ortho Pha rm.—Cont.
`
`(gonadorelin acetate) for Injection therapy may be moni-
`(gonadorelin acetate) for Injection therapy may be moni-
`tored by the following:
`tored by the following:
`1) Ovarian ultrasound—baseline, therapy day 7, therapy day
`1) Ovarian ultrasound—baseline, therapy day 7, therapy day
`14.
`14.
`2) Mid-luteal phase serum progesterone.
`2) Mid-luteal phase serum progesterone.
`3) Clinical observation of infusion site at each visit as needed.
`3) Clinical observation of infusion site at each visit as needed.
`4) Physical examination including pelvic at regularly sched-
`4) Physical examination including pelvic at regularly sched-
`uled visits.
`uled visits.
`DRUG INTERACTIONS: None are known. LUTREPULSE
`DRUG INTERACTIONS: None are known. LUTREPULSE
`for Injection should not be used concomitantly with other
`for Injection should not be used concomitantly with other
`ovulation stimulators.
`ovulation stimulators.
`DRUG/LABORATORY TEST INTERACTIONS: None are
`DRUG/LABORATORY TEST INTERACTIONS: None are
`known.
`known.
`CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF
`CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF
`FERTILITY: Since GnRH is a natural substance normally
`FERTILITY: Since GnRH is a natural substance normally
`present in humans, long-term studies in animals have not
`present in humans, long-term studies in animals have not
`been performed to evaluate carcinogenic potential.
`been performed to evaluate carcinogenic potential.
`Mutagenicity testing was not done.
`Mutagenicity testing was not done.
`PREGNANCY: Pregnancy Category B
`PREGNANCY: Pregnancy Category B
`Reproduction studies (teratology and embryo-toxicity) per-
`Reproduction studies (teratology and embryo-toxicity) per-
`formed in rats and rabbits have not revealed any evidence of
`formed in rats and rabbits have not revealed any evidence of
`harm to the fetus due to gonadorelin acetate There was no
`harm to the fetus due to gonadorelin acetate There was no
`evidence of teratogenicity when gonadorelin acetate was
`evidence of teratogenicity when gonadorelin acetate was
`administered intravenously up to 120 ug/kg/day (> 70 times
`administered intravenously up to 120 pg/kg/day ( > 70 times
`the recommended human dose of 5 fig per pulse) in rats and
`the recommended human dose of 5 u.g per pulse) in rats and
`rabbits.
`rabbits.
`Studies in pregnant women have shown that gonadorelin
`Studies in pregnant women have shown that gonadorelin
`acetate does not increase the risk of abnormalities when
`acetate does not increase the risk of abnormalities when
`administered during the first trimester of pregnancy. It ap-
`administered during the first trimester of pregnancy. It ap-
`pears that the possibility of fetal harm is remote, if the drug
`pears that the possibility of fetal harm is remote, if the drug
`is used during pregnancy. In clinical studies, 47 pregnant
`is used during pregnancy. In clinical studies, 47 pregnant
`patients have used gonadorelin acetate during the first tri-
`patients have used gonadorelin acetate during the first tri-
`mester of pregnancy (51 pregnancies) and the drug had no
`mester of pregnancy (51 pregnancies) and the drug had no
`apparent adverse effect on the course of pregnancy.
`apparent adverse effect on the course of pregnancy.
`Available follow-up reports on infants born to these women
`Available follow-up reports on infants born to these women
`reveal no adverse effects or complications that were attribut-
`reveal no adverse effects or complications that were attribut-
`able to gonadorelin acetate. Nevertheless, because the stud-
`able to gonadorelin acetate. Nevertheless, because the stud-
`ies in humans cannot rule out the possibility of harm, gona-
`ies in humans cannot rule out the possibility of harm, gona-
`dorelin acetate should be used during pregnancy only for
`dorelin acetate should be used during pregnancy only for
`maintenance of the corpus luteum in ovulation induction
`maintenance of the corpus luteum in ovulation induction
`cycles.
`cycles.
`NURSING MOTHERS: It is not known whether this drug
`NURSING MOTHERS: It is not known whether this drug
`is excreted in human milk. There is no indication for use of
`is excreted in human milk. There is no indication for use of
`LUTREPULSE (gonadorelin acetate) for Injection in a nurs-
`LUTREPULSE (gonadorelin acetate) for Injection in a nurs-
`ing woman.
`ing woman.
`PEDIATRIC USE: Safety and effectiveness in children
`PEDIATRIC USE: Safety and effectiveness in children
`under the age of 18 have not been established.
`under the age of 18 have not been established.
`ADVERSE REACTIONS
`ADVERSE REACTIONS
`Adverse reactions have been reported in approximately 10%
`Adverse reactions have been reported in approximately 10%
`of treatment regimens. Ten of 268 patients interrupted ther-
`of treatment regimens. Ten of 268 patients interrupted ther-
`apy because of an adverse reaction but subsequently re-
`apy because of an adverse reaction but subsequently re-
`sumed treatment. One other subject did not resume treat-
`sumed treatment. One other subject did not resume treat-
`ment.
`ment.
`In clinical studies involving 268 women, one case of moder-
`In cli