NOVARTIS EXHIBIT 2048
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 12
`
`

`
`s
`
`65
`2011
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`CEO: Edward Fotsch, MD
`President: David Tanzer
`Chief Medical Officer: Christine Cote, MD
`Chief Technology Officer: Nick Krym
`Chief Financial Officer: Dawn Carfora
`
`Vice President, Product Ma~agement & Operations: Valerie Berger
`Vice President, Emerging Products: Debra Del Guidice
`Vice President, Corporate Development, Copy Sales &
`General Counsel: Andrew Gelman
`Vice President, Sales: John Loucks
`Vice President, Marketing: Julie Baker
`Vice President, Business Development: Tom Dieker
`
`Senior Manager, Client Services: Lisa Caporuscio
`Manager, Clinical Services: Nermin Kerolous, PharmD
`Senior Drug Information Specialist,
`Database Management: Christine Sunwoo, PharmD
`Senior Drug Information Specialist,
`Product Development: Anila Pate!, PharmD
`Drug Information Specialists: Peter Leighton, PharmD;
`Kristine Mecca, PharmD; See-WonSeo, PharmD
`Manager, Editorial Services: Lori Murray
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`Copyright © 2010 PDR Network, LLC. Published by PDR Network, LLC at Montvale, NJ 07645-1725. All rights reserved. None of the content of this publication may be
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`
`ISBN: 978-1-56363-780-3
`
`NOVARTIS EXHIBIT 2048
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 12
`
`

`
`2864/PROGENICS • RELISTOR
`
`For the latest PDR product information.
`
`sure the tip of the needle is in the fluid. Slowly pull back
`on the plunger (Figure 11) to the mark that matches
`your prescribed dose (usually the 0.4 mL mark which is
`an 8 mg dose or the 0.6 mL mark which is a 12 mg
`dose).
`
`Injecting ,RELISTOR
`Step 4:
`1. Pinch the skin around the injection site as you were in(cid:173)
`structed (Figure 15).
`
`Figure 11
`
`You may see some fluid or bubbles inside the vial when
`the syringe is filled. This is normal.
`8. With the needle still in the vial, gently tap the syringe
`to make any air bubbles rise to the top (Figure 12).
`
`Figure 15
`
`2. Insert the full length of the needle into the skin at 45-
`degree angle with a "quick dart-like" motion (Figure 16).
`
`3. Let go of the skin and slowly push down on the plunger
`past the resistance point, until the syringe is empty and
`you hear a click (Figure 17).
`
`Fig~re 12
`
`9. Slowly push the plunger up until all air bubbles'are out
`of the syringe (Figure 13).
`
`Figure 17
`
`4. The click sound means th,at the needle (Figure 18) has
`been retracted (pulled back) into the syringe barrel
`(Figure 19).
`'
`
`Figure 13'
`
`10. Make sure the tip of the needle ,is in the fluid. Slowly
`pull back the plunger to draw the right amount of liquid
`back into the syringe (Figure 14).
`
`Figure 18
`
`Figure 19
`
`5. Hold a cotton ball or gauze over the injection site
`(Figure 20). Do not nib the injection site. Apply an adhe(cid:173)
`sive bandage to the injection site if needed.
`
`Figure 14
`
`Figure 20
`
`Check to be sure that you have the right dose of
`RELISTOR in the syringe.
`Note: A small air bubble may stay in the syringe. This
`is' okay and it will not affect the dose of medicine in the
`syringe.
`11. Slowly withdraw the needle from the vial (do not touch
`the needle or allow the needle to touch any surface).
`Safely throwaway the unused medicine in the vial. See
`Step 5.
`
`Step 5: Disposing of supplies
`• Do not re-use a syringe or needle.
`• Do' not recap a used needle.
`• Place used needles, syringes and vials in a closeable,
`puncture-resistant container. You may use a sharps con(cid:173)
`tainer (such as a red biohazard container), a hard plastic
`'container (such as a detergent bottle), or a metal con(cid:173)
`tainer (such as an empty coffee can). Ask your healthcare
`provider for instructions on the right way to throwaway
`
`(dispose of) the container. There .may be
`laws about how you should throwaway
`syringes.
`• H you have any questions, talk to your
`vider or pharmacist.
`WyethQb
`Marketed by:
`Wyeth Pharmaceuticals"Inc.
`Philadelphia, PA 19101
`ProgenicsQb
`Pharmaceuticals
`Under license from:
`Progeuies Pharmaceuticals, Inc.
`Tarrytown, NY 10591
`WI0531C005
`ETOI
`(09-2010)
`
`Purdue PharmaL.P.
`ONE STAMFORD FORUM
`STAMFORD, CT 06901-3431
`
`For Medical Inquiries:
`888-726-7535
`Adverse Drug Experiences:
`888·726-7535
`'
`Customer Service:
`800-877-5666
`FAX 800-877-3210
`
`BUTRANSTM
`[BYOO-trans)
`(bilprenorphine}
`Transdermal System for Transderlll,al
`
`HIGHLIGHTS OF PRESCRIBING INFORIVIAlnO
`These highlights do n.ot include'
`to use Butrans"" safely and effectiveJY.
`information for Blitrans.
`'
`Butrans (buprenorphil,e) Traiisdermal
`mal administration cm
`Initial U.S. Approval: 1981
`
`WARNING: POTENTIAL ,"UJ.,,,,,m .. :'.
`TANCE OF PROPER,PATIENT
`See full prescribing information ,f~r
`warning.
`• Butrans is indicated for the m~lnagelnen
`ate to severe chronic, pain in
`tinuous, around-the-clock
`tended period of time. (I)
`• Butrans contains buprenorphinQ
`opioid partial agonist and a
`substance. (9.1)
`• .Assess patients for their clinical·
`abuse or addiction prior'tJ) "nr,,~cl'ibil"O
`• Do, not exceed a dose of one
`system due to the risk of OTc
`(2.3)
`• Avoid exposing the Butrans aPI)liciaticlii
`rounding area to direct
`Temperature-dependent in,creaise!, In.
`release from the system may result
`death. (5.11)
`
`---DOSAGE ANl(>'Al[)M1INI~;TJ
`, • EachlButrans is intended to be
`.' In opioid-nalve 'patients, the
`should always be 5 mcg/hour.
`• For patients already receiving
`instructions. (2.2)
`• Do not increase the Butrans dose
`been exposed continuaJly to the
`hours. (2.3)
`,
`• After removal, wait a minimum of
`ing to the same site (2.1)
`.
`• When Butrans is no longer required
`the dose as part of a comprehensive
`--'---DOSAGE FORMS AND
`• Transdermal system, 5 mcg/hour, .
`20 mcg/hour. (3)
`,
`
`• Patients who have significant
`5.1,5.2)
`
`IMPORTANT NOTICE: Updated drug information is sent bi-monthly via the PDR® Update Insert. For monthly email updates,
`
`NOVARTIS EXHIBIT 2048
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 12
`
`

`
`CME for PDR-listed products at PDR.net
`
`BUTRANS • PURDUE/286S
`
`have known hypersensitivity to any of its
`the active ingredient, buprenorphine (4)
`of acute pain or in patients who require
`a short period of time (4)
`post-operative pain, including use
`day surgeries (4)
`mild pain (4)
`intermittent pain (e.g., use on an as-'
`
`caution in patients at risk of respira-
`1,7.2)
`in patients who are receiving other
`(CNS) depressants. (5.2, 7.2, 12.2)
`are expected when used with alCo(cid:173)
`other opioids, or illicit drugs. (5.3,
`
`with Long QT Syndrome, family history
`"S''Ildro"ne. or those taking Class IA or Class
`medicati,ons. (5.4, 12.2)
`increased intracranial pressure and
`such as level of consciousness or pupil-
`
`reactions ("=5%) include: nausea,
`site pruritus, dizziness, constipation,
`vomiting, application site erythema, dry
`apIJllca<l.on site rash.
`ADVERSE REACTIONS, contact
`7535 or FDA at 1-800-FDA-
`
`~-JL"'U'" INTERACTIONS~---­
`CYF3A4 enzymatic activity may alter
`bUIJre:norph:ine but the clinical signifi-
`not known. (7.1)
`may interact with Butrans resulting in
`CNS depression - use caution in prescrib(cid:173)
`patients receiving benzodiazepines or
`and warn patients against concomitant
`,aticm/mlism.e. (7.2)
`may enhance the action of Butrans and
`~ increased degree of respiratory depression.
`
`is not recommended for use during
`
`Breast-feeding is not advised 'in nioth-
`with Butrans. (8.3)
`Safety and effectiveness of Butrans have
`est:abliish,ad in patients below Hi years. (8.4)
`While no dose adjustment is recommended
`f age, administer Butrans ,with caution in
`(8.5)
`
`Butrans has not been evaluated in
`severe hepatic impairment and should be
`with caution. (8.6)
`DA'"T"'''''l' COUNSELING INFORMATION
`
`Revised: August 2010 '
`
`CONTENTS*
`
`5.11 Application of External Heat
`5.12 Patients with Fever
`5,13 Driving and Operating Machinery
`5.14 Seizures
`5.15 Special Risk Groups
`5.16 Use in PancreatidBiliary Tract Disease and
`Other Gastrointestinal Conditions
`5.17 Use in Addiction Treatment
`5.18 MAO Inhibitors
`6 ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`7 DRUG INTERACTIONS
`7.1 Metabolic Drug Interactions
`7.2 Non-Metabolic Drug Interactions
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Qeriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`8.8 Gender Differences
`9 DRUG'ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3
`Physical Dependence and Tolerance
`10 OVERDOSAGE
`10.1 Symptoms
`10.2 Treatment
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12,1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13,1 Carcinogenesis, Mutagenesis, Impairment of Fer-
`tility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Information for Patients and Caregivers
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`FULL PRESCRIBING INFORMATION
`
`IMPORTANCE OF PROPER PATIENT
`WARNING:
`POTENTIAL
`FOR
`,ABUSE, AND
`SELECTION,
`LIMITATIONS OF USE
`Proper Patient Selection
`Butrans is a transdermal formulation of buprenorphine
`indicated for the management of moderate to severe
`chronic pain in patients requiring a continuous, around(cid:173)
`the-clock opioid analgesic for an extended period of
`time. (1)
`Potential for Abuse
`Butrans contains buprenorphine which is a mu opioid
`partial agonist'and a Schedule III controUed substance.
`Butrans can be abused in a manner similar to other
`opioid agonists, legal or illicit. Consider the abuse po(cid:173)
`tential when prescribing or dispensing ,Butrans in situ(cid:173)
`ations wh!)re the physician or pharmacist is concerned
`about an increased risk of misuse, abuse, or diversion.
`(9)
`Persons at increased risk for opioid abuse include those
`with a personal or family history of substance abuse
`(including drug or alcohol abuse or addiction) or mental
`illness (e.g., major depression). Assess patients for
`their clinical risks for opioid abuse or addiction prior to
`being prescribed opioids. Routinely monitor aU pa(cid:173)
`tients receiving opioids for signs of misuse, abuse and
`addiction. (2.2)
`.Limitations of Use
`Do not exceed a dose of one 20 mcg/hour Butrans sys(cid:173)
`tem due to the risk of aTc interval prolongation. (2.3)
`Avoid exposing the Butrans application site and sur(cid:173)
`rounding area to direct external heat sources.
`Temperature-dependent increases in buprenorphine re(cid:173)
`lease from the system may result in overdose and
`death. (5.11)
`
`ery case, using non-opioid analgesics, opioids on an as(cid:173)
`needed basis andlor combination products, and chronic
`opioid therapy in a progressive plan of pain management
`such as outlined by the World Health Organization, the
`American Pain Society, and Federation of State Medical
`Boards,Model Policy,
`Butrans is for transdermal use (on intact skin) only.
`Do not use Butrans if the pouch seal is broken or the patch
`is cut, damaged, or changed in any way. Do not cut Butrans.
`Each Butrans is intended to be worn for 7 days.
`Apply Butrans to the upper outer arm, upper chest, upper
`back or the side of the chest. These four sites (each present
`on both sides, of the body) provide 8 possible application
`sites. Rotate Butrans among the 8 described skin sites.
`After Butrans removal, wait a minimum of 21 days before
`reapplying to the same skin site [see Clinical Pharma,cology
`(12.3)}.
`Apply Butrans -to a hairless or nearly hairless skin site, If
`none are available, the hair at the site should be clipped, not
`shaven. Do not apply Butrans to irritated skin. If the appli(cid:173)
`cation site must be cleaned, clean the site with water only.
`Do not use'soaps, alcohol, oils, lotions, or abrasive devices:
`Allow the'skin to dry before applying Butrans.
`If problems with adhesion of Butrans' occur, the edges may
`be taped with first aid tape,
`If Biltrans falls off during the 7 days dosing interval, dis(cid:173)
`pose of the transdermal system properly and place a -new'
`Butrans on at a different skin site [see How Supplied/ Stor-
`age and Handling (16)}.
`'
`2.2
`Initiation of Therapy
`It is critical to initiate the dosing regimen individually for
`each patient, Overestimating the Butrans dose when cori(cid:173)
`verting patients from another opioid medication can result
`in fatal overdose with the first dose [see Overdosage (1O)}.
`Consider the following when selecting the initial dose of
`Butrans:
`1. The total daily dose, potency, and specific characteristics
`of the opioid the patient has been taking previously;
`2, The reliability of the relative potency estimate used to
`calculate the equivalent buprenorphine dose needed
`(when converting from other
`'opioids or opioid(cid:173)
`combination products);
`3. The patient's degree of tolerance to the respiratory(cid:173)
`, depressant and sedating effects of opioids;
`4. The age, general condition, and medical status of the pa-
`tient;
`5. Concurrent non-opioid analgesic and other medications;
`6. The type and severity of the patient's pain;
`7. The balance between pain control and adverse drug ex(cid:173)
`periences;
`8. Risk factors for abuse, addiction, or diversion, including a
`prior history of abuse, addiction, or diversion.
`The following dosing recommendations, therefore, can only
`be considered as suggested approaches to what is actually a
`series of clinical decisions over time in' the management of
`the pain of each individual patient.
`Opioid-Nruve Patients
`For opioid-nruve patients, initiate treatment with Butrans
`5 mcglhour. Thereafter, individually titrate the 'dose as'de(cid:173)
`scribed in Section 2.3 Dose Titration to a level that provides
`adequate analgesia and minimizes side effects. Dose may be
`titrated to the next higher level after a minimum of 72
`hours.
`Conversion from Other Opioids to Butrans
`There is a potential for buprenorphine to precipitate with(cid:173)
`drawal in patients who are already on opioids. For conver(cid:173)
`sion from other opioids to 'Butrans (see Table 1), taper the
`patient's current around-the-clock opioids for up to 7 days to
`no more than 30 mg of morphine or equivalent per day be(cid:173)
`fore beginning treatment With Butrans. Patients may use
`short-acting analgesics as needed until analgesic efficacy
`with Butrans is attained.
`For patients whose daily dose was less than 30 mg of oral
`morphine or equivalent, initiate treatment with Butrans
`5 mcglhour. For patients whose daily dose was between 30
`and 80 mg morphine equivalents, initiate treatment with
`Butrans 10 mcglhour (see Table I), Thereafter, individually
`titrate the dose as described in Section 2.3 Dose Titration.
`
`Table 1: Dose Estimation for Conversion of Oral Morphine
`Equivalents to Butrans
`
`AND PRECAUTIONS
`, Respiratory Depression
`CNS Depression
`Interactions with Alcohol, Central Nervous Sys(cid:173)
`tem Depressants, and Illicit Drugs
`QTc Prolongation
`Head Injury
`Hypotensive Effects
`Misuse, Abuse, and Diversion of Opioids
`Hepatotoxicity
`Application Site Skin Reactions
`AnaphylactidAilergic Reactions
`
`INDICATIONS AND USAGE
`1
`Butrans is indicated for the management of moderate to se(cid:173)
`vere chronic pain in patients requiring a continuous,
`around-the-clock opioid analgesic for an extended period of
`time.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`General Principles
`Selection of patients for treatment with Butrans is governed
`by the same principles that apply to the use of similar opioid
`analgesics. Physicians should individualize treatment in ev-
`
`to opioid(cid:173)
`Use caution when prescribing Butrans
`experienced patients requiring high doses of opioids (more
`
`Visit PDR.net to register for Product Safety Alerts and to downlo.ad mobi/ePDR® - free to U.S. prescribers
`
`Qualls,
`riod of
`
`:.1)"
`
`,ersion
`
`nt'bas
`for'72
`.,e.
`aP!J~t:
`, taper
`
`a. (2.5) -~, and -ion (4,
`
`NOVARTIS EXHIBIT 2048
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 4 of 12
`
`

`
`2866/PUROUE • BUTRANS
`
`dence (9.2)}. Data are not available to
`• other risk of substantially decreased respiratory reserve
`than 80 rog/day of oral morphine equivalents). Butrans
`cidence of addiction in patients with chronic
`such as asthma, severe obesity, sleep apnea, myxedema,
`20 mcg/hour may not provide adequate analgesia for. pa-
`tients requiring greater than 80 mg/day oral morphine
`clinically significant kyphoscoliosis, and central nervous with opioids.
`system (CNS) depression
`equivalents.
`Abuse of Butrans poses a significant risk to
`• hypoxia
`could potentially result in overdose or
`2.3
`Dose Titration
`Based on the patient's requirement for supplemental short-
`• hypercapnia
`Abuse and Dependence (9)].
`• pre-existing respiratory depression
`Contact your state professional licensing board
`acting analgesics, upward titration may be instituted with a
`minimum Butrans titration interval of 72 hours, based on
`5.2
`CNS Depression
`trolled substances authority for infonuation on
`vent and detect abuse or diversion of this prod
`Butrans may cause somnolence, dizziness, alterations in
`5.8
`Hepatotoxicity
`the phanuacokinetic profile and time to reach steady state
`Aithough not observed in Butrans chronic pain
`judgment and alterations in levels of consciousness, includ-
`levels [see Clinical Pharmacology (12.3)}. Individually ti-
`ing coma.
`als, cases of cytolytic hepatitis and hepatitis
`trate the dose, under close supervision, to a level that pro-
`5.3
`Interactions with Alcohol, Central Nervous System
`have been observed in individuals
`videa adequate analgesia with tolerable side effects.
`The maximum Butrans dose is 20 mcglhour. Do not exceed
`Depressants, and Illicit Drugs
`buprenorphine for the treatment of opioid
`a dose of one 20 meg/hour Butrans system due to the risk Hypotension, profound sedation, coma or respiratory de-
`in clinical trials and through post-marketing
`of. aTe interval prolongation. In a clinical trial, Butrans
`pression may result i( Butrans is added to a regimen that
`reports. The spectrum of abnormalities
`40 mcglhour (given as two Butrans 20 mcglbour systems)
`includes other CNS depressants (e.g., sedatives, anxiolytics,
`sient asymptomatic elevations in
`resulted in prolongation of the QTc interval [see Warnings
`hypnotics, neuroleptics, muscle relaxants, other opioids).
`case reports of hepatic
`and Precautions (5.4) and Clinical Pharmacology (12.2)}.
`Therefore, use caution when deciding to initiate therapy
`syndrome, and hepatic en"ep,halopatlIY
`During periods of chanmng analgesic requirements, includ-
`'th B t
`.
`.
`t
`h
`takin
`th CNS d
`presence of pre-existing liver enzyme
`u rans m patlen s w 0 are
`goer
`epres-
`tion with hepatitis B or hepatitis C v
`,,-
`WI
`sants. Take into account the types of other medications be-
`usage of other potentially hepatotoxic
`ing initial titration, frequent contact is recommended be-
`tween the prescriber, other members of the healthcare
`ing taken, the duration of therapy with them, and· the pa-
`injection drug abuse may have
`·team, the patient, and the caregiver/family. Advise. patients
`tient's response to those medicines, including the degree of
`tributory role. In other cases, ;m",/lie;,mt.
`tolerance that has developed to CNS depression. Consider
`able to detenuine the etiology of the
`and caregiveralfamily members of the potential side· effects.
`2.4 Maintenance of Therapy and .Supplemental Analge-
`the patient's use, if any,· of alcohol and/or illicit drugs that
`sibility exists that buprenorphine had
`cause CNS depression. If the ·decision to begin Butrans is
`contributory role in the development of
`sla
`The intent of the titration period is to establish a· patient-
`made, start with a lower Butrans dose than usual.
`mality in some cases. For patients at
`specific weekly Butrans dose that will maintain adequate
`Consider using a lower initial dose of a CNS depressant
`atotoxicity (e.g., patients with a history
`analgesia with tolerable side effects for as long as pain man-
`when given to a patient currently taking Butrans due to the
`intake, intravenous drug abuse or liver
`agement is necessary. Immediate-release opioid and non-
`potential of additive CNS depressant effects.
`and periodic monitoring of liver function during
`opioid medications can be used as supplemental analgesia
`5.4
`OTc Prolongation
`with Butrans is recommended. A biological and
`dun·ng Butrans therapv
`evaluation is recommended when. a hepatic event
`A positive-controlled study of the effects of Butrans on the
`pected.
`o·
`During Chronic opioid analgesic therapy with Butrans, re-
`QTc' t
`1· h
`Ith
`b'
`t d
`t
`t d
`. 1· .
`II
`m erva m ea y su ~ec s emons ra e no c mica y
`5.9
`Application Site Skin Reactions
`assess the continued need for around-the-clock opioid anal-
`meaningful effect at a Butrans dose of 10 mcglhour; how-
`In rare cases, severe application site skin
`ever, a Butrans dose of 40 mcglhour (given as two Butrans
`signs of marked inflammation including
`gesic therapy periodically.
`and "vesicles" have occurred. Time Of
`2.5
`Cessation of Therapy
`20 mcglbour Transdermal Systems) was observed to prolong
`When the patient no longer requires therapy with Butrans,
`the QTc interval [see Clinical Pharmacology (12.2)}.
`from days to months following the
`taper the dose gradually to prevent signs and symptoms of Consider these observations in clinical decisions when pre-
`treatment. Instruct patients to promptly report
`withdrawal in the physically-dependent patient; consider
`scribing Butrans to patients with hypokalemia or clinically ment of severe application site reactions and
`introduction of an appropriate immediate-release opioid
`unstable cardiac disease; including:. unstable atrial flbrilla-
`therapy.
`medication. Undertake discontinuation of therapy as part of
`tion, symptomatic bradycardia, unstable congestive heart
`5.10
`Anaphylactic/Allergic Reactions
`a comprehensive treatment p l an . ·
`failure, or active myocardial ischemia. Avoid the use of Cases of acute and chronic hypeirsensitiviitv
`.
`2.6
`Patients with Hepatic Impairment
`Butrans in patients with a history of Long QT Syndrome or
`buprenorphine have been reported both
`clinical
`Start patients with mild to moderate hepatic impairment
`an immediate family member with this condition, or those
`in the post-marketing experience. The most common signa .
`with the Butrans 5 mcglhour dose. Thereafter, individually
`and symptoms include rashes, hives, and pruritus. Cases 01
`titrate the dose to a level that provides adequate analgesia
`bronchospasm, angioneurotic edema, and anaphylactic
`taking Class lAantiarrhythmic medications (e.g., qninidine,
`and tolerable side effects, under the close supervision of the
`shock have been reported. A history of hypersellEitivity to
`procainamide, disopyramide) or Class III antiarrhythmic
`buprenorphine is a contraindication to the use of Butrw.
`medications (e.g., sotalol, amiodarone, dofetilide).
`prescriber. Butrans has not been evaluated in patients with.
`severe hepatic impainuent. As Butrans is onlY intended for
`5.11
`Application of External Heat
`. . ' ...
`5.5
`Head Injury
`7.day application, consider use of an alternate analgesic
`The respiratory depressant effects .of opioids, .including Advise patients and their caregivers to avoid exposing the
`Butrans application site and surrounding area to _ix·.
`that may penuit more flexibility with the dosing in patients
`Butrans, include carbon dioxide retention, which can lead to
`an elevation of cerebrospinal fluid pressure. This effect may
`ternal' heat sources, such as heating pads or·· electric bla&
`with severe hepatic impainuent [see Warnings and Precau·
`be exaggerated in the presence of head injury, intracranial
`kets, heat or tanning lamps, saunas; hot tubs,· and ·heated
`water beds, etc., while wearing the system because an in-
`tions (5.1), Use In Specific Populations (8.6), and Clinical
`lesions, or other sources of pre-existing increased intracra-
`Pharmacology (12.3)}.
`nial pressure. Butrans may produce miosis that is indepen-
`crease in absorption of buprenorphine rilay occur [sf( Clin;
`t 1· ht
`8
`DOSAGE FORMS AND STRENGTHS
`d
`t
`b'
`d alte d '
`'th
`f
`ical Pharmacology (12.3)}. Advise patients against expOSuri
`f
`en 0' am len
`Ig
`,. an
`. re conSCIOusness, el er 0
`of the Butrans application site and surroundintarelj.to
`hot water or prolonged exposure to direct sunlight. TIiire
`Butrans is available as:
`which may obscure. neurologic signs associated with in-
`• Butrans 5 mcglhour Transdermal System (dimensions:
`creased intracranial pressure in persons with head injuries.
`is a potential for temperature-dependent increases1n
`45 mm by 45 mm)
`5.6
`Hypotensive Effects
`.
`buprenorphine released from the system resultingjn poasi.
`• Butrans 10 mcglhour Transdermal System (dimensions:
`Butran.s may cause severe hypotension. There is an added
`ble overdose and death.
`..
`..
`45 mm by 68 mm)
`risk to individuals whose ability to maintain blood pressure
`5.12
`Patients with Fever
`Patients· wearing Butrans systems who develop fever or jn.
`• Butrans 20 mcglhour Transdenual System (dimensions:
`has been compromised by a depleted blood volume, or after
`·72 min by 72 mm)
`concurrent administration with drugs suCh asphenothia-
`creased core body temperature due to strenuo~ exertion
`should be monitored for opioid side effects and the B~~
`4
`CONTRAINDICATIONS
`zines or other agents which compromise vasomotor tone.
`Buprenorphine may produce orthostatic hypotension in am-
`dose should be adjusted if necessary [see DoslIlJe ana.!,"·
`bulatory patients. Administer Butrans with caution to pa-
`ministration (2.4)).·
`.
`Butrans is contraindicated in:
`• patients who have significant respiratory depression
`tients in circulatory shock, since vasodilation produced by
`5.13
`Driving and Operating Machinery.
`. ..
`f
`Butrans may impair the· mental and phYSical abilities
`h d
`d
`di
`d bl d
`• patients who have severe bronchial asthma
`ch as
`t e rug may urther re uce car . ac output an
`00 pres-
`. .
`needed to perfonu potentially hazardous actiVities. su
`• patients who have or are suspected of having paralytic il-
`driving a car or operating machinery. Caution patients a~
`Sure.
`eus
`din 1
`5 7 Misuse, Abuse, and Diversion of Opioids
`• patients who have known hYPdiersensitivity to any ofits
`~~~4 g ~eizures
`Butrans contains buprenorphine, a partial agonist at the
`...
`mu opioid receptor and a Schedule III controlled substance.
`Butrans, as with other opioids, may aggravate seizure d!B".
`components or the active ingre ·ent, buprenorphine
`• the· management of acute· pain or in patients who require Opioid agonists have potential for being abused, are sought
`d
`1
`.
`th h Id
`d th efore may m·
`·th
`opioid analgesia for a short period of time
`or ers, may ower seizure
`res 0
`,an
`er
`,
`by drug abusers and people with addiction disorders, and
`duce seizures in some clinical settings. Use Butrans WI
`• the ma:riagement of post-operative pairi, including use af-
`caution in patients with a history of seizure disorders.
`are subject to criminal diversion.
`ter out-patient or day surgeries
`Butrans can be abused in a manner similar to other opioid
`5.15
`Special Risk Groups
`;..
`to
`Use Butrans with caution in the following condi. tlons'l~~e
`1 1
`'11"
`• the management of mild pain
`.
`C
`'d
`h·
`t
`t' l' b
`increased risk of adverse reactions: alcohohsm; de mum
`• the management of intenuittent pain (e.g., use on an as
`agomsts, ega or 1 !CIt. onsl er t IS po en la lor a use
`when prescribing or dispensing Butrans in situations where
`.
`. de-
`tremens,· adrenocortical insufficiency; eNS d,e.p.resslOn, 1JIl.
`needed basis. [pm])
`t ry c<
`the prescriber or pharmacist is concerned about an in-
`bilitation; kyphoscoliosis associated with respl~a ~"n"ri:ro-
`5 WARNINGS AND PRECAUTIONS
`creased risk of misuse, abuse, or diversion. Monitor'all pa-
`promise; myxedema or hypothyroidism; proststiC UJ~V Ii',
`5.1
`Respiratory Depression
`tients receiving opioids for signs of abuse, misuse, and ad-
`phy or urethral stricture; severe impairment. of heps
`,
`pulnionary or renal function; and toxic psychOSIS. d Other
`diction. Furthermore, assess patients for their potential for
`Respiratory depression is the chief hazard of Butrans. Res-
`piratory depression occurs more frequently in elderly or de-
`opioid abuse prior to being prescribed opioid therapy. Per-
`5.16
`Use in PancreaticlBiliary Tract Disease an
`. Use
`Gastrointestinal Conditions
`bilitated patients as well as those suffering from conditions
`sons at increased risk for opioid abuse include those with a
`Butrans may cause spasm of the sphincter of ~ddi~
`accompanied by hypoxia or hypercapnia when even moder-
`personal or family history of substance abuse (including
`ate therapeutic doses may dangerously decrease pulmonary
`drug ·or alcohol abuse) or menta! illness (e.g.,' depression),
`with caution in patients with biliary tract disease, mel use
`acute .pancreatitis. Opioids, including Butrans; may ca
`ventilation, and when opioids, including Butrans, are given Opioids may still be appropriate for use in these patients;
`in conjunction with other agents that depress respiration.
`however, they will require intensive monitoring for signs of
`increased serum amylase.
`.
`.• or
`The administration of Butrans may obscure t!,e dia~:ons.
`Profound sedation, unresponsiveness, infrequent deep
`abuse.
`clinical course in patients with acute abdommal C~\ of de-
`("sighing") breaths or atypical snoring frequeritly accom-
`Notwithstanding concerns. about abuse, addiction, and di-
`Use Butrans with caution in patients who are at n"
`pany opioid-induced respiratory depression.
`version, provide proper 'management of pain. However, all
`Use Butrans with extreme caution in patients with any of
`patients treated with opioid agonists require careful moni-
`veloping ileus.
`. .
`the following:
`toring for signs of abuse and addiction, since use of opioid
`5.17
`Use in Addiction Treatment
`• significant chronic obstructive pulmonary disease or cor
`agonist analgesic products carries the risk of addiction even
`Butrans has not been studied and is riot approved for
`pulmonale
`under appropriate medical use [see Drug Abuse and Depen-
`the management of addictive disorders.
`
`use in
`
`IMPORTANT NOTICE: Updated drug· information is sent bi-rrionthly via the PDR® Update Insert. For monthly email updates, register at PDR.net.
`
`NOVARTIS EXHIBIT 2048
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 5 of 12
`
`

`
`->,,,Ii,merltary CME for PDR-listed products at PDR.net
`
`BUTRANS • PURDUE/2867
`
`Inhibitors
`recommended for use in patients who have
`",.,'';'',PllJ''U'- inhibitors within 14 days, because severe and
`''''!I''"",,"C''''"'" potentiation by MAO inhibitors has been re-
`opioid analgesics.
`
`Table 4: Adverse Events Reported in TItration-to-Effect
`Placebo I ACtive-Controlled Clinical Trials with Incidence
`,,=2%
`
`MedDRA Preferred Term