EXHIBIT 30 

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 1 of 11 PageID: 1432
_________________________________________________________________________________________________________________________

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

FENTORA safely and effectively. See full prescribing information for

FENTORA.

FENTORA®

(fentanyl citrate) buccal tablet, CII

Initial U.S. Approval: 1968

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION

ERRORS, ABUSE POTENTIAL

See full prescribing information for complete boxed warning.

Due to the risk of fatal respiratory depression, FENTORA is

contraindicated in opioid non-tolerant patients (1) and in management

of acute or postoperative pain, including headache/migraines. (4)

Keep out of reach of children. (5.3)

Use with CYP3A4 inhibitors may cause fatal respiratory depression. (7)

When prescribing, do not convert patients on a mcg per mcg basis from

any other oral transmucosal fentanyl product to FENTORA. (2.1, 5.1)

When dispensing, do not substitute with any other fentanyl products.

(5.1)

Contains fentanyl, a Schedule II controlled substance with abuse

liability similar to other opioid analgesics. (9.1)

FENTORA is available only through a restricted program called the

TIRF REMS Access program. Outpatients, healthcare professionals

who prescribe to outpatients, pharmacies, and distributors are required

to enroll in the program. (5.11)

----------------------------RECENT MAJOR CHANGES---------------------------

Indications and Usage (1) 12/2011

Warnings and Precautions, TIRF REMS Access Program (5.11) 12/2011

----------------------------INDICATIONS AND USAGE---------------------------

FENTORA is an opioid agonist indicated for the management of breakthrough

pain in cancer patients 18 years of age and older who are already receiving and

who are tolerant to around-the-clock opioid therapy for their underlying

persistent cancer pain. (1)

Limitations of Use:

FENTORA may be dispensed only to patients enrolled in the TIRF REMS

Access program. (1)

----------------------DOSAGE AND ADMINISTRATION-----------------------

Patients must require and use around-the-clock opioids when taking

FENTORA. (1)

Initial dose of FENTORA: 100 mcg. (2.1)

Initiate titration using multiples of 100 mcg FENTORA tablet. Limit patient

access to only one strength of FENTORA at any one time. (2.1)

Individually titrate to a tolerable dose that provides adequate analgesia using

single FENTORA tablet. (2.1)

No more than two doses can be taken per breakthrough pain episode. (2.1)

Wait at least 4 hours before treating another episode of breakthrough pain

with FENTORA. (2.1)

Place entire tablet in buccal cavity; tablet is not to be split, sucked, chewed

or swallowed. (2.4)

---------------------DOSAGE FORMS AND STRENGTHS----------------------

Tablets: 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths. (3)

-------------------------------CONTRAINDICATIONS------------------------------

Opioid non-tolerant patients. (4)

Management of acute or postoperative pain, including headache/migraine

and dental pain. (4)

Intolerance or hypersensitivity to fentanyl or components of FENTORA. (4)

-----------------------WARNINGS AND PRECAUTIONS----------------------

Clinically significant respiratory and CNS depression can occur. Monitor

patients accordingly. (5.1)

Use with other CNS depressants and cytochrome P450 3A4 inhibitors may

increase depressant effects including hypoventilation, hypotension, and

profound sedation. Consider dosage adjustments if warranted. (5.4)

Titrate FENTORA cautiously in patients with chronic obstructive pulmonary

disease or preexisting medical conditions predisposing them to respiratory

depression and in patients susceptible to intracranial effects of CO2 retention.

(5.6, 5.7)

Application site reactions occurred in 10% of patients in clinical trials and

ranged from paresthesia to ulceration and bleeding. (5.8)

------------------------------ADVERSE REACTIONS-------------------------------

Most common (frequency 10%): nausea, dizziness, vomiting, fatigue, anemia,

constipation, edema peripheral, asthenia, dehydration and headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Cephalon, Inc.,

at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS-------------------------------

See Boxed Warning and Warnings and Precautions (5.4, 7)

-----------------------USE IN SPECIFIC POPULATIONS------------------------

Administer FENTORA with caution to patients with hepatic or renal

impairment. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and

MEDICATION GUIDE.

Revised: 12/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF RESPIRATORY DEPRESSION,

MEDICATION ERRORS, ABUSE POTENTIAL

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Initial Dose

2.2 Dose Titration

2.3 Maintenance Dosing

2.4 Administration of FENTORA

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Respiratory Depression

5.2 Important Information Regarding Prescribing and Dispensing

5.3 Patient/Caregiver Instructions

5.4 Additive CNS Depressant Effects

5.5 Effects on Ability to Drive and Use Machines

5.6 Chronic Pulmonary Disease

5.7 Head Injuries and Increased Intracranial Pressure

5.8 Application Site Reactions

5.9 Cardiac Disease

5.10 MAO Inhibitors

5.11 Transmucosal Immediate Release Fentanyl (TIRF) Risk

Evaluation and Mitigation Strategy (REMS) Access Program

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy  Category C

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal or Hepatic Impairment

8.7 Gender

8.8 Race

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse and Addiction

9.3 Physical Dependence and Withdrawal

10 OVERDOSAGE

10.1 Clinical Presentation

10.2 Immediate Management

10.3 Treatment of Overdosage (Accidental Ingestion) in the Opioid

Non-Tolerant Person

10.4 Treatment of Overdose in Opioid Tolerant Patients

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

1

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 2 of 11 PageID: 1433
££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££££

10.5 General Considerations for Overdose 16.2 Disposal of FENTORA

11 DESCRIPTION 16.3 How Supplied

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

17 PATIENT COUNSELING INFORMATION

17.1 Patient/Caregiver Instructions

12.2 Pharmacodynamics 17.2 Disposal of Unopened FENTORA Blister Packages When No

12.3 Pharmacokinetics Longer Needed

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

MEDICATION GUIDE

14

16

CLINICAL STUDIES

HOW SUPPLIED/STORAGE AND HANDLING

16.1 Storage and Handling

* Sections or subsections omitted from the full prescribing information

are not listed.

FULL PRESCRIBING INFORMATION

WARNING: RISK OF RESPIRATORY DEPRESSION,

MEDICATION ERRORS, ABUSE POTENTIAL

RESPIRATORY DEPRESSION

Fatal respiratory depression has occurred in patients treated with

FENTORA, including following use in opioid non-tolerant patients and

improper dosing. The substitution of FENTORA for any other

fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression, FENTORA is contraindicated

in the management of acute or postoperative pain including

headache/migraine and in opioid non-tolerant patients. [see

Contraindications (4)]

FENTORA must be kept out of reach of children. [see Patient

Counseling Information (17.3) and How Supplied/Storage and Handling

(16.1)]

The concomitant use of FENTORA with CYP3A4 inhibitors may result in

an increase in fentanyl plasma concentrations, and may cause potentially

fatal respiratory depression [see Drug Interactions (7)].

MEDICATION ERRORS

Substantial differences exist in the pharmacokinetic profile of

FENTORA compared to other fentanyl products that result in

clinically important differences in the extent of absorption of fentanyl

that could result in fatal overdose.

- When prescribing, do not convert patients on a mcg per mcg

basis from any other fentanyl products to FENTORA. (2.1)

- When dispensing, do not substitute a FENTORA prescription

for other fentanyl products.

ABUSE POTENTIAL

FENTORA contains fentanyl, an opioid agonist and a Schedule II

controlled substance, with an abuse liability similar to other opioid

analgesics. FENTORA can be abused in a manner similar to other

opioid agonists, legal or illicit. This should be considered when

prescribing or dispensing FENTORA in situations where the physician

or pharmacist is concerned about an increased risk of misuse, abuse or

diversion.

Because of the risk for misuse, abuse, addiction, and overdose, FENTORA

is available only through a restricted program required by the Food and

Drug Administration, called a Risk Evaluation and Mitigation Strategy

(REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF)

REMS Access program, outpatients, healthcare professionals who prescribe

to outpatients, pharmacies, and distributors must enroll in the program. [see

Warnings and Precautions (5.11)] Further information is available at

www.TIRFREMSAccess.com or by calling 1-866-822-1483.

INDICATIONS AND USAGE

FENTORA is indicated for the management of breakthrough pain in

cancer patients 18 years of age and older who are already receiving and who

are tolerant to around-the-clock opioid therapy for their underlying

persistent cancer pain. Patients considered opioid tolerant are those who are

taking around-the-clock medicine consisting of at least 60 mg of oral

morphine daily, at least 25 mcg/hr of transdermal fentanyl, at least 30 mg of

oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25

mg oral oxymorphone daily, or an equianalgesic dose of another opioid

daily for a week or longer. Patients must remain on around-the-clock

opioids while taking FENTORA.

This product must not be used in opioid non-tolerant patients because

life-threatening hypoventilation and death could occur at any dose in

patients not on a chronic regimen of opioids. For this reason, FENTORA is

contraindicated in the management of acute or postoperative pain.

FENTORA is intended to be used only in the care of opioid tolerant

cancer patients and only by healthcare professionals who are knowledgeable

of and skilled in the use of Schedule II opioids to treat cancer pain.

Limitations of Use:

As a part of the TIRF REMS Access program, FENTORA may be

dispensed only to outpatients enrolled in the program [see Warnings and

Precautions (5.11)]. For inpatient administration of FENTORA (e.g.,

hospitals, hospices, and long-term care facilities that prescribe for inpatient

use), patient and prescriber enrollment is not required.

2 DOSAGE AND ADMINISTRATION

Healthcare professionals who prescribe FENTORA on an outpatient

basis must enroll in the TIRF REMS Access program and comply with the

requirements of the REMS to ensure safe use of FENTORA [see Warnings

and Precautions (5.11)].

As with all opioids, the safety of patients using such products is

dependent on health care professionals prescribing them in strict conformity

with their approved labeling with respect to patient selection, dosing, and

proper conditions for use.

It is important to minimize the number of strengths available to

patients at any time to prevent confusion and possible overdose.

2.1 Initial Dose

FENTORA is not bioequivalent with other fentanyl products. Do

not convert patients on a mcg per mcg basis from other fentanyl

products. There are no conversion directions available for patients on

any other fentanyl products other than Actiq. (Note: This includes oral,

transdermal, or parenteral formulations of fentanyl.) All patients

should be titrated from the 100 mcg dose.

Patients on Actiq

The initial dose of FENTORA is always 100 mcg with the only exception

being patients already using Actiq.

a. For patients being converted from Actiq, prescribers must use the

Initial Dosing Recommendations for Patients on Actiq table below

(Table 1). The doses of FENTORA in this table are starting doses and

not intended to represent equianalgesic doses to Actiq. Patients must

be instructed to stop the use of Actiq and dispose of any remaining

units.

Table 1. Initial Dosing Recommendations for Patients on Actiq

Current Actiq Dose

(mcg)

Initial FENTORA Dose*

200 100 mcg tablet

400 100 mcg tablet

600 200 mcg tablet

800 200 mcg tablet

1200 2 x 200 mcg tablets

1600 2 x 200 mcg tablets

*From this initial dose, titrate patient to effective dose.

b. For patients converting from Actiq doses equal to or greater than 600

mcg, titration should be initiated with the 200 mcg FENTORA tablet

and should proceed using multiples of this tablet strength.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

2

1

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 3 of 11 PageID: 1434
All Other Patients

The initial dose of FENTORA is 100 mcg.

Repeat Dosing

a. In cases where the breakthrough pain episode is not relieved after 30

minutes, patients may take ONLY ONE additional dose using the

same strength for that episode. Thus patients should take a maximum

of two doses of FENTORA for any episode of breakthrough pain.

b. Patients MUST wait at least 4 hours before treating another episode

of breakthrough pain with FENTORA.

2.2 Dose Titration

a. From an initial dose, patients should be closely followed by the

prescriber and the dosage strength changed until the patient reaches a

dose that provides adequate analgesia with tolerable side effects.

Patients should record their use of FENTORA over several episodes

of breakthrough pain and discuss their experience with their physician

to determine if a dosage adjustment is warranted.

b. Patients whose initial dose is 100 mcg and who need to titrate to a

higher dose, can be instructed to use two 100 mcg tablets (one on each

side of the mouth in the buccal cavity) with their next breakthrough

pain episode. If this dosage is not successful, the patient may be

instructed to place two 100 mcg tablets on each side of the mouth in

the buccal cavity (total of four 100 mcg tablets). Titrate using

multiples of the 200 mcg FENTORA tablet for doses above 400 mcg

(600 mcg and 800 mcg). Note: Do not use more than 4 tablets

simultaneously.

c. In cases where the breakthrough pain episode is not relieved after 30

minutes, patients may take ONLY ONE additional dose of the same

strength for that episode. Thus patients should take a maximum of

two doses of FENTORA for any breakthrough pain episode. During

titration, one dose of FENTORA may include administration of 1 to 4

tablets of the same dosage strength (100 mcg or 200 mcg).

d. Patients MUST wait at least 4 hours before treating another episode

of breakthrough pain with FENTORA. To reduce the risk of overdose

during titration, patients should have only one strength of FENTORA

tablets available at any time.

e. Patients should be strongly encouraged to use all of their FENTORA

tablets of one strength prior to being prescribed the next strength. If

this is not practical, unused FENTORA should be disposed of safely

[see How Supplied/Storage and Handling (16.2)]. Dispose of any

unopened FENTORA tablets remaining from a prescription as soon as

they are no longer needed.

2.3 Maintenance Dosing

a. Once titrated to an effective dose, patients should generally use only

ONE FENTORA tablet of the appropriate strength per breakthrough

pain episode.

b. On occasion when the breakthrough pain episode is not relieved after

30 minutes, patients may take ONLY ONE additional dose using the

same strength for that episode.

c. Patients MUST wait at least 4 hours before treating another episode

of breakthrough pain with FENTORA.

d. Dosage adjustment of FENTORA may be required in some patients.

Generally, the FENTORA dose should be increased only when a

single administration of the current dose fails to adequately treat the

breakthrough pain episode for several consecutive episodes.

e. If the patient experiences greater than four breakthrough pain episodes

per day, the dose of the around-the-clock opioid used for persistent

pain should be re-evaluated.

2.4 Administration of FENTORA

Opening the Blister Package:

1. Instruct patients not to open the blister until ready to administer

FENTORA.

2. Separate a single blister unit from the blister card by bending and

tearing apart at the perforations.

3. Bend the blister unit along the line where indicated.

4. Peel back the blister backing to expose the tablet. Patients should

NOT attempt to push the tablet through the blister as this may

cause damage to the tablet.

5. Do not store the tablet once it has been removed from the blister

package as the tablet integrity may be compromised and, more

importantly, because this increases the risk of accidental exposure to

the tablet.

Tablet Administration:

Once the tablet is removed from the blister unit, the patient should

immediately place the entire FENTORA tablet in the buccal cavity (above

a rear molar, between the upper cheek and gum). Patients should not split

the tablet.

The FENTORA tablet should not be sucked, chewed or swallowed, as

this will result in lower plasma concentrations than when taken as directed.

The FENTORA tablet should be left between the cheek and gum until

it has disintegrated, which usually takes approximately 14-25 minutes.

After 30 minutes, if remnants from the FENTORA tablet remain, they

may be swallowed with a glass of water.

It is recommended that patients alternate sides of the mouth when

administering subsequent doses of FENTORA.

3 DOSAGE FORMS AND STRENGTHS

FENTORA tablets are flat-faced, round, beveled-edge in shape; are

white in color; and are available in 100 mcg, 200 mcg, 400 mcg, 600 mcg

and 800 mcg strengths. Each tablet strength is marked with a unique

identifier [see How Supplied/Storage and Handling (16.3)].

4 CONTRAINDICATIONS

FENTORA is contraindicated in opioid non-tolerant patients.

FENTORA is contraindicated in the management of acute or

postoperative pain including headache/migraine and dental pain. Lifethreatening respiratory depression and death could occur at any dose in

opioid non-tolerant patients.

Patients considered opioid tolerant are those who are taking aroundthe-clock medicine consisting of at least 60 mg of oral morphine daily, at

least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone

daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral

oxymorphone daily, or an equianalgesic dose of another opioid daily for a

week or longer.

FENTORA is contraindicated in patients with known intolerance or

hypersensitivity to any of its components or the drug fentanyl.

5 WARNINGS AND PRECAUTIONS

See Boxed Warning - WARNING: RISK OF RESPIRATORY

DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL

5.1 Respiratory Depression

Respiratory depression is the chief hazard of opioid agonists,

including fentanyl, the active ingredient in FENTORA. Respiratory

depression is more likely to occur in patients with underlying respiratory

disorders and elderly or debilitated patients, usually following large initial

doses in opioid non-tolerant patients, or when opioids are given in

conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge

to breathe and a decreased rate of respiration, often associated with the

sighing pattern of breathing (deep breaths separated by abnormally long

pauses). Carbon dioxide retention from opioid-induced respiratory

depression can exacerbate the sedating effects of opioids. This makes

overdoses involving drugs with sedative properties and opioids especially

dangerous.

5.2 Important Information Regarding Prescribing and Dispensing

FENTORA is not bioequivalent with other fentanyl products. Do

not convert patients on a mcg per mcg basis from other fentanyl

products. There are no conversion directions available for patients on

any other fentanyl products other than Actiq. (Note: This includes oral,

transdermal, or parenteral formulations of fentanyl.) For patients

being converted from Actiq, it is necessary to follow the instructions

found in Table 1 in Section 2.1, as Actiq and FENTORA are not

equivalent on a microgram per microgram basis. FENTORA is NOT a

generic version of Actiq. All patients should be titrated from the 100

mcg dose.

The initial dose of FENTORA should be 100 mcg. Titrate each patient

individually to provide adequate analgesia while minimizing side effects.

[see Dosage and Administration (2.1)]

When dispensing, DO NOT substitute a FENTORA prescription

for an Actiq prescription under any circumstances. FENTORA and

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

3

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 4 of 11 PageID: 1435
Actiq are not equivalent. Substantial differences exist in the

pharmacokinetic profile of FENTORA compared to other fentanyl products

including Actiq that result in clinically important differences in the rate and

extent of absorption of fentanyl. As a result of these differences, the

substitution of the same dose of FENTORA for the same dose of Actiq

or any other fentanyl product may result in a fatal overdose.

5.3 Patient/Caregiver Instructions

Patients and their caregivers must be instructed that FENTORA

contains a medicine in an amount which can be fatal to a child. Patients

and their caregivers must be instructed to keep tablets out of the reach of

children. [see How Supplied/Storage and Handling (16.1), and Medication

Guide for specific patient instructions.]

5.4 Additive CNS Depressant Effects

The concomitant use of FENTORA with other CNS depressants,

including other opioids, sedatives or hypnotics, general anesthetics,

phenothiazines, tranquilizers, skeletal muscle relaxants, sedating

antihistamines, and alcoholic beverages may produce increased depressant

effects (e.g., hypoventilation, hypotension, and profound sedation).

Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform

(e.g., erythromycin, ketoconazole, and certain protease inhibitors) may

increase fentanyl levels, resulting in increased depressant effects [see Drug

Interactions (7)].

Patients on concomitant CNS depressants must be monitored for a

change in opioid effects. Consideration should be given to adjusting the

dose of FENTORA if warranted.

5.5 Effects on Ability to Drive and Use Machines

Opioid analgesics impair the mental and/or physical ability required

for the performance of potentially dangerous tasks (e.g., driving a car or

operating machinery). Warn patients taking FENTORA of these dangers

and counsel them accordingly.

5.6 Chronic Pulmonary Disease

Because potent opioids can cause respiratory depression, titrate

FENTORA with caution in patients with chronic obstructive pulmonary

disease or pre-existing medical conditions predisposing them to respiratory

depression. In such patients, even normal therapeutic doses of FENTORA

may further decrease respiratory drive to the point of respiratory failure.

5.7 Head Injuries and Increased Intracranial Pressure

Administer FENTORA with extreme caution in patients who may be

particularly susceptible to the intracranial effects of CO2 retention such as

those with evidence of increased intracranial pressure or impaired

consciousness. Opioids may obscure the clinical course of a patient with a

head injury and should be used only if clinically warranted.

5.8 Application Site Reactions

In clinical trials, 10% of all patients exposed to FENTORA reported

application site reactions. These reactions ranged from paresthesia to

ulceration and bleeding. Application site reactions occurring in 1% of

patients were pain (4%), ulcer (3%), and irritation (3%). Application site

reactions tended to occur early in treatment were self-limited and only

resulted in treatment discontinuation for 2% of patients.

5.9 Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use

FENTORA with caution in patients with bradyarrhythmias.

5.10 MAO Inhibitors

FENTORA is not recommended for use in patients who have received

MAO inhibitors within 14 days, because severe and unpredictable

potentiation by MAO inhibitors has been reported with opioid analgesics.

5.11 Transmucosal Immediate Release Fentanyl (TIRF) Risk

Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose [see

Drug Abuse and Dependence (9)], FENTORA is available only through a

restricted program called the TIRF REMS Access program. Under the TIRF

REMS Access program, outpatients, healthcare professionals who prescribe

for outpatient use, pharmacies, and distributors must enroll in the program.

For inpatient administration (e.g., hospitals, hospices, and long-term care

facilities that prescribe for inpatient use) of FENTORA, patient and

prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

Healthcare professionals, who prescribe FENTORA for outpatient

use, must review the prescriber educational materials for the TIRF

REMS Access program, enroll in the program, and comply with the

REMS requirements.

To receive FENTORA, outpatients must understand the risks and

benefits and sign a Patient-Prescriber Agreement.

Pharmacies that dispense FENTORA must enroll in the program and

agree to comply with the REMS requirements.

Wholesalers and distributors that distribute FENTORA must enroll in

the program, and distribute only to authorized pharmacies.

Further information, including a list of qualified pharmacies/distributors, is

available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

The safety of FENTORA has been evaluated in 304 opioid-tolerant

cancer patients with breakthrough pain. The average duration of therapy

was 76 days with some patients being treated for over 12 months.

The most commonly observed adverse events seen with FENTORA

are typical of opioid side effects. Opioid side effects should be expected

and managed accordingly.

The clinical trials of FENTORA were designed to evaluate safety and

efficacy in treating patients with cancer and breakthrough pain; all patients

were taking concomitant opioids, such as sustained-release morphine,

sustained-release oxycodone or transdermal fentanyl, for their persistent

pain.

Because clinical trials are conducted under widely varying conditions,

adverse reaction rates observed in the clinical trials of a drug cannot be

directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in practice.

The adverse event data presented here reflect the actual percentage of

patients experiencing each adverse effect among patients who received

FENTORA for breakthrough pain along with a concomitant opioid for

persistent pain. There has been no attempt to correct for concomitant use of

other opioids, duration of FENTORA therapy or cancer-related symptoms.

Table 2 lists, by maximum dose received, adverse events with an

overall frequency of 5% or greater within the total population that occurred

during titration. The ability to assign a dose-response relationship to these

adverse events is limited by the titration schemes used in these studies.

Table 2.

Adverse Events Which Occurred During Titration at a Frequency of 5%

System Organ Class 100 mcg 200 mcg 400 mcg 600 mcg 800 mcg Total

MeDRA preferred (N=45) (N=34) (N=53) (N=56) (N=113) (N=304)*

term, n (%)

Gastrointestinal disorders

Nausea 4 (9) 5 (15) 10 (19) 13 (23) 18 (16) 50 (17)

Vomiting 0 2 (6) 2 (4) 7 (13) 3 (3) 14 (5)

General disorders and administration site conditions

Fatigue 3 (7) 1 (3) 9 (17) 1 (2) 5 (4) 19 (6)

Nervous system disorders

Dizziness 5 (11) 2 (6) 12 (23) 18 (32) 21 (19) 58 (19)

Somnolence 2 (4) 2 (6) 6 (12) 7 (13) 3 (3) 20 (7)

Headache 1 (2) 3 (9) 4 (8) 8 (14) 10 (9) 26 (9)

* Three hundred and two (302) patients were included in the safety analysis.

Table 3 lists, by successful dose, adverse events with an overall

frequency of 5% within the total population that occurred after a

successful dose had been determined.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

4

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 5 of 11 PageID: 1436
Table 3.

Adverse Events Which Occurred During Long-Term Treatment at a

Frequency of 5%

System Organ Class

MeDRA preferred

term,

n (%)

100

mcg

(N=19)

200

mcg

(N=31)

400

mcg

(N=44)

600

mcg

(N=48)

800

mcg

(N=58)

Total

(N=200)

Blood and lymphatic system disorders

Anemia 6 (32) 4 (13) 4 (9) 5 (10) 7 (13) 26 (13)

Neutropenia 0 2 (6) 1 (2) 4 (8) 4 (7) 11 (6)

Gastrointestinal disorders

Nausea 8 (42) 5 (16) 14 (32) 13 (27) 17 (31) 57 (29)

Vomiting 7 (37) 5 (16) 9 (20) 8 (17) 11 (20) 40 (20)

Constipation 5 (26) 4 (13) 5 (11) 4 (8) 6 (11) 24 (12)

Diarrhea 3 (16) 0 4 (9) 3 (6) 5 (9) 15 (8)

Abdominal pain 2 (11) 1 (3) 4 (9) 7 (15) 4 (7) 18 (9)

General disorders and administration site conditions

Edema peripheral 6 (32) 5 (16) 4 (9) 5 (10) 3 (5) 23 (12)

Asthenia 3 (16) 5 (16) 2 (5) 3 (6) 8 (15) 21 (11)

Fatigue 3 (16) 3 (10) 9 (20) 9 (19) 8 (15) 32 (16)

Infections and infestations

Pneumonia 1 (5) 5 (16) 1 (2) 1 (2) 4 (7) 12 (6)

Investigations

Weight decreased 1 (5) 1 (3) 3 (7) 2 (4) 6 (11) 13 (7)

Metabolism and nutrition disorders

Dehydration 4 (21) 0 4 (9) 6 (13) 7 (13) 21 (11)

Anorexia 1 (5) 2 (6) 4 (9) 3 (6) 6 (11) 16 (8)

Hypokalemia 0 2 (6) 0 1 (2) 8 (15) 11 (6)

Musculoskeletal and connective tissue disorders

Back pain 2 (11) 0 2 (5) 3 (6) 2 (4) 9 (5)

Arthralgia 0 1 (3) 3 (7) 4 (8) 3 (5) 11 (6)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Cancer pain 3 (16) 1 (3) 3 (7) 2 (4) 1 (2) 10 (5)

Nervous system disorders

Dizziness 5 (26) 3 (10) 5 (11) 6 (13) 6 (11) 25 (13)

Headache 2 (11) 1 (3) 4 (9) 5 (10) 8 (15) 20 (10)

Somnolence 0 1 (3) 4 (9) 4 (8) 8 (15) 17 (9)

Psychiatric disorders

Confusional state 3 (16) 1 (3) 2 (5) 3 (6) 5 (9) 14 (7)

Depression 2 (11) 1 (3) 4 (9) 3 (6) 5 (9) 15 (8)

Insomnia 2 (11) 1 (3) 3 (7) 2 (4) 4 (7) 12 (6)

Respiratory, thoracic, and mediastinal disorders

Cough 1 (5) 1 (3) 2 (5) 4 (8) 5 (9) 13 (7)

Dyspnea 1 (5) 6 (19) 0 7 (15) 4 (7) 18 (9)

In addition, a small number of patients (n=11) with Grade 1 mucositis

were included in clinical trials designed to support the safety of FENTORA.

There was no evidence of excess toxicity in this subset of patients.

The duration of exposure to FENTORA varied greatly, and included

open-label and double-blind studies. The frequencies listed below represent

the 1% of patients (and not listed in Tables 2 and 3 above) from three

clinical trials (titration and post-titration periods combined) who

experienced that event while receiving FENTORA. Events are classified by

system organ class.

Adverse Events ( 1%)

Blood and Lymphatic System Disorders: Thrombocytopenia,

Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper

Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain,

Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia,

Mouth Ulceration

General Disorders and Administration Site Conditions: Pyrexia,

Application Site Pain, Application Site Ulcer, Chest Pain, Chills,

Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: Oral Candidiasis, Urinary Tract Infection,

Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection,

Influenza, Tooth Abscess

Injury, Poisoning and Procedural Complications: Fall, Spinal

Compression Fracture

Investigations: Decreased Hemoglobin, Increased Blood Glucose,

Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders: Decreased Appetite,

Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia,

Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders: Pain in Extremity,

Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy,

Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine,

Neuropathy

Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood,

Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic and Mediastinal Disorders: Pharyngolaryngeal

Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds,

Wheezing

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis,

Cold Sweat

Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein

Thrombosis

7 DRUG INTERACTIONS

Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme

system; therefore potential interactions may occur when FENTORA is

given concurrently with agents that affect CYP3A4 activity.

The concomitant use of FENTORA with CYP3A4 inhibitors (e.g.,

indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,

nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin,

fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a

potentially dangerous increase in fentanyl plasma concentrations, which

could increase or prolong adverse drug effects and may cause potentially

fatal respiratory depression. Patients receiving FENTORA who begin

therapy with, or increase the dose of, CYP3A4 inhibitors should be

carefully monitored for signs of opioid toxicity over an extended period of

time. Dosage increase should be done cautiously [see Warnings and

Precautions (5.4)]. The concomitant use of FENTORA with CYP3A4

inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids,

modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin,

pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result

in a decrease in fentanyl plasma concentrations, which could decrease the

efficacy of FENTORA. Patients receiving FENTORA who stop therapy

with, or decrease the dose of, CYP3A4 inducers should be monitored for

signs of increased FENTORA activity and the dose of FENTORA should be

adjusted accordingly.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy  Category C

There are no adequate and well-controlled studies in pregnant women.

FENTORA should be used during pregnancy only if the potential benefit

justifies the potential risk to the fetus. No epidemiological studies of

congenital anomalies in infants born to women treated with fentanyl during

pregnancy have been reported.

Chronic maternal treatment with fentanyl during pregnancy has been

associated with transient respiratory depression, behavioral changes, or

seizures characteristic of neonatal abstinence syndrome in newborn infants.

Symptoms of neonatal respiratory or neurological depression were no more

frequent than expected in most studies of infants born to women treated

acutely during labor with intravenous or epidural fentanyl. Transient

neonatal muscular rigidity has been observed in infants whose mothers were

treated with intravenous fentanyl.

Fentanyl is embryocidal as evidenced by increased resorptions in

pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to

human equivalent doses indicates this is within the range of the human

recommended dosing for FENTORA.

Fentanyl citrate was not teratogenic when administered to pregnant

animals. Published studies demonstrated that administration of fentanyl (10,

100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day

gestation, via implanted microosmotic minipumps was not teratogenic (the

high dose was approximately 3-times the human dose of 1600 mcg per pain

episode on a mg/m2

basis). Intravenous administration of fentanyl (10 or 30

mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or

fetal toxic, and caused a slightly increased mean delivery time in the 30

mcg/kg/day group, but was not teratogenic.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

5

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 6 of 11 PageID: 1437
9

8.2 Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore, do

not use FENTORA for analgesia during labor and delivery (including

caesarean section) since it may cause respiratory depression in the fetus or

in the newborn infant.

8.3 Nursing Mothers

Fentanyl is excreted in human milk; therefore do not use FENTORA

in nursing women because of the possibility of sedation and/or respiratory

depression in their infants. Symptoms of opioid withdrawal may occur in

infants at the cessation of nursing by women using FENTORA.

8.4 Pediatric Use

The safety and efficacy of FENTORA have not been established in

pediatric patients below the age of 18 years.

8.5 Geriatric Use

Of the 304 patients with cancer in clinical studies of FENTORA, 69

(23%) were 65 years of age and older.

Patients over the age of 65 years tended to titrate to slightly lower

doses than younger patients.

Patients over the age of 65 years reported a slightly higher frequency

for some adverse events specifically vomiting, constipation, and abdominal

pain. Therefore, caution should be exercised in individually titrating

FENTORA in elderly patients to provide adequate efficacy while

minimizing risk.

8.6 Patients with Renal or Hepatic Impairment

Insufficient information exists to make recommendations regarding

the use of FENTORA in patients with impaired renal or hepatic function.

Fentanyl is metabolized primarily via human cytochrome P450 3A4

isoenzyme system and mostly eliminated in urine. If the drug is used in

these patients, it should be used with caution because of the hepatic

metabolism and renal excretion of fentanyl.

8.7 Gender

Both male and female opioid tolerant patients with cancer were

studied for the treatment of breakthrough cancer pain. No clinically relevant

gender differences were noted either in dosage requirement or in observed

adverse reactions.

8.8 Race

The pharmacokinetic effects of race with the use of FENTORA have

not been systematically evaluated. In studies conducted in healthy Japanese

subjects, systemic exposure was generally higher than that observed in U.S.

subjects.

DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

FENTORA contains fentanyl, a mu-opioid agonist and a Schedule II

controlled substance with high potential for abuse similar to

hydromorphone, methadone, morphine, oxycodone, and oxymorphone.

Fentanyl can be abused and is subject to misuse and criminal diversion.

9.2 Abuse and Addiction

Handle FENTORA appropriately to minimize the risk of diversion,

including restriction of access and accounting procedures as appropriate to

the clinical setting and as required by law.

Concerns about abuse, addiction, and diversion should not prevent the

proper management of pain. However, all patients treated with opioids

require careful monitoring for signs of abuse and addiction, since use of

opioid analgesic products carries the risk of addiction even under

appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic,

psychosocial, and environmental factors influencing its development and

manifestations. It is characterized by behaviors that include one or more of

the following: impaired control over drug use, compulsive use, continued

use despite harm, and craving. Drug addiction is a treatable disease,

utilizing a multidisciplinary approach, but relapse is common.

Drug-seeking behavior is very common in addicts and drug abusers.

FENTORA should be prescribed with caution to patients who have a higher

risk of substance abuse, including patients with bipolar disorder and/or

schizophrenia.

Patients with chronic pain may be at a higher risk for suicide.

Abuse and addiction are separate and distinct from physical

dependence and tolerance. Physicians should be aware that addiction may

not be accompanied by concurrent tolerance and symptoms of physical

dependence in all addicts. In addition, abuse of opioids can occur in the

absence of addiction and is characterized by misuse for non-medical

purposes, often in combination with other psychoactive substances. Since

FENTORA tablets may be diverted for non-medical use, careful record

keeping of prescribing information, including quantity, frequency, and

renewal requests is strongly advised.

Proper assessment of patients, proper prescribing practices, periodic

re-evaluation of therapy, and proper dispensing and storage are appropriate

measures that help to limit abuse of opioid drugs.

Healthcare professionals should contact their State Professional

Licensing Board, or State Controlled Substances Authority for information

on how to prevent and detect abuse or diversion of this product.

9.3 Physical Dependence and Withdrawal

The administration of FENTORA should be guided by the response of

the patient. Physical dependence, per se, is not ordinarily a concern when

one is treating a patient with cancer and chronic pain, and fear of tolerance

and physical dependence should not deter using doses that adequately

relieve the pain.

Opioid analgesics may cause physical dependence. Physical

dependence results in withdrawal symptoms in patients who abruptly

discontinue the drug. Withdrawal also may be precipitated through the

administration of drugs with opioid antagonist activity, e.g., naloxone,

nalmefene, or mixed agonist/antagonist analgesics (pentazocine,

butorphanol, buprenorphine, nalbuphine).

Physical dependence usually does not occur to a clinically significant

degree until after several weeks of continued opioid usage. Tolerance, in

which increasingly larger doses are required in order to produce the same

degree of analgesia, is initially manifested by a shortened duration of

analgesic effect, and subsequently, by decreases in the intensity of

analgesia.

10 OVERDOSAGE

10.1 Clinical Presentation

The manifestations of FENTORA overdosage are expected to be

similar in nature to intravenous fentanyl and other opioids, and are an

extension of its pharmacological actions with the most serious significant

effect being hypoventilation [see Clinical Pharmacology (12.2)].

10.2 Immediate Management

Immediate management of opioid overdose includes removal of the

FENTORA tablet, if still in the mouth, ensuring a patent airway, physical

and verbal stimulation of the patient, and assessment of level of

consciousness, as well as ventilatory and circulatory status.

10.3 Treatment of Overdosage (Accidental Ingestion) in the

Opioid Non-Tolerant Person

Provide ventilatory support, obtain intravenous access, and employ

naloxone or other opioid antagonists as clinically indicated. The duration of

respiratory depression following overdose may be longer than the effects of

the opioid antagonists action (e.g., the half-life of naloxone ranges from 30

to 81 minutes) and repeated administration may be necessary. Consult the

package insert of the individual opioid antagonist for details about such use.

10.4 Treatment of Overdose in Opioid Tolerant Patients

Provide ventilatory support and obtain intravenous access as clinically

indicated. Judicious use of naloxone or another opioid antagonist may be

warranted in some instances, but it is associated with the risk of

precipitating an acute withdrawal syndrome.

10.5 General Considerations for Overdose

Management of severe FENTORA overdose includes: securing a

patent airway, assisting or controlling ventilation, establishing intravenous

access, and GI decontamination by lavage and/or activated charcoal, once

the patients airway is secure. In the presence of hypoventilation or apnea,

ventilation should be assisted or controlled and oxygen administered as

indicated.

Patients with overdose should be carefully observed and appropriately

managed until their clinical condition is well-controlled.

Although muscle rigidity interfering with respiration has not been

seen following the use of FENTORA, this is possible with fentanyl and

other opioids. If it occurs, manage by the use of assisted or controlled

ventilation, by an opioid antagonist, and as a final alternative, by a

neuromuscular blocking agent.

11 DESCRIPTION

FENTORA (fentanyl buccal tablet) is a potent opioid analgesic,

intended for buccal mucosal administration.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

6

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 7 of 11 PageID: 1438
FENTORA is designed to be placed and retained within the buccal

cavity for a period sufficient to allow disintegration of the tablet and

absorption of fentanyl across the oral mucosa.

FENTORA employs the OraVescent®drug delivery technology,

which generates a reaction that releases carbon dioxide when the tablet

comes in contact with saliva. It is believed that transient pH changes

accompanying the reaction may optimize dissolution (at a lower pH) and

membrane permeation (at a higher pH) of fentanyl through the buccal

mucosa.

Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-

piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic

compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is

freely soluble in organic solvents and sparingly soluble in water (1:40). The

molecular weight of the free base is 336.5 (the citrate salt is 528.6). The

pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the

following structural formula:

All tablet strengths are expressed as the amount of fentanyl free base,

e.g., the 100 microgram strength tablet contains 100 micrograms of fentanyl

free base.

Inactive Ingredients: Mannitol, sodium starch glycolate, sodium

bicarbonate, sodium carbonate, citric acid, and magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fentanyl is a pure opioid agonist whose principal therapeutic action is

analgesia. Other members of the class known as opioid agonists include

substances such as morphine, oxycodone, hydromorphone, codeine, and

hydrocodone.

12.2 Pharmacodynamics

Pharmacological effects of opioid agonists include anxiolysis,

euphoria, feelings of relaxation, respiratory depression, constipation,

miosis, cough suppression, and analgesia. Like all pure opioid agonist

analgesics, with increasing doses there is increasing analgesia, unlike with

mixed agonist/antagonists or non-opioid analgesics, where there is a limit to

the analgesic effect with increasing doses. With pure opioid agonist

analgesics, there is no defined maximum dose; the ceiling to analgesic

effectiveness is imposed only by side effects, the more serious of which

may include somnolence and respiratory depression.

Analgesia

The analgesic effects of fentanyl are related to the blood level of the

drug, if proper allowance is made for the delay into and out of the CNS (a

process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which

toxicity occurs increase with increasing tolerance with any and all opioids.

The rate of development of tolerance varies widely among individuals. As a

result, the dose of FENTORA should be individually titrated to achieve the

desired effect [see Dosage and Administration (2.1)].

Central Nervous System

The precise mechanism of the analgesic action is unknown although

fentanyl is known to be a mu opioid receptor agonist. Specific CNS opioid

receptors for endogenous compounds with opioid-like activity have been

identified throughout the brain and spinal cord and play a role in the

analgesic effects of this drug.

Fentanyl produces respiratory depression by direct action on brain

stem respiratory centers. The respiratory depression involves both a

reduction in the responsiveness of the brain stem to increases in carbon

dioxide and to electrical stimulation.

Fentanyl depresses the cough reflex by direct effect on the cough

center in the medulla. Antitussive effects may occur with doses lower than

those usually required for analgesia. Fentanyl causes miosis even in total

darkness. Pinpoint pupils are a sign of opioid overdose but are not

pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin

may produce similar findings).

Gastrointestinal System

Fentanyl causes a reduction in motility associated with an increase in

smooth muscle tone in the antrum of the stomach and in the duodenum.

Digestion of food is delayed in the small intestine and propulsive

contractions are decreased. Propulsive peristaltic waves in the colon are

decreased, while tone may be increased to the point of spasm resulting in

constipation. Other opioid-induced effects may include a reduction in

gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi,

and transient elevations in serum amylase.

Cardiovascular System

Fentanyl may produce release of histamine with or without associated

peripheral vasodilation. Manifestations of histamine release and/or

peripheral vasodilation may include pruritus, flushing, red eyes, sweating,

and/or orthostatic hypotension.

Endocrine System

Opioid agonists have been shown to have a variety of effects on the

secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and

luteinizing hormone (LH) in humans. They also stimulate prolactin, growth

hormone (GH) secretion, and pancreatic secretion of insulin and glucagon

in humans and other species, rats and dogs. Thyroid stimulating hormone

(TSH) has been shown to be both inhibited and stimulated by opioids.

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dosedependent respiratory depression. The risk of respiratory depression is less

in patients receiving chronic opioid therapy who develop tolerance to

respiratory depression and other opioid effects. During the titration phase of

the clinical trials, somnolence, which may be a precursor to respiratory

depression, did increase in patients who were treated with higher doses of

another oral transmucosal fentanyl citrate (Actiq). Peak respiratory

depressive effects may be seen as early as 15 to 30 minutes from the start of

oral transmucosal fentanyl citrate product administration and may persist

for several hours.

Serious or fatal respiratory depression can occur even at recommended

doses. Fentanyl depresses the cough reflex as a result of its CNS activity.

Although not observed with oral transmucosal fentanyl products in clinical

trials, fentanyl given rapidly by intravenous injection in large doses may

interfere with respiration by causing rigidity in the muscles of respiration.

Therefore, physicians and other healthcare providers should be aware of this

potential complication.

See Boxed Warning – WARNING: RISK OF RESPIRATORY DEPRESSION,

MEDICATION ERRORS, ABUSE POTENTIAL, Contraindications (4),

Warnings and Precautions (5.2) and Overdosage (10).

12.3 Pharmacokinetics

Fentanyl exhibits linear pharmacokinetics. Systemic exposure to

fentanyl following administration of FENTORA increases linearly in an

approximate dose-proportional manner over the 100- to 800-mcg dose

range.

Absorption

Following buccal administration of FENTORA, fentanyl is readily

absorbed with an absolute bioavailability of 65%. The absorption profile of

FENTORA is largely the result of an initial absorption from the buccal

mucosa, with peak plasma concentrations following venous sampling

generally attained within an hour after buccal administration.

Approximately 50% of the total dose administered is absorbed

transmucosally and becomes systemically available. The remaining half of

the total dose is swallowed and undergoes more prolonged absorption from

the gastrointestinal tract.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

7

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 8 of 11 PageID: 1439
In a study that compared the absolute and relative bioavailability of Mean pharmacokinetic parameters are presented in Table 5. Mean

FENTORA and Actiq (oral transmucosal fentanyl citrate), the rate and plasma concentration versus time profiles are presented in Figure 2.

extent of fentanyl absorption were considerably different (approximately

30% greater exposure with FENTORA) (Table 4). Table 5. Pharmacokinetic Parameters* Following Single

100, 200, 400, and 800 mcg Doses of FENTORA in Healthy Subjects

Table 4. Pharmacokinetic Parameters* in Adult Subjects

Receiving FENTORA or Actiq

Pharmacokinetic

Parameter (mean)

FENTORA 400 mcg Actiq 400 mcg

(adjusted dose)***

Absolute Bioavailability 65% ± 20% 47% ± 10.5%

Fraction Absorbed

Transmucosally

48% ± 31.8% 22% ± 17.3%

Tmax (minute)** 46.8 (20-240) 90.8 (35-240)

Cmax (ng/mL) 1.02 ± 0.42 0.63 ± 0.21

AUC0-tmax

(ng hr/mL)

0.40 ± 0.18 0.14 ± 0.05

AUC0-inf

(ng hr/mL)

6.48 ± 2.98 4.79 ± 1.96

Pharmacokinetic

Parameter

(mean±SD)

100 mcg 200 mcg 400 mcg 800 mcg

Cmax

(ng/mL)

0.25 ± 0.14 0.40 ± 0.18 0.97 ± 0.53 1.59 ± 0.90

Tmax minute**

(range)

45.0

(25.0 - 181.0)

40.0

(20.0 - 180.0)

35.0

(20.0 - 180.0)

40.0

(25.0 - 180.0)

AUC0-inf

(ng hr/mL)

0.98 ± 0.37 2.11 ± 1.13 4.72 ± 1.95 9.05 ± 3.72

AUC0-tmax

(ng hr/mL)

0.09 ± 0.06 0.13 ± 0.09 0.34 ± 0.23 0.52 ± 0.38

T1/2, hr** 2.63

(1.47 - 13.57)

4.43

(1.85 - 20.76)

11.09

(4.63 - 20.59)

11.70

(4.63 - 28.63)

* Based on venous sampling.

** Data for Tmax presented as median (range).

Figure 2. Mean Plasma Concentration Versus Time Profiles Following

Single 100, 200, 400, and 800 mcg Doses of FENTORA in Healthy

Subjects

* Based on venous blood samples.

** Data for Tmax presented as median (range).

*** Actiq (OTFC) data was dose adjusted (800 mcg to 400 mcg).

Similarly, in another bioavailability study exposure following

administration of FENTORA was also greater (approximately 50%)

compared to Actiq.

Due to differences in drug delivery, measures of exposure (Cmax,

AUC0-tmax, AUC0-inf) associated with a given dose of fentanyl were

substantially greater with FENTORA compared to Actiq (see Figure 1).

Therefore, caution must be exercised when switching patients from one

product to another [see Dosage and Administration (2.1) and Warnings and

Precautions (5.1)]. Figure 1 includes an inset which shows the mean

plasma concentration versus time profile to 6 hours. The vertical line

denotes the median Tmax for FENTORA. ðÚðÔ

ðÚÔ

Ô

Ôðð 31⁄21

Óðð 31⁄21

Ïðð 31⁄21

Ëðð 31⁄21

Actiq data was dose adjusted (800 mcg to 400 mcg).

Figure 1. Mean Plasma Concentration Versus Time Profiles Following

Single Doses of FENTORA and Actiq in Healthy Subjects

ð Î Ôð ÔÎ Óð ÓÎ

Ã·3a øo ̈aÆ ‹±­a flo3·2·­ ̈Æø ̈·±2  ̄ ̧± ́Æ ̃

Dwell time (defined as the length of time that the tablet takes to fully

disintegrate following buccal administration), does not appear to affect

early systemic exposure to fentanyl.

The effect of mucositis (Grade 1) on the pharmacokinetic profile of

FENTORA was studied in a group of patients with (N = 8) and without

mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet

was administered, followed by sampling at appropriate intervals. Mean

summary statistics (standard deviation in parentheses, expected tmax where

range was used) are presented in Table 6.

Table 6. Pharmacokinetic Parameters in Patients with Mucositis

Patient status Cmax (ng/mL) tmax (min) AUC0-tmax

(ng·hr/mL)

AUC0-8 (ng·hr/mL)

Mucositis 1.25 ± 0.78 25.0 (15 - 45) 0.21 ± 0.16 2.33 ± 0.93

No mucositis 1.24 ± 0.77 22.5 (10 - 121) 0.25 ± 0.24 1.86 ± 0.86

Distribution

Fentanyl is highly lipophilic. The plasma protein binding of fentanyl

is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both

albumin and lipoproteins contribute to some extent. The mean oral volume

of distribution at steady state (Vss/F) was 25.4 L/kg.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

8

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 9 of 11 PageID: 1440
Metabolism

The metabolic pathways following buccal administration of

FENTORA have not been characterized in clinical studies. The progressive

decline of fentanyl plasma concentrations results from the uptake of

fentanyl in the tissues and biotransformation in the liver. Fentanyl is

metabolized in the liver and in the intestinal mucosa to norfentanyl by

cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not

found to be pharmacologically active [see Drug Interactions (7)].

Elimination

Disposition of fentanyl following buccal administration of FENTORA

has not been characterized in a mass balance study. Fentanyl is primarily

(more than 90%) eliminated by biotransformation to N-dealkylated and

hydroxylated inactive metabolites. Less than 7% of the administered dose

is excreted unchanged in the urine, and only about 1% is excreted

unchanged in the feces. The metabolites are mainly excreted in the urine,

while fecal excretion is less important.

The total plasma clearance of fentanyl following intravenous

administration is approximately 42 L/h.

Gender

Systemic exposure was higher for women than men (mean Cmax and

AUC values were approximately 28% and 22% higher, respectively). The

observed differences between men and women were largely attributable to

differences in weight.

Race

In studies conducted in healthy Japanese subjects, systemic exposure

was generally higher than that observed in US subjects (mean Cmax and

AUC values were approximately 50% and 20% higher, respectively). The

observed differences were largely attributed to the lower mean weight of the

Japanese subjects compared to U.S. subjects (57.4 kg versus 73 kg).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the

carcinogenic potential of fentanyl.

Fentanyl citrate was not mutagenic in the in vitro Ames reverse

mutation assay in S. typhimurium or E. coli, or the mouse lymphoma

mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse

micronucleus assay.

Fentanyl impairs fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg

SC. Conversion to human equivalent doses indicates this is within the range

of the human recommended dosing for FENTORA.

14 CLINICAL STUDIES

The efficacy of FENTORA was demonstrated in a double-blind, placebocontrolled, cross-over study in opioid tolerant patients with cancer and

breakthrough pain. Patients considered opioid tolerant were those who were

taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of

transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of

oral hydromorphone daily or an equianalgesic dose of another opioid daily for

a week or longer.

In this trial, patients were titrated in an open-label manner to a

successful dose of FENTORA. A successful dose was defined as the dose in

which a patient obtained adequate analgesia with tolerable side effects.

Patients who identified a successful dose were randomized to a sequence of

10 treatments with 7 being the successful dose of FENTORA and 3 being

placebo. Patients used one tablet of study drug (either FENTORA or

Placebo) per breakthrough pain episode.

Patients assessed pain intensity on a scale that rated the pain as

0=none to 10=worst possible pain. With each episode of breakthrough pain,

pain intensity was assessed first and then treatment was administered. Pain

intensity (0-10) was then measured at 15, 30, 45 and 60 minutes after the

start of administration. The sum of differences in pain intensity scores at 15

and 30 minutes from baseline (SPID30) was the primary efficacy measure.

Sixty-five percent (65%) of patients who entered the study achieved a

successful dose during the titration phase. The distribution of successful

doses is shown in Table 7. The median dose was 400 mcg.

Table 7. Successful Dose of FENTORA Following Initial Titration

FENTORA Dose n (%)

(N=80)

100 mcg 13 (16)

200 mcg 11 (14)

400 mcg 21 (26)

600 mcg 10 (13)

800 mcg 25 (31)

The LS mean (SE) SPID30 for FENTORA-treated episodes was 3.0 (0.12)

while for placebo-treated episodes it was 1.8 (0.18).

Figure 3. Mean Pain Intensity Differences (PID) at Each Time Point

During the Double-Blind Treatment Period

PID=pain intensity difference; SEM=standard error of the mean

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Storage and Handling

FENTORA is supplied in individually sealed, child-resistant blister

packages. The amount of fentanyl contained in FENTORA can be fatal to a

child. Patients and their caregivers must be instructed to keep

FENTORA out of the reach of children. [see Boxed Warning -

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION

ERRORS, ABUSE POTENTIAL, Overdosage (10), and Patient/Caregiver

Instructions (17.1)]

Store at 20 to 25oC (68 to 77oF) with excursions permitted between

15° and 30°C (59° to 86°F) until ready to use. (See USP Controlled Room

Temperature.)

Protect FENTORA from freezing and moisture. Do not use if the

blister package has been tampered with.

16.2 Disposal of FENTORA

Patients and members of their household must be advised to

dispose of any tablets remaining from a prescription as soon as they are

no longer needed. Information is available in the Patient Counseling

Information (17.2) and in the Medication Guide. If additional assistance is

required, call Cephalon, Inc., at 1-800-896-5855.

To dispose of unused FENTORA, remove FENTORA tablets from

blister packages and flush down the toilet. Do not flush FENTORA

blister packages or cartons down the toilet. If you need additional

assistance with disposal of FENTORA, call Cephalon, Inc., at 1-800-896-

5855.

16.3 How Supplied

Each carton contains 7 blister cards with 4 white tablets in each card.

The blisters are child-resistant, encased in peelable foil, and provide

protection from moisture. Each tablet is debossed on one side with , and

the other side of each dosage strength is uniquely identified by the

debossing on the tablet as described in the table below. In addition, the

dosage strength is indicated on the blister package and the carton. See

blister package and carton for product information.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

9

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 10 of 11 PageID: 1441
Dosage

Strength

Debossing Carton/Blister

Package Color

NDC Number

100 mcg 1 Blue NDC 63459-541-28

200 mcg 2 Orange NDC 63459-542-28

400 mcg 4 Sage green NDC 63459-544-28

600 mcg 6 Magenta (pink) NDC 63459-546-28

800 mcg 8 Yellow NDC 63459-548-28

Note: Carton/blister package colors are a secondary aid in product

identification. Please be sure to confirm the printed dosage before

dispensing.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

17.1 Patient/Caregiver Instructions

Before initiating treatment with FENTORA, explain the statements

below to patients and/or caregivers. Instruct patients to read the

Medication Guide each time FENTORA is dispensed because new

information may be available.

TIRF REMS Access Program

o Outpatients must be enrolled in the TIRF REMS Access program

before they can receive FENTORA.

o Allow patients the opportunity to ask questions and discuss any

concerns regarding FENTORA or the TIRF REMS Access

program.

o As a component of the TIRF REMS Access program, prescribers

must review the contents of the FENTORA Medication Guide with

every patient before initiating treatment with FENTORA.

o Advise the patient that FENTORA is available only from

pharmacies that are enrolled in the TIRF REMS Access program,

and provide them with the telephone number and website for

information on how to obtain the drug.

o Advise the patient that only enrolled healthcare providers may

prescribe FENTORA.

o Patient must sign the Patient-Prescriber Agreement to acknowledge

that they understand the risks of FENTORA.

o Advise patients that they may be requested to participate in a

survey to evaluate the effectiveness of the TIRF REMS Access

program.

Patients and their caregivers must be instructed that children,

especially small children, exposed to FENTORA are at high risk of

FATAL RESPIRATORY DEPRESSION. Patients and their

caregivers must be instructed to keep FENTORA tablets out of the

reach of children. [see How Supplied/Storage and Handling (16.1),

Warnings and Precautions (5.3) and Medication Guide for specific

patient instructions.]

Instruct patients not to take FENTORA for acute pain, postoperative

pain, pain from injuries, headache, migraine or any other short-term

pain, even if they have taken other opioid analgesics for these

conditions.

Instruct patients on the meaning of opioid tolerance and that

FENTORA is only to be used as a supplemental pain medication for

patients with pain requiring around-the-clock opioids, who have

developed tolerance to the opioid medication, and who need additional

opioid treatment of breakthrough pain episodes.

Instruct patients that, if they are not taking an opioid medication on a

scheduled basis (around-the-clock), they should not take FENTORA.

Instruct patients that the titration phase is the only period in which they

may take more than ONE tablet to achieve a desired dose (e.g., two 100

mcg tablets for a 200 mcg dose).

Instruct patients that, if the breakthrough pain episode is not relieved

after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE

OF FENTORA USING THE SAME STRENGTH FOR THAT

EPISODE. Thus, patients should take a maximum of two doses of

FENTORA for any breakthrough pain episode.

Instruct patients that they MUST wait at least 4 hours before treating

another episode of breakthrough pain with FENTORA.

Instruct patients NOT to share FENTORA and that sharing FENTORA

with anyone else could result in the other individuals death due to

overdose.

Make patients aware that FENTORA contains fentanyl which is a

strong pain medication similar to hydromorphone, methadone,

morphine, oxycodone, and oxymorphone.

Instruct patients that the active ingredient in FENTORA, fentanyl, is a

drug that some people abuse. FENTORA should be taken only by the

patient it was prescribed for, and it should be protected from theft or

misuse in the work or home environment.

Instruct patients not to open the blister until ready to use FENTORA

and not to store the tablet in a temporary container such as a pill box,

once it has been removed from the blister package.

Instruct patients that FENTORA tablets are not to be swallowed whole;

this will reduce the effectiveness of the medication. Tablets are to be

placed between the cheek and gum above a molar tooth and allowed to

dissolve. After 30 minutes if remnants of the tablet still remain,

patients may swallow it with a glass of water.

Caution patients to talk to their doctor if breakthrough pain is not

alleviated or worsens after taking FENTORA.

Instruct patients to use FENTORA exactly as prescribed by their doctor

and not to take FENTORA more often than prescribed.

Caution patients that FENTORA can affect a persons ability to

perform activities that require a high level of attention (such as driving

or using heavy machinery). Warn patients taking FENTORA of these

dangers and counsel them accordingly.

Warn patients to not combine FENTORA with alcohol, sleep aids, or

tranquilizers except by the orders of the prescribing physician, because

dangerous additive effects may occur, resulting in serious injury or

death.

Inform female patients that if they become pregnant or plan to become

pregnant during treatment with FENTORA, they should ask their doctor

about the effects that FENTORA (or any medicine) may have on them

and their unborn children.

Physicians and dispensing pharmacists must specifically question

patients or caregivers about the presence of children in the home (on a

full time or visiting basis) and counsel them regarding the dangers to

children from inadvertent exposure.

17.2 Disposal of Unopened FENTORA Blister Packages When No

Longer Needed

Patients and members of their household must be advised to dispose

of any unopened blister packages remaining from a prescription as soon as

they are no longer needed.

To dispose of unused FENTORA, remove FENTORA tablets from

blister packages and flush down the toilet. Do not flush the FENTORA

blister packages or cartons down the toilet.

Detailed instructions for the proper storage, administration, disposal,

and important instructions for managing an overdose of FENTORA are

provided in the FENTORA Medication Guide. Instruct patients to read this

information in its entirety and provide an opportunity to have their

questions answered.

In the event that a caregiver requires additional assistance in disposing

of excess unusable tablets that remain in the home after a patient has

expired, instruct them to call the Cephalon toll-free number (1-800-896-

5855) or seek assistance from their local DEA office.

FENTORA TIRF REMS Prescribing Information with MG

Version : December 20, 2011

ŒaoaÆa21⁄2a ×‹Ê ÌðÍÏÍÎÌ

10

Case 3:11-cv-02506-JAP-TJB Document 77-1 Filed 06/22/12 Page 11 of 11 PageID: 1442