EXHIBIT 1008 
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1008
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`

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`NDA20-747/S-017
`Page 2
`
`ACTIQ®
`(oral transmucosal fentanyl citrate)
`
`CII
`
`PHYSICIANS AND OTHER HEALTHCARE PROVIDERS MUST BECOME FAMILIAR WITH THE IMPORTANT
`WARNINGS IN THIS LABEL.
`
`Actiq is indicated only for the management of breakthrough cancer pain in patients with
`malignancies who are already receiving and who are tolerant to opioid therapy for their
`underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at
`least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another
`opioid for a week or longer.
`
`Because life-threatening hypoventilation could occur at any dose in patients not taking chronic opiates,
`Actiq is contraindicated in the management of acute or postoperative pain. This product must not be
`used in opioid non-tolerant patients.
`
`Actiq is intended to be used only in the care of cancer patients and only by oncologists and pain
`specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.
`
`Patients and their caregivers must be instructed that Actiq contains a medicine in an amount
`which can be fatal to a child. Patients and their caregivers must be instructed to keep all units
`out of the reach of children and to discard opened units properly. (See Information for Patients
`and Their Caregivers for disposal instructions.)
`
`WARNING: May be habit forming
`
`DESCRIPTION
`Actiq (oral transmucosal fentanyl citrate) is a solid formulation of fentanyl citrate, a potent opioid
`analgesic, intended for oral transmucosal administration. Actiq is formulated as a white to off-white
`solid drug matrix on a handle that is radiopaque and is fracture resistant (ABS plastic) under normal
`conditions when used as directed.
`
`Actiq is designed to be dissolved slowly in the mouth in a manner to facilitate transmucosal absorption.
`The handle allows the Actiq unit to be removed from the mouth if signs of excessive opioid effects
`appear during administration.
`
`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:
`
`

`
`CH COOH
`2
`
`HO-C-COOH
`
`CHCOOH
`2
`
`
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`NDA20-747/S-017
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`
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`CH CH CON
`3
`2
`
`N-CH CH
`2
`2
`
`
`
`Actiq is available in six strengths equivalent to 200, 400, 600, 800, 1200, or 1600 mcg fentanyl base
`that is identified by the text on the solid drug matrix, the dosage unit handle tag, the blister package,
`and the shelf carton.
`
`Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry
`flavor, magnesium stearate, modified food starch, and confectioner’s sugar.
`
`CLINICAL PHARMACOLOGY AND PHARMACOKINETICS
`Pharmacology:
`Fentanyl, a pure opioid agonist, acts primarily through interaction with opioid mu-receptors located in
`the brain, spinal cord and smooth muscle. The primary site of therapeutic action is the central nervous
`system (CNS). The most clinically useful pharmacologic effects of the interaction of fentanyl with
`mu-receptors are analgesia and sedation.
`
`Other opioid effects may include somnolence, hypoventilation, bradycardia, postural hypotension,
`pruritus, dizziness, nausea, diaphoresis, flushing, euphoria and confusion or difficulty in concentrating
`at clinically relevant doses.
`
`Clinical Pharmacology
`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 opioid non-tolerant
`individuals, fentanyl provides effects ranging from analgesia at blood levels of 1 to 2 ng/mL, all the
`way to surgical anesthesia and profound respiratory depression at levels of 10-20 ng/mL.
`
`In general, the minimum effective concentration and the concentration at which toxicity occurs rise
`with increasing tolerance to any and all opioids. The rate of development of tolerance varies widely
`among individuals. As a result, the dose of Actiq should be individually titrated to achieve the desired
`effect (see DOSAGE AND ADMINISTRATION).
`
`Gastrointestinal (GI) Tract and Other Smooth Muscle:
`Opioids increase the tone and decrease contractions of the smooth muscle of the gastrointestinal (GI)
`tract. This results in prolongation in GI transit time and may be responsible for the constipating effect
`of opioids. Because opioids may increase biliary tract pressure, some patients with biliary colic may
`experience worsening of pain.
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`While opioids generally increase the tone of urinary tract smooth muscle, the overall effect tends to
`vary, in some cases producing urinary urgency, in others, difficulty in urination.
`
`Respiratory System:
`All opioid mu-receptor agonists, including fentanyl, produce dose dependent 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 Actiq. In studies of opioid non-tolerant subjects, respiratory rate and
`oxygen saturation typically decrease as fentanyl blood concentration increases. Typically, peak
`respiratory depressive effects (decrease in respiratory rate) are seen 15 to 30 minutes from the start of
`oral transmucosal fentanyl citrate (OTFC®) administration and may persist for several hours.
`
`Serious or fatal respiratory depression can occur, even at recommended doses, in vulnerable
`individuals. As with other potent opioids, fentanyl has been associated with cases of serious and fatal
`respiratory depression in opioid non-tolerant individuals.
`
`Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with Actiq
`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 BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE
`REACTIONS, and OVERDOSAGE for additional information on hypoventilation.)
`
`Pharmacokinetics
`Absorption:
`The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination
`of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed
`fentanyl from the GI tract. Both the blood fentanyl profile and the bioavailability of fentanyl will vary
`depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction
`swallowed.
`
`Absolute bioavailability, as determined by area under the concentration-time curve, of 15 mcg/kg in
`12 adult males was 50% compared to intravenous fentanyl.
`
`Normally, approximately 25% of the total dose of Actiq is rapidly absorbed from the buccal mucosa
`and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva
`and then is slowly absorbed from the GI tract. About 1/3 of this amount (25% of the total dose)
`escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, the
`generally observed 50% bioavailability of Actiq is divided equally between rapid transmucosal and
`slower GI absorption. Therefore, a unit dose of Actiq, if chewed and swallowed, might result in lower
`peak concentrations and lower bioavailability than when consumed as directed.
`
`Dose proportionality among four of the available strengths of Actiq (200, 400, 800, and 1600 mcg) has
`been demonstrated in a balanced crossover design in adult subjects. Mean serum fentanyl levels
`following these four doses of Actiq are shown in Figure 1. The curves for each dose level are similar
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`in shape with increasing dose levels producing increasing serum fentanyl levels. Cmax and AUC0→∞
`increased in a dose-dependent manner that is approximately proportional to the Actiq administered.
`
`
`Figure 1.
`Mean Serum Fentanyl Concentration (ng/mL)
`in Adult Subjects Comparing 4 Doses of Actiq
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`0
`
`Mean Serum Fentanyl Concentration (ng/mL)
`
`
`
`240
`
`480
`
`720
`Minutes
`
`960
`
`1200
`
`1440
`
`200 µg
`
`400 µg
`
`800 µg
`
`1600 µg
`
`
`
`The pharmacokinetic parameters of the four strengths of Actiq tested in the dose-proportionality study
`are shown in Table 1. The mean Cmax ranged from 0.39 - 2.51 ng/mL. The median time of maximum
`plasma concentration (Tmax) across these four doses of Actiq varied from 20 - 40 minutes (range of 20-
`480 minutes) as measured after the start of administration.
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`Distribution:
`Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly
`distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles
`and fat. 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 free fraction of
`fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.
`
`Metabolism:
`Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450
`3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies (see
`PRECAUTIONS: Drug Interactions for additional information).
`
`Elimination:
`Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and
`hydroxylated inactive metabolites. Less than 7% of the 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 was 0.5 L/hr/kg (range
`0.3 - 0.7 L/hr/kg). The terminal elimination half-life after OTFC administration is about 7 hours.
`
`Table 1.
`Pharmacokinetic Parameters in Adult Subjects
`Receiving 200, 400, 800, and 1600 mcg
`Units of Actiq
`
`
`200 mcg
`
`
`400 mcg
`
`
`
`800mcg
`
`
`1600 mcg
`
`
`20
`(20-480)
`
`
`
`2.51 (23)
`
`
`
`1026 (67)
`
`
`25
`(20-120)
`
`
`
`1.55 (30)
`
`
`
`573 (64)
`
`
`40
`(20-120)
`
`
`25
`(20-240)
`
`
`
`0.75 (33)
`
`
`
`0.39 (23)
`
`
`
`243 (67)
`
`
`
`102 (65)
`
`
`
`358 (45)
`
`
`
`381 (55)
`
`
`
`386 (115)
`
`
`
`193 (48)
`
`
`Pharmacokinetic
`Parameter
`
`Tmax, minute
`median (range)
`
`
`Cmax, ng/mL
`mean (%CV)
`
`
`AUC0-1440,
`ng/mL minute
`mean (%CV)
`
`
`t1/2, minute
`mean (%CV)
`
`
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`Special Populations:
`Elderly Patients:
`Elderly patients have been shown to be twice as sensitive to the effects of fentanyl when administered
`intravenously, compared with the younger population. While a formal study evaluating the safety
`profile of Actiq in the elderly population has not been performed, in the 257 opioid tolerant cancer
`patients studied with Actiq, approximately 20% were over age 65 years. No difference was noted in
`the safety profile in this group compared to those aged less than 65 years, though they did titrate to
`lower doses than younger patients (see PRECAUTIONS).
`
`Patients with Renal or Hepatic Impairment:
`Actiq should be administered with caution to patients with liver or kidney dysfunction because of the
`importance of these organs in the metabolism and excretion of drugs and effects on plasma-binding
`proteins (see PRECAUTIONS).
`
`Although fentanyl kinetics are known to be altered in both hepatic and renal disease due to alterations
`in metabolic clearance and plasma proteins, individualized doses of Actiq have been used successfully
`for breakthrough cancer pain in patients with hepatic and renal disorders. The duration of effect for the
`initial dose of fentanyl is determined by redistribution of the drug, such that diminished metabolic
`clearance may only become significant with repeated dosing or with excessively large single doses.
`For these reasons, while doses titrated to clinical effect are recommended for all patients, special care
`should be taken in patients with severe hepatic or renal disease.
`
`Gender
`Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough
`cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in
`observed adverse events.
`
`CLINICAL TRIALS
`Breakthrough Cancer Pain:
`Actiq was investigated in clinical trials involving 257 opioid tolerant adult cancer patients experiencing
`breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-
`severe pain occurring in cancer patients experiencing persistent cancer pain otherwise controlled with
`maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal
`fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer.
`
`In two dose titration studies 95 of 127 patients (75%) who were on stable doses of either long-acting
`oral opioids or transdermal fentanyl for their persistent cancer pain titrated to a successful dose of
`Actiq to treat their breakthrough cancer pain within the dose range offered (200, 400, 600, 800, 1200
`and 1600 mcg). In these studies 11% of patients withdrew due to adverse events and 14% withdrew
`due to other reasons. A “successful” dose was defined as a dose where one unit of Actiq could be used
`consistently for at least two consecutive days to treat breakthrough cancer pain without unacceptable
`side effects.
`
`The successful dose of Actiq for breakthrough cancer pain was not predicted from the daily
`maintenance dose of opioid used to manage the persistent cancer pain and is thus best determined by
`dose titration.
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` A
`
` double-blind placebo controlled crossover study was performed in cancer patients to evaluate the
`effectiveness of Actiq for the treatment of breakthrough cancer pain. Of 130 patients who entered the
`study 92 patients (71%) achieved a successful dose during the titration phase. The distribution of
`successful doses is shown in Table 2.
`
`
`
`Table 2.
`Successful Dose of Actiq
`Following Initial Titration
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Actiq Dose
`
`200 mcg
`400 mcg
`600 mcg
`800 mcg
`1200 mcg
`1600 mcg
`
`
`
`
`
`
`
`
`
`
`Total No (%)
`(N=92)
`
`13 (14)
`19 (21)
`14 (15)
`18 (20)
`13 (14)
`15 (16)
`
`Mean ±SD
`
` 789±468 mcg
`
`
`On average, patients over 65 years of age titrated to a mean dose that was about 200 mcg less than the
`mean dose to which younger adult patients were titrated.
`
`Actiq produced statistically significantly more pain relief compared with placebo at 15, 30, 45 and 60
`minutes following administration (see Figure 2).
`
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`Figure 2.
`
`
`
`
`Pain Relief (PR) Scores (Mean±SD) During the Double-Blind Phase - All Patients with Evaluable
`Episodes on Both Actiq and Placebo (N=86)
`
`
`Actiq®
`Placebo
`*
`
`*
`
`*
`
`*
`
`Pain Relief Scores
`4
`
`Complete
`
`0123
`
`None
`
`0
`
`15
`
`*P-values <0.0001
`
`30
`Minutes
`
`45
`
`60
`
`
`
`
`In this same study patients also rated the performance of medication to treat their breakthrough cancer
`pain using a different scale ranging from “poor” to “excellent.” On average, placebo was rated “fair”
`and Actiq was rated “good.”
`
`INDICATIONS AND USAGE
`(See BOX WARNING and CONTRAINDICATIONS)
`Actiq is indicated only for the management of breakthrough cancer pain in patients with malignancies
`who are already receiving and who are tolerant to opioid therapy for their underlying persistent
`cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg
`morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a
`week or longer.
`
`Because life-threatening hypoventilation could occur at any dose in patients not taking chronic opiates,
`Actiq is contraindicated in the management of acute or postoperative pain. This product must not be
`used in opioid non-tolerant patients.
`
`Actiq is intended to be used only in the care of cancer patients and only by oncologists and pain
`specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.
`
`Actiq should be individually titrated to a dose that provides adequate analgesia and minimizes side
`effects. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should
`be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should
`be decreased (see DOSAGE AND ADMINISTRATION).
`
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`Patients and their caregivers must be instructed that Actiq contains a medicine in an amount that can be
`fatal to a child. Patients and their caregivers must be instructed to keep all units out of the reach of
`children and to discard opened units properly in a secured container.
`
`CONTRAINDICATIONS
`Because life-threatening hypoventilation could occur at any dose in patients not taking chronic opiates,
`Actiq is contraindicated in the management of acute or postoperative pain. The risk of respiratory
`depression begins to increase with fentanyl plasma levels of 2.0 ng/mL in opioid non-tolerant
`individuals (see Pharmacokinetics). This product must not be used in opioid non-tolerant patients.
`
`Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, 50 mcg
`transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer.
`
`Actiq is contraindicated in patients with known intolerance or hypersensitivity to any of its components
`or the drug fentanyl.
`
`WARNINGS
`See BOX WARNING
`The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general
`anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, potent
`inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease
`inhibitors), and alcoholic beverages may produce increased depressant effects. Hypoventilation,
`hypotension, and profound sedation may occur.
`
`Actiq 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.
`
`Pediatric Use: The appropriate dosing and safety of Actiq in opioid tolerant children with
`breakthrough cancer pain have not been established below the age of 16 years.
`
`Patients and their caregivers must be instructed that Actiq contains a medicine in an amount
`which can be fatal to a child. Patients and their caregivers must be instructed to keep both used and
`unused dosage units out of the reach of children. While all units should be disposed of immediately
`after use, partially consumed units represent a special risk to children. In the event that a unit is not
`completely consumed it must be properly disposed as soon as possible. (See SAFETY AND
`HANDLING, PRECAUTIONS, and PATIENT LEAFLET for specific patient instructions.)
`
`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.
`
`PRECAUTIONS
`General
`The initial dose of Actiq to treat episodes of breakthrough cancer pain should be 200 mcg. Each
`patient should be individually titrated to provide adequate analgesia while minimizing side effects.
`
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`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). Patients taking Actiq should be warned of
`these dangers and should be counseled accordingly.
`
`The use of concomitant CNS active drugs requires special patient care and observation. (See
`WARNINGS.)
`
`Hypoventilation (Respiratory Depression)
`As with all opioids, there is a risk of clinically significant hypoventilation in patients using Actiq.
`Accordingly, all patients should be followed for symptoms of respiratory depression. Hypoventilation
`may occur more readily when opioids are given in conjunction with other agents that depress
`respiration.
`
`Chronic Pulmonary Disease
`Because potent opioids can cause hypoventilation, Actiq should be titrated with caution in patients with
`chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to
`hypoventilation. In such patients, even normal therapeutic doses of Actiq may further decrease
`respiratory drive to the point of respiratory failure.
`
`Head Injuries and Increased Intracranial Pressure
`Actiq should only be administered 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.
`
`Cardiac Disease
`Intravenous fentanyl may produce bradycardia. Therefore, Actiq should be used with caution in
`patients with bradyarrhythmias.
`
`Hepatic or Renal Disease
`Actiq should be administered with caution to patients with liver or kidney dysfunction because of the
`importance of these organs in the metabolism and excretion of drugs and effects on plasma binding
`proteins (see PHARMACOKINETICS).
`
`Information for Patients and Their Caregivers
`Patients and their caregivers must be instructed that Actiq contains medicine in an amount that
`could be fatal to a child. Patients and their caregivers must be instructed to keep both used and
`unused dosage units out of the reach of children. Partially consumed units represent a special risk to
`children. In the event that a unit is not completely consumed it must be properly disposed as soon as
`possible. (See SAFETY AND HANDLING, WARNINGS, and PATIENT LEAFLET for specific
`patient instructions.)
`
`Frequent consumption of sugar-containing products may increase the risk of dental decay (each Actiq
`unit contains approximately 2 grams of sugar [hydrated dextrates]. The occurrence of dry mouth
`associated with the use of opioid medications (such as fentanyl) may add to this risk.
`
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`Post-marketing reports of dental decay have been received in patients taking Actiq (see ADVERSE
`REACTIONS – Post-Marketing Experience). In some of these patients, dental decay occurred despite
`reported oral hygiene. Therefore, patients using Actiq should consult their dentist to ensure appropriate
`oral hygiene.
`
`Diabetic patients should be advised that Actiq contains approximately 2 grams of sugar per unit.
`
`Patients and their caregivers should be provided with an Actiq Welcome Kit, which contains
`educational materials and safe storage containers to help patients store Actiq and other medicines out
`of the reach of children. Patients and their caregivers should also have an opportunity to watch the
`patient safety video, which provides proper product use, storage, handling and disposal directions.
`Patients should also have an opportunity to discuss the video with their health care providers. Health
`care professionals should call 1-800-896-5855 to obtain a supply of welcome kits or videos for patient
`viewing.
`
`Disposal of Used Actiq Units
`Patients must be instructed to dispose of completely used and partially used Actiq units.
`
`1) After consumption of the unit is complete and the matrix is totally dissolved, throw away the
`handle in a trash container that is out of the reach of children.
`
`
`2) If any of the drug matrix remains on the handle, place the handle under hot running tap water until
`all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach
`of children.
`
`
`3) Handles in the child-resistant container should be disposed of (as described in steps 1 and 2) at
`least once a day.
`
`
`If the patient does not entirely consume the unit and the remaining drug cannot be immediately
`dissolved under hot running water, the patient or caregiver must temporarily store the Actiq unit
`in the specially provided child-resistant container out of the reach of children until proper
`disposal is possible.
`
`Disposal of Unopened Actiq Units When No Longer Needed
`Patients and members of their household must be advised to dispose of any unopened units remaining
`from a prescription as soon as they are no longer needed.
`
`To dispose of the unused Actiq units:
`
`1) Remove the Actiq unit from its blister package using scissors, and hold the Actiq by its handle over
`the toilet bowl.
`
`2) Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet.
`
`3) Dispose of the handle in a place that is out of the reach of children.
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`4) Repeat steps 1, 2, and 3 for each Actiq unit. Flush the toilet twice after 5 units have been cut and
`deposited into the toilet.
`
`Do not flush the entire Actiq units, Actiq handles, blister packages, or cartons down the toilet. The
`handle should be disposed of where children cannot reach it (see SAFETY AND HANDLING).
`
`Detailed instructions for the proper storage, administration, disposal, and important instructions for
`managing an overdose of Actiq are provided in the Actiq Patient Leaflet. Patients should be
`encouraged to read this information in its entirety and be given an opportunity to have their questions
`answered.
`
`In the event that a caregiver requires additional assistance in disposing of excess unusable units that
`remain in the home after a patient has expired, they should be instructed to call the toll-free number (1-
`800-896-5855) or seek assistance from their local DEA office.
`
`Laboratory Tests
`The effects of Actiq on laboratory tests have not been evaluated.
`
`Drug Interactions
`See WARNINGS.
`
`Fentanyl is metabolized in the liver and intestinal mucosa to norfentanyl by the cytochrome P450 3A4
`isoform. Drugs that inhibit P450 3A4 activity may increase the bioavailability of swallowed fentanyl
`(by decreasing intestinal and hepatic first pass metabolism) and may decrease the systemic clearance of
`fentanyl. The expected clinical results would be increased or prolonged opioid effects. Drugs that
`induce cytochrome P450 3A4 activity may have the opposite effects. However, no in vitro or in vivo
`studies have been performed to assess the impact of those potential interactions on the administration
`of Actiq. Thus patients who begin or end therapy with potent inhibitors of CYP450 3A4 such as
`macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole and
`itraconazole), and protease inhibitors (e.g., ritanovir) while receiving Actiq should be monitored for a
`change in opioid effects and, if warranted, the dose of Actiq should be adjusted.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`Because animal carcinogenicity studies have not been conducted with fentanyl citrate, the potential
`carcinogenic effect of Actiq is unknown.
`
`Standard mutagenicity testing of fentanyl citrate has been conducted. There was no evidence of
`mutagenicity in the Ames Salmonella or Escherichia mutagenicity assay, the in-vitro mouse
`lymphoma mutagenesis assay, and the in-vivo micronucleus cytogenetic assay in the mouse.
`
`Reproduction studies in rats revealed a significant decrease in the pregnancy rate of all experimental
`groups. This decrease was most pronounced in the high dose group (1.25 mg/kg subcutaneously) in
`which one of twenty animals became pregnant.
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`Pregnancy - Category C
`Fentanyl has been shown to impair fertility and to have an embryocidal effect with an increase in
`resorptions in rats when given for a period of 12 to 21 days in doses of 30 mcg/kg IV or 160 mcg/kg
`subcutaneously.
`
`No evidence of teratogenic effects has been observed after administration of fentanyl citrate to rats.
`There are no adequate and well-controlled studies in pregnant women. Actiq should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Labor and Delivery
`Actiq is not indicated for use in labor and delivery.
`
`Nursing Mothers
`Fentanyl is excreted in human milk; therefore Actiq should not be used in nursing women because of
`the possibility of sedation and/or respiratory depression in their infants.
`
`Pediatric Use
`See WARNINGS.
`
`Geriatric Use
`Of the 257 patients in clinical studies of Actiq in breakthrough cancer pain, 61 (24%) were 65 and
`over, while 15 (6%) were 75 and over.
`
`Those patients over the age of 65 titrated to a mean dose that was about 200 mcg less than the mean
`dose titrated to by younger patients. Previous studies with intravenous fentanyl showed that elderly
`patients are twice as sensitive to the effects of fentanyl as the younger population.
`
`No difference was noted in the safety profile of the group over 65 as compared to younger patients in
`Actiq clinical trials. However, greater sensitivity in older individuals cannot be ruled out. Therefore,
`caution should be exercised in individually titrating Actiq in elderly patients to provide adequate
`efficacy while minimizing risk.
`
`ADVERSE REACTIONS
`Pre-Marketing Clinical Trial Experience
`The safety of Actiq has been evaluated in 257 opioid tolerant chronic cancer pain patients. The
`duration of Actiq use varied during the open-label study. Some patients were followed for over 21
`months. The average duration of therapy in the open-label study was 129 days.
`
`The adverse events seen with Actiq are typical opioid side effects. Frequently, these adverse events
`will cease or decrease in intensity with continued use of Actiq, as the patient is titrated to the proper
`dose. Opioid side effects should be expected and managed accordingly.
`
`The most serious adverse effects associated with all opioids are respiratory depression (potentially
`leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. All patients
`should be followed for symptoms of respiratory depression.
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`Because the clinical trials of Actiq were designed to evaluate safety and efficacy in treating
`breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release
`morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented
`here reflect the actual percentage of patients experiencing each adverse effect among patients who
`received Actiq for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain.
`There has been no attempt to correct for concomitant use of other opioids, duration of Actiq therapy, or
`cancer-related symptoms. Adverse events are included regardless of causality or severity.
`
`Three short-term clinical trials with similar titration schemes were conducted in 257 patients with
`malignancy and breakthrough cancer pain. Data are available for 254 of these patients. The goal of
`titration in these trials was to find the dose of Actiq that provided adequate analgesia with acceptable
`side effects (successful dose). Patients were titrated from a low dose to a successful dose in a manner
`similar to current titration dosing guidelines. Table 3 lists by dose groups, adverse events with an
`overall frequency of 1% or greater that occurred during titration and are commonly associated with
`opioid administration or are of particular clinical interest. The ability to assign a dose-response
`relationship to these adverse events is limited by the titration schemes used in these studies. Adverse
`events are listed in descending order of frequency within each body system.
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`NDA20-7