2.1 Initial Dose

Individually titrate ACTIQ to a dose that provides adequate analgesia and minimizes side effects. The initial dose of ACTIQ to treat episodes of breakthrough cancer pain is always 200 mcg. The ACTIQ unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg ACTIQ units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose.

2.2 Dose Titration

From this initial dose, closely follow patients and change the dosage level until the patient reaches a dose that provides adequate analgesia using a single ACTIQ dosage unit per breakthrough cancer pain episode. 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. Patients should record their use of ACTIQ over several episodes of breakthrough cancer pain and review their experience with their physicians to determine if a dosage adjustment is warranted.

In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the ACTIQ unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode. Thus, patients should take a maximum of two doses of ACTIQ for any breakthrough pain episode.

Patients must wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ. To reduce the risk of overdosing during titration, patients should have only one strength of ACTIQ available at any one time.

ACTIQ Titration Process
See Boxed Warning

*Available dosage strengths include: 200, 400, 600, 800, 1200, and 1600 mcg.

2.3 Maintenance Dosing

Once titrated to an effective dose, patients should generally use ONLY ONE ACTIQ unit of the appropriate strength per breakthrough pain episode.

On those occasions when the breakthrough pain episode is not relieved 15 minutes after completion of the ACTIQ unit, patient may take ONLY ONE additional dose using the same strength for that episode.

Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ. Once a successful dose has been found (i.e., an average episode is treated with a single unit), patients should limit consumption to four or fewer units per day.

Dosage adjustment of ACTIQ may be required in some patients in order to continue to provide adequate relief of breakthrough pain.

Generally, the ACTIQ 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.

If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated.

2.4 Administration of ACTIQ

Open the blister package with scissors immediately prior to product use. The patient should place the ACTIQ unit in his or her mouth between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. The ACTIQ unit should be sucked, not chewed. A unit dose of ACTIQ, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed [see Clinical Pharmacology (12.3)].

The ACTIQ unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in ACTIQ clinical trials. If signs of excessive opioid effects appear before the unit is consumed, remove the drug matrix from the patient’s mouth immediately and decrease future doses.

2.5 Discontinuation of ACTIQ

For patients requiring discontinuation of opioids, a gradual downward titration is recommended because it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.

5.1 Important Information Regarding Prescribing and Dispensing

When prescribing, DO NOT convert a patient to ACTIQ from any other fentanyl product on a mcg per mcg basis as ACTIQ and other fentanyl products are not equivalent on a microgram per microgram basis.

ACTIQ is NOT a generic version of Fentora®. When dispensing, DO NOT substitute an ACTIQ prescription for a Fentora prescription under any circumstances. Fentora and ACTIQ are not equivalent. Substantial differences exist in the pharmacokinetic profile of ACTIQ compared to other fentanyl products including Fentora that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of ACTIQ for any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of ACTIQ should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects [see Dosage and Administration (2.2)].

5.2 Respiratory Depression

As with all opioids, there is a risk of clinically significant respiratory depression in patients using ACTIQ. Accordingly, follow all patients for symptoms of respiratory depression. Respiratory depression may occur more readily when opioids are given in conjunction with other agents that depress respiration.

5.3 Patient/Caregiver Instructions

Patients and their caregivers must be instructed that ACTIQ contains a medicine in an amount which can be fatal to a child. Death has been reported in children who have accidentally ingested ACTIQ. 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 How Supplied/Storage and Handling (16.1, 16.2), Patient Counseling Information (17.1), and Medication Guide].

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.

ACTIQ could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

5.4 Additive CNS Depressant Effects

The concomitant use of ACTIQ 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., respiratory depression, 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 ACTIQ 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 ACTIQ of these dangers and counsel them accordingly.

5.6 Chronic Pulmonary Disease

Because potent opioids can cause respiratory depression, titrate ACTIQ with caution in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of ACTIQ may further decrease respiratory drive to the point of respiratory failure.

5.7 Head Injuries and Increased Intracranial Pressure

Administer ACTIQ 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 Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use ACTIQ with caution in patients with bradyarrhythmias.

5.9 MAO Inhibitors

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.

5.10 ACTIQ REMS (Risk Evaluation and Mitigation Strategy) Program

Because of the risk for misuse, abuse, addiction, and overdose, ACTIQ is available only through a restricted distribution program called the ACTIQ REMS PROGAM. Healthcare professionals (who prescribe for outpatient use), as well as outpatients, pharmacies and distributors must be enrolled in and comply with the ACTIQ REMS program to prescribe, receive, dispense, and distribute ACTIQ, respectively. This program provides educational materials and patient counseling.

An overview of the requirements for prescribers, pharmacies, patients and distributors is included below.

• Healthcare professionals, who prescribe ACTIQ for outpatient use, must review the prescriber educational materials, enroll in the Program, and commit to comply with the REMS requirements.

• To receive ACTIQ, outpatients must understand the risks and benefits of the drug and sign a Patient-Prescriber Agreement with their healthcare provider; outpatients will be enrolled by the pharmacy at the time their first prescription is filled.

• Outpatient pharmacies, that dispense ACTIQ for outpatient use, must enroll in the Program, train their pharmacy staff on the REMS requirements, and agree to comply with the REMS requirements.

• Inpatient pharmacies, that dispense ACTIQ for inpatient use, must enroll in the Program, train their pharmacy staff on the REMS requirements, and agree to comply with the REMS requirements.

• Wholesalers and distributors, that distribute ACTIQ must enroll in the Program, and commit to distributing only to authorized enrolled pharmacies.

To learn more about the specific REMS requirements and to enroll in the ACTIQ REMS PROGRAM program, call 1-888-688-6885 or visit the ACTIQ REMS PROGRAM at www.actiqandfentorarems.com.

6.1 Clinical Studies 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 reactions seen with ACTIQ are typical opioid side effects. Frequently, these adverse reactions will cease or decrease in intensity with continued use of ACTIQ, as the patient is titrated to the proper dose. Expect opioid side effects and manage them accordingly.

The most serious adverse reactions associated with all opioids including ACTIQ are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression.

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 reactions are included regardless of causality or severity.

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.

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 1 lists, by dose groups, adverse reactions 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 reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system.

Table 1. Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients)

*Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.
Dose Group	Percentage of Patients Reporting Event
	200- 600 mcg (n=230)	800- 1400 mcg (n=138)	1600 mcg (n=54)	>1600 mcg (n=41)	Any Dose* (n=254)
Body As A Whole
Asthenia	6	4	0	7	9
Headache	3	4	6	5	6
Accidental       Injury	1	1	4	0	2
Digestive
Nausea	14	15	11	22	23
Vomiting	7	6	6	15	12
Constipation	1	4	2	0	4
Nervous
Dizziness	10	16	6	15	17
Somnolence	9	9	11	20	17
Confusion	1	6	2	0	4
Anxiety	3	0	2	0	3
Abnormal Gait	0	1	4	0	2
Dry Mouth	1	1	2	0	2
Nervousness	1	1	0	0	2
Vasodilatation	2	0	2	0	2
Hallucinations	0	1	2	2	1
Insomnia	0	1	2	0	1
Thinking       Abnormal	0	1	2	0	1
Vertigo	1	0	0	0	1
Respiratory
Dyspnea	2	3	6	5	4
Skin
Pruritus	1	0	0	5	2
Rash	1	1	0	2	2
Sweating	1	1	2	2	2
Special Senses
Abnormal Vision	1	0	2	0	2

The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection
Cardiovascular: Migraine
Digestive: Diarrhea, dyspepsia, flatulence
Metabolic and Nutritional: Peripheral edema, dehydration
Nervous: Hypesthesia
Respiratory: Pharyngitis, cough increased

The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system.

Body as a Whole: Flu syndrome, abscess, bone pain
Cardiovascular: Deep thrombophlebitis, hypertension, hypotension
Digestive: Anorexia, eructation, esophageal stenosis, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis
Hemic and Lymphatic: Anemia, leukopenia
Metabolic and Nutritional: Edema, hypercalcemia, weight loss
Musculoskeletal: Myalgia, pathological fracture, myasthenia
Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder
Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased
Skin and Appendages: Alopecia, exfoliative dermatitis
Special Senses: Taste perversion
Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection

A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study and are commonly associated with opioid administration or are of particular clinical interest. Adverse reactions are listed in descending order of frequency within each body system.

Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients)

* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.
Dose Group	Percentage of Patients Reporting Event
	200- 600 mcg (n=98)	800- 1400 mcg (n=83)	1600 mcg (n=53)	>1600 mcg (n=27)	Any Dose* (n=152)
Body As A Whole
Asthenia	25	30	17	15	38
Headache	12	17	13	4	20
Accidental Injury	4	6	4	7	9
Hypertonia	2	2	2	0	3
Digestive
Nausea	31	36	25	26	45
Vomiting	21	28	15	7	31
Constipation	14	11	13	4	20
Intestinal Obstruction	0	2	4	0	3
Cardiovascular
Hypertension	1	1	0	0	1
Nervous
Dizziness	12	10	9	0	16
Anxiety	9	8	8	7	15
Somnolence	8	13	8	7	15
Confusion	2	5	13	7	10
Depression	9	4	2	7	9
Insomnia	5	1	8	4	7
Abnormal Gait	5	1	0	0	4
Dry Mouth	3	1	2	4	4
Nervousness	2	2	0	4	3
Stupor	4	1	0	0	3
Vasodilatation	1	1	4	0	3
Thinking Abnormal	2	1	0	0	2
Abnormal Dreams	1	1	0	0	1
Convulsion	0	1	2	0	1
Myoclonus	0	0	4	0	1
Tremor	0	1	2	0	1
Vertigo	0	0	4	0	1
Respiratory
Dyspnea	15	16	8	7	22
Skin
Rash	3	5	8	4	8
Sweating	3	2	2	0	4
Pruritus	2	0	2	0	2
Special Senses
Abnormal Vision	2	2	0	0	3
Urogenital
Urinary Retention	1	2	0	0	2

The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain
Cardiovascular: Deep thrombophlebitis, migraine, palpitation, vascular disorder
Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage
Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia
Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia
Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder
Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder
Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased
Skin and Appendages: Skin ulcer, alopecia
Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion
Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis

The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system.

Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, injection site pain, mucous membrane disorder, neck rigidity
Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia
Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder
Hemic and Lymphatic: Bleeding time increased
Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst
Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder
Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma
Respiratory: Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration
Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash
Special Senses: Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness
Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis

6.2 Postmarketing Experience

Adverse reactions are reported voluntarily from a population of uncertain size, and, therefore, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to ACTIQ.

The following adverse reactions have been identified during postapproval use of ACTIQ (which contains approximately 2 grams of sugar per unit):

Digestive: Dental decay of varying severity including dental caries, tooth loss, and gum line erosion.

General Disorders and Administration Site Conditions: Application site reactions including irritation, pain, and ulcer.

8.1 Pregnancy

Pregnancy Category C

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. 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 in newborn infants characteristic of neonatal abstinence syndrome.

In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.

Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Fentanyl is embryocidal in rats 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 ACTIQ.

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.

8.2 Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore do not use ACTIQ during labor and delivery.

8.3 Nursing Mothers

Fentanyl is excreted in human milk; therefore, do not use ACTIQ 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 ACTIQ.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below 16 years of age have not been established.

In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with ACTIQ. The study was too small to allow conclusions on safety and efficacy in this patient population. Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received ACTIQ at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) Cmax and AUC0-8 values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng•h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (N = 9).

8.5 Geriatric Use

Of the 257 patients in clinical studies of ACTIQ in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in ACTIQ clinical trials.

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, exercise caution when individually titrating ACTIQ 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 ACTIQ 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 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 reactions.

9.1 Controlled Substance

Fentanyl is a Schedule II controlled substance that can produce drug dependence of the morphine type. ACTIQ may be subject to misuse, abuse and addiction.

9.2 Abuse

Manage the handling of ACTIQ to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law [see How Supplied/Storage aAnd Handling (16.1, 16.2)].

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, because 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.

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 nonmedical purposes, often in combination with other psychoactive substances. Since ACTIQ 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 Dependence

Guide the administration of ACTIQ by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with chronic cancer 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.

10.1 Clinical Presentation

The manifestations of ACTIQ 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 respiratory depression [see Clinical Pharmacology (12.2)].

10.2 Immediate Management

Immediate management of opioid overdose includes removal of the ACTIQ unit, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, 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 antagonist’s 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 ACTIQ overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient’s airway is secure. In the presence of respiratory depression or apnea, assist or control ventilation, and administer oxygen as indicated.

Although muscle rigidity interfering with respiration has not been seen following the use of ACTIQ, this is possible with fentanyl and other opioids. If it occurs, manage it by using assisted or controlled ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

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 ACTIQ should be individually titrated to achieve the desired effect [see Dosage and Administration (2.2)].

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 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. 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: Importance Of Proper Patient Selection, Dosing, and Potential for Abuse, Contraindications (4), Warnings and Precautions (5.2), Adverse Reactions (6), and Overdosage (10)].

12.3 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 (n=11). Mean serum fentanyl levels following these four doses of ACTIQ are shown in Figure 1. The curves for each dose level are similar 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

The pharmacokinetic parameters of the four strengths of ACTIQ tested in the dose-proportionality study are shown in Table 3. 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.

Table 3. Pharmacokinetic Parameters* in Adult Subjects Receiving 200, 400, 800, and 1600 mcg Units of ACTIQ

* Based on arterial blood samples.
Pharmacokinetic Parameter	200 mcg	400 mcg	800 mcg	1600 mcg
Tmax, minute median (range)	40 (20-120)	25 (20-240)	25 (20-120)	20 (20-480)
Cmax, ng/mL mean (%CV)	0.39 (23)	0.75 (33)	1.55 (30)	2.51 (23)
AUC0-1440, ng/mL minute mean (%CV)	102 (65)	243 (67)	573 (64)	1026 (67)
t1/2, minute mean (%CV)	193 (48)	386 (115)	381 (55)	358 (45)

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 Drug Interactions (7)].

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 ACTIQ administration is about 7 hours.

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, and was not clastogenic in the in vivo mouse micronucleus assay.

Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for ACTIQ.

16.1 Storage and Handling

ACTIQ is supplied in individually sealed child-resistant blister packages. The amount of fentanyl contained in ACTIQ can be fatal to a child. Patients and their caregivers must be instructed to keep ACTIQ out of the reach of children [see Boxed Warning - Warning: Importance Of Proper Patient Selection, Dosing, and Potential For Abuse, Warnings and Precautions (5), and Patient Counseling Information (17.1)].

Store at 20-25°C (68-77°F) with excursions permitted between 15° and 30°C (59° to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect ACTIQ from freezing and moisture. Do not use if the blister package has been opened.

16.2 Disposal of ACTIQ

Patients must be advised to dispose of any units remaining from a prescription as soon as they are no longer needed. While all units should be disposed of immediately after use, partially consumed units represent a special risk because they are no longer protected by the child resistant blister package, yet may contain enough medicine to be fatal to a child [see Patient Counseling Information (17.5)].

A temporary storage bottle is provided as part of the ACTIQ Child Safety Kit [see Patient Counseling Information (17.4)]. This container is to be used by patients or their caregivers in the event that a partially consumed unit cannot be disposed of promptly. Instructions for usage of this container are included in the Medication Guide.

Patients and members of their household must be advised to dispose of any units remaining from a prescription as soon as they are no longer needed. Instructions are included in Patient Counseling Information (17.6) and in the Medication Guide. If additional assistance is required, call Cephalon, Inc., at 1-800-896-5855.

16.3 How Supplied

ACTIQ is supplied in six dosage strengths. Each unit is individually wrapped in a child-resistant, protective blister package. These blister packages are packed 30 per shelf carton for use when patients have been titrated to the appropriate dose.

Each dosage unit has a white to off-white color. Each individual solid drug matrix is marked with “ACTIQ” and the strength of the unit (“200” ,“400”, “600”, “800” ,“1200”, or “1600”). The dosage strength is also marked on the handle tag, the blister package and the carton. See blister package and carton for product information.

Dosage Strength (fentanyl base)	Carton/Blister Package Color	NDC Number
200 mcg	Gray	NDC 63459-502-30
400 mcg	Blue	NDC 63459-504-30
600 mcg	Orange	NDC 63459-506-30
800 mcg	Purple	NDC 63459-508-30
1200 mcg	Green	NDC 63459-512-30
1600 mcg	Burgundy	NDC 63459-516-30

Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

17.1 Patient/Caregiver Instructions

1. Instruct patients and their caregivers that ACTIQ is available only through a restricted distribution program called the ACTIQ REMS PROGRAM. Review the risks, benefits, and appropriate use of ACTIQ with each patient and their caregivers, as well as how ACTIQ will be distributed through the ACTIQ REMS PROGRAM. Patients must be enrolled in the ACTIQ REMS PROGRAM to receive ACTIQ. Patients must sign the Patient-Prescriber Agreement Form to confirm that they understand the risks, appropriate use and storage of ACTIQ.
2. Patients and their caregivers must be instructed that children exposed to ACTIQ are at high risk of FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be instructed to keep ACTIQ out of the reach of children [See How Supplied/Storage and Handling (16.1), Warnings and Precautions (5.2 and 5.3) and Medication Guide for specific patient instructions.]
3. Provide patients and their caregivers with a Medication Guide and review it with them each time ACTIQ is dispensed because new information may be available.
4. Instruct patients and their caregivers 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 How Supplied/Storage and Handling (16.1), Warnings and Precautions (5.3), and Patient Counseling Information (17.5)].
5. Instruct patients not to take ACTIQ 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.
6. Instruct patients on the meaning of opioid tolerance and that ACTIQ 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.
7. Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take ACTIQ.
8. Instruct patients that, if the breakthrough pain episode is not relieved 15 minutes after finishing the ACTIQ unit, they may take ONLY ONE ADDITIONAL UNIT OF ACTIQ USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take no more than two units of ACTIQ for any breakthrough pain episode.
9. Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ.
10. Instruct patients NOT to share ACTIQ and that sharing ACTIQ with anyone else could result in the other individual’s death due to overdose.
11. Make patients aware that ACTIQ contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
12. Instruct patients that the active ingredient in ACTIQ, fentanyl, is a drug that some people abuse. ACTIQ 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.
13. Caution patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking ACTIQ.
14. Instruct patients to use ACTIQ exactly as prescribed by their doctor and not to take ACTIQ more often than prescribed.
15. Caution patients that ACTIQ can affect a person’s ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Warn patients taking ACTIQ of these dangers and counsel them accordingly.
16. Warn patients to not combine ACTIQ 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.
17. Inform female patients that if they become pregnant or plan to become pregnant during treatment with ACTIQ, they should ask their doctor about the effects that ACTIQ (or any medicine) may have on them and their unborn children.

17.2 Dental Care

Because each ACTIQ unit contains approximately 2 grams of sugar (hydrated dextrates), frequent consumption may increase the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk.

Post-marketing reports of dental decay have been received in patients taking ACTIQ [see Adverse Reactions (6.2)]. In some of these patients, dental decay occurred despite reported routine oral hygiene. As dental decay in cancer patients may be multi-factorial, patients using ACTIQ should consult their dentist to ensure appropriate oral hygiene.

17.3 Diabetic Patients

Advise diabetic patients that ACTIQ contains approximately 2 grams of sugar per unit.

17.4 ACTIQ Child Safety Kit

Provide patients and their caregivers who have children in the home or visiting with an ACTIQ Child Safety Kit, which contains educational materials and safe interim storage containers to help patients store ACTIQ and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call Cephalon, Inc., at 1-800-896-5855 or visit www.actiq.com.

17.5 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. Dispose of handles in the child-resistant container (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.

17.6 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.
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. Dispose of the handle where children cannot reach it [see How Supplied/Storage and Handling (16.1)].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ACTIQ are provided in the ACTIQ Medication Guide. Encourage patients to read this information in its entirety and give them 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, instruct them to call the toll-free number for Cephalon, Inc., (1-800-896-5855) or seek assistance from their local DEA office.

Read this Medication Guide completely before you start using ACTIQ and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Share this important information with members of your household and other caregivers.

What is the most important information I should know about ACTIQ?

ACTIQ can cause life-threatening breathing problems which can lead to death:

1. Do not use ACTIQ if you are not opioid tolerant.
2. If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using ACTIQ. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.
3. Use ACTIQ exactly as prescribed by your healthcare provider.
   • You must not use more than 2 units of ACTIQ for each episode of breakthrough cancer pain.
   • You must wait at least 4 hours before treating a new episode of breakthrough pain. See the Medication Guide section “How should I use ACTIQ?” and the Patient Instructions for Use at the end of this Medication Guide about how to use ACTIQ the right way.
4. Do not switch from ACTIQ to other medicines that contain fentanyl without talking with your healthcare provider. The amount of fentanyl in a dose of ACTIQ is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of ACTIQ  that may be different than other fentanyl containing medicines you may have been taking.
5. Do not use ACTIQ for short-term pain that you would expect to go away in a few days, such as:

• pain after surgery
• headache or migraine
• dental pain

6. Never give ACTIQ to anyone else, even if they have the same symptoms you have. It may harm them or even cause death.

ACTIQ  is a federally controlled substance (CII) because it is a strong opioid (narcotic) pain medicine that can be misused by people who abuse  prescription medicines or street drugs.

• Prevent theft, misuse or abuse. Keep ACTIQ in a safe place to protect it from being stolen. ACTIQ can be a target for people who abuse opioid (narcotic) medicines or street drugs.
• Selling or giving away this medicine is against the law.

ACTIQ is available only through a program called the ACTIQ REMS program. To receive ACTIQ, you must:

• talk to your healthcare provider
• understand the benefits and risks of ACTIQ
• agree to all of the instructions
• sign the Patient-Prescriber Agreement form 

What is ACTIQ?

• ACTIQ is a prescription medicine that contains the medicine fentanyl. 
• ACTIQ is used to manage breakthrough pain in adults with cancer (16 years of age and older) who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. 
• ACTIQ is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant).  Do not use  ACTIQ if you are not opioid tolerant.
• ACTIQ is a lozenge (attached to a handle) that you place between your cheek and lower gum and suck on to dissolve.
• You must stay under your healthcare provider’s care while using ACTIQ.
• ACTIQ is only:
  • available through the ACTIQ REMS program
  • given to people who are opioid tolerant

It is not known if ACTIQ is safe and effective in children under 16 years of age.

Who should not use ACTIQ?

Do not use ACTIQ:

• if you are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for your cancer pain, and your body is used to these medicines.
• for short-term pain  that you would expect to go away in a few days, such as:
  • pain after surgery
  • headache or migraine
  • dental pain
• if you are allergic to any of the ingredients in ACTIQ.  See the end of this Medication Guide for a complete list of ingredients in ACTIQ.

What should I tell my healthcare provider before using ACTIQ?

Before using ACTIQ, tell your healthcare provider if you:

• have trouble breathing or lung problems such as asthma, wheezing, or shortness of breath
• have or had a head injury or brain problem
• have liver or kidney problems
• have seizures
• have a slow heart rate or other heart problems
• have low blood pressure
• have mental problems including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)
• have a past or present drinking problem (alcoholism), or a family history of drinking problems
• have a past or present drug abuse or addiction problem, or a family history of a drug abuse problem or addiction problem
• have diabetes. Each ACTIQ  unit contains about ½ teaspoon (2 grams) of sugar.
• have any other medical conditions
• are pregnant or plan to become pregnant.  ACTIQ  may cause serious harm to your unborn baby.
• are breastfeeding or plan to breastfeed. ACTIQ  passes into your breast milk. It can cause serious harm to your baby. You should not use ACTIQ while breastfeeding.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may cause serious or life-threatening side effects when taken with ACTIQ. Sometimes, the doses of certain medicines and ACTIQ may  need to be changed if used together.  

• Do not take any medicine while using ACTIQ until you have talked to your healthcare provider. Your healthcare provider will tell you if it is safe to take other medicines while you are using ACTIQ.
• Be very careful about taking other  medicines that may make you sleepy, such as other pain medicines, anti-depressants,  sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use ACTIQ?

Before you can begin to use ACTIQ:

• Your healthcare provider will explain the ACTIQ REMS program to you.
• You will sign the ACTIQ REMS program Patient-Prescriber Agreement form.
• ACTIQ is only available at pharmacies that are part of the ACTIQ REMS program. Your healthcare provider will let you know the pharmacy closest to your home where you can have your ACTIQ prescription filled.

Using ACTIQ:

• Use ACTIQ exactly as prescribed.Do not use ACTIQ more often than prescribed.

• Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you.

• See the detailed Patient Instructions for Use at the end of this Medication Guide for information about how to use ACTIQ the right way. 
• Finish the ACTIQ unit completely in 15 minutes to get the most relief. If you finish ACTIQ  too quickly, you will swallow more of the medicine and get less relief.
• Do not bite or chew ACTIQ. You will get less relief for your breakthrough cancer pain.
• You may drink some water before using ACTIQ  but you should not drink or eat anything while using ACTIQ.
• You must not use more than 2 units of ACTIQ for each episode of breakthrough cancer pain:
  • Use 1 unit for an episode of breakthrough cancer pain. Finish the unit over 15 minutes.
  • If your breakthrough cancer pain is not relieved 15 minutes after you finished the ACTIQ unit, use only 1 more dose of ACTIQ at this time.
  • If your breakthrough pain does not get better after the second unit of ACTIQ, call your healthcare provider for instructions. Do not use another unit of ACTIQ at this time.
• Wait at least 4 hours before treating a new episode of breakthrough cancer pain with ACTIQ.
• It is important for you to keep taking your around-the-clock opioid pain medicine while using ACTIQ.
• Talk to your healthcare provider if your dose of ACTIQ does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of ACTIQ needs to be changed.
• Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day. The dose of your around-the-clock opioid pain medicine may need to be adjusted.
• If you begin to feel dizzy, sick to your stomach, or very sleepy before ACTIQ is completely dissolved, remove ACTIQ from your mouth.
• If you use too  much ACTIQ or overdose, you or your caregiver should call for emergency medical help or have someone take you to the nearest hospital emergency room right away. 

What should I avoid while using ACTIQ?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how ACTIQ  affects you. ACTIQ  can make you sleepy. Ask your healthcare provider when it is okay to do these activities.

• Do not drink alcohol while using ACTIQ. It can increase your chance of getting dangerous side effects.

What are the possible side effects of ACTIQ?

ACTIQ can cause serious side effects, including:

1. Breathing problems that can become life-threatening. See “What is the most important information I should know about ACTIQ?”

   Call your healthcare provider or get emergency medical help right away if you:

   • have trouble breathing
   • have drowsiness with slowed breathing
   • have slow shallow breathing (little chest movement with breathing)
   • feel faint, very dizzy, confused, or have other unusual symptoms

   These symptoms can be a sign that you have used too much ACTIQ or the dose is too high for you. These symptoms may lead to serious problems or death if not treated right away. If you have any of these symptoms, do not use any more ACTIQ until you have talked to your healthcare provider.

2. Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.
3. Physical dependence. Do not stop taking ACTIQ or any other opioid, without talking to your healthcare provider. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependency is not the same as drug addiction.
4. A chance of abuse or addiction. This chance is higher if you are or have ever been addicted to or abused other medicines, street drugs, or alcohol, or if you have a history of mental health problems.

The most common side effects of ACTIQ  are:

• nausea
• vomiting
• dizziness
• sleepiness 
• weakness
• headache
• anxiety
• confusion
• depression
• rash
• trouble sleeping

Constipation (not often enough or hard bowel movements) is a very common side effect of pain medicines (opioids) including ACTIQ and is unlikely to go away without treatment. Talk to your healthcare provider about dietary changes, and the use of laxatives (medicines to treat constipation) and stool softeners to prevent or treat constipation while taking ACTIQ.

ACTIQ contains sugar. Cavities and tooth decay can happen in people taking ACTIQ. When taking ACTIQ, you should talk to your dentist about proper care of your teeth.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of ACTIQ. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ACTIQ?

• Always keep ACTIQ in a safe place away from children and from anyone for whom it has not been prescribed. Protect ACTIQ from theft.
• You can use the ACTIQ Child Safety Kit to help you store ACTIQ and your other medicines out of the reach of children. It is very important that you use the items in the ACTIQ Child Safety Kit to help protect the children in your home or visiting your home.
• If you were not offered a Child Safety Kit when you received your medicine, call Cephalon, Inc., at 1-800-896-5855 or visit www.actiq.com to request one.

The ACTIQ Child Safety Kit contains important information on the safe storage and handling of ACTIQ.

The Child Safety Kit includes:

• A child-resistant lock that you use  to secure the storage space where you keep ACTIQ (See Figure 1).

Figure 1

• A portable locking pouch for you to keep a small supply of ACTIQ nearby. The rest of your ACTIQ must be kept in a locked storage space.
  • Keep this pouch secured with its lock and keep it out of the reach and sight of children (See Figure 2).

Figure 2

• A child-resistant temporary storage bottle (See Figure 3).  

Figure 3

• Store ACTIQ at room temperature, 59°F to 86°F (15°C to 30°C) until ready to use.
• Do not freeze ACTIQ.
• Keep ACTIQ in the original sealed child-resistant blister package. Do not open the blister package until you are ready to use ACTIQ.
• Keep ACTIQ dry.

How should I dispose of ACTIQ units when they are no longer needed?

Disposing of ACTIQ units after use:

Partially used ACTIQ units may contain enough medicine to be harmful or fatal to a child or other adults who have not been prescribed ACTIQ. You must properly dispose of the ACTIQ  handle right away after use even if there is little or no medicine left on it.

After you have finished the ACTIQ unit and the medicine is totally gone, throw the handle away in a place that is out of the reach of children.

If any medicine remains on the used ACTIQ unit after you have finished:

• Place the used ACTIQ unit under hot running water until the medicine is gone, and then throw the handle away out of the reach of children and pets (See Figure 4).

 Figure 4

Temporary Storage of Used ACTIQ Units:

• If you did not finish the entire ACTIQ unit and you cannot dissolve the medicine under hot running water right away, put the used ACTIQ unit in the temporary storage bottle that you received in the ACTIQ Child Safety Kit. Push the used ACTIQ unit into the opening on the top until it falls completely into the bottle. Never leave unused or partially used ACTIQ units where children or pets can get to them (See Figure 5).

 Figure 5

Disposing of Used ACTIQ Units from the Temporary Storage Bottle:

You must dispose of all used ACTIQ units in the temporary storage bottle at least one time each day, as follows:

1. To open the temporary storage bottle, push down on the cap until you are able to twist the cap to the left to remove it (See Figure 6).
   
   
   Figure 6
2. Remove one ACTIQ unit from the temporary storage bottle. Hold the ACTIQ by its handle over the toilet bowl.
3. Using wire-cutting pliers, cut the medicine end off so that it falls into the toilet.
4. Throw the handle away in a place that is out of the reach of children.
5. Repeat these 3 steps for each ACTIQ handle that is in the storage bottle. There should not be more than 4 handles in the temporary storage bottle for 1 day.
6. Flush the toilet twice.

Do not flush entire unused ACTIQ units, ACTIQ handles, or blister packages down the toilet. 

Disposing of unopened ACTIQ units: Dispose of any unopened ACTIQ units remaining from a prescription as soon as they are no longer needed, as follows:

1. Remove all ACTIQ from the locked storage space (See Figure 7).
   
   
   Figure 7
2. Remove one ACTIQ unit from its blister package by using scissors to cut the marked end and then peeling back the blister backing (See Figures 8A and 8B).
   
   
   Figure 8A
   
   
   Figure 8B
3. Hold the ACTIQ by its handle over the toilet bowl. Using wire-cutting pliers, cut the medicine end off so that it falls into the toilet (See Figures 9A and 9B). 
   
   
   Figure 9A
   
   
   Figure 9B
4. Throw the handle away in a place that is out of the reach of children (See Figure 10).
   
   
   Figure 10
5. Repeat steps 1 through 4 for each ACTIQ unit.
6. Flush the toilet twice after 5 ACTIQ units have been cut (See Figure 11). Do not flush more than 5 ACTIQ units at a time.

Figure 11

• Do not flush entire unused ACTIQ units, ACTIQ handles, or blister packages down the toilet.

If you need help with disposal of ACTIQ, call Cephalon, Inc., at 1-800-896-5855, or call your local Drug Enforcement Agency (DEA) office.

General information about ACTIQ

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use ACTIQ only for the purpose for which it was prescribed.Do not give ACTIQ to other people, even if they have the same symptoms you have.  ACTIQ can harm other people and even cause death. Sharing ACTIQ is against the law.

This Medication Guide summarizes the most important information about ACTIQ. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about ACTIQ that is written for healthcare professionals. You can also call the ACTIQ REMS program at 1-888-688-6885 or visit actiqandfentorarems.com.

What are the ingredients of ACTIQ?

Active Ingredient: fentanyl citrate

Inactive Ingredients: sugar, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, modified food starch and confectioner’s sugar.

Patient Instructions for Use

Before you use ACTIQ, it is important that you read the Medication Guide and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you use ACTIQ the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use ACTIQ.

When you get an episode of breakthrough cancer pain, use the dose of ACTIQ prescribed by your healthcare provider as follows:

• You may drink some water before using ACTIQ  but you should not drink or eat anything while using ACTIQ.
• Each unit of ACTIQ is sealed in its own blister package (See Figure12). Do not open the blister package until you are ready to use ACTIQ.

Figure 12

• When you are ready to use ACTIQ, cut open the package using scissors, peel back the blister backing, and remove the ACTIQ unit (See Figures 13A and 13B). The end of the unit marked with “ACTIQ” and the strength number of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”) is the end that is to be placed in your mouth. Hold the ACTIQ unit by the handle (See Figure 14).

    Figure 13A

 Figure 13B

Figure 14

1. Place ACTIQ in your mouth between your cheeks and gums and actively suck on the medicine.
2. Move ACTIQ around in your mouth, especially along the inside of your cheeks (See Figure 15).
   
   
   Figure 15
3. Twirl the handle often.
4. Finish the ACTIQ unit completely in 15 minutes to get the most relief. If you finish ACTIQ  too quickly, you will swallow more of the medicine and get less relief.
5. Do not bite or chew ACTIQ. You will get less relief for your breakthrough cancer pain.

• If you cannot finish the entire ACTIQ unit and cannot dissolve the medicine under hot tap water right away, immediately put the ACTIQ unit in the temporary storage bottle for safe keeping (See Figure 16).
  • Push the ACTIQ unit into the opening on the top until it falls completely into the bottle. You must properly dispose of the ACTIQ unit as soon as you can.

Figure 16

See “How should I dispose of ACTIQ units when they are no longer needed?” for proper disposal of ACTIQ.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:
Cephalon, Inc.

Frazer, PA 19355

Revised July 2011

ACTIQ is a trademark of Cephalon, Inc. or its affiliates.

ACT-010

ACTMG-010

© 2000-2011 Cephalon, Inc. All rights reserved.