Actiq

Actiq information, interactions and side effects, 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 fracture resistant (ABS plastic) under normal conditions when used as directed.

ACTIQ is designed to be dissolved slowly in the mouth 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 (octanolwater 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:

Actiq

Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, and edible glue (modified food starch and confectioner’s sugar).

INDICATIONS

ACTIQ (oral transmucosal fentanyl citrate) is indicated for the management of breakthrough pain in cancer patients 16 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking ACTIQ.

This product must not be used in opioid non-tolerant patients because life-threatening respiratory depression and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, ACTIQ is contraindicated in the management of acute or postoperative pain.

ACTIQ is intended to be used only in the care of opioid-tolerant 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.

Limitations of Use

As a part of the TIRF REMS Access program, ACTIQ may be dispensed only to outpatients enrolled in the program. For inpatient administration of ACTIQ (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

DOSAGE AND ADMINISTRATION

Healthcare professionals who prescribe ACTIQ on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of ACTIQ.

As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

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.

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

fentacitrate4

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.

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.

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.

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.

HOW SUPPLIED

Dosage Forms And Strengths

Each dosage unit has white to off-white color and is a solid drug matrix on a handle. Each strength is marked on the individual solid drug matrix and the handle tag. ACTIQ is available in 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg strengths.

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.

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

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.

A temporary storage bottle is provided as part of the ACTIQ Child Safety Kit. 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 1800-896-5855.

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.

SIDE EFFECTS

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)

 

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
  ThinkingAbnormal 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
* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.

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 Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients)

 

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
* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once.

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

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.

DRUG INTERACTIONS

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when ACTIQ is given concurrently with agents that affect CYP3A4 activity. The concomitant use of ACTIQ with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression. Patients receiving ACTIQ concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done conservatively.

Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations of fentanyl, thus should be avoided.

Drugs that induce cytochrome P450 3A4 activity may have the opposite effects.

Concomitant use of ACTIQ with an MAO inhibitor, or within 14 days of discontinuation, is not recommended.

Drug Abuse And Dependence

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.

Abuse and Addiction

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.

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 nonmedical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of patients, proper prescribing practices, periodic reevaluation 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.

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.

This monograph has been modified to include the generic and brand name in many instances.

PRECAUTIONS

Respiratory Depression

Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in ACTIQ. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

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.

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.

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.

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.

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.

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.

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.

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.

Cardiac Disease

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

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.

Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose, ACTIQ is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of ACTIQ, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

  • Healthcare professionals, who prescribe ACTIQ for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
  • To receive ACTIQ, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
  • Pharmacies that dispense ACTIQ must enroll in the program, and agree to comply with the REMS requirements.
  • Wholesalers and distributors that distribute ACTIQ must enroll in the program, and distribute only to authorized pharmacies.
    Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Patient Counseling Information

Patient/Caregiver Instructions

  • Before initiating treatment with ACTIQ, explain the statements below to patients and/or caregivers. Instruct patients to read the Medication Guide each time ACTIQ is dispensed because new information may be available.
    • Outpatients must be enrolled in the TIRF REMS Access program before they can receive ACTIQ.
    • Allow patients the opportunity to ask questions and discuss any concerns regarding ACTIQ or the TIRF REMS Access program.
    • As a component of the TIRF REMS Access program, prescribers must review the contents of the ACTIQ Medication Guide with every patient before initiating treatment with ACTIQ.
    • Advise the patient that ACTIQ is available only from pharmacies that are enrolled in the TIRF REMS Access program, and provide them with the telephone number and website for information on how to obtain the drug.
    • Advise the patient that only enrolled healthcare providers may prescribe ACTIQ.
    • Patient must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of ACTIQ.
    • Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access program.
  • Patients and their caregivers must be instructed that children 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take ACTIQ.
  • 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.
  • Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ.
  • Instruct patients NOT to share ACTIQ and that sharing ACTIQ with anyone else could result in the other individual’s death due to overdose.
  • Make patients aware that ACTIQ contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
  • 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.
  • Caution patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking ACTIQ.
  • Instruct patients to use ACTIQ exactly as prescribed by their doctor and not to take ACTIQ more often than prescribed.
  • 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.
  • 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.
  • 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.
  • 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.

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. 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.

Diabetic Patients

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

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.

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.

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.

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.

Nonclinical Toxicology

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.

Use In Specific Populations

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.

Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore do not use ACTIQ during labor and delivery (including caesarean section) since it may cause respiratory depression in the fetus or in the newborn infant.

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.

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&bullh/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).

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.

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.

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.

This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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.

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.

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.

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.

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.

CONTRAINDICATIONS

ACTIQ is contraindicated in opioid non-tolerant patients. ACTIQ is contraindicated in the management of acute or postoperative pain including headache/migraine and dental pain. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.

Patients considered opioid tolerant are those who are taking around-theclock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.

ACTIQ is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl. Anaphylaxis and hypersensitivity have been reported in association with the use of ACTIQ.

This monograph has been modified to include the generic and brand name in many instances.

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