Actiq

Dosage Form: lozenge
FULL PRESCRIBING INFORMATION

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL

RESPIRATORY DEPRESSION

Fatal respiratory depression has occurred in patients treated with Actiq, including following use in opioid non-tolerant patients and improper dosing.The substitution of Actiq for any other fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression, Actiq is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see Contraindications (4)]

Death has been reported in children who have accidentally ingested Actiq. Actiq must be kept out of reach of children. [see Patient Counseling Information (17.3) and How Supplied/Storage and Handling (16.1)] 

The concomitant use of Actiq with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions (7)].

MEDICATION ERRORS

Substantial differences exist in the pharmacokinetic profile of Actiq compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.

 

- When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Actiq. [see Dosage and Administration (2.1)]

- When dispensing, do not substitute an Actiq prescription for other fentanyl products.

ABUSE POTENTIAL

Actiq contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics.

Actiq can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Actiq in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, Actiq is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [see Warnings and Precautions (5.10)] Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

Indications and Usage for Actiq

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 [see Warnings and Precautions (5.10)]. 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.

Actiq 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 [see Warnings and Precautions (5.10)].

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

See Boxed Warning

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

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 [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.

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.

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

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-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.

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.

Warnings and Precautions

See Boxed Warning - WARNING:RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL

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 [see Dosage and Administration (2.2)].

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 (17.3), 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.

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.

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 [see Drug Abuse and Dependence (9)], 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.

Adverse Reactions

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