ACTIQ® (fentanyl citrate)

ACTIQ® (fentanyl citrate) oral transmucosal lozenge

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ACTIQ® (fentanyl citrate)

ACTIQ (fentanyl citrate) oral transmucosal lozenge is a solid formulation of fentanyl, an opioid agonist, intended for oral transmucosal administration. ACTIQ is formulated as a white to offwhite 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 (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4.

Indications and usage

ACTIQ is an opioid agonist 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, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equal analgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking ACTIQ.

Limitations of Use

  • Not for use in opioid non-tolerant patients.
  • Not for use in the management of acute or postoperative pain, including headache/migraine or dental pain.
  • As a part of the TIRF REMS, ACTIQ may be dispensed by outpatient pharmacies only to outpatients enrolled in the program.
  • For inpatient administration of ACTIQ, patient and prescriber enrollment are not required.

Mechanism of Action

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Dosage and administration

  • Patients must require and use around-the-clock opioids when taking ACTIQ.
  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
  • Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.
  • Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with ACTIQ. Consider prescribing naloxone based on the patient’s risk factors for overdose
  • Initial dose of ACTIQ: 200 mcg. Prescribe an initial supply of six 200 mcg ACTIQ units.
  • Individually titrate to a tolerable dose that provides adequate analgesia using single ACTIQ dosage unit per breakthrough cancer pain episode.
  • No more than two doses can be taken per breakthrough pain episode.
  • Wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ.
  • Limit consumption to four or fewer units per day once successful dose is found.
  • When opioid therapy is no longer required, consider discontinuing ACTIQ along with a gradual downward of other opioids to minimize possible withdrawal effects.

Contraindications

  • Opioid non-tolerant patients.
  • Significant respiratory depression.
  • Management of acute or postoperative pain including headache/migraines and dental pain.
  • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.
  • Known or suspected gastrointestinal obstruction, including paralytic ileus.
  • Known hypersensitivity to fentanyl or components of ACTIQ.

Warnings and precautions

  • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.
  • Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure: Death has been reported in children who have accidentally ingested ACTIQ.
  • Addiction, Abuse, and Misuse: ACTIQ contains fentanyl, a Schedule II controlled substance. As an opioid, ACTIQ exposes users to the risks of addiction, abuse, and misuse
  • Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue ACTIQ if serotonin syndrome is suspected.
  • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
  • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of ACTIQ in patients with circulatory shock.
  • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of ACTIQ in patients with impaired consciousness or coma.
  • Neonatal Opioid Withdrawal Syndrome: Prolonged use of ACTIQ during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be lifethreatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
  • Increased Risk of Seizures in Patients with Seizure Disorders: The fentanyl in ACTIQ may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ACTIQ therapy.
  • Risks of Driving and Operating Machinery: ACTIQ may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ACTIQ and know how they will react to the medication.
  • Cardiac Disease: Intravenous fentanyl may produce bradycardia. Therefore, use ACTIQ with caution in patients with bradyarrhythmias.

Adverse reactions

Most common (frequency ≥5%): nausea, dizziness, somnolence, vomiting, asthenia, and headache, dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia.

Drug interactions

Inhibitors of CYP3A4: The concomitant use of ACTIQ and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of ACTIQ is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.

Examples; Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.

CYP3A4 Inducers: The concomitant use of ACTIQ and CYP3A4 inducers can decrease the plasma concentration of fentanyl, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl.

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After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression

Examples: Rifampin, carbamazepine, phenytoin

Benzodiazepines and Other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Examples: Phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: May reduce the analgesic effect of ACTIQ and/or precipitate withdrawal symptoms.

Examples: Butorphanol, nalbuphine, pentazocine, buprenorphrine

Muscle Relaxants: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Examples: cyclobenzaprine, metaxalone

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Use in specific populations

Pregnancy: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with ACTIQ in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

Lactation: Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ACTIQ.

Females and Males of Reproductive Potential Infertility: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible

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

Geriatric use: 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.

Drug abuse and dependence

Controlled Substance: ACTIQ contains fentanyl, a Schedule II controlled substance.

Abuse: ACTIQ contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine oxycodone, oxymorphone, and tapentadol. ACTIQ can be abused and is subject to misuse, addiction, and criminal diversion

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Overdosage

Acute overdose with ACTIQ can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations

Treatment of Overdose

In case of overdose, priorities are: removal of the ACTIQ unit, if still in the mouth, the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

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