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Fentanyl may interact with:
- Monoamine oxidase inhibitors (MAOIs), including isocarboxazid (Marplan) and phenelzine (Nardil)
- Agonist/antagonist analgesics, such as pentazocine (Talwin) and butorphanol (Stadol)
- Partial agonist analgesics, such as buprenorphine (Buprenex)
Tell your doctor about any medications, illegal or recreational drugs, herbal remedies, and supplements you're taking.
Fentanyl and Alcohol
Drinking alcohol while using fentanyl may cause low blood pressure, profound sedation, coma, respiratory depression, and death.
Fentanyl and Grapefruit
Potentially fatal respiratory depression may occur if you consume grapefruit juice or grapefruit products while taking fentanyl.
Respiratory depression can also occur if you're taking fentanyl with cytochrome inhibitors.
Actiq Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:More common
- Black, tarry stools
- blurred vision
- chest pain
- decreased urine
- difficult or labored breathing
- dry mouth
- fever or chills
- increased thirst
- irregular heartbeat
- loss of appetite
- lower back or side pain
- mood changes
- muscle pain or cramps
- nausea or vomiting
- numbness or tingling in the hands, feet, or lips
- painful or difficult urination
- pale skin
- pounding in the ears
- rapid breathing
- sore throat
- sunken eyes
- swelling of the hands, ankles, feet, or lower legs
- tightness in the chest
- troubled breathing with exertion
- ulcers, sores, or white spots in the mouth
- unusual bleeding or bruising
- unusual tiredness or weakness
- wrinkled skin
- Abdominal or stomach pain
- change in walking and balance
- clumsiness or unsteadiness
- decreased awareness or responsiveness
- decreased frequency of urination
- muscle twitching or jerking
- pounding in the ears
- rhythmic movement of the muscles
- seeing, hearing, or feeling things that are not there
- severe constipation
- severe sleepiness
- shakiness in the legs, arms, hands, or feet
- slow or fast heartbeat
- thinking abnormalities
- trembling or shaking of the hands or feet
Get emergency help immediately if any of the following symptoms of overdose occur:Symptoms of overdose
- Extremely shallow or slow breathing
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- Back pain
- difficulty having a bowel movement (stool)
- difficulty with moving
- feeling sad or empty
- lack or loss of strength
- loss of interest or pleasure
- muscle stiffness
- pain in the joints
- sleepiness or unusual drowsiness
- trouble concentrating
- trouble sleeping
- weight loss
- Changes in vision
- excessive muscle tone
- feeling of constant movement of self or surroundings
- feeling of warmth or heat
- flushing or redness of the skin, especially on the face and neck
- irritation, pain, or sores at the site of application
- itching skin
- muscle tension or tightness
- sensation of spinning
- Tooth pain
- trouble with gums
- trouble with teeth
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
How do I store and/or throw out Actiq?
- Store at room temperature. Do not freeze.
- Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
- Follow the information that comes with Actiq for throwing out doses that are not needed. Check with your pharmacist if you have questions about how to throw out this medicine.
Indications and Usage for Actiq
Actiq 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, 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 of oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when 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 and dental pain [see Contraindications (4)]. • As a part of the TIRF REMS Access program, Actiq may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions (5.7)]. 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.
Warnings and Precautions
5.1 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Actiq, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Actiq.
To reduce the risk of respiratory depression, proper dosing and titration of Actiq are essential [see Dosage and Administration (2)]. Overestimating the Actiq dosage can result in a fatal overdose with the first dose. The substitution of Actiq for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].
Actiq could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.
Accidental ingestion of even one dose of Actiq, especially by children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions (5.1, 5.2)].
5.2 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure
Death has been reported in children who have accidentally ingested Actiq.
Patients and their caregivers must be informed that Actiq contains a medicine in an amount which can be fatal to a child. Healthcare providers 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.
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 Patient Counseling Information (17)].
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.
5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
Concomitant use of Actiq with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.1)], particularly when an inhibitor is added after a stable dose of Actiq is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Actiq-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Actiq with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Actiq-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Actiq until stable drug effects are achieved [see Drug Interactions (7)].
Concomitant use of Actiq with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using Actiq with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].
5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol)
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Actiq with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Actiq is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].
Risk of Medication Errors
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 other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute an Actiq prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and Actiq are not equivalent. Substantial differences exist in the pharmacokinetic profile of Actiq compared to other fentanyl products including other TIRF formulations 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 (2.3)].
5.6 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 [see Drug Abuse and Dependence (9)].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Actiq. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Actiq, and monitor all patients receiving Actiq for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Actiq, but use in such patients necessitates intensive counseling about the risks and proper use of Actiq along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Actiq. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.6)], 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.
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 life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].
5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of Actiq in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: Actiq-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Actiq [see Warnings and Precautions (5.1)].
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.1)].
Monitor such patients closely, particularly when initiating and titrating Actiq and when Actiq is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.1)]. Alternatively, consider the use of non-opioid analgesics in these patients.
5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Actiq with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Actiq if serotonin syndrome is suspected.
5.11 Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
5.12 Severe Hypotension
Actiq may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Actiq. In patients with circulatory shock, Actiq may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Actiq in patients with circulatory shock.
5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Actiq may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Actiq.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Actiq in patients with impaired consciousness or coma.
5.14 Risks of Use in Patients with Gastrointestinal Conditions
Actiq is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in Actiq may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
5.15 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.
5.16 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.
Intravenous fentanyl may produce bradycardia. Therefore, use Actiq with caution in patients with bradyarrhythmias.
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 [see Drug Interactions (7)].
Table 3 includes clinically significant drug interactions with Actiq.
Table 3: Clinically Significant Drug Interactions with Actiq
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 [see Warnings and Precautions (5.3)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
If concomitant use is necessary, consider dosage reduction of Actiq until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Actiq dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice
The concomitant use of Actiq and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.3)].
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
If concomitant use is necessary, consider increasing the Actiq dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Actiq dosage reduction and monitor for signs of respiratory depression.
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.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.10)].
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Actiq if serotonin syndrome is suspected.
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), 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 [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)].
The use of Actiq is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
May reduce the analgesic effect of Actiq and/or precipitate withdrawal symptoms.
Avoid concomitant use.
Butorphanol, nalbuphine, pentazocine, buprenorphrine
Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Actiq and/or the muscle relaxant as necessary.
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Monitor patients for signs of urinary retention or reduced gastric motility when Actiq is used concomitantly with anticholinergic drugs.
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 [see Clinical Pharmacology (12.2)].
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.
The opioid antagonists, naloxone or nalmefene, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Actiq, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
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 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 (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:
Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, and edible glue (modified food starch and confectioner’s sugar).
Serious side effects have been reported with Actiq including the following:
Breathing problems that can become life-threatening. Call your healthcare provider or get emergency medical help right away if you:
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.
- 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
Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.
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.
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.
Actiq can cause drowsiness and vision changes. Do not drive or operate heavy machinery until you know how Actiq affects you.
Avoid drinking alcohol with Actiq. It can increase your chance of getting dangerous side effects.
Do not take Actiq
- if you are allergic to fentanyl or to any of its ingredients
- 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 headache/migraines and dental pain
The following serious adverse reactions are described, or described in greater detail, in other sections:
- Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Interactions with Benzodiazepines and Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
- Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
- Severe Hypotension [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
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.
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 most serious adverse reactions associated with ACTIQ are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock.
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.
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. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration. 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 |
|800- 1400 mcg |
|1600 mcg |
|>1600 mcg |
|Any Dose* |
|Body As A Whole|
|*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
Digestive: Diarrhea, dyspepsia, flatulence
Metabolic and Nutritional: Peripheral edema, dehydration
Nervous: Hypesthesia, migraine
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: bone pain
Cardiovascular: Deep thrombophlebitis, hypertension, hypotension
Digestive: Anorexia, eructation, 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. 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 |
|800- 1400 mcg |
|1600 mcg |
|>1600 mcg |
|Any Dose |
|Body As A Whole|
|*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, 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, migraine
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, 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 Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst
Hemic and Lymphatic: Bleeding time increased
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
The following adverse reactions have been identified during post approval use of ACTIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Digestive
Dental decay: Dental decay, including dental caries, tooth loss, and gum line erosion.Nervous System Disorders
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.Endocrine Disorders
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.Immune System Disorders
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in ACTIQ.
General Disorders And Administration Site Conditions: Application site reactions including irritation, pain, and ulcer, and drug withdrawal syndrome.
Read the entire FDA prescribing information for Actiq (Fentanyl Citrate)Read More »