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Why is this medication prescribed?
Fentanyl is used to treat breakthrough pain (sudden episodes of pain that occur despite round the clock treatment with pain medication) in cancer patients at least 18 years of age (or at least 16 years of age if taking Actiq brand lozenges) who are taking regularly scheduled doses of another narcotic (opiate) pain medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl is in a class of medications called narcotic (opiate) analgesics. It works by changing the way the brain and nervous system respond to pain.
Uses of Actiq
- It is used to ease pain.
- This medicine is not for mild pain or pain that only lasts a short time (like headaches, toothaches, or pain after surgery).
If OVERDOSE is suspected
If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Consumer Information Use and Disclaimer
- If your symptoms or health problems do not get better or if they become worse, call your doctor.
- Do not share your drugs with others and do not take anyone else's drugs.
- Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
- Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
- This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Actiq is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
- If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
This information should not be used to decide whether or not to take Actiq or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Actiq. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
Review Date: October 4, 2017
Actiq - Clinical Pharmacology
Mechanism of Action
Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.
Effects on the Central Nervous System
The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu-opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and electrical stimulation.
Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2)]. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).
In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals.
The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.
Concentration-Adverse Reaction Relationships
There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].
All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. During the titration phase of the clinical trials, somnolence, which may be a precursor to respiratory depression, did increase in patients who were treated with higher doses of Actiq. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours.
Serious or fatal respiratory depression can occur even at recommended doses. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration. [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4), Adverse Reactions (6), and Overdosage (10)].
The absorption pharmacokinetics of fentanyl from the oral transmucosal dosage form is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the GI tract. Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed.
Absolute bioavailability, as determined by area under the concentration-time curve, of 15 mcg/kg in 12 adult males was 50% compared to intravenous fentanyl.
Normally, approximately 25% of the total dose of Actiq is rapidly absorbed from the buccal mucosa and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the GI tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, the generally observed 50% bioavailability of Actiq is divided equally between rapid transmucosal and slower GI absorption. Therefore, a unit dose of Actiq, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed.
Dose proportionality among four of the available strengths of Actiq (200, 400, 800, and 1600 mcg) has been demonstrated in a balanced crossover design in adult subjects (n=11). Mean serum fentanyl levels following these four doses of Actiq are shown in Figure 1. The curves for each dose level are similar in shape with increasing dose levels producing increasing serum fentanyl levels. Cmax and AUC0→∞ increased in a dose-dependent manner that is approximately proportional to the Actiq administered.
Figure 1. Mean Serum Fentanyl Concentration (ng/mL) in Adult Subjects Comparing 4 Doses of Actiq
The pharmacokinetic parameters of the four strengths of Actiq tested in the dose-proportionality study are shown in Table 4. The mean Cmax ranged from 0.39 - 2.51 ng/mL. The median time of maximum plasma concentration (Tmax) across these four doses of Actiq varied from 20 - 40 minutes (range of 20 – 480 minutes) as measured after the start of administration.
* Based on arterial blood samples.
Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.
The total plasma clearance of fentanyl was 0.5 L/hr/kg (range 0.3 – 0.7 L/hr/kg). The terminal elimination half-life after Actiq administration is about 7 hours.
Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see Drug Interactions (7)].
Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.
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].
- As a part of the TIRF REMS Access program, ACTIQ may be dispensed only to outpatients enrolled in the program [see WARNINGS AND PRECAUTIONS]. 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.
Side Effects of Actiq
Serious side effects have been reported with Actiq. See the “Actiq Precautions” section.
Common side effects of Actiq include the following:
This is not a complete list of Actiq side effects. Ask your doctor or pharmacist for more information.
Tell your doctor if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:
- Barbiturates such as phenobarbital (Luminal)
- Buprenorphine (Buprenex, Subutex, in Suboxone)
- Butorphanol (Stadol)
- Carbamazepine (Carbatrol, Epitol, Tegretol)
- Efavirenz (in Atripla, Sustiva)
- Modafinil (Provigil)
- Nalbuphine (Nubain)
- Nalmefene (Revex)
- Naloxone (Narcan)
- Nevirapine (Viramune)
- Oral steroids such as dexamethasone (Decadron, Dexpak), methylprednisolone (Medrol), and prednisone
- Oxcarbazepine (Trileptal)
- Other pain medications
- Pentazocine (Talwin)
- Phenytoin (Dilantin, Phenytek)
- Pioglitazone (Actos, in Actoplus Met, in Duetact)
- Rifabutin (Mycobutin)
- Rifampin (Rifadin, Rimactane, in Rifamate, in Rifater)
- Sedatives, sleeping pills, or tranquilizers
Also tell your doctor or pharmacist if you are taking any of the following medications or if you have stopped taking them within the past two weeks: monoamine oxidase (MAO) inhibitors including isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate).
This is not a complete list of Actiq drug interactions. Ask your doctor or pharmacist for more information.
Actiq and Pregnancy
Tell your doctor if you are pregnant or plan to become pregnant.
The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.
Actiq falls into category C. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.
Actiq and Lactation
Tell your doctor if you are breastfeeding or plan to breastfeed.
Actiq has been detected in human breast milk. Therefore, do not use Actiq if you are nursing 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.