Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Fentanyl is an opioid agonist whose principal therapeutic action is analgesia. Pharmacodynamics 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]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see ADVERSE REACTIONS]. 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]. 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. Concentration-Efficacy Relationships 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]. Respiratory System 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 , ADVERSE REACTIONS and OVERDOSE]. Pharmacokinetics Absorption 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. Table 4. Pharmacokinetic Parameters * in Adult Subjects Receiving 200, 400, 800, and 1600 mcg Units of ACTIQ Pharmacokinetic Parameter 200 mcg 400 mcg 800 mcg 1600 mcg Tmax, minute median (range) 40 (20-120) 25 (20-240) 25 (20-120) 20 (20-480) Cmax, ng/mL mean (%CV) 0.39 (23) 0.75 (33) 1.55 (30) 2.51 (23) AUC0 -1440, ng/mL minute mean (%CV) 102 (65) 243 (67) 573 (64) 1026 (67) t1/2, minute mean (%CV) 193 (48) 386 (115) 381 (55) 358 (45) * Based on arterial blood samples . Distribution 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. Elimination 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. Metabolism 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]. Excretion 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. Clinical Studies ACTIQ was investigated in clinical trials involving 257 opioid tolerant adult cancer patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in cancer patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer. In two dose titration studies 95 of 127 patients (75%) who were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain titrated to a successful dose of ACTIQ to treat their breakthrough cancer pain within the dose range offered (200, 400, 600, 800, 1200, and 1600 mcg). A “successful” dose was defined as a dose where one unit of ACTIQ could be used consistently for at least two consecutive days to treat breakthrough cancer pain without unacceptable side effects. In these studies 11% of patients withdrew due to adverse reactions and 14% withdrew due to other reasons. The successful dose of ACTIQ for breakthrough cancer pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and is thus best determined by dose titration. A double-blind placebo controlled crossover study was performed in cancer patients to evaluate the effectiveness of ACTIQ for the treatment of breakthrough cancer pain. Of 130 patients who entered the study 92 patients (71%) achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 5. Table 5. Successful Dose of ACTIQ Following Initial Titration ACTIQ Dose Total No. (%) (N=92) 200 mcg 13 (14) 400 mcg 19 (21) 600 mcg 14 (15) 800 mcg 18 (20) 1200 mcg 13 (14) 1600 mcg 15 (16) Mean +/- SD 789 +/- 468 mcg On average, patients over 65 years of age titrated to a mean dose that was about 200 mcg less than the mean dose to which younger adult patients were titrated. ACTIQ was administered beginning at Time 0 minutes and produced more pain relief compared with placebo at 15, 30, 45, and 60 minutes as measured after the start of administration (see Figure 2). The differences were statistically significant. Figure 2. Pain Relief (PR) Scores (Mean±SD) During the Double-Blind Phase – All Patients with Evaluable Episodes on Both ACTIQ and Placebo (N=86) 10 minutes = Start of administration of ACTIQ 215 minutes = First time to measure pain relief

SUBLIMAZE (fentanyl citrate) Injection DESCRIPTION SUBLIMAZE (fentanyl citrate) Injection is a potent narcotic analgesic. Each milliliter of solution contains fentanyl citrate equivalent to 50 mcg of fentanyl base, adjusted to pH 4.0 to 7.5 with sodium hydroxide. SUBLIMAZE is chemically identified as N-(l-phenethyl-4-piperidyl) propionanilide citrate (1:1) with a molecular weight of 528.60. The empirical formula is C22H28N20•C6H807. The structural formula of SUBLIMAZE is: SUBLIMAZE is a sterile, non-pyrogenic, preservative free aqueous solution for intravenous or intramuscular injection.

Find Lowest Prices on ACTIQ® (fentanyl citrate) Oral Transmucosal Lozenge WARNING LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME Life-Threatening Respiratory Depression Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ACTIQ, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ACTIQ or following a dose increase [see WARNINGS AND PRECAUTIONS]. The substitution of ACTIQ for any other fentanyl product may result in fatal overdose [see WARNINGS AND PRECAUTIONS]. 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]. Accidental Ingestion Accidental ingestion of even one dose of ACTIQ, especially by children, can result in a fatal overdose of fentanyl [see WARNINGS AND PRECAUTIONS]. Death has been reported in children who have accidentally ingested ACTIQ. ACTIQ must be kept out of reach of children [see PATIENT INFORMATION and HOW SUPPLIED]. Cytochrome P450 3A4 Interaction The concomitant use of ACTIQ with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving ACTIQ and any CYP3A4 inhibitor or inducer [see WARNINGS AND PRECAUTIONS , DRUG INTERACTIONS , CLINICAL PHARMACOLOGY]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see WARNINGS AND PRECAUTIONS , DRUG INTERACTIONS]. Reserve concomitant prescribing of ACTIQ and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Risk of 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 and that could result in fatal overdose [see DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS]. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ACTIQ [see DOSAGE AND ADMINISTRATION]. When dispensing, do not substitute an ACTIQ prescription for other fentanyl products . Addiction, Abuse, and Misuse ACTIQ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ACTIQ, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS AND PRECAUTIONS]. Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk for misuse, abuse, addiction, and overdose, ACTIQ is available only through a restricted program 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]. Further information 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 neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts . If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS AND PRECAUTIONS]. DESCRIPTION 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).

INDICATIONS SUBLIMAZE (fentanyl citrate) is indicated: for analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises. for use as a narcotic analgesic supplement in general or regional anesthesia. for administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. for use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures. DOSAGE AND ADMINISTRATION 50 mcg = 0.05 mg = 1 mL Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used and the surgical procedure involved. Dosage should be reduced in elderly or debilitated patients (see PRECAUTIONS). Vital signs should be monitored routinely. Premedication — Premedication (to be appropriately modified in the elderly, debilitated and those who have received other depressant drugs) — 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 mL) may be administered intramuscularly 30 to 60 minutes prior to surgery. Adjunct to General Anesthesia — See Dosage Range Chart Adjunct to Regional Anesthesia - 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 mL) may be administered intramuscularly or slowly intravenously, over one to two minutes, when additional analgesia is required. Postoperatively (recovery room) - 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 mL) may be administered intramuscularly for the control of pain, tachypnea and emergence delirium. The dose may be repeated in one to two hours as needed. Usage in Children: For induction and maintenance in children 2 to 12 years of age, a reduced dose as low as 2 to 3 mcg/kg is recommended. DOSAGE RANGE CHART TOTAL DOSAGE Low Dose — 2 mcg/kg (0.002 mg/ kg) (0.04 mL/kg) SUBLIMAZE. SUBLIMAZE in small doses is most useful for minor, but painful, surgical procedures. In addition to the analgesia during surgery, SUBLIMAZE may also provide some pain relief in the immediate postoperative period. Moderate Dose — 2 to 20 mcg/kg (0.002 to 0.02 mg/kg) (0.04 to 0.4 mL/kg) SUBLIMAZE. Where surgery becomes more major, a larger dose is required. With this dose, in addition to adequate analgesia, one would expect to see some abolition of the stress response. However, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. High Dose — 20 to 50 mcg/kg (0.02 to 0.05 mg/kg) (0.4 to 1 mL/kg) SUBLIMAZE. During open heart surgery and certain more complicated neurosurgical and orthopedic procedures where surgery is more prolonged, and in the opinion of the anesthesiologist, the stress response to surgery would be detrimental to the well being of the patient, dosages of 20 to 50 mcg/kg (0.02 to 0.05 mg) (0.4 to 1 mL) of SUBLIMAZE with nitrous oxide/oxygen have been shown to attenuate the stress response as defined by increased levels of circulating growth hormone, catecholamine, ADH and prolactin. When dosages in this range have been used during surgery, postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this technique would be to produce "stress free" anesthesia. DOSAGE RANGE CHART MAINTENANCE DOSAGE Low Dose — 2 mcg/kg (0.002 mg/kg) (0.04 mL/kg) SUBLIMAZE. Additional dosages of SUBLIMAZE are infrequently needed in these minor procedures. Moderate Dose — 2 to 20 mcg/kg (0.002 to 0.02 mg/kg) (0.04 to 0.4 mL/kg) SUBLIMAZE. 25 to 100 mcg (0.025 to 0.1 mg) (0.5 to 2.0 mL) may be administered intravenously or intramuscularly when movement and/ or changes in vital signs indicate surgical stress or lightening of analgesia. High Dose — 20 to 50 mcg/kg (0.02 to 0.05 mcg/kg) (0.4 to 1.0 mL/kg) SUBLIMAZE. Maintenance dosage (ranging from 25 mcg (0.025 mg) (0.5 mL) to one half the initial loading dose) will be dictated by the changes in vital signs which indicate stress and lightening of analgesia. However, the additional dosage selected must be individualized especially if the anticipated remaining operative time is short. As a General Anesthetic When attenuation of the responses to surgical stress is especially important, doses of 50 to 100 mcg/kg (0.05 to 0.1 mg/kg) (1 to 2 mL/kg) may be administered with oxygen and a muscle relaxant. This technique has been reported to provide anesthesia without the use of additional anesthetic agents. In certain cases, doses up to 150 mcg/kg (0.15 mg/kg) (3 mL/kg) may be necessary to produce this anesthetic effect. It has been used for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated, and for certain complicated neurological and orthopedic procedures. As noted above, it is essential that qualified personnel and adequate facilities be available for the management of respiratory depression. See WARNINGS and PRECAUTIONS for use of SUBLIMAZE (fentanyl citrate) with other CNS depressants, and in patients with altered response. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIED SUBLIMAZE (fentanyl citrate) Injection is available as: NDC 17478-030-02 50 mcg/mL of fentanyl base, 2 mL ampules in packages of 10 NDC 17478-030-05 50 mcg/mL of fentanyl base, 5 mL ampules in packages of 10 NDC 17478-030-10 50 mcg/mL of fentanyl base, 10 mL ampules in packages of 5 NDC- 17478-030-20 50 mcg/mL of fentanyl base, 20 mL ampules in packages of 5 NDC 17478-030-25 50 mcg/mL of fentanyl base, 2 mL ampules in packages of 25 NDC 17478-030-55 50 mcg/mL of fentanyl base, 5 mL ampules in packages of 25 Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. PROTECT FROM LIGHT. Manufactured by: Akorn, Inc. Lake Forest, IL 60045. Rev. 04/12

INDICATIONS 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. DOSAGE AND ADMINISTRATION Important Dosage And Administration Instructions 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]. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS AND PRECAUTIONS]. It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS AND PRECAUTIONS]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with ACTIQ and adjust the dosage accordingly [see WARNINGS AND PRECAUTIONS]. Instruct patients and caregivers to take steps to store ACTIQ securely and to properly dispose of unused ACTIQ as soon as no longer needed [see WARNINGS AND PRECAUTIONS , PATIENT INFORMATION]. Other TIRF formulations and ACTIQ are not equivalent. DO NOT substitute an ACTIQ prescription for any other TIRF formulation under any circumstances. Do not convert patients on a mcg per mcg basis from any other fentanyl product to ACTIQ [see WARNINGS AND PRECAUTIONS]. Initial Dosage 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. Repeat Dosing In cases where the breakthrough pain episode is not relieved after 15 minutes after completion of the ACTIQ unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of ACTIQ for any episode of breakthrough pain. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ. Dose Titration From an initial dose, closely follow patients and change the dosage strength 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. 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]. 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 When opioid therapy is no longer required, consider discontinuing ACTIQ along with a gradual downward of other opioids to minimize possible withdrawal effects. Disposal Of ACTIQ After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day. If the temporary storage bottle provided as part of the ACTIQ Child Safety Kit is available, partially consumed units may be stored in the specially provided child-resistant container out of the reach of children until proper disposal is possible. Unopened units remaining from a prescription must be properly disposed as soon as they are no longer needed. To dispose of the unused ACTIQ units: Remove the ACTIQ unit from its blister package using scissors, and hold ACTIQ by its handle over the toilet bowl. Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet. Dispose of the handle in a place that is out of the reach of children. Repeat steps 1, 2, and 3 for each ACTIQ unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet. Do not flush the entire ACTIQ units, ACTIQ handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it. In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office. HOW SUPPLIED Dosage Forms And Strengths Solid oral transmucosal lozenge: Each dosage unit has white to off-white color and is a solid drug matrix on a handle. Each strength is marked on the individual solid drug matrix and the handle tag. ACTIQ is available in 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg strengths. Storage And Handling ACTIQ is supplied in six dosage strengths. Each unit is individually wrapped in a child-resistant, protective blister package. These blister packages are packed 30 per shelf carton for use when patients have been titrated to the appropriate dose. Each dosage unit has a white to off-white color. Each individual solid drug matrix is marked with “ACTIQ” and the strength of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”). The dosage strength is also marked on the handle tag, the blister package and the carton. See blister package and carton for product information. Dosage Strength (fentanyl base) Carton/Blister Package Color NDC Number 200 mcg Gray NDC 63459-502-30 400 mcg Blue NDC 63459-504-30 600 mcg Orange NDC 63459-506-30 800 mcg Purple NDC 63459-508-30 1200 mcg Green NDC 63459-512-30 1600 mcg Burgundy NDC 63459-516-30 Note: Colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing. Store at 20-25°C (68-77°F) with excursions permitted between 15° and 30°C (59° to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect ACTIQ from freezing and moisture. Do not use if the blister package has been opened. Distributed by: Teva Pharmaceuticals USA, Inc. call 1-888-483-8279 North Wales, PA 19454. Revised: Dec 2016

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION ACTIQ® (AK-tik) (fentanyl citrate) Oral Transmucosal Lozenge IMPORTANT: Do not use ACTIQ unless you are regularly using another opioid pain medicine around-theclock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant. Keep ACTIQ in a safe place away from children. Get emergency medical help right away if: a child takes ACTIQ. ACTIQ can cause an overdose and death in any child who uses it. an adult who has not been prescribed ACTIQ uses it. an adult who is not already taking opioids around-the-clock, uses ACTIQ. These are medical emergencies that can cause death. If possible, remove ACTIQ from the mouth. ACTIQ is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain in adults (16 years of age and older) with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain. ACTIQ is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant). Do not use ACTIQ if you are not opioid tolerant. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about ACTIQ: Get emergency help right away if you take too much ACTIQ (overdose). When you first start taking ACTIQ, when your dose is changed, or if you take too much (overdose), serious or lifethreatening breathing problems that can lead to death may occur. Taking ACTIQ with other medicines that may make you sleepy, such as other pain medicines, antidepressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death. Never give anyone else your ACTIQ. They could die from taking it. Store ACTIQ away from children and in a safe place to prevent stealing or abuse. Selling or giving away ACTIQ is against the law. If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using ACTIQ. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain. ACTIQ is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program. To receive ACTIQ, you must: talk to your healthcare provider understand the benefits and risks of ACTIQ agree to all of the instructions sign the Patient-Prescriber Agreement form ACTIQ is only available at pharmacies that are part of the TIRF REMS Access program. Your healthcare provider will let you know the pharmacy closest to your home where you can have your ACTIQ prescription filled. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Do not take ACTIQ if: You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain, and your body is used to these medicines. You have severe asthma, trouble breathing, or other lung problems. You have a bowel blockage or have narrowing of the stomach or intestines. You are allergic to any of the ingredients in ACTIQ. See the end of this Medication Guide for a complete list of ingredients in ACTIQ. You have short-term pain that you would expect to go away in a few days, such as: pain after surgery headache or migraine dental pain Before taking ACTIQ, tell your healthcare provider if you have a history of: troubled breathing or lung problems such as asthma, wheezing, or shortness of breath head injury, seizures slow heart rate or other heart problems low blood pressure mental problems [including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)] problems urinating liver, kidney, thyroid problems pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, or mental health problems diabetes. Each ACTIQ unit contains about ½ teaspoon (2 grams) of sugar. Tell your healthcare provider if you are: Pregnant or planning to become pregnant. Prolonged use of ACTIQ during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. ACTIQ passes into breast milk and may harm your baby. taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking ACTIQ with certain other medicines can cause serious side effects that could lead to death. When taking ACTIQ: Do not change your dose. Take ACTIQ exactly as prescribed by your healthcare provider. Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you. See the detailed Patient Instructions for Use at the end of this Medication Guide for information about how to use ACTIQ. Finish the unit completely in 15 minutes to get the most relief. If you finish ACTIQ too quickly, you will swallow more of the medicine and get less relief. Do not bite or chew. You will get less relief for your breakthrough cancer pain. You may drink some water before using ACTIQ but you should not drink or eat anything while using ACTIQ. You must not use more than 2 units of ACTIQ during each episode of breakthrough cancer pain: Use 1 unit for an episode of breakthrough cancer pain. Finish the unit over 15 minutes. If your breakthrough cancer pain is not relieved 15 minutes after you finished the ACTIQ unit, use only 1 more unit of ACTIQ at this time. If your breakthrough pain does not get better after the second unit of ACTIQ, call your healthcare provider for instructions. Do not use another unit of ACTIQ at this time. Wait at least 4 hours before treating a new episode of breakthrough cancer pain with ACTIQ. It is important for you to keep taking your around-the-clock opioid pain medicine. Talk to your healthcare provider if your dose of ACTIQ does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of ACTIQ needs to be changed. Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day. The dose of your around-the-clock opioid pain medicine may need to be adjusted. If you begin to feel dizzy, sick to your stomach, or very sleepy before ACTIQ is completely dissolved, remove ACTIQ from your mouth. Do not stop taking ACTIQ 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. After you stop taking, or when ACTIQ is no longer needed, see “How should I dispose of ACTIQ units when they are no longer needed?” for proper disposal of ACTIQ. DO NOT Drive or operate heavy machinery, until you know how ACTIQ affects you. ACTIQ can make you sleepy, dizzy, or lightheaded. DO NOT Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ACTIQ may cause you to overdose and die. DO NOT Switch from ACTIQ to other medicines that contain fentanyl without talking to your healthcare provider. The amount of fentanyl in a dose of ACTIQ is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of ACTIQ that may be different than other fentanyl containing medicines you may have been taking. The possible side effects of ACTIQ: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, weakness, anxiety, depression, rash, trouble sleeping. Call your healthcare provider if you have any of these symptoms and they are severe. Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down. ACTIQ contains sugar. Cavities and tooth decay can happen in people taking ACTIQ. When taking ACTIQ, you should talk to your dentist about proper care of your teeth. Get emergency medical help if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. 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. These are not all the possible side effects of ACTIQ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov How should I store ACTIQ? Always keep ACTIQ in a safe place away from children and from anyone for whom it has not been prescribed. Protect ACTIQ from theft. You can use the ACTIQ Child Safety Kit to help you store ACTIQ and your other medicines out of the reach of children. It is very important that you use the items in the ACTIQ Child Safety Kit to help protect the children in your home or visiting your home. If you were not offered a Child Safety Kit when you received your medicine, call 888-534- 3119. The ACTIQ Child Safety Kit contains important information on the safe storage and handling of ACTIQ. The Child Safety Kit includes: A child-resistant lock that you use to secure the storage space where you keep ACTIQ (See Figure 1). Figure 1 A portable locking pouch for you to keep a small supply of ACTIQ nearby. The rest of your ACTIQ must be kept in a locked storage space. Keep this pouch secured with its lock and keep it out of the reach and sight of children (See Figure 2). Figure 2 A child-resistant temporary storage bottle (See Figure 3). Figure 3 Store ACTIQ at room temperature, 59°F to 86°F (15°C to 30°C) until ready to use. Do not freeze ACTIQ. Keep ACTIQ in the original sealed child-resistant blister package. Do not open the blister package until you are ready to use ACTIQ. Keep ACTIQ dry. How should I dispose of ACTIQ units when they are no longer needed? Disposing of ACTIQ units after use: Partially used ACTIQ units may contain enough medicine to be harmful or fatal to a child or other adults who have not been prescribed ACTIQ. You must properly dispose of the ACTIQ handle right away after use even if there is little or no medicine left on it. After you have finished the ACTIQ unit and the medicine is totally gone, throw the handle away in a place that is out of the reach of children. If any medicine remains on the used ACTIQ unit after you have finished: Place the used ACTIQ unit under hot running water until the medicine is gone, and then throw the handle away out of the reach of children and pets (See Figure 4). Figure 4 Temporary Storage of Used ACTIQ Units : If you did not finish the entire ACTIQ unit and you cannot dissolve the medicine under hot running water right away, put the used ACTIQ unit in the temporary storage bottle that you received in the ACTIQ Child Safety Kit. Push the used ACTIQ unit into the opening on the top until it falls completely into the bottle. Never leave unused or partially used ACTIQ units where children or pets can get to them (See Figure 5). Figure 5 Disposing of Used ACTIQ Units from the Temporary Storage Bottle: You must dispose of all used ACTIQ units in the temporary storage bottle at leas t one time each day, as follows: To open the temporary storage bottle, push down on the cap until you are able to twist the cap to the left to remove it (See Figure 6). Figure 6 Remove one ACTIQ unit from the temporary storage bottle. Hold the ACTIQ by its handle over the toilet bowl. Using wire-cutting pliers, cut the medicine end off so that it falls into the toilet. Throw the handle away in a place that is out of the reach of children. Repeat these 3 steps for each ACTIQ handle that is in the storage bottle. There should not be more than 4 handles in the temporary storage bottle for 1 day. Flush the toilet twice. Do not flush entire unused ACTIQ units, ACTIQ handles, or blister packages down the toilet. Disposing of unopened ACTIQ units: Dispose of any unopened ACTIQ units remaining from a prescription as soon as they are no longer needed, as follows: Remove all ACTIQ from the locked storage space (See Figure 7). Figure 7 Remove one ACTIQ unit from its blister package by using scissors to cut off the marked end and then peel back the blister backing (See Figures 8A and 8B). Hold ACTIQ by its handle over the toilet bowl. Use wire-cutting pliers to cut the medicine end off so that it falls into the toilet (See Figures 9A and 9B). Throw the handle away in a place that is out of the reach of children (See Figure 10). Figure 10 Repeat steps 1 through 4 for each ACTIQ unit. Flush the toilet twice after the medicine ends from 5 ACTIQ units have been cut off (See Figure 11). Do not flush more than 5 ACTIQ units at a time. Figure 11 Do not flush entire unused ACTIQ units, ACTIQ handles, or blister packages down the toilet. If you need help with disposal of ACTIQ, call Teva Pharmaceuticals at 1-888-483-8279, or call your local Drug Enforcement Agency (DEA) office. General information about ACTIQ Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use ACTIQ only for the purpose for which it was prescribed. Do not give ACTIQ to other people, even if they have the same symptoms you have. ACTIQ can harm other people and even cause death. Sharing ACTIQ is against the law. This Medication Guide summarizes the most important information about ACTIQ. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about ACTIQ that is written for healthcare professionals. For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483. What are the ingredients of ACTIQ? Active Ingredient: fentanyl citrate Inactive Ingredients: sugar, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, modified food starch and confectioner’s sugar. Patient Instructions for Use Before you use ACTIQ, it is important that you read the Medication Guide and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you use ACTIQ the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use ACTIQ. When you get an episode of breakthrough cancer pain, use the dose of ACTIQ prescribed by your healthcare provider as follows: You may drink some water before using ACTIQ but you should not drink or eat anything while using ACTIQ. Each unit of ACTIQ is sealed in its own blister package (See Figure 12). Do not open the blister package until you are ready to use ACTIQ. Figure 12 When you are ready to use ACTIQ, cut open the package using scissors. Peel back the blister backing, and remove the ACTIQ unit (See Figures 13A and 13B). The end of the unit printed with “ACTIQ” and the strength number of the unit (“200”, “400”, “600”, “800”, “1200”, or “1600”) is the medicine end that is to be placed in your mouth. Hold the ACTIQ unit by the handle (See Figure 14). Figure 14 Place the medicine end of the ACTIQ unit in your mouth between your cheeks and gums and actively suck on the medicine. Move the medicine end of the ACTIQ unit around in your mouth, especially along the inside of your cheeks (See Figure 15). Figure 15 Twirl the handle often. Finish the ACTIQ unit completely over 15 minutes to get the most relief. If you finish ACTIQ too quickly, you will swallow more of the medicine and get less relief. Do not bite or chew ACTIQ. You will get less relief for your breakthrough cancer pain. If you cannot finish all of the medicine on the ACTIQ unit and cannot dissolve the medicine under hot tap water right away, immediately put the ACTIQ unit in the temporary storage bottle for safe keeping (See Figure 16). Push the ACTIQ unit into the opening on the top until it falls completely into the bottle. You must properly dispose of the ACTIQ unit as soon as you can. Figure 16 See “How should I dispose of ACTIQ units when they are no longer needed?” for proper disposal of ACTIQ. This Medication Guide has been approved by the U.S. Food and Drug Adminis tration.

OVERDOSE Manifestations The manifestations of SUBLIMAZE (fentanyl citrate) overdosage are an extension of its pharmacologic actions (see CLINICAL PHARMACOLOGY) as with other opioid analgesics. The intravenous LD50 of SUBLIMAZE is 3 mg/kg in rats, 1 mg/kg in cats, 14 mg/kg in dogs and 0.03 mg/kg in monkeys. Treatment In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be assisted or controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal tube might be indicated. If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assisted or controlled respiration. The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. A specific narcotic antagonist such as nalorphine, levallorphan or naloxone should be available for use as indicated to manage respiratory depression. This does not preclude the use of more immediate countermeasures. The duration of respiratory depression following overdosage of SUBLIMAZE may be longer than the duration of narcotic antagonist action. Consult the package insert of the individual narcotic antagonists for details about use. CONTRAINDICATIONS SUBLIMAZE (fentanyl citrate) is contraindicated in patients with known intolerance to the drug or other opioid agonists.

SIDE EFFECTS As with other narcotic analgesics, the most common serious adverse reactions reported to occur with SUBLIMAZE (fentanyl citrate) are respiratory depression, apnea, rigidity, and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm and anaphylaxis. It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary. When a tranquilizer is used with SUBLIMAZE, the following adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with SUBLIMAZE. Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of SUBLIMAZE with a neuroleptic agent. Drug Abuse And Dependence SUBLIMAZE (fentanyl citrate) is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused. DRUG INTERACTIONS Other CNS depressant drugs (e.g. barbiturates, tranquilizers, narcotics and general anesthetics) will have additive or potentiating effects with SUBLIMAZE. When patients have received such drugs, the dose of SUBLIMAZE required will be less than usual. Following the administration of SUBLIMAZE, the dose of other CNS depressant drugs should be reduced.

SIDE EFFECTS 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 (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 Rash 1 1 0 2 2 Sweating 1 1 2 2 2 Pruritus 1 0 0 5 2 Special Senses Abnormal Vision 1 0 2 0 2 *Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection 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 (n=98) 800- 1400 mcg (n=83) 1600 mcg (n=53) >1600 mcg (n=27) Any Dose (n=152) Body As A Whole Asthenia 25 30 17 15 38 Headache 12 17 13 4 20 Accidental Injury 4 6 4 7 9 Hypertonia 2 2 2 0 3 Digestive Nausea 31 36 25 26 45 Vomiting 21 28 15 7 31 Constipation 14 11 13 4 20 Intestinal Obstruction 0 2 4 0 3 Cardiovascular Hypertension 1 1 0 0 1 Nervous Dizziness 12 10 9 0 16 Anxiety 9 8 8 7 15 Somnolence 8 13 8 7 15 Confusion 2 5 13 7 10 Depression 9 4 2 7 9 Insomnia 5 1 8 4 7 Abnormal Gait 5 1 0 0 4 Dry Mouth 3 1 2 4 4 Nervousness 2 2 0 4 3 Stupor 4 1 0 0 3 Vasodilatation 1 1 4 0 3 Thinking Abnormal 2 1 0 0 2 Abnormal Dreams 1 1 0 0 1 Convulsion 0 1 2 0 1 Myoclonus 0 0 4 0 1 Tremor 0 1 2 0 1 Vertigo 0 0 4 0 1 Respiratory Dyspnea 15 16 8 7 22 Skin Rash 3 5 8 4 8 Sweating 3 2 2 0 4 Pruritus 2 0 2 0 2 Special Senses Abnormal Vision 2 2 0 0 3 Urogenital Urinary Retention 1 2 0 0 2 *Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain Cardiovascular: Deep thrombophlebitis, 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 Postmarketing Experience 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. DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with ACTIQ. Table 3: Clinically Significant Drug Interactions with ACTIQ Inhibitors of CYP3A4 Clinical Impact: 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]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see CLINICAL PHARMACOLOGY ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. Intervention: 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. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of ACTIQ and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see WARNINGS AND PRECAUTIONS]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see CLINICAL PHARMACOLOGY ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: 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. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: 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. Intervention: 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]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see WARNINGS AND PRECAUTIONS]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ACTIQ if serotonin syndrome is suspected. 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), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs ) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see WARNINGS AND PRECAUTIONS] or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS AND PRECAUTIONS]. Intervention: The use of ACTIQ is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of ACTIQ and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphrine Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: 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. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when ACTIQ is used concomitantly with anticholinergic drugs. 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 [see WARNINGS AND PRECAUTIONS]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. 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. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. ACTIQ, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to the Abuse of ACTIQ ACTIQ is for oral transmucosal use only. Abuse of ACTIQ poses a risk of overdose and death. The risk is increased with concurrent abuse of ACTIQ with alcohol and other central nervous system depressants. 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. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use In Specific Populations].

WARNINGS SUBLIMAZE (fentanyl citrate) SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS. AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE. See also discussion of narcotic antagonists in PRECAUTIONS and OVERDOSAGE. If SUBLIMAZE is administered with a tranquilizer, the user should become familiar with the special properties of each drug, particularly the widely differing duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available. As with other potent narcotics, the respiratory depressant effect of SUBLIMAZE may persist longer than the measured analgesic effect. The total dose of all narcotic analgesics administered should be considered by the practitioner before ordering narcotic analgesics during recovery from anesthesia. It is recommended that narcotics, when required, should be used in reduced doses initially, as low as ¼ to # those usually recommended. SUBLIMAZE may cause muscle rigidity, particularly involving the muscles of respiration. This rigidity has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration. In addition, skeletal muscle movements of various groups in the extremities, neck and external eye have been reported during induction of anesthesia with fentanyl; these reported movements have, on rare occasions, been strong enough to pose patient management problems. This effect is related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to ¼ of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of SUBLIMAZE; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when SUBLIMAZE is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of SUBLIMAZE and a full paralyzing dose of a neuromuscular blocking agent when SUBLIMAZE is used in rapidly administered anesthetic dosages. The neuromuscular blocking agent used should be compatible with the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of SUBLIMAZE. Where moderate or high doses are used (above 10 mcg/kg), there must be adequate facilities for postoperative observation, and ventilation if necessary, of patients who have received SUBLIMAZE. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. SUBLIMAZE may also produce other signs and symptoms characteristic of narcotic analgesics including euphoria, miosis, bradycardia and bronchoconstriction. Severe and unpredictable potentiation by MAO inhibitors has been reported for other narcotic analgesics. Although this has not been reported for fentanyl, there are insufficient data to establish that this does not occur with fentanyl. Therefore, when fentanyl is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is indicated. Head Injuries and Increased Intracranial Pressure SUBLIMAZE should be used with caution in patients who may be particularly susceptible to respiratory depression, such as comatose patients who may have a head injury or brain tumor. In addition, SUBLIMAZE may obscure the clinical course of patients with head injury. PRECAUTIONS General The initial dose of SUBLIMAZE (fentanyl citrate) should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining incremental doses. Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of SUBLIMAZE. Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics, can alter respiration by blocking intercostal nerves. Through other mechanisms (see CLINICAL PHARMACOLOGY) SUBLIMAZE can also alter respiration. Therefore, when SUBLIMAZE is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients selected for these forms of anesthesia. When a tranquilizer is used with SUBLIMAZE, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of SUBLIMAZE are employed, even relatively small dosages of diazepam may cause cardiovascular depression. When SUBLIMAZE is used with a tranquilizer, hypotension can occur. If it occurs, the possibility of hypovolemia should also be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve venous return to the heart should be considered when operative conditions permit. Care should be exercised in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, the administration of pressor agents other than epinephrine should be considered. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity. Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of SUBLIMAZE combined with a neuroleptic. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia. When SUBLIMAZE is used with a neuroleptic and the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly. Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest. Neuroleptic agents should be administered with extreme caution in the presence of risk factors for development of prolonged QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, including baseline prolonged QT interval, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOIs), 5) concomitant treatment with other drug products known to prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g. diuretics) that may cause electrolyte imbalance. ECG monitoring is indicated when a neuroleptic agent is used in conjunction with SUBLIMAZE as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia. Vital signs should be monitored routinely. Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by SUBLIMAZE may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to COi stimulation which may persist into or recur in the postoperative period. Respiratory depression secondary to chest wall rigidity has been reported in the postoperative period. Intraoperative hyperventilation may further alter postoperative response to C02- Appropriate postoperative monitoring should be employed to ensure that adequate spontaneous breathing is established and maintained in the absence of stimulation prior to discharging the patient from the recovery area. Impaired Respiration SUBLIMAZE should be used with caution in patients with chronic obstructive pulmonary disease, patients with decreased respiratory reserve, and others with potentially compromised respiration. In such patients, narcotics may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration. Impaired Hepatic or Renal Function SUBLIMAZE should be administered with caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs. Cardiovascular Effects SUBLIMAZE may produce bradycardia, which may be treated with atropine. SUBLIMAZE should be used with caution in patients with cardiac bradyarrhythmias. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies have been conducted with SUBLIMAZE. Reproduction studies in rats revealed a significant decrease in the pregnancy rate of all experimental groups. This decrease was most pronounced in the high dosed group (1.25 mg/kg — 12.5X human dose) in which one of twenty animals became pregnant. Pregnancy Category C SUBLIMAZE has been shown to impair fertility and to have an embryocidal effect in rats when given in doses 0.3 times the upper human dose for a period of 12 days. No evidence of teratogenic effects have been observed after administration of SUBLIMAZE to rats. There are no adequate and well-controlled studies in pregnant women. SUBLIMAZE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery There are insufficient data to support the use of SUBLIMAZE in labor and delivery. Therefore, such use is not recommended. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SUBLIMAZE is administered to a nursing woman. Pediatric Use The safety and efficacy of SUBLIMAZE in children under two years of age have not been established. Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included the combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS 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 OVERDOSE]. Carbon dioxide (CO ) 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]. 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 Risk Of Medication Errors]. ACTIQ Could Be Fatal To Individuals For Whom It Is Not Prescribed And For Those Who Are Not Opioidtolerant. 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 Life-Threatening Respiratory Depression, Increased Risk Of Overdose In Children Due To Accidental Ingestion Or Exposure]. 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 INFORMATION] . 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. 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 [seeLife-Threatening Respiratory Depression], 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]. 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]. 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]. 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 and PATIENT INFORMATION]. 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 ]. 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]. 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 INFORMATION]. 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 Addiction, Abuse, And Misuse], 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 , PATIENT INFORMATION]. 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 Life-Threatening Respiratory Depression]. 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 Life-Threatening Respiratory Depression]. Monitor such patients closely, particularly when initiating and titrating ACTIQ and when ACTIQ is given concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression]. Alternatively, consider the use of non-opioid analgesics in these patients. 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]. 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. 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. 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]. 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. 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. 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. 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. 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 [see DRUG INTERACTIONS]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ACTIQ or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion 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 [see WARNINGS AND PRECAUTIONS]. Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store ACTIQ securely and to dispose of unused ACTIQ [see WARNINGS AND PRECAUTIONS , PATIENT INFORMATION, Disposal of Used ACTIQ Units]. Instruct patients and caregivers to keep both used and unused ACTIQ out of the reach of children [see WARNINGS AND PRECAUTIONS]. Inform patients and their caregivers that, in the event that a unit is not completely consumed, it must be properly disposed as soon as possible [see WARNINGS AND PRECAUTIONS , PATIENT INFORMATION, Disposal of Used ACTIQ Units]. ACTIQ Child Safety Kit Provide patients and their caregivers who have children in the home or visiting with an ACTIQ Child Safety Kit, which contains educational materials and safe interim storage containers to help patients store ACTIQ and other medicines out of the reach of children. To obtain a supply of Child Safety Kits, health care professionals can call 1-888-534-3119. Interactions With Benzodiazepines And Other CNS Depressants (Including Alcohol) Inform patients and caregivers that potentially fatal additive effects may occur if ACTIQ is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. Addiction, Abuse, And Misuse Inform patients that the use of ACTIQ, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share ACTIQ with others and to take steps to protect ACTIQ from theft or misuse. Transmucosal Immediate-Release Fentanyl (TIRF) REMS Advise patients of the following information pertaining to the TIRF REMS Inform outpatients that they must be enrolled in the TIRF REMS Access program before they can receive ACTIQ. Allow patients the opportunity to ask questions and discuss any concerns regarding ACTIQ or the TIRF REMS Access program. As required by the TIRF REMS Access program, review the contents of the ACTIQ Medication Guide with every patient before initiating treatment with ACTIQ. Advise the patient that ACTIQ is available only from pharmacies that are enrolled in the TIRF REMS Access program, and provide them with the telephone number and website for information on how to obtain the drug. Advise the patient that only enrolled healthcare providers may prescribe ACTIQ. Inform the patient that they must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of ACTIQ. Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access program [see WARNINGS AND PRECAUTIONS]. Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see WARNINGS AND PRECAUTIONS , DRUG INTERACTIONS]. MAOI Interaction Inform patients to avoid taking ACTIQ while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ACTIQ [see WARNINGS AND PRECAUTIONS ;DRUG INTERACTIONS]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS AND PRECAUTIONS]. Important Administration Instructions [see DOSAGE AND ADMINISTRATION] Instruct patients not to take ACTIQ for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions. Instruct patients on the meaning of opioid tolerance and that ACTIQ is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes. Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-theclock), they should not take ACTIQ. Instruct patients that, if the breakthrough pain episode is not relieved 15 minutes after finishing the ACTIQ unit, they may take only one additional unit of ACTIQ using the same strength for that episode. Thus, patients should take no more than two units of ACTIQ for any breakthrough pain episode. Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with ACTIQ. Instruct patients NOT to share ACTIQ and that sharing ACTIQ with anyone else could result in the other individual's death due to overdose. Make patients aware that ACTIQ contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Caution patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking ACTIQ. Instruct patients to use ACTIQ exactly as prescribed by their doctor and not to take ACTIQ more often than prescribed. Hypotension Inform patients that ACTIQ may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS AND PRECAUTIONS]. Anaphylaxis Inform patients that anaphylaxis have been reported with ingredients contained in ACTIQ. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS , ADVERSE REACTIONS] Pregnancy Neonatal Opioid Withdrawal Syndrome Inform patients that prolonged use of ACTIQ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS AND PRECAUTIONS , Use In Specific Populations]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that ACTIQ can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use In Specific Populations]. Lactation Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use In Specific Populations]. Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use In Specific Populations]. Driving Or Operating Heavy Machinery Inform patients that ACTIQ may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS AND PRECAUTIONS]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY]. Dental Decay Because each ACTIQ unit contains approximately 2 grams of sugar (hydrated dextrates), frequent consumption may increase the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medications (such as fentanyl) may add to this risk. Post-marketing reports of dental decay have been received in patients taking ACTIQ [see ADVERSE REACTIONS]. In some of these patients, dental decay occurred despite reported routine oral hygiene. As dental decay in cancer patients may be multi-factorial, patients using ACTIQ should consult their dentist to ensure appropriate oral hygiene. Diabetic Patients Advise diabetic patients that ACTIQ contains approximately 2 grams of sugar per unit. Disposal Of Used ACTIQ Units Instruct patients on proper disposal of completely used and partially used ACTIQ units as follows: After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day. If the patient does not entirely consume the unit and the remaining drug cannot be immediately dissolved under hot running water, the patient or caregiver must temporarily store the ACTIQ unit in the specially provided child-resistant container out of the reach of children until proper disposal is possible. Disposal Of Unopened ACTIQ Units When No Longer Needed Patients and members of their household must be advised to dispose of any unopened units remaining from a prescription as soon as they are no longer needed. To dispose of the unused ACTIQ units: Remove the ACTIQ unit from its blister package using scissors, and hold the ACTIQ by its handle over the toilet bowl. Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet. Dispose of the handle in a place that is out of the reach of children. Repeat steps 1, 2, and 3 for each ACTIQ unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet. Do not flush the entire ACTIQ units, ACTIQ handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it. Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ACTIQ are provided in the ACTIQ Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered. In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 1.13 and 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, respectively, based on an AUC comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed. Mutagenesis Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay. Impairment Of Fertility In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 4.0-times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm. The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 2.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for ACTIQ. Use In Sepcific Populations Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS]. Available data with ACTIQ in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions 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 [see WARNINGS AND PRECAUTIONS]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. ACTIQ is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ACTIQ, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data Fentanyl (25, 50, or 100 mcg/kg) citrate was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6 to 17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (the no observed effect level of 50 mcg/kg is equivalent to 0.7 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses >100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 3.5 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison). Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.2 times the 1600 mcg dose of ACTIQ on a mg/m2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (1 times the 1600 mcg dose of ACTIQ based on a mg/m2 basis). No evidence of teratogenicity was reported. No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 3 times the human dose of 1600 mcg ACTIQ per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 3.4 times higher than the mean C observed following administration of 1600 mcg dose of ACTIQ in humans. In a postnatal development study, pregnant rats were treated from GD 6 through Lactation Day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity was noted at doses >100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at >100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is 0.6 times the exposure of a single human dose of 1600 mcg per pain episode, based on an AUC comparison. Lactation Risk Summary 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. Clinical Considerations Monitor infants exposed to ACTIQ through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 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 [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY , Nonclinical Toxicology]. Pediatric Use Safety and effectiveness in pediatric patients below 16 years of age have not been established. In a clinical study, 15 opioid-tolerant pediatric patients with breakthrough pain, ranging in age from 5 to 15 years, were treated with ACTIQ. The study was too small to allow conclusions on safety and efficacy in this patient population. Twelve of the fifteen opioid-tolerant children and adolescents aged 5 to 15 years in this study received ACTIQ at doses ranging from 200 mcg to 600 mcg. The mean (CV%; range) dose-normalized (to 200 mcg) C and AUC values were 0.87 ng/mL (51%; 0.42-1.30) and 4.54 ng h/mL (42%; 2.37-6.0), respectively, for children ages 5 to <11 years old (N = 3) and 0.68 ng/mL (72%; 0.15-1.44) and 8.38 (192%; 0.84-50.78), respectively, for children ages ≥11 to <16 y (N = 9). Geriatric Use Of the 257 patients in clinical studies of ACTIQ in breakthrough cancer pain, 61 (24%) were 65 years of age and older, while 15 (6%) were 75 years of age and older. Those patients over the age of 65 years were titrated to a mean dose that was about 200 mcg less than the mean dose titrated to by younger patients. No difference was noted in the safety profile of the group over 65 years of age as compared to younger patients in ACTIQ clinical trials. Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger population. Therefore, exercise caution when individually titrating ACTIQ in elderly patients to provide adequate efficacy while minimizing risk. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of ACTIQ slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see WARNINGS AND PRECAUTIONS]. Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Patients With Renal Or Hepatic Impairment Insufficient information exists to make recommendations regarding the use of ACTIQ in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. Sex Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions.