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Fentanyl Buccal
Tablets
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
Serious life-threatening and/or fatal respiratory depression has occurred in patients treated with fentanyl buccal tablets, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of fentanyl buccal tablets or following a dose increase. The substitution of fentanyl buccal tablets for any other fentanyl product may result in fatal overdose [see WARNINGS AND PRECAUTIONS].
Due to the risk of respiratory depression, fentanyl buccal tablets are contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [see CONTRAINDICATIONS].
Accidental ingestion of even one dose of fentanyl buccal tablets, 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 transmucosal immediate-release fentanyl products. Fentanyl buccal tablets must be kept out of reach of children [see WARNINGS AND PRECAUTIONS].
The concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets and any CYP3A4 inhibitor or inducer [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
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].
Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablets 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].
Fentanyl buccal tablets expose 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 fentanyl buccal tablets, and monitor all patients regularly for the development of these behaviors or conditions [see WARNINGS AND PRECAUTIONS].
Because of the risk for misuse, abuse, addiction, and overdose, fentanyl buccal tablets are 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.
Prolonged use of fentanyl buccal tablets 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].
Fentanyl buccal tablets are an opioid agonist, intended for buccal mucosal administration. Fentanyl buccal tablets are designed to be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet and absorption of fentanyl across the oral mucosa.
Fentanyl buccal tablets employ the OraVescent® drug delivery technology, which generates a reaction that releases carbon dioxide when the tablet comes in contact with saliva. It is believed that transient pH changes accompanying the reaction may optimize dissolution (at a lower pH) and membrane permeation (at a higher pH) of fentanyl through the buccal mucosa.
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:
 |
All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 microgram strength tablet contains 100 micrograms of fentanyl free base.
Mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.
Fentanyl buccal tablets are indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.
Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg per hour of transdermal fentanyl, 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 while taking fentanyl buccal tablets.
The initial dose of fentanyl buccal tablets is always 100 mcg with the only exception being patients already using ACTIQ.
a. For patients being converted from ACTIQ, prescribers must use the Initial Dosing Recommendations for Patients on ACTIQ table below (Table 1). The doses of fentanyl buccal tablets in this table are starting doses and not intended to represent equianalgesic doses to ACTIQ. Patients must be instructed to stop the use of ACTIQ and dispose of any remaining units.
Table 1: Initial Dosing
Recommendations for Patients on ACTIQ
| Current ACTIQ Dose (mcg) | Initial Fentanyl Buccal Tablets Dose* |
| 200 | 100 mcg tablet |
| 400 | 100 mcg tablet |
| 600 | 200 mcg tablet |
| 800 | 200 mcg tablet |
| 1200 | 2 x 200 mcg tablets |
| 1600 | 2 x 200 mcg tablets |
| *From this initial dose, titrate patient to effective dose. | |
b. For patients converting from ACTIQ doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg fentanyl buccal tablets and should proceed using multiples of this tablet strength.
Once the tablet is removed from the blister unit, the patient should immediately place the entire fentanyl buccal tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or place the entire fentanyl buccal tablet under the tongue. Patients should not split the tablet. The fentanyl buccal tablet should not be crushed, sucked, chewed or swallowed whole, as this will result in lower plasma concentrations than when taken as directed. The fentanyl buccal tablet should be left between the cheek and gum or under the tongue until it has disintegrated, which usually takes approximately 14-25 minutes. After 30 minutes, if remnants from the fentanyl buccal tablet remain, they may be swallowed with a glass of water. It is recommended that patients alternate sides of the mouth when administering subsequent doses of fentanyl buccal tablets in the buccal cavity.
For patients no longer requiring opioid therapy, consider discontinuing fentanyl buccal tablets along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, fentanyl buccal tablets therapy can usually be discontinued immediately. [see Drug Abuse And Dependence)
To dispose of unused fentanyl buccal tablets, remove fentanyl buccal tablets from blister packages and flush down the toilet. Do not flush fentanyl buccal tablets blister packages or cartons down the toilet. If you need additional assistance with disposal of fentanyl buccal tablets, call Teva Pharmaceuticals at 1-888-483-8279.
Fentanyl buccal tablets are flat-faced, round, beveled-edge in shape; are white in color; and are available in 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths as fentanyl base. Each tablet strength is marked with a unique identifier [see HOW SUPPLIED/Storage And Handling].
Fentanyl buccal tablets are supplied in individually
sealed, child-resistant blister packages. Each carton contains 7 blister cards
with 4 white tablets in each card. The blisters are child-resistant, encased in
peelable foil, and provide protection from moisture. Each tablet is debossed on
one side with 
, and the other side of
each dosage strength is uniquely identified by the debossing on the tablet as
described in the table below. In addition, the dosage strength is indicated on
the blister package and the carton. See blister package and carton for product
information.
| Dosage Strength | Debossing | Carton/Blister Package Color | NDC Number |
| 100 mcg | 1 | Blue | NDC 0093-1150-28 |
| 200 mcg | 2 | Orange | NDC 0093-1151-28 |
| 400 mcg | 4 | Sage green | NDC 0093-1153-28 |
| 600 mcg | 6 | Magenta (pink) | NDC 0093-1154-28 |
| 800 mcg | 8 | Yellow | NDC 0093-1155-28 |
Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.
Store at 20 to 25°C (68 to 77°F) with excursions permitted between 15° and 30°C (59° to 86°F) until ready to use. (See USP Controlled Room Temperature.) Protect fentanyl buccal tablets from freezing and moisture. Do not use if the blister package has been tampered with.
Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454. Revised: Dec 2016
The following serious adverse reactions are described, or described in greater detail, in other sections:
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 fentanyl buccal tablets has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months.
The clinical trials of fentanyl buccal tablets were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain.
The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received fentanyl buccal tablets for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of fentanyl buccal tablets therapy or cancer-related symptoms.
Table 2 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.
Table 2: Adverse Events Which Occurred During
Titration at a Frequency of ≥ 5%
| System Organ Class MeDRA preferredterm, n (%) | 100 mcg (N=45) |
200 mcg (N=34) |
400 mcg (N=53) |
600 mcg (N=56) |
800 mcg (N=113) |
Total (N=304)* |
| Gastrointestinal disorders | ||||||
| Nausea | 4 (9) | 5 (15) | 10 (19) | 13 (23) | 18 (16) | 50 (17) |
| Vomiting | 0 | 2 (6) | 2 (4) | 7 (13) | 3 (3) | 14 (5) |
| General disorders and administration site conditions | ||||||
| Fatigue | 3 (7) | 1 (3) | 9 (17) | 1 (2) | 5 (4) | 19 (6) |
| Nervous system disorders | ||||||
| Dizziness | 5 (11) | 2 (6) | 12 (23) | 18 (32) | 21 (19) | 58 (19) |
| Somnolence | 2 (4) | 2 (6) | 6 (12) | 7 (13) | 3 (3) | 20 (7) |
| Headache | 1 (2) | 3 (9) | 4 (8) | 8 (14) | 10 (9) | 26 (9) |
| *Three hundred and two (302) patients were included in the safety analysis. | ||||||
Table 3 lists, by successful dose, adverse events with an overall frequency of ≥5% within the total population that occurred after a successful dose had been determined.
Table 3: Adverse Events
Which Occurred During Long-Term Treatment at a Frequency of ≥ 5%
| System Organ Class MeDRA preferred term, n (%) | 100 mcg (N=19) |
200 mcg (N=31) |
400 mcg (N=44) |
600 mcg (N=48) |
800 mcg (N=58) |
Total (N=200) |
| Blood and lymphatic system disorders | ||||||
| Anemia | 6 (32) | 4 (13) | 4 (9) | 5 (10) | 7 (13) | 26 (13) |
| Neutropenia | 0 | 2 (6) | 1 (2) | 4 (8) | 4 (7) | 11 (6) |
| Gastrointestinal disorders | ||||||
| Nausea | 8 (42) | 5 (16) | 14 (32) | 13 (27) | 17(31) | 57 (29) |
| Vomiting | 7 (37) | 5 (16) | 9 (20) | 8 (17) | 11 (20) | 40 (20) |
| Constipation | 5 (26) | 4 (13) | 5 (11) | 4 (8) | 6 (11) | 24 (12) |
| Diarrhea | 3 (16) | 0 | 4 (9) | 3 (6) | 5 (9) | 15 (8) |
| Abdominal pain | 2 (11) | 1 (3) | 4 (9) | 7 (15) | 4 (7) | 18 (9) |
| General disorders and administration site conditions | ||||||
| Edema peripheral | 6 (32) | 5 (16) | 4 (9) | 5 (10) | 3 (5) | 23 (12) |
| Asthenia | 3 (16) | 5 (16) | 2 (5) | 3 (6) | 8 (15) | 21 (11) |
| Fatigue | 3 (16) | 3 (10) | 9 (20) | 9 (19) | 8 (15) | 32 (16) |
| Infections and infestations | ||||||
| Pneumonia | 1 (5) | 5 (16) | 1 (2) | 1 (2) | 4 (7) | 12 (6) |
| Investigations | ||||||
| Weight decreased | 1 (5) | 1 (3) | 3 (7) | 2 (4) | 6 (11) | 13 (7) |
| Metabolism and nutrition disorders | ||||||
| Dehydration | 4 (21) | 0 | 4 (9) | 6 (13) | 7 (13) | 21 (11) |
| Anorexia | 1 (5) | 2 (6) | 4 (9) | 3 (6) | 6 (11) | 16 (8) |
| Hypokalemia | 0 | 2 (6) | 0 | 1 (2) | 8 (15) | 11 (6) |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 2 (11) | 0 | 2 (5) | 3 (6) | 2 (4) | 9 (5) |
| Arthralgia | 0 | 1 (3) | 3 (7) | 4 (8) | 3 (5) | 11 (6) |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||||||
| Cancer pain | 3 (16) | 1 (3) | 3 (7) | 2 (4) | 1 (2) | 10 (5) |
| Nervous system disorders | ||||||
| Dizziness | 5 (26) | 3 (10) | 5 (11) | 6 (13) | 6 (11) | 25 (13) |
| Headache | 2 (11) | 1 (3) | 4 (9) | 5 (10) | 8 (15) | 20 (10) |
| Somnolence | 0 | 1 (3) | 4 (9) | 4 (8) | 8 (15) | 17 (9) |
| Psychiatric disorders | ||||||
| Confusional state | 3 (16) | 1 (3) | 2 (5) | 3 (6) | 5 (9) | 14 (7) |
| Depression | 2 (11) | 1 (3) | 4 (9) | 3 (6) | 5 (9) | 15 (8) |
| Insomnia | 2 (11) | 1 (3) | 3 (7) | 2 (4) | 4 (7) | 12 (6) |
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Cough | 1 (5) | 1 (3) | 2 (5) | 4 (8) | 5 (9) | 13 (7) |
| Dyspnea | 1 (5) | 6 (19) | 0 | 7 (15) | 4 (7) | 18 (9) |
In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of fentanyl buccal tablets. There was no evidence of excess toxicity in this subset of patients.
In clinical trials, 10% of all patients exposed to fentanyl buccal tablets reported application site reactions. These reactions ranged from paresthesias to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.
The duration of exposure to fentanyl buccal tablets varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving fentanyl buccal tablets. Events are classified by system organ class.
Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia
Cardiac Disorders: Tachycardia
Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration
General Disorders and Administration Site Conditions: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain
Hepatobiliary Disorders: Jaundice
Infections and Infestations: Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess
Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture
Investigations: Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count
Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake
Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain
Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy
Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness
Renal and Urinary Disorders: Renal Failure
Respiratory, Thoracic and Mediastinal Disorders: Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing
Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat
Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis
The following adverse reactions have been identified during post approval use of fentanyl. 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.
Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
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 [see CLINICAL PHARMACOLOGY].
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in fentanyl buccal tablets.
Drug withdrawal syndrome
Table 4 includes clinically significant drug interactions with fentanyl buccal tablets.
Table 4: Clinically
Significant Drug Interactions with Fentanyl Buccal Tablets
| Inhibitors of CYP3A4 | |
| Clinical Impact: | The concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets and CYP3A4 inducers can decrease the plasma concentration of fentanyl [seeCLINICAL 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 fentanyl buccal tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets are used concomitantly with anticholinergic drugs. |
Fentanyl buccal tablets contain fentanyl, a Schedule II controlled substance.
Fentanyl buccal tablets contain fentanyl, a substance with high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Fentanyl buccal tablets 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 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 [see Drug Abuse And Dependence]. 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.
Fentanyl buccal tablets, 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 Fentanyl Buccal Tablets
Fentanyl buccal tablets are for oral transmucosal use only. Abuse of fentanyl buccal tablets poses a risk of overdose and death. This risk is increased with concurrent abuse of fentanyl buccal tablets with alcohol and other central nervous system depressants.
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].
Included as part of the PRECAUTIONS section.
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of fentanyl buccal tablets, 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 fentanyl buccal tablets.
To reduce the risk of respiratory depression, proper dosing and titration of fentanyl buccal tablets are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the fentanyl buccal tablets dosage can result in a fatal overdose with the first dose. The substitution of fentanyl buccal tablets for any other fentanyl product may result in fatal overdose [see Risk of Medication Errors].
Fentanyl buccal tablets could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.
Accidental ingestion of even one dose of fentanyl buccal tablets, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.
Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.
Patients and their caregivers must be informed that fentanyl buccal tablets contain 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 fentanyl buccal tablets are provided in the fentanyl buccal tablets Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.
Concomitant use of fentanyl buccal tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Life-Threatening Respiratory Depression], particularly when an inhibitor is added after a stable dose of fentanyl buccal tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl buccal tablets-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl buccal tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl buccal tablets-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl buccal tablets until stable drug effects are achieved [see DRUG INTERACTIONS].
Concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets 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].
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets are 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].
When prescribing, do not convert a patient to fentanyl buccal tablets from any other fentanyl product on a mcg per mcg basis as fentanyl buccal tablets and other fentanyl products are not equivalent on a microgram per microgram basis.
Fentanyl buccal tablets are not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a fentanyl buccal tablets prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and fentanyl buccal tablets are not equivalent. Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablets 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 fentanyl buccal tablets or any other fentanyl product may result in a fatal overdose.
There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see DOSAGE AND ADMINISTRATION].Therefore, for opioid tolerant patients, the initial dose of fentanyl buccal tablets should always be 100 mcg. Individually titrate each patient's dose to provide adequate analgesia while minimizing side effects [see DOSAGE AND ADMINISTRATION].
Fentanyl buccal tablets contain fentanyl, a Schedule II controlled substance. As an opioid, fentanyl buccal tablets expose 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 fentanyl buccal tablets. 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 fentanyl buccal tablets, and monitor all patients receiving fentanyl buccal tablets for the development of these behaviors or 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 fentanyl buccal tablets, but use in such patients necessitates intensive counseling about the risks and proper use of fentanyl buccal tablets 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 fentanyl buccal tablets. 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.
Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse And Dependence], fentanyl buccal tablets are 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 fentanyl buccal tablets, patient and prescriber enrollment is not required.
Required components of the TIRF REMS Access program are:
Prolonged use of fentanyl buccal tablets 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].
The use of fentanyl buccal tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
fentanyl buccal tablets-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 fentanyl buccal tablets [see Life-Threatening Respiratory Depression].
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 fentanyl buccal tablets and when fentanyl buccal tablets are given concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression]. Alternatively, consider the use of non-opioid analgesics in these patients.
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl buccal tablets 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 fentanyl buccal tablets if serotonin syndrome is suspected.
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.
Fentanyl buccal tablets 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 fentanyl buccal tablets. In patients with circulatory shock, fentanyl buccal tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of fentanyl buccal tablets in patients with circulatory shock.
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), fentanyl buccal tablets 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 fentanyl buccal tablets.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of fentanyl buccal tablets in patients with impaired consciousness or coma.
Fentanyl buccal tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The fentanyl in fentanyl buccal tablets 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.
The fentanyl in fentanyl buccal tablets 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 fentanyl buccal tablets therapy.
Fentanyl buccal tablets 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 fentanyl buccal tablets and know how they will react to the medication.
Intravenous fentanyl may produce bradycardia. Therefore, use fentanyl buccal tablets with caution in patients with bradyarrhythmias.
Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding [see ADVERSE REACTIONS].
Fentanyl buccal tablets are 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].
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl buccal tablets 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.
Inform patients that potentially fatal additive effects may occur if fentanyl buccal tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients that the use of fentanyl buccal tablets, 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 fentanyl buccal tablets with others and to take steps to protect fentanyl buccal tablets from theft or misuse.
Advise patients of the following information pertaining to the TIRF REMS
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 healthcare providers if they are taking, or plan to take serotonergic medications [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients to avoid taking fentanyl buccal tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl buccal tablets [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS].
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].
[see DOSAGE AND ADMINISTRATION]
Inform patients that fentanyl buccal tablets 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].
Inform patients that anaphylaxis have been reported with ingredients contained in fentanyl buccal tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS].
Neonatal Opioid Withdrawal Syndrome
Inform patients that prolonged use of fentanyl buccal tablets 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 fentanyl buccal tablets can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use In Specific Populations, Nonclinical Toxicology].
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].
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].
Inform patients that fentanyl buccal tablets 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].
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY].
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 2.3-and 3.4-times the exposure of a single human dose of 800 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.
Fentanyl citrate was not mutagenic in the Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay.
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 8.6 times the exposure of a single human dose of 800 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 5.7-times the exposure of a single human dose of 800 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 fentanyl buccal tablets.
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS]. Available data with fentanyl buccal tablets 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.
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. Fentanyl buccal tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl buccal tablets, 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.
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) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 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 7.5-times the exposure of a single human dose of 800 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 (0.4 times the 800 mcg dose of fentanyl buccal tablets on a mg/m² basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of fentanyl buccal tablets 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 6 times the human dose of 800 mcg fentanyl buccal tablets per pain episode on a mg/m² basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean Cmax observed following administration of 800 mcg dose of fentanyl buccal tablets 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 approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.
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 fentanyl buccal tablets.
Monitor infants exposed to fentanyl buccal tablets 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.
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].
The safety and efficacy of fentanyl buccal tablets have not been established in pediatric patients below the age of 18 years.
Of the 304 patients with cancer in clinical studies of fentanyl buccal tablets, 69 (23%) were 65 years of age and older. Patients over the age of 65 years tended to titrate to slightly lower doses than younger patients. Patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. Therefore, caution should be exercised in individually titrating fentanyl buccal tablets 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 fentanyl buccal tablets 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.
Insufficient information exists to make recommendations regarding the use of fentanyl buccal tablets 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.
Both male and female opioid tolerant patients with cancer 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.
The pharmacokinetic effects of race with the use of fentanyl buccal tablets have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects.
Acute overdose with fentanyl buccal tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY].
In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl buccal tablets, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.
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 to 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.
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.
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.
Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. 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].
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3-to 5minute 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 [see DOSAGE AND ADMINISTRATION].
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 [see DOSAGE AND ADMINISTRATION].
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].
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. 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].
Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of fentanyl buccal tablets increases linearly in an approximate dose-proportional manner over the 100-to 800-mcg dose range.
Following buccal administration of fentanyl buccal tablets, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of fentanyl buccal tablets is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after buccal administration. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract.
In a study that compared the absolute and relative bioavailability of fentanyl buccal tablets and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with fentanyl buccal tablets) (Table 5).
Table 5: Pharmacokinetic
Parameters* in Adult Subjects Receiving Fentanyl Buccal Tablets or ACTIQ
| Pharmacokinetic Parameter (mean) | Fentanyl Buccal Tablets 400 mcg | ACTIQ 400 mcg (adjusted dose)*** |
| Absolute Bioavailability | 65% ± 20% | 47% ± 10.5% |
| Fraction Absorbed Transmucosally | 48% ± 31.8% | 22% ± 17.3% |
| Tmax (minute)** | 46.8 (20-240) | 90.8 (35-240) |
| Cmax (ng/mL) | 1.02 ± 0.42 | 0.63 ± 0.21 |
| AUC0-tmax (ng•hr/mL) | 0.40 ± 0.18 | 0.14 ± 0.05 |
| AUC0-inf (ng•hr/mL) | 6.48 ± 2.98 | 4.79 ± 1.96 |
| * Based on venous blood
samples. ** Data for Tmax presented as median (range). ***ACTIQ data was dose adjusted (800 mcg to 400 mcg). |
||
Similarly, in another bioavailability study exposure following administration of fentanyl buccal tablets was also greater (approximately 50%) compared to Actiq.
Due to differences in drug delivery, measures of exposure (Cmax, AUC0-tmax, AUC0-inf) associated with a given dose of fentanyl were substantially greater with fentanyl buccal tablets compared to ACTIQ (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tmax for fentanyl buccal tablets.
Figure 1: Mean Plasma Concentration Versus Time
Profiles Following Single Doses of Fentanyl Buccal Tablets and ACTIQ in Healthy
Subjects
 |
Mean pharmacokinetic parameters are presented in Table 6. Mean plasma concentration versus time profiles are presented in Figure 2.
Table 6: Pharmacokinetic
Parameters* Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl
Buccal Tablets in Healthy Subjects
| Pharmacokinetic Parameter (mean±SD) | 100 mcg | 200 mcg | 400 mcg | 800 mcg |
| Cmax (ng/mL) | 0.25 ± 0.14 | 0.40 ± 0.18 | 0.97 ± 0.53 | 1.59 ± 0.90 |
| Tmax, minute** (range) | 45.0 (25.0 -181.0) | 40.0 (20.0 - 180.0) | 35.0 (20.0 - 180.0) | 40.0 (25.0 - 180.0) |
| AUC0-inf (ng•hr/mL) | 0.98 ± 0.37 | 2.11 ± 1.13 | 4.72 ± 1.95 | 9.05 ± 3.72 |
| AUC0-tmax (ng•hr/mL) | 0.09 ± 0.06 | 0.13 ± 0.09 | 0.34 ± 0.23 | 0.52 ± 0.38 |
| T½, hr** | 2.63 (1.47 - 13.57) | 4.43 (1.85 -20.76) | 11.09 (4.63 - 20.59) | 11.70 (4.63 - 28.63) |
| * Based on venous sampling. ** Data for Tmax presented as median (range). |
||||
Figure 2: Mean Plasma Concentration Versus Time
Profiles Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal
Tablets in Healthy Subjects
 |
Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.
The effect of mucositis (Grade 1) on the pharmacokinetic profile of fentanyl buccal tablets was studied in a group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean summary statistics (standard deviation in parentheses, expected tmax where range was used) are presented in Table 7.
Table 7: Pharmacokinetic
Parameters in Patients with Mucositis
| Patient status | Cmax (ng/mL) | tmax (min) | AUC0-tmax (ng•hr/mL) | AUC0-8 (ng•hr/mL) |
| Mucositis | 1.25 ± 0.78 | 25.0 (15 -45) | 0.21 ± 0.16 | 2.33 ± 0.93 |
| No mucositis | 1.24 ± 0.77 | 22.5 (10 - 121) | 0.25 ± 0.24 | 1.86 ± 0.86 |
Following sublingual tablet placement, systemic exposure (as measured by AUC and Cmax) of fentanyl is equivalent to systemic exposure following buccal tablet placement.
Fentanyl is highly lipophilic. 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 mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.
Metabolism
The metabolic pathways following buccal administration of fentanyl buccal tablets have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active [see DRUG INTERACTIONS].
Excretion
Disposition of fentanyl following buccal administration of fentanyl buccal tablets has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered 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.
The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
Systemic exposure was higher for women than men (mean Cmax and AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.
In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects (mean Cmax and AUC values were approximately 50% and 20% higher, respectively). The observed differences were largely attributed to the lower mean weight of the Japanese subjects compared to U.S. subjects (57.4 kg versus 73 kg).
The efficacy of fentanyl buccal tablets was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.
In this trial, patients were titrated in an open-label manner to a successful dose of fentanyl buccal tablets. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects. Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of fentanyl buccal tablets and 3 being placebo. Patients used one tablet of study drug (either fentanyl buccal tablets or placebo) per breakthrough pain episode.
Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-10) was then measured at 15, 30, 45, and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure.
Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 8. The median dose was 400 mcg.
Table 8: Successful Dose of
Fentanyl Buccal Tablets Following Initial Titration
| Fentanyl Buccal Tablets Dose | n (%) (N=80) |
| 100 mcg | 13 (16) |
| 200 mcg | 11(14) |
| 400 mcg | 21(26) |
| 600 mcg | 10(13) |
| 800 mcg | 25 (31) |
The LS mean (SE) SPID30 for fentanyl buccal tablets-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18).
Figure 3: Mean Pain Intensity Differences (PID) at
Each Time Point During the Double -Blind Treatment Period
 |
Medication Guide
Fentanyl Buccal Tablets
IMPORTANT
Do not use fentanyl buccal tablets unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant. Keep fentanyl buccal tablets in a safe place away from children. Get emergency help right away if:
These are medical emergencies that can cause death. If possible, try to remove fentanyl buccal tablets from the mouth.
Fentanyl buccal tablets are:
Important information about fentanyl buccal tablets:
Do not take fentanyl buccal tablets if:
Before taking fentanyl buccal tablets, tell your healthcare provider if you have a history of:
Tell your healthcare provider if you are:
When taking fentanyl buccal tablets:
The possible side effects of fentanyl buccal tablets:
Get emergency medical help if you have:
These are not all the possible side effects of fentanyl buccal tablets. 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 fentanyl buccal tablets?
How should I dispose of unused fentanyl buccal tablets when they are no longer needed?
General information about fentanyl buccal tablets
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use fentanyl buccal tablets only for the purpose for which it was prescribed. Do not give fentanyl buccal tablets to other people, even if they have the same symptoms you have. Fentanyl buccal tablets can harm other people and even cause death. Sharing fentanyl buccal tablets is against the law.
This Medication Guide summarizes the most important information about fentanyl buccal tablets. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about fentanyl buccal tablets that is written for health 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 in fentanyl buccal tablets?
Active Ingredient: fentanyl citrate
Inactive Ingredients: mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.
Patient Instructions for Use
Before you use fentanyl buccal tablets, it is important that you read the Medication Guide and these Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use fentanyl buccal tablets the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use fentanyl buccal tablets.
When you get an episode of breakthrough cancer pain, use the dose of fentanyl buccal tablets prescribed by your healthcare provider as follows:
Figure 1
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Figure 2
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Figure 3
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OR,
Figure 4a, Figure 4b, Figure 4c and Figure 4d
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This Medication Guide has been approved by the U.S. Food and Drug Administration.
