Dosage Form: buccal tablet, oral tablet
FULL PRESCRIBING INFORMATION
RESPIRATORY DEPRESSION
Fatal respiratory depression has occurred in patients treated with Fentora, including following use in opioid non-tolerant patients and improper dosing.The substitution of Fentora for any other fentanyl product may result in fatal overdose.
Due to the risk of respiratory depression, Fentora is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see Contraindications (4)]
Fentora must be kept out of reach of children. [see Patient Counseling Information (17.3) and How Supplied/Storage and Handling (16.1)]
The concomitant use of Fentora with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions (7)].
MEDICATION ERRORS
Substantial differences exist in the pharmacokinetic profile of Fentora compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.
- When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Fentora. [see Dosage and Administration (2.1)]
- When dispensing, do not substitute a Fentora prescription for other fentanyl products.
ABUSE POTENTIAL
Fentora contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentora can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Fentora in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.
Because of the risk for misuse, abuse, addiction, and overdose, Fentora 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 (5.11)] Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.
Indications and Usage for Fentora
Fentora is 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 daily, at least 25 mcg/hr of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids while taking Fentora.
This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, Fentora is contraindicated in the management of acute or postoperative pain.
Fentora is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.
Limitations of Use:
As a part of the TIRF REMS Access program, Fentora may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions(5.11)]. For inpatient administration of Fentora (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.
Fentora Dosage and Administration
Healthcare professionals who prescribe Fentora 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 Fentora [see Warnings and Precautions (5.11)].
As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.
It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
Initial Dose
Fentora is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) All patients should be titrated from the 100 mcg dose.
Patients on Actiq
The initial dose of Fentora 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 Fentora 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 Fentora 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 Fentora tablet and should proceed using multiples of this tablet strength.
All Other Patients
The initial dose of Fentora is 100 mcg.
Repeat Dosing
a. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of Fentora for any episode of breakthrough pain.
b. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentora.
Dose Titration
a. From an initial dose, patients should be closely followed by the prescriber and the dosage strength changed until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of Fentora over several episodes of breakthrough pain and discuss their experience with their physician to determine if a dosage adjustment is warranted.
b. Patients whose initial dose is 100 mcg and who need to titrate to a higher dose, can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this dosage is not successful, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the 200 mcg Fentora tablet for doses above 400 mcg (600 mcg and 800 mcg). Note: Do not use more than 4 tablets simultaneously.
c. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of Fentora for any breakthrough pain episode. During titration, one dose of Fentora may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg).
d. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentora. To reduce the risk of overdose during titration, patients should have only one strength of Fentora tablets available at any time.
e. Patients should be strongly encouraged to use all of their Fentora tablets of one strength prior to being prescribed the next strength. If this is not practical, unused Fentora should be disposed of safely [see How Supplied/Storage and Handling (16.2)]. Dispose of any unopened Fentora tablets remaining from a prescription as soon as they are no longer needed.
Maintenance Dosing
a. Once titrated to an effective dose, patients should generally use only ONE Fentora tablet of the appropriate strength per breakthrough pain episode.
b. On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode.
c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with Fentora.
d. Dosage adjustment of Fentora may be required in some patients. Generally, the Fentora 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
e. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the around-the-clock opioid used for persistent pain should be re-evaluated.
Administration of Fentora
Opening the Blister Package
- Instruct patients not to open the blister until ready to administer Fentora.
- Separate a single blister unit from the blister card by bending and tearing apart at the perforations.
- Bend the blister unit along the line where indicated.
- Peel back the blister backing to expose the tablet. Patients should NOT attempt to push the tablet through the blister as this may cause damage to the tablet.
- Do not store the tablet once it has been removed from the blister package as the tablet integrity may be compromised and, more importantly, because this increases the risk of accidental exposure to the tablet.
Tablet Administration:
Once the tablet is removed from the blister unit, the patient should immediately place the entire Fentora tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Patients should not split the tablet.
The Fentora tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed.
The Fentora tablet should be left between the cheek and gum until it has disintegrated, which usually takes approximately 14-25 minutes.
After 30 minutes, if remnants from the Fentora 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 Fentora.
Dosage Forms and Strengths
Fentora 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. Each tablet strength is marked with a unique identifier [see How Supplied/Storage and Handling (16.3)].
Contraindications
Fentora is contraindicated in opioid non-tolerant patients.
Fentora is contraindicated in the management of acute or postoperative pain including headache/migraine and dental pain. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.
Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.
Fentora is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.
Warnings and Precautions
See Boxed Warning - WARNING:RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL.
Respiratory Depression
Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in Fentora. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
Important Information Regarding Prescribing and Dispensing
Fentora is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) For patients being converted from Actiq, it is necessary to follow the instructions found in Table 1 in Section 2.1,.as Actiq and Fentora are not equivalent on a microgram per microgram basis. Fentora is NOT a generic version of Actiq. All patients should be titrated from the 100 mcg dose.
The initial dose of Fentora should be 100 mcg. Titrate each patient individually to provide adequate analgesia while minimizing side effects. [see Dosage and Administration (2.1)]
When dispensing, DO NOT substitute a Fentora prescription for an Actiq prescription under any circumstances. Fentora and Actiq are not equivalent. Substantial differences exist in the pharmacokinetic profile of Fentora compared to other fentanyl products including Actiq that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of Fentora for the same dose of Actiq or any other fentanyl product may result in a fatal overdose.
Patient/Caregiver Instructions
Patients and their caregivers must be instructed that Fentora contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep tablets out of the reach of children. [see How Supplied/Storage and Handling (16.1), and Medication Guide for specific patient instructions.]
Additive CNS Depressant Effects
The concomitant use of Fentora with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions (7)].
Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of Fentora if warranted.
Effects on Ability to Drive and Use Machines
Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking Fentora of these dangers and counsel them accordingly.
Chronic Pulmonary Disease
Because potent opioids can cause respiratory depression, titrate Fentora with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of Fentora may further decrease respiratory drive to the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure
Administer Fentora with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.
Application Site Reactions
In clinical trials, 10% of all patients exposed to Fentora reported application site reactions. These reactions ranged from paresthesia 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.
Cardiac Disease
Intravenous fentanyl may produce bradycardia. Therefore, use Fentora with caution in patients with bradyarrhythmias.
MAO Inhibitors
Fentora 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.
Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program
Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence (9)], Fentora 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 Fentora, patient and prescriber enrollment is not required.
Required components of the TIRF REMS Access program are:
- Healthcare professionals, who prescribe Fentora 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 Fentora, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense Fentora must enroll in the program and agree to comply with the REMS requirements.
- Wholesalers and distributors that distribute Fentora 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.
Adverse Reactions
Clinical Studies Experience
The safety of Fentora 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 most commonly observed adverse events seen with Fentora are typical of opioid side effects. Opioid side effects should be expected and managed accordingly.
The clinical trials of Fentora 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.
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 adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received Fentora 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 Fentora 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 preferred term, 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 Fentora. There was no evidence of excess toxicity in this subset of patients.
The duration of exposure to Fentora 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 Fentora. Events are classified by system organ class.
Adverse Events (≥1%)
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
Drug Interactions
Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme system; therefore potential interactions may occur when Fentora is given concurrently with agents that affect CYP3A4 activity.
The concomitant use of Fentora with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving Fentora who begin therapy with, or increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increase should be done cautiously [see Warnings and Precautions (5.4)]. The concomitant use of Fentora with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of Fentora. Patients receiving Fentora who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of increased Fentora activity and the dose of Fentora should be adjusted accordingly.
USE IN SPECIFIC POPULATIONS
Pregnancy
Category C
There are no adequate and well-controlled studies in pregnant women. Fentora should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
Fentanyl is embryocidal as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for Fentora.
Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/m2 basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not terat
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