FentaNYL

Serious side effects have been reported oral, topical, inhalational, and injectable forms of fentanyl. See the “Fentanyl Precautions” section.

Common side effects of fentanyl include the following:

• Drowsiness
• Nausea
• Stomach pain
• Vomiting
• Constipation
• Gas
• Heartburn
• Loss of appetite
• Weight loss
• Difficulty urinating
• Weakness
• Headache
• Vision changes
• Anxiety
• Depression
• Hallucinations
• Changes in thinking or dreams
• Dry mouth
• Difficulty sleeping
• Sweating
• Reddening of the face, neck, or chest
• Swelling of the extremities
• Hives, rash, and itching

Irritation at the site of application may also occur after administration of oral, topical, and inhalational forms of fentanyl.

This is not a complete list of fentanyl side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Take fentanyl exactly as prescribed.

This medication comes in nasal spray, sublingual spray, sublingual tablet, lozenge, and transdermal patch forms. The dose and frequency of administration will vary with the indication and dosage form.

Instructions for use of nasal spray:

To use fentanyl nasal spray, begin by blowing your nose, if you have a runny nose. Remove the protective cap from the bottle tip and hold the bottle so that the nozzle is between your first and second fingers and your thumb is on the bottom. Sit upright and insert the tip of the bottle approximately 1/2 inch into one nostril, pointing the tip toward the bridge of your nose. Close your other nostril with your finger. Press down firmly on the finger grips until you hear a ''click'' sound. You may not feel the spray go into your nose, but as long as the number in the counting window increases by one, the spray has been given. Breathe in gently through your nose and out through your mouth one time after spraying. Do not sniff after spraying the medication into your nose. If your doctor wants you to use two sprays, repeat the adminsitration, using your other nostril. Stay sitting down for at least 1 minute after using fentanyl nasal spray. Do not blow your nose for at least 30 minutes after using fentanyl nasal spray.

Instructions for use of sublingual spray:

To use the sublingual spray, first remove the fentanyl sublingual spray unit from the blister package by cutting along the dashed line with a pair of scissors. Swallow any saliva in your mouth. Hold the fentanyl sublingual spray unit upright using your index and middle fingers and thumb. Point the nozzle into your mouth and under your tongue. Squeeze your fingers and thumb together to spray the medication under your tongue. Hold the medication under your tongue for 30 to 60 seconds. Do not spit out the medication or rinse your mouth. The fentanyl sublingual spray is a one-time use unit and will remain locked after use.

Instructions for use of sublingual tablets:

Place ABSTRAL (fentanyl) sublingual tablets on the floor of the mouth directly under the tongue immediately after removal from the blister pack. Do not chew, suck, or swallow ABSTRAL tablets. Allow ABSTRAL tablets to completely dissolve in the sublingual cavity. Do not eat or drink anything until the tablet is completely dissolved. If you have a dry mouth, use water to moisten the buccal mucosa before taking ABSTRAL.

Instructions for use of lozenges:

Place ACTIQ in your mouth between your cheeks and gums and actively suck on the medicine. Move the lozenge around in your mouth, especially along the inside of your cheeks. Twirl the handle often. Finish the ACTIQ unit completely in 15 minutes to get the most relief. If you finish ACTIQ too quickly, you will swallow more of the medicine and get less relief. Do not bite or chew ACTIQ. You will get less relief for your breakthrough cancer pain.

Instructions for use of transdermal patches:

A fentanyl transdermal system may be applied to the chest, back, flank, or upper arm in a place where there is no hair. Patches should not be placed on skin that is oily, burned, cut, irritated, or damaged. Avoid areas that are sensitive or that move around a lot. Do not shave the area where the patch will be placed.

A patch may be applied at any time of the day, but you should change the patch around the same time every 3 days. Do not wear more than one patch at a time, unless directed by your doctor. Before applying the patch, clean the skin and pat the area dry. Open the patch’s protective pouch and peel the plastic backing away from the patch. Take care not to touch the sticky side of the patch. Press the patch to the skin with the palm of your hand for at least 30 seconds. Make sure it sticks well, especially at the edges. Wash your hands after applying the patch. After 3 days, remove the patch and apply a new one in a different spot. If the patch falls off before 3 days, do not replace it with a new patch; wait until 3 days after you put it on to apply a new patch.

Injection:

This medication is also available in an injectable form to be given directly into a vein (IV) or the muscle (IM) by a healthcare professional.

(FEN ta nil)

• Fentanyl Citrate
• Fentanyl HCl
• Fentanyl Hydrochloride
• Fentanyl Patch
• OTFC (Oral Transmucosal Fentanyl Citrate)

Binds with stereospecific receptors at many sites within the CNS, increases pain threshold, alters pain reception, inhibits ascending pain pathways

Absorption

Transdermal, patch: Initial application: Drug is released at a nearly constant rate from the transdermal matrix system into the skin, where it accumulates; this results in a depot of fentanyl in the outer layer of skin. Fentanyl is absorbed into systemic circulation from the depot. This results in a gradual increase in serum concentration over the first 12 to 24 hours, followed by fairly constant concentrations for the remainder of the dosing interval. Absorption is decreased in cachectic patients (compared to normal size patients). Exposure to external heat increases drug absorption from patch.

Transdermal, device: At the activation of each dose, an electrical current is activated for 10 minutes, which moves a dose of fentanyl from the drug-containing reservoir through the skin and into the systemic circulation. Fentanyl concentrations increase slowly with device activation and continue to increase for ~5 minutes after the completion of each 10 minute dose. Absorption of fentanyl from the device increases as a function of time and is independent of frequency of dosing.

Transmucosal, buccal tablet and buccal film: Rapid, ~50% from the buccal mucosa; remaining 50% swallowed with saliva and slowly absorbed from GI tract.

Transmucosal, lozenge: Rapid, ~25% from the buccal mucosa; 75% swallowed with saliva and slowly absorbed from GI tract

Distribution

Highly lipophilic, redistributes into muscle and fat; Note: IV fentanyl exhibits a 3-compartment distribution model. Changes in blood pH may alter ionization of fentanyl and affect its distribution between plasma and CNS

Vdss: Children: 0.05 to 14 years of age (after long-term continuous infusion): ~15 L/kg (range: 5 to 30 L/kg)

Vdss: Adults: 4 to 6 L/kg

Metabolism

Hepatic, primarily via CYP3A4 by N-dealkylation (to norfentanyl) and hydroxylation to other inactive metabolites

Excretion

Urine 75% (primarily as metabolites, <7% to 10% as unchanged drug); feces ~9%

Clearance: Newborn infants: Clearance may be significantly correlated to gestational age and birth weight (Saarenmaa 2000)

Plasma concentrations with transdermal use were approximately twice as high in pediatric patients 1.5 to 5 years of age, who are not opioid-tolerant, compared with adults. Pharmacokinetic parameters in older pediatric patients were similar to those seen in adults.

Systemic exposure was higher in Japanese subjects after administration of buccal fentanyl (Fentora); this difference was largely attributed to differences in weight.

Injection: Surgery: Adjunct to general or regional anesthesia; preoperative medication; analgesic during anesthesia and in the immediate postoperative period.

Transdermal device (eg, Ionsys): Postoperative pain, acute: Short-term management of acute postoperative pain severe enough to require an opioid analgesic in the hospital and for which alternative treatments are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. Not for home use. Transdermal device is for use only in patients in the hospital. Discontinue treatment with the device before patients leave the hospital. The device is for use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

Transdermal patch (eg, Duragesic): Chronic pain: Management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Not indicated as an as-needed analgesic.

Transmucosal lozenge (eg, Actiq), buccal tablet (Fentora), buccal film (Onsolis), intranasal (Lazanda), sublingual tablet (Abstral), sublingual spray (Subsys): Cancer pain: Management of breakthrough cancer pain in opioid-tolerant patients ≥18 years (Abstral, Fentora, Lazanda, Onsolis, Subsys) and ≥16 years (Actiq) who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Limitations of use: Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine, dental pain, or in the emergency department. As a part of the TIRF REMS Access program, these products may be dispensed only to outpatients enrolled in the program. For inpatient administration (eg, hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.

Note: "Opioid-tolerant" patients are defined as patients who are taking at least:

Oral morphine 60 mg/day, or

Transdermal fentanyl 25 mcg/hour, or

Oral oxycodone 30 mg/day, or

Oral hydromorphone 8 mg/day, or

Oral oxymorphone 25 mg/day, or

Oral hydrocodone 60 mg/day, or

Equianalgesic dose of another opioid for at least 1 week

Elderly have been found to be twice as sensitive as younger patients to the effects of fentanyl. A wide range of doses may be used. When choosing a dose, take into consideration the following patient factors: age, weight, physical status, underlying disease states, other drugs used, type of anesthesia used, and the surgical procedure to be performed.

Transmucosal lozenge (eg, Actiq): In clinical trials, patients who were >65 years of age were titrated to a mean dose that was 200 mcg less than that of younger patients.

>10%:

Central nervous system: Confusion, dizziness, drowsiness, fatigue, headache, sedation

Endocrine & metabolic: Dehydration

Gastrointestinal: Constipation, nausea, vomiting

Local: Application site erythema (transdermal device)

Neuromuscular & skeletal: Weakness

Respiratory: Dyspnea

1% to 10%:

Cardiovascular: Atrial fibrillation, bigeminy, cardiac arrhythmia, chest pain, deep vein thrombosis, edema, hypertension, hypotension, myocardial infarction, orthostatic hypotension, palpitations, peripheral edema, pulmonary embolism (nasal spray), sinus tachycardia, syncope, tachycardia, vasodilatation

Central nervous system: Abnormal dreams, abnormal gait, abnormality in thinking, agitation, altered sense of smell, amnesia, anxiety, ataxia, chills, depression, disorientation, dysphoria, euphoria, hallucination, hypertonia, hypoesthesia, hypothermia, insomnia, irritability, lack of concentration, lethargy, malaise, mental status changes, migraine, nervousness, neuropathy, paranoia, paresthesia, restlessness, speech disturbance, stupor, vertigo, withdrawal syndrome

Dermatologic: Alopecia, cellulitis, decubitus ulcer, diaphoresis, erythema, exfoliation of skin (application site, transdermal device), hyperhidrosis, local papules (application site, transdermal device), night sweats, pallor, papule, pruritus, pustules (application site, transdermal device), skin rash, vesicobullous rash (application site, transdermal device)

Endocrine & metabolic: Hot flash, hypercalcemia, hyperglycemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, weight loss

Gastrointestinal: Abdominal distention, abdominal pain, anorexia, decreased appetite, diarrhea, dysgeusia, dyspepsia, dysphagia (buccal tablet/film/sublingual spray), flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal ulcer (gingival, lip, mouth; transmucosal use/nasal spray), gingival pain (buccal tablet), gingivitis (lozenge), glossitis (lozenge), hematemesis, intestinal obstruction, periodontal abscess (lozenge/buccal tablet), rectal pain, stomatitis (lozenge/buccal tablet/sublingual tablet/sublingual spray), tongue disease (sublingual tablet), xerostomia

Genitourinary: Urinary retention (3%), difficulty in micturition, dysuria, erectile dysfunction, mastalgia, urinary incontinence, urinary tract infection, urinary urgency, vaginal hemorrhage, vaginitis

Hematologic & oncologic: Anemia (3%), bruise, leukopenia, lymphadenopathy, neutropenia, thrombocytopenia

Hepatic: Ascites, increased serum alkaline phosphatase, increased serum AST, jaundice

Hypersensitivity: Hypersensitivity reaction

Infection: Abscess

Local: Application site burning (transdermal device), application site discharge (transdermal device), application site edema (transdermal device), application site irritation, application site itching (transdermal device), application site pain, application site rash (transdermal device), application site vesicles (transdermal device)

Neuromuscular & skeletal: Arthralgia, back pain, leg cramps, limb pain, myalgia, tremor

Ophthalmic: Blepharoptosis, blurred vision, diplopia, dry eye syndrome, strabismus, swelling of eye, visual disturbance

Renal: Renal failure

Respiratory: Apnea, asthma, atelectasis, bronchitis, cough, dyspnea (exertional), epistaxis, flu-like symptoms, hemoptysis, hyperventilation, hypoventilation, hypoxia, laryngitis, nasal congestion (nasal spray), nasal discomfort (nasal spray), nasopharyngitis, pharyngitis, pharyngolaryngeal pain, pneumonia, postnasal drip (nasal spray), rhinitis, rhinorrhea (nasal spray), sinusitis, upper respiratory tract infection, wheezing

Miscellaneous: Fever, wound healing impairment

<1% (Limited to important or life-threatening): Allergic dermatitis, anaphylactoid reaction, angina pectoris, bradycardia, bronchoconstriction, chest wall rigidity, clonus, cyanosis, drug dependence (physical and psychological; with prolonged use), eczema, esophageal stenosis, exfoliative dermatitis, fecal impaction, flushing, genitourinary tract spasm, gingival hemorrhage, gum line erosion, hematuria, hostility, hypoglycemia, hypogonadism (Brennan 2013; Debono 2011), impaired consciousness, local hemorrhage, local hypersensitivity reaction, localized infection, local tissue necrosis, loss of consciousness, muscle spasm, muscle twitching, nocturia, oliguria, pancytopenia, pleural effusion, polyuria, respiratory distress, seizure, sexual disorder, skin erosion, Stevens-Johnson syndrome, swelling, swollen tongue, tonic-clonic seizures, tooth loss, upper abdominal pain