Sublimaze

Black Box Warnings

Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death; assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions

Life-threatening respiratory depression

• Serious, life-threatening, or fatal respiratory depression may occur
• Monitor for respiratory depression, especially during initiation or following a dose increase

Accidental ingestion

• Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose

Neonatal opioid withdrawal syndrome

• Prolonged use 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

Risks from concomitant use with benzodiazepines or other CNS depressants

• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death; reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; follow patients for signs and symptoms of respiratory depression and sedation

Contraindications

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Hypersensitivity to drug or components of the formulation

Within 2 weeks of monoamine oxidase inhibitor (MAOI) use

Cautions

Caution in acute pancreatitis, addison disease, benign prostatic hyperplasia, cardiac arrhythmias, central nervous system (CNS) depression, drug abuse or dependence, emotional lability, gallbladder disease, gastrointestinal (GI) disorder, pseudomembranous colitis, GI surgery, head injury, hypothyroidism or untreated myxedema, intracranial hypertension, brain tumor, toxic psychosis, urethral stricture, urinary tract surgery, seizures, acute alcoholism, delirium tremens, shock, cor pulmonale, chronic pulmonary disease, emphysema, hypercapnia, kyphoscoliosis, severe obesity, renal or hepatic impairment, elderly or debilitated patients

Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected

Therapy 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); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Therapy may increase frequency of seizures in patients with seizure disorders and in other clinical settings associated with seizures; monitor patients for worsened seizure control during therapy

Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients

Warn patients not to drive or operate dangerous machinery unless they are tolerant to effects of drug and know how they will react to medication

While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of opioid

Concomitant use 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, particularly when an inhibitor is added after a stable dose of fentanyl injection is achieved; similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl-injection treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions; when using fentanyl Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl-Injection treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl injection until stable drug effects are achieved

Concomitant use of fentanyl injection 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 injection with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur

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; reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; follow patients for signs and symptoms of respiratory depression and sedation

Profound sedation, respiratory depression, coma, and death may result from concomitant administration 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

Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with 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

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; monitor closely

Monoamine oxidase inhibitors (MAOIs) may potentiate effects of opioid, opioid’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of initiating or stopping MAOIs

Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of 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

Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

Opioid pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

Risks of potentially fatal respiratory depression, pruritus (despite little histamine release), and abuse or addiction

May produce bradycardia, which may be treated with atropine

Pregnancy

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; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly; opioids cross 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; opioid sulfate is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions which temporarily reduce strength, duration, and frequency of uterine contractions

Fertility

• Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether effects on fertility are reversible

Lactation

Opioid is secreted into human milk; in women with normal opioid metabolism (normal CYP2D6 activity), the amount of opioid secreted into human milk is low and dose-dependent; some women are ultra-rapid metabolizers of opioid; these women achieve higher-than-expected serum levels of opioid's active metabolite, opioid, leading to higher-than-expected levels of opioid in breast milk and potentially dangerously high serum opioid levels in their breastfed infants that can potentially lead to serious adverse reactions, including death, in nursing infants

Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Mechanism of Action

Narcotic agonist-analgesic of opiate receptors; inhibits ascending pain pathways, thus altering response to pain; increases pain threshold; produces analgesia, respiratory depression, and sedation

Absorption

Bioavailability: 50%

Onset: IV, immediate; IM, 7-15 min

Duration: IV, 0.5-1 hr; IM, 1-2 hr

Peak plasma time: IV (≤100 mcg), 30-60 min; IM, 1-2 hr

Concentration: 0.2-2 ng/mL (adverse effects occur at >2 ng/mL) 

Distribution

Protein bound: 80-85%

Vd: 4-6 L/kg 

Metabolism

Metabolized in liver by CYP3A4 

Elimination

Half-life: 2-4 hr

Total plasma clearance: 8.3 mL/min/kg

Excretion: Urine (75%), feces (9%) 

As with other narcotic analgesics, the most common serious adverse reactions reported to occur with SUBLIMAZE (fentanyl citrate) are respiratory depression, apnea, rigidity, and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm and anaphylaxis.

It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary.

When a tranquilizer is used with SUBLIMAZE, the following adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with SUBLIMAZE.

Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of SUBLIMAZE with a neuroleptic agent.

Drug Abuse And Dependence

SUBLIMAZE (fentanyl citrate) is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused.

Read the entire FDA prescribing information for Sublimaze (Fentanyl Citrate)

Fentanyl is a prescription medication used to treat breakthrough cancer pain. It can also be used as part of surgical anesthesia.

Fentanyl belongs to a group of drugs called opioid agonists or narcotic pain medications. These work by changing the way the brain and nervous system respond to pain.

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

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.

Common side effects of fentanyl include difficulty breathing, nausea, upset stomach, and difficulty urinating.

Fentanyl can also cause changes in vision, drowsiness, and dizziness. Do not drive or operate heavy machinery until you know how fentanyl affects you.

The oral, topical, and inhalational forms of fentanyl are prescription medications used to treat breakthrough cancer pain. Fentanyl injection may also be used as premedication prior to surgery, for anesthesia induction, as an adjunct to regional anesthesia, or for pain control in the post-operative setting.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

A doctor or other trained health professional will give you or your child this medicine in a hospital. This medicine is given as a shot into a muscle or vein.

It is very important that your doctor check you closely while you or your child are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it.

This medicine may cause a serious allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Do not use too much of this medicine or use it more often than your doctor tells you to. This can be life-threatening. Symptoms of an overdose include: extreme dizziness or weakness, slow heartbeat or breathing, seizures, trouble breathing, and cold, clammy skin. Call your doctor right away if you notice these symptoms.

Dizziness, lightheadedness, or fainting may occur with this medicine, especially when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.

This medicine will add to the effects of alcohol and other central nervous system (CNS) depressants. CNS depressants are medicines that slow down the nervous system, which may cause drowsiness or make you less alert. Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds, sedatives, tranquilizers, or sleeping pills, prescription pain medicine or narcotics, barbiturates or seizure medicines, muscle relaxants, or anesthetics (numbing medicines), including some dental anesthetics. This effect may last for a few days after you stop using this medicine. Check with your medical doctor or dentist before taking any of the above while you or your child are receiving this medicine.

This medicine may make you dizzy, drowsy, confused, or disoriented. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

If you have been using this medicine regularly for several weeks or longer, do not change your dose or suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble sleeping.

This medicine may increase risk for muscle rigidity and movement. Tell your doctor if you have stiff or rigid muscles after using this medicine.

Check with your doctor right away if you have anxiety, restlessness, a fast heartbeat, fever, sweating, muscle spasms, twitching, nausea, vomiting, diarrhea, or see or hear things that are not there. These may be symptoms of a serious condition called serotonin syndrome. Your risk may be higher if you also take certain other medicines that affect serotonin levels in your body.

Using too much of this medicine may cause reduced infertility (unable to have children). Talk with your doctor before using this medicine if you plan to have children.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• It is used to ease pain.
• It is used during surgery.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If you need to store Sublimaze at home, talk with your doctor, nurse, or pharmacist about how to store it.

As with other narcotic analgesics, the most common serious adverse reactions reported to occur with Sublimaze (fentanyl citrate) are respiratory depression, apnea, rigidity, and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm and anaphylaxis.

It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary.

When a tranquilizer is used with Sublimaze, the following adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with Sublimaze.

Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of Sublimaze with a neuroleptic agent.

50 mcg = 0.05 mg = 1 mL

Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used and the surgical procedure involved. Dosage should be reduced in elderly or debilitated patients (see PRECAUTIONS).

Vital signs should be monitored routinely.

Usage in Children: For induction and maintenance in children 2 to 12 years of age, a reduced dose as low as 2 to 3 mcg/kg is recommended.

As a General Anesthetic

When attenuation of the responses to surgical stress is especially important, doses of 50 to 100 mcg/kg (0.05 to 0.1 mg/kg) (1 to 2 mL/kg) may be administered with oxygen and a muscle relaxant. This technique has been reported to provide anesthesia without the use of additional anesthetic agents. In certain cases, doses up to 150 mcg/kg (0.15 mg/kg) (3 mL/kg) may be necessary to produce this anesthetic effect. It has been used for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated, and for certain complicated neurological and orthopedic procedures.

As noted above, it is essential that qualified personnel and adequate facilities be available for the management of respiratory depression.

See WARNINGS and PRECAUTIONS for use of Sublimaze (fentanyl citrate) with other CNS depressants, and in patients with altered response.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.