April 30, 2017
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Ionsys

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Ionsys

Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including fentanyl, 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 IONSYS, the risk is greatest during the initiation of therapy. Monitor patients closely for respiratory depression, especially within the first 2472 hours of initiating therapy with IONSYS.

Accidental exposure to the hydrogel component of IONSYS, especially in children, can result in respiratory depression and death due to an overdose of fentanyl.

Following accidental contact with IONSYS or its components, immediately rinse the affected area thoroughly with water. Do not use soap, alcohol, or other solvent because they may enhance the drug's ability to penetrate the skin. The individual exposed should be monitored for signs of respiratory or central nervous system depression.

If IONSYS is not handled correctly using gloves, healthcare professionals are at risk of accidental exposure to a fatal overdose of fentanyl.

IONSYS is for hospital use only. Use of IONSYS outside of the hospital setting can lead to accidental exposure in others for whom it is not prescribed, causing fatal respiratory depression. Prior to the patient leaving the hospital, medical personnel must remove IONSYS and dispose of it properly.

IONSYS Risk Evaluation And Mitigation Strategy (REMS) Program

IONSYS is available only through a restricted program under a REMS called the IONSYS REMS Program because of the risk of respiratory depression resulting from accidental exposure [see Life-Threatening Respiratory Depression].

Notable requirements of the IONSYS REMS Program include the following:

  • Healthcare facilities that dispense and administer IONSYS must be certified in the IONSYS REMS program and comply with the REMS requirements.
  • Hospitals must only dispense IONSYS for hospital use.

Further information about the IONSYS REMS Program is available at www.ionsysrems.com, or by calling 1-877-488-6835.

Addiction, Abuse, And Misuse

IONSYS contains fentanyl, a Schedule II controlled substance. As an opioid, IONSYS exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed IONSYS. 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 IONSYS, and monitor all patients receiving IONSYS 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 IONSYS, but use in such patients necessitates intensive counseling about the risks and proper use of IONSYS 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 IONSYS. 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.

Risks Of Concomitant Use Or Discontinuation Of Cytochrome P450 3A4 Inhibitors And Inducers

Concomitant use of IONSYS 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, depression [see Life-Threatening Res piratory Depression] , particularly when an inhibitor is added after a stable dose of IONSYS is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in IONSYS-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using IONSYS with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in IONSYS-treated patients, monitor patients closely at frequent intervals for respiratory depression and sedation [see DRUG INTERACTIONS].

Concomitant use of IONSYS 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 IONSYS with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see DRUG INTERACTIONS].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of IONSYS 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.

Risk Of Injury During Magnetic Resonance Imaging (MRI) Procedure

The IONSYS device is considered MR Unsafe. IONSYS contains metal parts and must be removed and properly disposed of before an MRI procedure to avoid injury to the patient and damage to IONSYS. It is unknown if exposure to an MRI procedure increases release of fentanyl from IONSYS. Monitor any patients wearing IONSYS with inadvertent exposure to an MRI for signs of central nervous system and respiratory depression.

Risk Of IONSYS Use During Other Procedures Or Near Certain Equipment

Cardioversion, Defibrillation, Radiographic Imaging Procedures Other Than MRI, Or Diathermy

Use of IONSYS during cardioversion, defibrillation, X-ray, CT, or diathermy can damage IONSYS from the strong electromagnetic fields set up by these procedures. IONSYS contains radio-opaque components and may interfere with an X-ray image or CT scan. Remove and properly dispose of IONSYS prior to cardioversion, defibrillation, X-ray, CT, or diathermy [see DOSAGE AND ADMINISTRATION].

Synthetic Materials And Electronic Security Systems

Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge and damage to IONSYS. Avoid exposing IONSYS to electronic security systems to reduce the possibility of damage to IONSYS. See IONSYS Important Device Instructions for additional details.

Communications Equipment And Radio Frequency Identification Transmitters

Use of IONSYS near communications equipment (e.g., base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast Radio) and Radio Frequency Identification (RFID) transmitters can damage IONSYS. Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between IONSYS and communications equipment or the RFID transmitter ranges between 0.12 and 23 meters. See IONSYS Important Device Instructions for detailed instructions regarding recommended separation distances.

Other Electromechanical Devices Including Pacemakers Or Electrical Monitoring Equipment

The low-level electrical current provided by IONSYS does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment.

If exposure to the procedures listed above, electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs, and if IONSYS does not appear to function normally [see DOSAGE AND ADMINISTRATION] , remove IONSYS and replace with a new IONSYS. See IONSYS Important Device Instructions for additional details including information on troubleshooting device malfunction and electromagnetic compatibility.

Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients

The use of IONSYS in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients With Chronic Pulmonary Disease

IONSYS-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 the recommended dosage of IONSYS [see Life-Threatening Res piratory Depression].

Elderly, Cachectic, Or Debilitated Patients

Life -threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely; particularly when initiating IONSYS and when IONSYS is used concomitantly with other drugs that depress respiration [see ]. Alternatively, consider theLife-Threatening Res piratory Depression use of non-opioid analgesics in these patients.

Serotonin Syndrome With Concomitant Use Of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl, the active opioid ingredient of IONSYS, 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 at the recommended dosage.

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 IONSYS if serotonin syndrome is suspected.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

IONSYS 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 IONSYS. In patients with circulatory shock, IONSYS may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of IONSYS in patients with circulatory shock.

Risks Of Use In Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors). IONSYS 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 IONSYS.

Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of IONSYS in patients with impaired consciousness or coma. IONSYS is not suitable for use in patients who are not alert and able to follow directions.

Risks Of Use In Patients with Gastrointestinal Conditions

IONSYS is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralyticileus.

The fentanyl in IONSYS may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

Increased Risk Of Seizures In Patients With Seizure Disorders

The fentanyl in IONSYS 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 IONSYS therapy.

Topical Skin Reactions

Topical skin reactions (erythema, sweating, vesicles, papules/pustules) may occur with use of IONSYS and are typically limited to the application site area. If a severe skin reaction is observed, remove IONSYS and discontinue further use.

Bradycardia

IONSYS may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with IONSYS.

Withdrawal

Avoid the 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, including IONSYS. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

Do not abruptly discontinue IONSYS [see Drug Abuse and Dependence].

Hepatic Impairment

Insufficient data are available on the use of IONSYS in patients with impaired hepatic function. Since fentanyl is eliminated by hepatic metabolism and fentanyl clearance may decrease in patients with hepatic disease, monitor patients with hepatic impairment for signs of sedation and respiratory depression [see Use in Specific Populations and CLINICAL PHARMACOLOGY].

Renal Impairment

A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Monitor for signs of sedation and respiratory depression in patients with renal impairment [see Use in Specific Populations and CLINICAL PHARMACOLOGY].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of IONSYS during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be lifethreatening 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].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Life-Threatening Respiratory Depression
  • Inform patients of the risk of respiratory depression, including information that the risk is greatest when starting IONSYS, and that it can occur even at the recommended dosage [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
  • Advise patients not to leave the hospital with IONSYS [see WARNINGS AND PRECAUTIONS].
  • Advise patients not to let anyone else activate the dosing button on the IONSYS since only the patient knows how much pain he or she is experiencing. Patients should be cautioned that allowing others to activate the device may result in a potentially fatal overdose [see DOSAGE AND ADMINISTRATION].
Accidental Exposure
  • Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS].
  • Advise patients not to let anyone touch IONSYS if it falls off accidentally and to contact their nurse, pharmacist, or doctor immediately. Accidental exposure to the fentanyl hydrogel may result in a fatal overdose of fentanyl.
  • Instruct patients not to remove or reposition IONSYS and that IONSYS must be removed only by medical personnel [see WARNINGS AND PRECAUTIONS].
  • Instruct patients not to touch the sticky side of IONSYS and not to touch the gels. Caution patients that fentanyl is rapidly absorbed by the eyes and mouth and could be harmful or fatal if absorbed this way. Advise patients to inform a health care provider if accidental exposure occurs and to immediately rinse the affected area with copious amounts of water. Soap, alcohol, or other solvents should not be used because they may enhance permeability [see WARNINGS AND PRECAUTIONS].
  • Instruct patients to keep IONSYS out of the reach of children at all times [see WARNINGS AND PRECAUTIONS].
Addiction, Abuse And Misuse
  • Inform patients that the use of IONSYS, even when taken as recommended can result in addiction, abuse and misuse, which can lead to overdose and death [see WARNINGS AND PRECAUTIONS].
Interactions With Benzodiazepines And Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if IONSYS is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially lifethreatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

MAOI Interaction

Inform patients to avoid taking IONSYS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking IONSYS [see DRUG INTERACTIONS].

Important Administration Instructions

Advise patients that the level of current (62 microA/cm²) provided by IONSYS is generally imperceptible to the patient.

Anaphylaxis
  • Inform patients that anaphylaxis have been reported with ingredients contained in IONSYS. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS].
  • Advise patients to inform the health care provider of any allergies to fentanyl, cetylpiridinium chloride (e.g., Cepacol®) and or any components of IONSYS.
Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations].

Disposal Of Unused IONSYS

Advise patients that only their health care provider should remove IONSYS from them and properly dispose of IONSYS prior to them leaving the hospital.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 0.033 mg/kg/day in males or 0.1 mg/kg/day in females. These lifetime doses in rats are approximately 0.1 and 0.3, respectively, the maximum recommended human dose (MRHD) of 3.2 mg/day by transdermal administration based on a mg/m² body surface area comparison and a 60 kg human body weight.

Mutagenesis

Fentanyl is not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay), the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the in vitro chromosomal aberration assays using either human lymphocytes or Chinese hamster ovary cells.

Impairment Of Fertility

The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD) via continuous intravenous infusion for 14 days prior to mating until Day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.2 times the maximum available daily human dose on a mg/m² basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the MRHD for a period of 12 days.

Use In Specific Populations

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS]. Available data with IONSYS in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

There are no studies with the use of IONSYS in pregnant women. Limited published data on fentanyl use during pregnancy are insufficient to establish any drug-associated risks. In animal reproduction and developmental studies, at doses within the dosing range of humans, there was an increased risk for early embryonic lethality, decreased pup survival, and delays in developmental landmarks of surviving pups [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 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. IONSYS is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including IONSYS, 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 and respiratory depression. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

The potential effects of fentanyl on embryo-fetal development were studied in rat and rabbit models.

Published literature reports that administration of fentanyl (0, 0.01, 0.1, or 0.5 mg/kg/day) to pregnant female Sprague-Dawley rats from Gestation Day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity. The high dose is approximately 1.5 times the daily maximum recommended human dose (MRHD) of 3.2 mg/day based on a mg/m² body surface area basis and a 60 kg human body weight.

In contrast, the intravenous administration of fentanyl at doses of 0, 0.01, or 0.03 mg/kg (equivalent to 0.03 and 0.09 times, respectively, the MHRD) to pregnant female rats from Gestation Day 6 to 18 resulted in evidence of embryo toxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from Gestation Day 6 to 18. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity (decreased body weight and sedation). Under the conditions of the assay, there was no evidence for fentanyl-induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (2.4 times the MRHD).

The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Pregnant female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion (equivalent to 0.08, 0.3, and 1.2 times, respectively, the MRHD) from Gestation Day 6 through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Post-Natal Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Post- Natal Day 28 which recovered by Post-Natal Day 50). No adverse effects were observed at 0.08 times the MRHD.

Lactation

Risk Summary

Limited published literature reports that fentanyl is present in human milk at low levels, which resulted in an estimated infant dose of 0.38% of the maternal weight-adjusted dosage. There are no reports of adverse effects on the breastfed infant and no information on the effects on milk production.

The developmental and health benefits from breastfeeding should be considered along with the mother's clinical need for IONSYS and any potential effects on the breastfed infant from IONSYS or from the underlying maternal condition.

Clinical Considerations

Infants exposed to IONSYS through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

Females And Males Of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Nonclinical Toxicology].

Pediatric Use

The efficacy and safety of IONSYS have not been established in pediatric patients under 18 years of age.

Geriatric Use

IONSYS 40 mcg has been studied in 499 patients 65 years or older; 174 of whom were 75 years or older. No major differences in safety or effectiveness were observed between these subjects and younger subjects. However, the incidence of the following events was slightly higher ( ≥ 1%) in patients ≥ 65 years compared with patients who were 18 to 64 years of age: hypotension (4% versus 3%), confusion (2% versus < 1%), hypokalemia (3% versus 1%), hypoxia (3% versus 2%), and hypoventilation (2% versus < 1%).

In a pharmacokinetic study of IONSYS conducted in 63 healthy volunteers (25 subjects older than 65 years), age did not significantly affect the extent of drug absorption. Literature suggests that the clearance of fentanyl may be reduced and the terminal half-life prolonged in the elderly.

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 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.

Hepatic Impairment

Insufficient data are available on the use of IONSYS in patients with impaired hepatic function. Since fentanyl is eliminated by hepatic metabolism and fentanyl clearance may decrease in patients with hepatic disease, monitor patients with hepatic impairment closely for signs of central nervous system and respiratory depression, especially when initiating treatment with IONSYS.

Renal Impairment

Approximately 10% of administered fentanyl is excreted unchanged by the kidney. Insufficient data are available on the use of IONSYS in patients with impaired renal function to determine effects on renal clearance of fentanyl. Monitor patients with renal impairment closely for signs of central nervous system and respiratory depression, especially when initiating treatment with IONSYS.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/18/2017

Warnings
Precautions

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