Drug Safety-related Labeling Changes (SrLC)

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IONSYS (NDA-021338)

(FENTANYL HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/16/2016 (SUPPL-7)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion:

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; IONSYS REMS; ADDICTION, ABUSE, AND MISUSE;  CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of IONSYS. Monitor for respiratory depression, especially during initiation of IONSYS. Only the patient should activate IONSYS dosing.

IONSYS Risk Evaluation and Mitigation Strategy (REMS) Program

• IONSYS is for use only in patients in the hospital. Discontinue treatment with
• IONSYS before patients leave the hospital.

• Because of the risk of respiratory depression from accidental exposure, IONSYS is available through a restricted program called the IONSYS REMS Program. Healthcare facilities that dispense IONSYS must be certified in this program and comply with the REMS requirements.

Addiction, Abuse, and Misuse

IONSYS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.

Cytochrome P450 3A4 Interaction

The concomitant use of IONSYS with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving IONSYS and any CYP3A4 inhibitor or inducer.

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 of IONSYS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

4 Contraindications

Revised bullet as below:

• Known or suspected gastrointestinal obstruction, including paralytic ileus

5 Warnings and Precautions

5.1 Life-Threatening Respiratory Depression

(Additions and/or revisions underlined)     

Serious, life-threatening, or fatal respiratory depression has been reported ….

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 24-72 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 …

5.10 Adrenal Insufficiency

Newly added subsection:

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.

5.11 Severe Hypotension

Subheading title revised as shown above.

IONSYS may cause severe hypotension including orthostatic hypotension …

5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

Additions and/or revisions underlined:

In patients who may be susceptible to the intracranial effects of CO2 retention …. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with IONSYS …

5.13 Risks of Use in Patients with Gastrointestinal Conditions

Additions and/or revisions underlined:

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

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 …

 

5.14 Increased Risk of Seizures in Patients with Seizure Disorders

Additions and/or revisions underlined:

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 …

5.15 Topical Skin Reactions

Subsection formed from existing and new underlined information:

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.

5.17 Withdrawal

Newly added subsection:

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.

5.20 Neonatal Opioid Withdrawal Syndrome

Newly added subsection:

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 life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

5.3 Addiction, Abuse, and Misuse

(Additions and/or revisions underlined)     

ONSYS contains fentanyl, a Schedule II controlled substance. As an opioid, IONSYS exposes users to the risks of addiction, abuse, and misuse.

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 … 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 …

5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

(Additions and/or revisions underlined)     

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, 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 HCYP3A4 inhibitors or discontinuing CYP3A4 inducers in IONSYS-treated patients, monitor patients closely at frequent intervals for respiratory depression and sedation.

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.

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Additions and/or revisions underlined)     

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.

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.

5.7 Risk of IONSYS Use during Other Procedures or Near Certain Equipment

(Additions and/or revisions underlined)     

Communications Equipment and Radio Frequency Identification Transmitters

… See IONSYS Important Device Instructions for detailed instructions regarding recommended separation distances.

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(Additions and/or revisions underlined)     

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.

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly …

Monitor such patients closely; particularly when initiating IONSYS and when IONSYS is used concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Newly added subsection:

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). 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.

6 Adverse Reactions

The following serious adverse reactions are described elsewhere in the labeling:

Revisions underlined as below:      

• Life-Threatening respiratory Depression

• Addiction, Abuse, and Misuse

• Interactions with Benzodiazepines or Other CNS Depressants

• Serotonin Syndrome

• Adrenal Insufficiency

• Severe Hypotension

• Gastrointestinal  Adverse Reactions

• Seizures

• Withdrawal

• Neonatal Opioid Withdrawal Syndrome

6.1 Clinical Trials Experience

(All mentions of table 3 have been revised to read table 1)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug …

The most common adverse reactions (greater than or equal to 2%) in the placebo-controlled studies, regardless of relationship to study medication, are listed in Table 1.

Other Adverse Reactions

Other adverse reactions that were reported (excluding adverse reactions listed in Table 1) in …

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of fentanyl (replacing IONSYS)…

Addition of the following:

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in IONSYS.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

7 Drug Interactions

Information has been organized into a table; please refer to label

Table 2 includes clinically significant drug interactions with IONSYS.

Table 2:     Clinically Significant Drug Interactions with IONSYS Inhibitors of CYP3A4

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. 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 … and delays in developmental landmarks of surviving pups.

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 ….

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.

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 … 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...

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Limited published literature reports that fentanyl is present ….

The developmental and health benefits from breastfeeding should be considered along with the mother’s clinical need …

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 breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

Newly added subsection:

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.

8.5 Geriatric Use

Additions and/or revisions underlined:

IONSYS 40 mcg has been studied in 499 patients …  

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.

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Addition of Medication Guide; please refer to label.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Exposure

·         Inform patients that accidental exposure, especially in children, may result in respiratory depression or death …

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.

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications

MAOI Interaction

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

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.

• Advise patients to inform the health care provider of any allergies to fentanyl …

  Infertility

  Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

  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.

Other

Additions and/or revisions to incorporate the opioid analgesic template language.