Drug Safety-related Labeling Changes (SrLC)

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ABSTRAL (NDA-022510)

(FENTANYL CITRATE)

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

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10/07/2019 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Life-Threatening Respiratory Depression

Newly added information to end of subsection:

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Additions and/or revisions underlined:

5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ABSTRAL 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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).

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions with ABSTRAL

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

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

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

Important information about ABSTRAL:

• Never give anyone else your ABSTRAL. They could die from taking it. Selling or giving away ABSTRAL is against the law.

• Store ABSTRAL securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

How should I dispose of unopened ABSTRAL® tablets when they are no longer needed?

• Dispose of expired, unwanted, or unused ABSTRAL by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

PATIENT COUNSELING INFORMATION

Storage and Disposal of Unused and Used ABSTRAL:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ABSTRAL securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving ABSTRAL unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused ABSTRAL should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

12/16/2016 (SUPPL-15)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions underlined)

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISK FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME

Life-Threatening Respiratory Depression

Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ABSTRAL, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory

depression, especially during initiation of ABSTRAL or following a dose increase. The substitution of

ABSTRAL for any other fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression …

Accidental Ingestion

Accidental ingestion of even one dose of ABSTRAL, especially by children, can result in a fatal overdose of fentanyl.

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. ABSTRAL must be kept out of reach of children.

Cytochrome P450 3A4 Interaction

The concomitant use of ABSTRAL with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse 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 ABSTRAL 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 ABSTRAL 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.

Risk of Medication Errors

Substantial differences exist in the pharmacokinetic profile of ABSTRAL compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose …

Addiction, Abuse, and Misuse

ABSTRAL exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ABSTRAL, and monitor all patients regularly for the development of these behaviors and conditions.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ABSTRAL 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.

4 Contraindications

Additions and/or revisions underlined:

ABSTRAL is contraindicated in:

• Opioid non-tolerant patients: Life threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.

• Acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency department.

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

• Known or suspected gastrointestinal obstruction, including paralytic ileus.

• Known hypersensitivity to fentanyl (e.g., anaphylaxis).

5 Warnings and Precautions

5.1 Life-Threatening Respiratory Depression

(Subsection heading revised; additions and/or revisions underlined)

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids 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. 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 ABSTRAL, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of ABSTRAL.

To reduce the risk of respiratory depression, proper dosing and titration of ABSTRAL are essential. Overestimating the ABSTRAL dosage can result in a fatal overdose with the first dose. The substitution of ABSTRAL for any other fentanyl product may result in fatal overdose.

ABSTRAL could be fatal to individuals for whom it is not prescribed and for those who are not opioid- tolerant.

Accidental ingestion of even one dose of ABSTRAL, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.

5.10 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 ABSTRAL 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 within the recommended dosage range.

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 ABSTRAL if serotonin syndrome is suspected.

5.11 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.

5.12 Severe Hypotension

(Newly added subsection)

ABSTRAL 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 these patients for signs of hypotension after initiating or titrating the dosage of ABSTRAL. In patients with circulatory shock, ABSTRAL may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ABSTRAL in patients with circulatory shock.

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

(Newly added subsection)

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), ABSTRAL 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 ABSTRAL.

Opioids may obscure the clinical course of a patient with a head injury. Avoid the use of ABSTRAL in patients with impaired consciousness or coma.

5.14 Risk of Use in Patients with Gastrointestinal Conditions

(Newly added subsection)

ABSTRAL is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in ABSTRAL 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.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

(Newly added subsection)

The fentanyl in ABSTRAL 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 ABSTRAL therapy.

5.16 Risks of Driving and Operating Machinery

(Newly added subsection)

ABSTRAL may impair the mental or physical abilities needed to perform of potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ABSTRAL and know how they will react to the medication.

5.2 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure

Death has been reported in children who have accidentally ingested transmucosal immediate–release fentanyl products.

Patients and their caregivers must be informed that ABSTRAL contains a medicine in an amount which can be fatal to a child. Healthcare providers and dispensing pharmacists …

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible.

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of ABSTRAL are provided in the ABSTRAL Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

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

(Subsection heading revised; additions and/or revisions underlined)

Concomitant use of ABSTRAL 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 ABSTRAL is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ABSTRAL treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using ABSTRAL with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ABSTRAL-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ABSTRAL until stable drug effects are achieved..

Concomitant use of ABSTRAL 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 ABSTRAL 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.

5.4 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 ABSTRAL with benzodiazepines or other CNS depressants, including other opioids, (e.g., non-benzodiazepine sedatives or /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 (7)].

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.

Advise both patients and caregivers about the risks of respiratory depression and sedation when ABSTRAL is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

5.5 Risk of Medication Errors

When prescribing, DO NOT convert a patient to ABSTRAL from any other fentanyl products on a mcg per mcg basis from other fentanyl products as ABSTRAL and other fentanyl products are not equivalent on a microgram per microgram basis.

ABSTRAL is not a generic version of other transmucosal immediate-release fentanyl (TIRF) formulations. When dispensing, do not substitute an ABSTRAL prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and ABSTRAL are not equivalent. Substantial differences exist in the pharmacokinetic profile of ABSTRAL compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of ABSTRAL or any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of ABSTRAL should always be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects.

5.6 Addiction, Abuse, and Misuse

(Additions and/or revisions underlined)

ABSTRAL contains fentanyl, a Schedule II controlled substance. As an opioid, ABSTRAL 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 ABSTRAL. 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 ABSTRAL, and monitor all patients receiving ABSTRAL for the development of these behaviors and 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 ABSTRAL, but use in such patients necessitates intensive counseling about the risks and proper use of ABSTRAL 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 ABSTRAL. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.  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.

5.8 Neonatal Opioid Withdrawal Syndrome

(Newly added subsection)

Prolonged use of ABSTRAL 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.

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

(Newly added subsection)

The use of ABSTRAL 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: ABSTRAL 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 recommended dosages of ABSTRAL.

Elderly, Cachectic, or Debilitated Patients: 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 such patients closely, particularly when initiating and titrating ABSTRAL and when ABSTRAL is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

6 Adverse Reactions

(Addition of the following line listing)

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Life-Threatening Respiratory Depression

• Interactions with Benzodiazepines and Other CNS Depressants

• Addiction, Abuse, and Misuse

• Neonatal Opioid Withdrawal Syndrome

• Serotonin Syndrome

• Adrenal Insufficiency

• Severe Hypotension

• Gastrointestinal Adverse Reactions

• Seizures

6.1 Clinical Trials Experience

(Replace Studies with Trials and events with reactions)

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

6.2 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 ABSTRAL.

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

7 Drug Interactions

Table 4 includes clinically significant drug interactions with ABSTRAL.

Table 4: Clinically Significant Drug Interactions with ABSTRAL

(Information converted into table format; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy - Category C

(Additions and/or revisions underlined)

There are no adequate and well-controlled studies in pregnant women.

Risk Summary                                                                    

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.

Available data with ABSTRAL in pregnant women are insufficient to inform a drug-associated risk for

major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the heath of the mother or the use of medications. 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.

Chronic 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 of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. 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. ABSTRAL is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ABSTRAL, 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 for signs of excess sedation and respiratory depression.

Data

Human Data

In women treated acutely with intravenous …

Animal Data

Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of ABSTRAL on a mg/m2 basis) and 160 mcg/kg subcutaneously the range of (2 times the 800 mcg dose of ABSTRAL based on a mg/m2 basis). There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg ABSTRAL per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 6 times higher than the mean Cmax observed following administration of 800 mcg dose of ABSTRAL in humans.

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ABSTRAL.

Clinical Considerations

 infants exposed to ABSTRAL through breast milk 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

(Additions and/or revisions underlined)

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 underlined)

Of the 270 opioid tolerant patients with breakthrough cancer pain in the Phase 3 clinical studies … titrating ABSTRAL in elderly patients to provide adequate efficacy while minimizing risk …

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. Titrate the dosage of ABSTRAL slowly in geriatric patients 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.

8.7 Sex

(Sex replaces gender in this subsection; revision underlined)

Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in efficacy or in observed adverse reactions.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

IMPORTANT:

Do not use ABSTRAL unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer for your cancer pain and your body is used to these medicines (this means that you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.

ABSTRAL is:

• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage breakthrough pain …

• An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

  Important information about ABSTRAL:

• Get emergency help right away if you take too much ABSTRAL (overdose). When you first start taking ABSTRAL, when your dose is changed, or if you take too much (overdose), serious life-threatening breathing problems that can lead to death may occur.

• Taking ABSTRAL with other opioid medicines that may make you sleepy, such as other pain medicines, anti- depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death.

• Never give anyone else your ABSTRAL. They could die from taking it. Store ABSTRAL away from children and in a safe place to prevent stealing or abuse. Selling or giving away ABSTRAL is against the law.

• If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using ABSTRAL. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.

• ABSTRAL is only available only through a program called the Transmucosal Immediate-Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program. To receive ABSTRAL, you must:

• talk to your healthcare provider

• understand the benefits and risks of ABSTRAL

• agree to all of the instructions

• sign the Patient-Prescriber Agreement form

• Be very careful about taking other medicines that may make you sleepy, such as other pain medicines, anti- depressant medicines, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers.

  Do not take ABSTRAL if:

• You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain ….

• You have severe asthma, trouble breathing, or other lung problems.

• You have a bowel blockage or have narrowing of the stomach or intestines.

• You have short-term pain that you would expect to go away in a few days, such as:

• pain after surgery

• headache or migraine

• dental pain

  Before taking ABSTRAL, tell your healthcare provider if you have a history of:

• Troubled breathing …

• head injury

• seizures

• problems urinating

• liver, kidney, thyroid problems

• pancreas or gallbladder problems

• abuse of street or prescription drugs, alcohol addiction, or mental health problems

  Tell your healthcare provider if you are:

• pregnant or planning to become pregnant. Prolonged use of ABSTRAL may during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.

• breastfeeding or plan to breastfeed.. ABSTRAL passes into your breast milk and may harm your baby.

• taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking ABSTRAL with certain other medicines can cause serious side effects that could lead to death.

  When taking ABSTRAL:

• Do not change your dose. Take ABSTRAL exactly as prescribed by your healthcare provider.

• See the detailed Instructions for Use at the end of this Medication Guide for information about how to use ABSTRAL.

• Use ABSTRAL tablets whole.

• Do not crush, split, suck, or chew ABSTRAL tablets, or swallow the tablets whole. You will get less relief for your breakthrough cancer pain.

• Wait 30 minutes after using ABSTRAL. If there is any of the ABSTRAL tablet left in your mouth, you may drink a glass of water to help you swallow the left over medicine.

• Use 1 dose of ABSTRAL for an episode of breakthrough cancer pain.

• If your breakthrough cancer pain does not get better within 30 minutes after taking the first dose of ABSTRAL, you can use only 1 more dose …

• Wait at least 4 hours before treating a new episode of breakthrough cancer pain with ABSTRAL:

  • If you only need to take 1 dose of ABSTRAL for an episode of breakthrough pain, you must wait 4 hours from the time of that dose to take a dose of ABSTRAL for a new episode of breakthrough pain.

  • If you need to use 2 doses of ABSTRAL for an episode of breakthrough pain, you must wait 4 hours after the second dose to take a dose of ABSTRAL for a new episode of breakthrough pain.

• It is important for you to keep taking your around-the-clock opioid pain medicine while using ABSTRAL.

  If you begin to feel dizzy, sick to your stomach, or very sleepy before the tablet is completely dissolved, rinse your mouth with water and spit the remaining pieces of the tablet into a sink or toilet right away. Rinse the sink or flush the toilet to dispose of any remaining tablet pieces.

• Do not stop taking ABSTRAL without talking to your healthcare provider.

• After you stop taking, or when ABSTRAL is no longer needed, see “How should I dispose of unused ABSTRAL tablets when they are no longer needed?” for proper disposal of ABSTRAL.

• DO NOT Drive or operate heavy machinery, until you know how ABSTRAL affects you. ABSTRAL can make you sleepy, dizzy, or lightheaded.

• DO NOT Drink alcohol while using ABSTRAL. It can increase your chance of getting dangerous side effects. or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ABSTRAL may cause you to overdose and die.

• DO NOT Switch from ABSTRAL to other medicines that contain fentanyl without talking with your healthcare provider. The amount of fentanyl in a dose of ABSTRAL is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of ABSTRAL that may be different than other fentanyl medicines you may have been taking.

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is

greatest when starting ABSTRAL or when the dosage is increased, and that it can occur even at recommended dosages. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Increased Risk of Overdose and Death in Children Due to Accidental Ingestion

• Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.
• Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.
• Instruct patients to take steps to store ABSTRAL securely and to dispose of unused ABSTRAL by removing them from the blister cards and flushing down the toilet.
• Instruct patients and caregivers to keep both used and unused ABSTRAL out of the reach of children.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if ABSTRAL is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.

Addiction, Abuse, and Misuse

Inform patients that the use of ABSTRAL even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death. Instruct patients not to share ABSTRAL with others and to take steps to protect ABSTRAL from theft or misuse.

Transmucosal Immediate-Release Fentanyl (TIRF) REMS

Advise patients of the following information pertaining to the TIRF REMS

• Inform outpatients that they must be enrolled in the TIRF REMS Access program before they can receive ABSTRAL.
• As required by the TIRF REMS Access program, review the contents of the ABSTRAL Medication Guide with every patient before initiating treatment with ABSTRAL.
• Advise the patient that only enrolled healthcare providers may prescribe ABSTRAL.
• Inform the patient that they must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of ABSTRAL.

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 healthcare providers if they are taking, or plan to take serotonergic medications.

MAOI Interaction

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

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

Important Administration Instructions

• Inform patients on the meaning of opioid tolerance and that ABSTRAL is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication …
• Advise patients that, if they are not taking an opioid medication …
• Instruct patients to place ABSTRAL tablets on the floor of the mouth directly under the tongue immediately after removal from the blister unit.
• Instruct patients not to chew, suck, or swallow ABSTRAL tablets.
• Instruct patients to allow ABSTRAL tablets to completely dissolve in the sublingual cavity.
• Advise patients not to eat or drink anything until the tablet is completely dissolved.
• In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking ABSTRAL. Instruct patients not to take more than 2 doses of ABSTRAL for each episode of breakthrough cancer pain.
• Instruct patients to wait two hours before …

Hypotension

Inform patients that ABSTRAL may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in ABSTRAL. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform patients that prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treate.

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that ABSTRAL can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy.

Lactation

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs.

Infertility

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

Driving or Operating Heavy Machinery

Inform patients that ABSTRAL may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe cons and when to seek medical attention.

Disposal of Unused ABSTRAL

• In the event that a caregiver requires additional assistance in disposing of excess units that remain in the home after the drug is no longer needed, instruct them to call the toll-free number for Sentynl Therapeutics, Inc. 1-888-227-8725 or seek assistance from their local DEA office.

Other

(While the prior label was in PLR format, this label converts the label to the recommended Opioid Template)