Label Changes for:

Duragesic (fentanyl transdermal system)

April 2014

Changes have been made to the BOXED WARNING, WARNINGS and PRECAUTIONS sections of the safety label.

Including:

Avinza (morphine sulfate) Extended-Release Capsules
Butrans (buprenorphine) Transdermal System
Dolophine (methadone hydrochloride) Tablets
Duragesic (fentanyl transdermal system)
Embeda (morphine sulfate and naltrexone hydrochloride) Extended-Release Capsules
Exalgo (hydromorphone HCl) Extended-Release Tablets
Kadian (morphine sulfate) Extended-Release Capsules
MS Contin (morphine sulfate) Extended-Release Tablets
Nucynta ER (tapentadol) extended-release tablets
Opana ER (oxymorphone hydrochloride) Extended-Release Tablets
Oxycontin (oxycodone hydrochloride) Extended-Release Tablets
Palladone (hydromorphone hydrochloride) Extended-Release Capsules

 

The following information is a standard template for labeling changes for all ER/LA opioid analgesics included in this regulatory action; however, there are minor differences between products related to drug-specific characteristics.


 

BOXED WARNING

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL (last warning only for products that have an interaction with alcohol)

Addiction, Abuse, and Misuse

[[Tradename]] 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 [Tradename], and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of [Tradename]. Monitor for respiratory depression, especially during initiation of [Tradename] or following a dose increase. Instruct patients to swallow [Tradename] (formulation; e.g., tablets, capsules) whole; crushing, chewing, or dissolving [Tradename] (formulation) can cause rapid release and absorption of a potentially fatal dose of (active opioid) [see Warnings and Precautions(5.2)].

Accidental Exposure

Accidental [ingestion/exposure] of even one dose of [Tradename], especially by children, can result in a fatal overdose of (active opioid) [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of [TRADENAME] 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 [see Warnings and Precautions (5.3)].

Interaction with Alcohol (This subheading and text should be included in the boxed warning only for products that have an interaction with alcohol.)

Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking [Tradename]. The co-ingestion of alcohol with [Tradename] may result in increased plasma levels and a potentially fatal overdose of (active opioid) [see Warnings and Precautions (5.4)].

 

1 INDICATIONS AND USAGE

[Tradename] is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use

  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve [Tradename] for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
  • [Tradename] is not indicated as an as-needed (prn) analgesic.
     

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse (Replaces subsection “Abuse Potential”)

[Tradename] contains (active opioid), a Schedule II controlled substance. As an opioid, [Tradename] exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As modified-release products such as [Tradename] deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of (active opioid) present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed [Tradename] and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing [Tradename], and monitor all patients receiving [Tradename] 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of [Tradename] for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as [Tradename], but use in such patients necessitates intensive counseling about the risks and proper use of [Tradename] along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of [Tradename] by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the (active opioid) and can result in overdose and death [see Overdosage (10)].

5.2 Life-threatening Respiratory Depression (Now incorporates subsection “Accidental Exposure”)

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, 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 (10)]. 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 [Tradename], the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with [Tradename] and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of [Tradename] are essential [see Dosage and Administration (2)]. Overestimating the [Tradename] dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental [ingestion/exposure] of even one dose of [Tradename], especially by children, can result in respiratory depression and death due to an overdose of (active opioid).

5.3 Neonatal Opioid Withdrawal Syndrome (New)

Prolonged use of OPANA ER during pregnancy can result in withdrawal signs 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. 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.

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. 

5.4 Interactions with Central Nervous System Depressants (Replaces subsections “Interactions with CNS Depressants and Illicit Drugs” and “Interactions with Alcohol”)

Include this paragraph only for products that have an interaction with alcohol.

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on [Tradename] therapy. The co-ingestion of alcohol with [Tradename] may result in increased plasma levels and a potentially fatal overdose of (active opioid) [see Clinical Pharmacology (12.3)]. Hypotension, profound sedation, coma, respiratory depression, and death may result if [Tradename] is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of [Tradename] in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin [Tradename] is made, start with [Tradename] X mg every X hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.x)].

5.5 Use in Elderly, Cachectic, and 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 and titrating [Tradename] and when [Tradename] is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].

7 DRUG INTERACTIONS

7.1 Alcohol (Include this subsection for products with an interaction with alcohol.) Concomitant use of alcohol with [Tradename] can result in an increase of (active opioid) plasma levels and potentially fatal overdose of (active opioid). Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on [Tradename] therapy [see Clinical Pharmacology (12.3)].
7.X CNS Depressants

The concomitant use of [Tradename] with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and [Tradename] for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)].

7.X Drugs Affecting Cytochrome P450 Isoenzymes (Include subsection only for products that have an effect on cytochrome P450 isoenzymes)

7.x Inhibitors of CYP3A4 and 2D6

Because the CYP3A4 isoenzyme plays a major role in the metabolism of (active opioid), drugs that inhibit CYP3A4 activity may cause decreased clearance of (active opioid) which could lead to an increase in (active opioid) plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP 2D6 and 3A4 inhibitors. If co-administration with [Tradename] is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].

7.xInducers of CYP3A4

CYP450 3A4 inducers may induce the metabolism of (active opioid) and, therefore, may cause increased clearance of the drug which could lead to a decrease in (active opioid) plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to (active opioid). If co-administration with [Tradename] is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].

After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)].

Teratogenic Effects - Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. [Tradename] should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Follow with drug-specific nonclinical data.

17 PATIENT COUNSELING INFORMATION

Addiction, Abuse, and Misuse

Inform patients that the use of [Tradename], even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share [Tradename] with others and to take steps to protect [Tradename] from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening of respiratory depression, including information that the risk is greatest when starting [Tradename] or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental [Ingestion/Exposure]

Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store [Tradename] securely and to dispose of unused [Tradename] by flushing the (formulation) down the toilet.

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that chronic use of [Tradename] during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3)].

Interactions with Alcohol and other CNS Depressants

For products with an interaction with alcohol, include the following as the first paragraph under this subheading:

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the counter products that contain alcohol, during treatment with [Tradename]. The co-ingestion of alcohol with [Tradename] may result in increased plasma levels and a potentially fatal overdose of (active opioid) [see Warnings and Precautions (5.4)]. Inform patients that potentially serious additive effects may occur if [Tradename] is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.

MEDICATION GUIDE

In addition to the changes described above, the new safety information should be included in the medication guide for the class of ER/LA opioid analgesics, of which [Tradename] is a member. Amend the following updated medication guide with appropriate product-specific information:

Medication Guide

TRADENAME (phonetic pronunciation) (drug substance) Drug formulation, CII

TRADENAME is:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
  • A long-acting (extended-release) 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.
  • Not for use to treat pain that is not around-the-clock.

Important information about TRADENAME:

  • Get emergency help right away if you take too much TRADENAME (overdose). When you first start taking TRADENAME, when your dose is changed, or if you take too much (overdose), serious or life threatening breathing problems that can lead to death may occur.
  • Never give anyone your TRADENAME. They could die from taking it. Store TRADENAME away from children and in a safe place to prevent stealing or abuse. Selling or giving away TRADENAME is against the law.

Do not take TRADENAME if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.

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

  • head injury, seizures, liver, kidney, thyroid problems
  • problems urinating ? 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. TRADENAME may harm your unborn baby. Long-term (chronic) use during pregnancy can cause life-threatening withdrawal symptoms in your newborn baby.
  • breastfeeding. TRADENAME passes into breast milk and may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking TRADENAME with certain other medicines can cause serious side effects.

When taking TRADENAME:

  • Do not change your dose. Take TRADENAME exactly as prescribed by your healthcare provider.
  • Take your prescribed dose every x hours, at the same time every day. Do not take more than your prescribed dose in x hours. If you miss a dose, take your next dose at your usual time the next day.
  • Do not cut, break, chew, crush, dissolve, snort, or inject TRADENAME because this may cause you to overdose and die.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • Do not stop taking TRADENAME without talking to your healthcare provider.
  • After you stop taking TRADENAME, flush any unused tablets down the toilet.

While taking TRADENAME DO NOT:

  • Drive or operate heavy machinery until you know how TRADENAME affects you. TRADENAME can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol, or use prescription or over-the-counter medicines containing alcohol. Using products containing alcohol during treatment with TRADENAME may cause you to overdose and die.

The possible side effects of TRADENAME are:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, low blood pressure when changing positions, or you are feeling faint.

These are not all the possible side effects of TRADENAME. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

This Medication Guide has been approved by the U.S. Food and Drug Administration Issue: [Month] 2014

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