1. Respiratory depression: 21, 22, 30, 31, 32, 33, 34, 35, 40, 43 TIRFs (Actiq®, Fentora®, Subsys®), Lazanda®, Duragesic®, Hydromorphone (Dilaudid, Exalgo®), Methadone, Morphine Sulfate: ArymoTM ER, Avinza®, Kadian®, and MS Contin®, Morphabond ER®, Nucynta ER®/ Opana ER®, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM, Roxybond®), Zohydro ER™ (hydrocodone ER), Buprenorphine (Belbuca and Butrans), benzhydrocodone/acetaminophen (Apadaz®), codeine polistirex and chlorpheniramine (Tuzistra XR), codeine phosphate and chlorpheniramine maleate (Tuxarin®), levorphanol, Qdolo® (tramadol), Seglentis® (tramadol/celecoxib)

Fatal respiratory depression has occurred in patients treated with the above listed opioid products, including following use in opioid-intolerant patients and improper dosing. Be sure to monitor for sign and symptoms of respiratory depression, especially during initiation of the drugs. The substitution of fentanyl sublingual/buccal for any other fentanyl product may result in fatal overdose. Because of the risk of respiratory depression, fentanyl products are contraindicated for use as an as-needed analgesic, or in the management of acute or postoperative pain, including headache/migraine and in opioid-intolerant patients. In addition, the concomitant use of fentanyl sublingual with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations and may cause potentially fatal respiratory depression.

For hydromorphone and ER products like morphine ER, oxycodone ER, hydrocodone ER, tapentadol ER, and oxymorphone ER products, instruct patients to swallow a whole tablet. Crushing, chewing, snorting, or dissolving tablets can cause rapid release and absorption that could lead to fatal overdose and even death. Note: Avinza® capsule contents may be sprinkled on applesauce and swallowed without chewing19. Hydromorphone is a potent Schedule II controlled opioid agonist. Schedule II opioid agonists have the highest potential for abuse and risk of producing respiratory depression. Alcohol, other opioids, and CNS depressants (sedative-hypnotics) potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death.

2. Medication errors: 32, 33 TIRFs (Actiq®, Fentora®, Subsys®), Lazanda®, codeine phosphate and chlorpheniramine maleate (Tuxarin®), codeine polistirex and chlorpheniramine (Tuzistra XR), Qdolo® (tramadol)

Substantial differences exist in the pharmacokinetic profile of fentanyl sublingual/buccal compared with other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose. When prescribing, do not convert patients on a mcg-per-mcg basis from any other fentanyl products to fentanyl sublingual/buccal. When dispensing, do not substitute a fentanyl sublingual/buccal prescription for other fentanyl products.

3. Addiction and Abuse potential: 21, 22, 30, 31, 32, 33, 34, 42, 43 TIRFs (Actiq®, Fentora®, Subsys®), Lazanda®, Duragesic®, Hydromorphone (Dilaudid, Exalgo®), Methadone, Morphine Sulfate: ArymoTM ER, Avinza®, Kadian®, and MS Contin®, Morphabond ER®, Nucynta ER®/ Opana ER®, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM, Roxybond®), Zohydro ER™ (hydrocodone ER), Buprenorphine (Belbuca and Butrans), benzhydrocodone/acetaminophen (Apadaz®), codeine phosphate and chlorpheniramine maleate (Tuxarin®), codeine polistirex and chlorpheniramine (Tuzistra XR), levorphanol, Qdolo® (tramadol), Seglentis® (tramadol/celecoxib)

All opioid analgesics regardless of formulation are classified as Schedule II controlled substance, with high abuse liability. They expose patients and drug users to the risk of opioid addiction, abuse, and misuse, which can lead to overdose and death. Diversion, addiction, and abuse potential should be considered when prescribing or dispensing opioid analgesics. Providers must monitor all patients regularly for the development of these behaviors or conditions. Due to the risk for misuse, abuse, addiction, and overdose, some products such as fentanyl sublingual/buccal is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access Program, outpatients, health care providers who prescribe to outpatients, pharmacies, and distributors must enroll in the program. Further information is available at http://www.TIRFREMSaccess.com or by calling 1-866-822-1483.

4. Cytochrome P450 3A4 interaction: 30, 31 TIRFs (Actiq®, Fentora®, Subsys®), Lazanda®, Duragesic®, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM ,Roxybond®), Zohydro ER™ (hydrocodone ER), benzhydrocodone/acetaminophen (Apadaz®), codeine polistirex and chlorpheniramine (Tuzistra XR), codeine phosphate and chlorpheniramine maleate (Tuxarin®), Qdolo® (tramadol), Seglentis® (tramadol/celecoxib)

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

5. Accidental exposure 21, 22, 30, 31, 32, 33, 34, 42, 43: Duragesic®, Hydromorphone (Dilaudid, Exalgo®), Methadone, Morphine Sulfate: ArymoTM ER, Avinza®, Kadian®, and MS Contin®, Morphabond ER® , Nucynta ER®/ Opana ER®, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM Roxybond®), Zohydro ER™, Buprenorphine (Belbuca and Butrans), benzhydrocodone/acetaminophen (Apadaz®), codeine polistirex and chlorphniramine (Tuzistra XR), codeine phosphate and chlorpheniramine maleate (Tuxarin®), levorphanol, Qdolo® (tramadol), Seglentis® (tramadol/celecoxib)

Deaths due to a fatal overdose of the above listed opioid analgesics have occurred when children and adults were accidentally exposed to the drugs. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure. Accidental ingestion of even 1 dose, especially in children, can result in a fatal overdose and death.

6. Neonatal opioid withdrawal syndrome: 21, 22, 30, 31, 32, 33, 34, 44, 43
Prolonged use of opioid analgesics especially Duragesic®, Hydromorphone (Dilaudid, Exalgo®), Methadone, Morphine Sulfate: ArymoTM ER, Avinza®, Kadian®, and MS Contin®, Morphabond ER® , Nucynta ER®/ Opana ER® (tapentadol ER, and oxymorphone ER), Zohydro ER™, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM, Roxybond®), Buprenorphine (Belbuca and Butran), benzhydrocodone/acetaminophen (Apadaz®), codeine phosphate and chlorpheniramine maleate (Tuxarin®), codeine polistirex and chlorpheniramine (Tuzistra XR), Qdolo® (tramadol), levorphanol , Seglentis® (tramadol/celecoxib)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.

7. Exposure to heat: Duragesic® (31)

Exposure of the fentanyl application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl and death. Patients wearing fentanyl systems who develop fever or increased core body temperature due to strenuous exertion are also at risk for increased fentanyl exposure and may require an adjustment in the dose of fentanyl to avoid overdose and death.

8. Life-threatening QT prolongation: Methadone 29

QT interval prolongation and serious arrhythmia like torsades de pointes have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Closely monitor patients for changes in cardiac rhythm during initiation and titration of methadone.

9. Treatment of opioid addiction: Methadone29

For detoxification and maintenance of opioid dependence, methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8, including limitations on unsupervised administration.

10. Interaction with alcohol 21, 22, 30, 31, 32, 33, 34, 35, 40: Morphine Sulfate: Avinza®, Kadian®, and MS Contin®, Nucynta ER®/ Opana ER®, Zohydro ER™, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM, Roxybond®), Buprenorphine (Belbuca and Butran), benzhydrocodone/acetaminophen (Apadaz®)

When using with alcohol, all opioid analgesic products have the potential to cause excessive sedation and may increase blood concentration of certain opioids like tapentadol, oxymorphone, and morphine. This could lead to fatal overdose and death. Instruct patients to avoid alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking opioid analgesics.

11. Information about oral morphine and oxycodone solution23, 29 : Morphine Sulfate: Avinza®, Kadian®, and MS Contin®, Oxycodone (Oxycontin®, oxycodone concentrate, OxaydoTM, Roxybond®)

Morphine oral solution is available in 10 mg per 5 mL, 20 mg per 5 mL, and 100 mg per 5 mL (20 mg/mL) concentrations. The 100 mg per 5 mL (20 mg/mL) concentration is indicated for use in opioid-tolerant patients only. Take care when prescribing and administering morphine oral solution to avoid dosing errors due to confusion between different concentrations and between milligrams and milliliters, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. Keep morphine oral solution out of the reach of children. In case of accidental ingestion, seek emergency medical help immediately.

Oxycodone concentrated oral solution is available as a 20 mg/mL concentration and is indicated for use in opioid-tolerant patients only. Take care when prescribing and administering oxycodone concentrated oral solution to avoid dosing errors due to confusion between milligram and milliliter, and other oxycodone solutions with different concentrations, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. Keep oxycodone out of the reach of children. In case of accidental ingestion, seek emergency medical help immediately.

12. Abuse Deterrent Technology: Oxaydo™ (37)

This formulation incorporates Acura's patented AVERSION® (abuse-deterrent) Technology which Acura states is a patented mixture of gelling ingredients and nasal irritants designed to address common forms of opioid abuse. OXAYDO can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing in situations where there is concern about an increased risk of misuse or abuse. OXAYDO may be abused by crushing, chewing, snorting or injecting the product and these practices pose a significant risk to the abuser that could result in overdose and death.

A Risk Evaluation and Mitigation Strategy (REMS) is included in the label of the several medications. A REMS is a safety strategy to manage known or potential serious risks associated with a medication and to enable patients to have continued access to such medicines by managing their safe use. Refer to the individual product labels for details on the REMS programs.

13. Risks from Concomitant Use with Benzodiazepines or other CNS Depressants: ArymoTM ER 42, Morphabond ER® 43, benzhydrocodone/acetaminophen (Apadaz®), codeine polistirex and chlorphniramine (Tuzistra XR), codeine phosphate and chlorpheniramine maleate (Tuxarin®), levorphanol, Qdolo® (tramadol), Seglentis® (tramadol/celecoxib)

Concomitant use of opioid with benzodiazepines or other CNS depressants may result in profound sedation, respiratory depressions, coma, and death.

14. Life threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. TUXARIN ER, TUZISTRA XR are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of TUXARIN ER, TUZISTRA XR for adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. 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. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

Life-threatening respiratory depression and death have occurred in children who received Qdolo® (tramadol). Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Qdolo® is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Qdolo® in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

15. Hepatotoxicity: benzhydrocodone/acetaminophen (Apadaz®)

APADAZ contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed

4000 milligrams per day, and often involve more than one acetaminophen-containing product.

16. Cardiovascular thrombotic events (Seglentis®)

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use. SEGLENTIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

17. Gastrointestinal bleeding, ulceration, and perforation (Seglentis®)

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms.

Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious (GI) events.

18. Ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children (Seglentis®)

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. SEGLENTIS is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of SEGLENTIS in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

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