Naltrexone

1 INDICATIONS AND USAGE Treatment with naltrexone for extended-release injectable suspension should be part of a comprehensive management program that includes psychosocial support. Naltrexone for extended-release injectable suspension contains naltrexone, an opioid antagonist, and is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with naltrexone for extended-release injectable suspension. Patients should not be actively drinking at the time of initial naltrexone for extended-release injectable suspension administration (1.1) . Naltrexone for extended-release injectable suspension is indicated for the prevention of relapse to opioid dependence, following opioid detoxification (1.2) . Naltrexone for extended-release injectable suspension should be part of a comprehensive management program that includes psychosocial support (1) . 1.1 Alcohol Dependence Naltrexone for extended-release injectable suspension is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with naltrexone for extended-release injectable suspension. Patients should not be actively drinking at the time of initial naltrexone for extended-release injectable suspension administration. 1.2 Opioid Dependence Naltrexone for extended-release injectable suspension is indicated for the prevention of relapse to opioid dependence, following opioid detoxification.

2 DOSAGE AND ADMINISTRATION Naltrexone for extended-release injectable suspension must be prepared and administered by a healthcare provider (2.1 , 2.6) . Prior to initiating naltrexone for extended-release injectable suspension, an opioid-free duration of a minimum of 7–10 days is recommended for patients, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization (2.1) . The recommended dose of naltrexone for extended-release injectable suspension is 380 mg delivered intramuscularly (deep) as a gluteal injection, every 4 weeks or once a month, alternating buttocks for each subsequent injection, using the carton components provided (2.1) . Naltrexone for extended-release injectable suspension must ONLY be administered as a deep intramuscular gluteal injection ( 2.1 ) . See Full Prescribing Information for complete Directions for Use (2.6) . 2.1 Important Dosage and Administration Information Naltrexone for extended-release injectable suspension must be prepared and administered by a healthcare provider. Naltrexone for extended-release injectable suspension must ONLY be administered as a deep intramuscular gluteal injection. Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial [see Dosage and Administration ( 2.6 ) ] . Prior to initiating naltrexone for extended-release injectable suspension, an opioid-free duration of a minimum of 7–10 days is recommended for patients, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization [see Warnings and Precautions ( 5.3 ) ]. The recommended dose of naltrexone for extended-release injectable suspension is 380 mg delivered intramuscularly (deep) as a gluteal injection every 4 weeks or once a month, alternating buttocks for each subsequent injection, using the carton components provided [see How Supplied/Storage and Handling ( 16 ) ] . The needles provided in the carton are customized needles. Naltrexone for extended-release injectable suspension must not be injected using any other needle. The needle lengths (either 1 1/2 or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that needle length is adequate for intramuscular administration. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate reaches the intramuscular mass. For very lean patients, the 1 1/2-inch needle may be appropriate to prevent the needle contacting the periosteum. Either needle may be used for patients with average body habitus. Healthcare providers should ensure that the naltrexone for extended-release injectable suspension injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the provided needles. If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible. Pretreatment with oral naltrexone is not required before using naltrexone for extended-release injectable suspension. 2.2 Patient Access to an Opioid Reversal Agent for the Emergency Treatment of Opioid Overdose At the initial naltrexone for extended-release injectable suspension injection and with each subsequent injection, inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose after naltrexone for…

5 WARNINGS AND PRECAUTIONS Vulnerability to Opioid Overdose : Following naltrexone for extended-release injectable suspension treatment, opioid tolerance is reduced from pretreatment baseline and patients are vulnerable to potentially fatal overdose at the end of a dosing interval, after missing a dose, or after discontinuing naltrexone for extended-release injectable suspension treatment. Attempts to overcome blockade may also lead to fatal overdose. Strongly consider recommending or prescribing an opioid reversal agent (e.g., naloxone, nalmefene) for the emergency treatment of opioid overdose (5.1) . Injection Site Reactions : Naltrexone for extended-release injectable suspension must be prepared and administered by a healthcare provider. In some cases, injection site reactions may be very severe. Some cases of injection site reactions required surgical intervention (5.2) . Precipitation of Opioid Withdrawal : Opioid-dependent and opioid-using patients, including those being treated for alcohol dependence, should be opioid-free before starting naltrexone for extended-release injectable suspension treatment, and should notify healthcare providers of any recent opioid use. An opioid-free duration of a minimum of 7-10 days is recommended for patients to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization (5.3) . Hepatotoxicity : Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone for extended-release injectable suspension treatment during the clinical development program and in the postmarketing period. Discontinue use of naltrexone for extended-release injectable suspension in the event of symptoms or signs of acute hepatitis (5.4) . Depression and Suicidality : Monitor patients for the development of depression or suicidal thinking (5.5) . When Reversal of Naltrexone for Extended-Release Injectable Suspension B lockade Is Required for Pain Management : In an emergency situation in patients receiving naltrexone for extended-release injectable suspension, suggestions for pain management include regional analgesia or use of non-opioid analgesics (5.6) . Eosinophilic Pneumonia : Patients who develop dyspnea and hypoxemia should seek medical attention immediately. Consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics (5.7) . Hypersensitivity Reactions Including Anaphylaxis : Cases of urticaria, angioedema, and anaphylaxis have been observed with the use of naltrexone for extended-release injectable suspension (5.8) . 5.1 Vulnerability to Opioid Overdose After opioid detoxification, patients are likely to have reduced tolerance to opioids. Naltrexone for extended-release injectable suspension blocks the effects of exogenous opioids for approximately 28 days after administration. However, as the blockade wanes and eventually dissipates completely, patients who have been treated with naltrexone for extended-release injectable suspension may respond to lower doses of opioids than previously used, just as they would have shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment. Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after naltrexone for extended-release injectable suspension treatment is discontinued, especially at the end of a dosing interval (i.e., near the end of the month that naltrexone for extended-release injectable suspension was administered), or after a dose of naltrexone for extended-release injectable suspension is missed. It is important that patients inform family member…

4 CONTRAINDICATIONS Naltrexone for extended-release injectable suspension is contraindicated in: Patients receiving opioid analgesics [see Warnings and Precautions ( 5.3 ) ] . Patients with current physiologic opioid dependence [see Warnings and Precautions ( 5.3 ) ] . Patients in acute opioid withdrawal [see Warnings and Precautions ( 5.3 ) ] . Any individual who has failed the naloxone challenge test or has a positive urine screen for opioids [see Warnings and Precautions ( 5.3 ) ] . Patients who have previously exhibited hypersensitivity to naltrexone, PLG, carboxymethylcellulose, or any other components of the diluent [see Warnings and Precautions ( 5.8 ) ]. Naltrexone for extended-release injectable suspension is contraindicated in: Patients receiving opioid analgesics (4) . Patients with current physiologic opioid dependence (4) . Patients in acute opioid withdrawal (4) . Any individual who has failed the naloxone challenge test or has a positive urine screen for opioids (4) . Patients who have previously exhibited hypersensitivity to naltrexone, polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other components of the diluent (4) .

7 DRUG INTERACTIONS Patients taking naltrexone for extended-release injectable suspension may not benefit from opioid-containing medicines. Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations and opioid analgesics. Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations, and opioid analgesics (7) .

8.1 Pregnancy Risk Summary The available data from published case series with naltrexone for extended-release injectable suspension use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are clinical considerations (see Clinical Considerations ). Reproduction and developmental animal studies have not been conducted for naltrexone for extended-release injectable suspension. Daily oral administration of naltrexone to female rats and rabbits increased the incidence of early fetal loss at exposures ≥ 11 times and ≥ 2 times the human exposure, respectively. Daily oral administration of naltrexone to pregnant rats and rabbits during the period of organogenesis did not induce malformation at exposures up to 175 times and 14 times the human exposure, respectively (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and embryo-fetal risk Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Published studies have demonstrated that alcohol is associated with fetal harm including growth restriction, facial abnormalities, central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Data Animal Data Reproduction and developmental studies have not been conducted for naltrexone for extended-release injectable suspension. Studies with naltrexone administered via the oral route have been conducted in pregnant rats and rabbits. Daily oral administration of naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥30 mg/kg/day (11 times the human exposure based on an AUC (0-28d) comparison) and to rabbits at oral doses ≥60 mg/kg/day (2 times the human exposure based on an AUC (0-28d) comparison). Daily oral administration of naltrexone to rats and rabbits during the period of organogenesis did not induce malformations at doses up to 200 mg/kg/day (175- and 14‑times the human exposure based on an AUC (0-28d) comparison, respectively).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Accidental Opioid Overdose [see Warnings and Precautions ( 5.1 ) ] Injection Site Reactions [see Warnings and Precautions ( 5.2 ) ] Precipitated Opioid Withdrawal [see Warnings and Precautions ( 5.3 ) ] Hepatotoxicity [see Warnings and Precautions ( 5.4 ) ] Depression and Suicidality [see Warnings and Precautions ( 5.5 ) ] Eosinophilic Pneumonia [see Warnings and Precautions ( 5.7 ) ] Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 ) ] The adverse events seen most frequently in association with naltrexone for extended-release injectable suspension therapy for alcohol dependence (i.e., those occurring in ≥5% and at least twice as frequently with naltrexone for extended-release injectable suspension than placebo) include nausea, vomiting, injection site reactions (including induration, pruritus, nodules and swelling), muscle cramps, dizziness or syncope, somnolence or sedation, anorexia, decreased appetite or other appetite disorders (6) . The adverse events seen most frequently in association with naltrexone for extended-release injectable suspension therapy in opioid-dependent patients (i.e., those occurring in ≥2% of patients treated with naltrexone for extended-release injectable suspension and at least twice as frequently with naltrexone for extended-release injectable suspension than placebo) were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache (6) . To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials during the premarketing development of naltrexone for extended-release injectable suspension, more than 1100 patients with alcohol and/or opioid dependence have been treated with naltrexone for extended-release injectable suspension. Approximately 700 patients have been treated for 6 months or more, and more than 400 for 1 year or longer. Adverse Events Leading to Discontinuation of Treatment Alcohol Dependence In controlled trials of 6 months or less in alcohol-dependent patients, 9% of alcohol-dependent patients treated with naltrexone for extended-release injectable suspension discontinued treatment due to an adverse event, as compared to 7% of the alcohol-dependent patients treated with placebo. Adverse events in the naltrexone for extended-release injectable suspension 380 mg group that led to more dropouts than in the placebo-treated group were injection site reactions (3%), nausea (2%), pregnancy (1%), headache (1%), and suicide-related events (0.3%). In the placebo group, 1% of patients withdrew due to injection site reactions, and 0% of patients withdrew due to the other adverse events. Opioid Dependence In a controlled trial of 6 months, 2% of opioid-dependent patients treated with naltrexone for extended-release injectable suspension discontinued treatment due to an adverse event, as compared to 2% of the opioid-dependent patients treated with placebo. Common Adverse Reactions Alcohol Dependence Table 1 lists all treatment-emergent clinical adverse reactions, regardless of causality, occurring in ≥5% of patients with alcohol dependence, for which the incidence was greater in the combined naltrexone for extended-releaser injectable suspension group than in the placebo group. A majority of patients treated with naltrexone for extended-release injectable suspension in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”. Table 1: Treatment-emergent Adverse Reactions (Reactions in ≥5% of patie…