Naltrexone

11 DESCRIPTION Naltrexone for extended-release injectable suspension is supplied as a microsphere formulation of naltrexone for suspension, to be administered by deep intramuscular injection by a healthcare practitioner. Naltrexone for extended-release injectable suspension contains naltrexone base anhydrous as the active pharmaceutical ingredient. Naltrexone is an opioid antagonist with little, if any, opioid agonist activity. Naltrexone is morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-(5α) (CAS Registry # 16590-41-3). The molecular formula is C 20 H 23 NO 4 and its molecular weight is 341.41 in the anhydrous form (ie, < 1% maximum water content). The structural formula is: Naltrexone base anhydrous is an off-white to a light tan powder with a melting point of 168 °C to 170 °C (334 °F to 338 °F). It is insoluble in water and is soluble in ethanol. Naltrexone for extended-release injectable suspension is provided in a carton containing one vial of naltrexone for extended-release injectable suspension microspheres, one vial of diluent, one 5-mL syringe, one 1-inch 20-gauge preparation needle, two 1 1/2-inch 20-gauge, and two 2-inch 20-gauge administration needles with needle protection device. Naltrexone for extended-release injectable suspension microspheres consist of a sterile, off-white to light tan powder that is available in a dosage strength of 380 mg of naltrexone per vial. Naltrexone base anhydrous is incorporated in a biodegradable matrix of 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres. The diluent is a clear, colorless solution. Each mL of diluent contains 30.0 mg of carboxymethylcellulose sodium, 1.0 mg of polysorbate 20, 9.0 mg of sodium chloride, and sodium hydroxide and hydrochloric acid as pH adjusters, in water for injection. The pH of the diluent is in the range of 5.8 to 7.2. Structural Formula

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 members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose [see Patient Counseling Information ( 17 ) ]. There is also the possibility that a patient who is treated with naltrexone for extended-release injectable suspension could overcome the opioid blockade effect of naltrexone for extended-release injectable suspension. Although naltrexone for extended-release injectable suspension is a potent antagonist with a prolonged pharmacological effect, the blockade produced by naltrexone for extended-release injectable suspension is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Any attempt by a patient to overcome the antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade [see Patient Counseling Information ( 17 ) ] . Patient Access to an Opioid Overdose 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 of the risks for opioid overdose described above, both at the initial naltrexone for extended-release injectable suspension injection and with each subsequent injection, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered. 5.2 Injection Site Reactions 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. Naltrexone for extended-release injectable suspension injections may be followed by pain, tenderness, induration, swelling, erythema, bruising, or pruritus; however, in some cases injection site reactions may be very severe. In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision. In the postmarketing period, additional cases of injection site reaction with features including induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported. Some cases required surgical intervention, including debridement of necrotic tissue. Some cases resulted in significant scarring. The reported cases occurred primarily in female patients. Naltrexone for extended-release injectable suspension is administered as a deep intramuscular gluteal injection, and inadvertent subcutaneous injection of naltrexone for extended-release injectable suspension may increase the likelihood of severe injection site reactions. 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 the proper needle is selected and that the 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. Patients should be informed that any concerning injection site reactions should be brought to the attention of the healthcare provider [see Patient Counseling Information ( 17 ) ] . Patients exhibiting signs of abscess, cellulitis, necrosis, or extensive swelling should be evaluated by a physician to determine if referral to a surgeon is warranted. 5.3 Precipitation of Opioid Withdrawal The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the administration of an opioid antagonist to an opioid-dependent patient , the resulting withdrawal syndrome can be severe enough to require hospitalization. Review of postmarketing cases of precipitated opioid withdrawal in association with naltrexone treatment has identified cases with symptoms of withdrawal severe enough to require hospital admission, and in some cases, management in the intensive care unit. To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or exacerbation of a pre-existing subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting naltrexone for extended-release injectable suspension treatment. An opioid-free interval of a minimum of 7–10 days is recommended for patients previously dependent on short-acting opioids. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks. If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed. In every case, healthcare providers should always be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use. Patients treated for alcohol dependence with naltrexone for extended-release injectable suspension should also be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone for extended-release injectable suspension. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids. 5.4 Hepatotoxicity Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone for extended-release injectable suspension exposure during the clinical development program and in the postmarketing period. Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials and postmarketing period. Although patients with clinically significant liver disease were not systematically studied, clinical trials did include patients with asymptomatic viral hepatitis infections. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae including acute liver injury. Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of naltrexone for extended-release injectable suspension should be discontinued in the event of symptoms and/or signs of acute hepatitis. 5.5 Depression and Suicidality Alcohol- and opioid-dependent patients, including those taking naltrexone for extended-release injectable suspension, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with naltrexone for extended-release injectable suspension should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider. Alcohol Dependence In controlled clinical trials of naltrexone for extended-release injectable suspension administered to adults with alcohol dependence, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in patients treated with naltrexone for extended-release injectable suspension than in patients treated with placebo (1% vs 0%). In some cases, the suicidal thoughts or behavior occurred after study discontinuation, but were in the context of an episode of depression that began while the patient was on study drug. Two completed suicides occurred, both involving patients treated with naltrexone for extended-release injectable suspension. Depression-related events associated with premature discontinuation of study drug were also more common in patients treated with naltrexone for extended-release injectable suspension (~1%) than in placebo-treated patients (0%). In the 24-week, placebo-controlled pivotal trial in 624 alcohol-dependent patients, adverse events involving depressed mood were reported by 10% of patients treated with naltrexone for extended-release injectable suspension 380 mg, as compared to 5% of patients treated with placebo injections. Opioid Dependence In an open-label, long-term safety study conducted in the US, adverse events of a suicidal nature (depressed mood, suicidal ideation, suicide attempt) were reported by 5% of opioid-dependent patients treated with naltrexone for extended-release injectable suspension 380 mg (n=101) and 10% of opioid-dependent patients treated with oral naltrexone (n=20). In the 24-week, placebo-controlled pivotal trial that was conducted in Russia in 250 opioid-dependent patients, adverse events involving depressed mood or suicidal thinking were not reported by any patient in either treatment group (naltrexone for extended-release injectable suspension 380 mg or placebo). 5.6 When Reversal of Naltrexone for Extended-Release Injectable Suspension Blockade 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. If opioid therapy is required as part of anesthesia or analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy must be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation. Irrespective of the drug chosen to reverse naltrexone for extended-release injectable suspension blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation. 5.7 Eosinophilic Pneumonia In clinical trials with naltrexone for extended-release injectable suspension, there was one diagnosed case and one suspected case of eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with antibiotics and corticosteroids. Similar cases have been reported in postmarketing use. Should a person receiving naltrexone for extended-release injectable suspension develop progressive dyspnea and hypoxemia, the diagnosis of eosinophilic pneumonia should be considered [see Adverse Reactions ( 6 ) ] . Patients should be warned of the risk of eosinophilic pneumonia, and advised to seek medical attention should they develop symptoms of pneumonia. Clinicians should consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics. 5.8 Hypersensitivity Reactions Including Anaphylaxis Cases of urticaria, angioedema, and anaphylaxis have been observed with use of naltrexone for extended-release injectable suspension in the clinical trial setting and in postmarketing use. Patients should be warned of the risk of hypersensitivity reactions, including anaphylaxis. In the event of a hypersensitivity reaction, patients should be advised to seek immediate medical attention in a healthcare setting prepared to treat anaphylaxis. The patient should not receive any further treatment with naltrexone for extended-release injectable suspension. 5.9 Intramuscular Injections As with any intramuscular injection, naltrexone for extended-release injectable suspension should be administered with caution to patients with thrombocytopenia or any coagulation disorder (e.g., hemophilia and severe hepatic failure). 5.10 Alcohol Withdrawal Use of naltrexone for extended-release injectable suspension does not eliminate nor diminish alcohol withdrawal symptoms. 5.11 Interference with Laboratory Tests Naltrexone for extended-release injectable suspension may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine. For further information, reference to the specific immunoassay instructions is recommended.

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 patients with alcohol dependence treated with naltrexone for extended-release injectable suspension and occurring more frequently in the combined naltrexone for extended-release injectable suspension group than in the placebo group) Body System Adverse Reaction / Preferred Term Placebo Naltrexone for Extended-Release Injectable Suspension N=214 400 mg N=25 380 mg N=205 190 mg N=210 All N=440 N % N % N % N % N % a) Includes the preferred terms: diarrhea NOS; frequent bowel movements; gastrointestinal upset; loose stools b) Includes the preferred terms: abdominal pain NOS; abdominal pain upper; stomach discomfort; abdominal pain lower c) Includes the preferred terms: nasopharyngitis; pharyngitis streptococcal; pharyngitis NOS d) Includes the preferred terms: anxiety NEC; anxiety aggravated; agitation; obsessive compulsive disorder; panic attack; nervousness; posttraumatic stress e) Includes the preferred terms: malaise; fatigue (these two comprise the majority of cases); lethargy; sluggishness f) Includes the preferred terms: muscle cramps; spasms; tightness; twitching; stiffness; rigidity g) Includes the preferred terms: rash NOS; rash papular; heat rash h) Includes the preferred terms: headache NOS; sinus headache; migraine; frequent headaches Gastrointestinal Disorders Nausea 24 11 8 32 68 33 53 25 129 29 Vomiting NOS 12 6 3 12 28 14 22 10 53 12 Diarrhea a ) 21 10 3 12 27 13 27 13 57 13 Abdominal pain b ) 17 8 4 16 23 11 23 11 50 11 Dry Mouth 9 4 6 24 10 5 8 4 24 5 Infections & Infestations Pharyngitis c ) 23 11 0 0 22 11 35 17 57 13 Psychiatric Disorders Insomnia, sleep disorder 25 12 2 8 29 14 27 13 58 13 Anxiety d ) 17 8 2 8 24 12 16 8 42 10 Depression 9 4 0 0 17 8 7 3 24 5 General Disorders & Administration Site Conditions Any ISR 106 50 22 88 142 69 121 58 285 65 Injection site tenderness 83 39 18 72 92 45 89 42 199 45 Injection site induration 18 8 7 28 71 35 52 25 130 30 Injection site pain 16 7 0 0 34 17 22 10 56 13 Other ISR (primarily nodules, swelling) 8 4 8 32 30 15 16 8 54 12 Injection site pruritus 0 0 0 0 21 10 13 6 34 8 Injection site ecchymosis 11 5 0 0 14 7 9 4 23 5 Asthenic conditions e ) 26 12 3 12 47 23 40 19 90 20 Musculoskeletal & Connective Tissue Disorders Arthralgia, arthritis, joint stiffness 11 5 1 4 24 12 12 6 37 9 Back pain, back stiffness 10 5 1 4 12 6 14 7 27 6 Muscle cramps f ) 3 1 0 0 16 8 5 2 21 5 Skin & Subcutaneous Tissue Disorders Rash g ) 8 4 3 12 12 6 10 5 25 6 Nervous System Disorders Headache h ) 39 18 9 36 51 25 34 16 94 21 Dizziness, syncope 9 4 4 16 27 13 27 13 58 13 Somnolence, sedation 2 1 3 12 8 4 9 4 20 5 Metabolism & Nutrition Disorders Anorexia, appetite decreased NOS, appetite disorder NOS 6 3 5 20 30 14 13 6 48 11 Opioid Dependence In the open-label, long-term safety study conducted in the US, the commonly reported adverse reactions among the opioid-dependent patients in the study were similar to those commonly observed events in the alcohol-dependent populations in naltrexone for extended-release injectable suspension clinical trials as displayed in Table 1, above. For example, injection site reactions of all types, nausea and diarrhea occurred in more than 5% of patients on naltrexone for extended-release injectable suspension in the open-label study. In contrast, 48% percent, of the opioid-dependent patients had at least one adverse event in the “Infections and Infestations” Body System. Adverse Reactions/Preferred Terms of nasopharyngitis, upper respiratory tract infection, urinary tract infection, and sinusitis were most commonly reported. In the placebo-controlled study in opioid-dependent patients conducted in Russia, the overall frequency of adverse events was lower than in the U.S. population described above. Table 2 lists treatment-emergent clinical adverse events, regardless of causality, occurring in ≥2% of patients with opioid dependence, for which the incidence was greater in the naltrexone for extended-release injectable suspension group than in the placebo group. All adverse events were assessed as having a maximum intensity of “mild” or “moderate.” Table 2: Treatment-emergent Clinical Adverse Events (Events in ≥2% of patients with opioid dependence treated with naltrexone for extended-release injectable suspension and occurring more frequently in the naltrexone for extended-release injectable suspension group than in the placebo group) Body System Adverse Event / Preferred Term Placebo N=124 Naltrexone for Extended-Release Injectable Suspension 380 mg N=126 n % n % Investigations Alanine aminotransferase increased 7 6 16 13 Aspartate aminotransferase increased 3 2 13 10 Gamma-glutamyltransferase increased 4 3 9 7 Infections and Infestations Nasopharyngitis 3 2 9 7 Influenza 5 4 6 5 Psychiatric Disorders Insomnia 1 1 8 6 Vascular Disorders Hypertension 4 3 6 5 General Disorders and Administration Site Conditions Injection site pain 1 1 6 5 Gastrointestinal Disorders Toothache 2 2 5 4 Nervous System Disorders Headache 3 2 4 3 Laboratory Tests Eosinophil Count In clinical trials, subjects on naltrexone for extended-release injectable suspension had increases in eosinophil counts relative to subjects on placebo. With continued use of naltrexone for extended-release injectable suspension, eosinophil counts returned to normal over a period of several months. Platelet Count Naltrexone for extended-release injectable suspension 380 mg was associated with a decrease in platelet count. In clinical trials, alcohol-dependent patients treated with naltrexone for extended-release injectable suspension experienced a mean maximal decrease in platelet count of 17.8 × 10 3 /µL, compared to 2.6 × 10 3 /µL in placebo patients. After 24 weeks of treatment, opioid-dependent patients treated with naltrexone for extended-release injectable suspension experienced a mean maximal decrease in platelet count of 62.8 × 10 3 /µL, compared to 39.9 × 10 3 /µL in placebo patients. In randomized controlled trials, naltrexone for extended-release injectable suspension was not associated with an increase in bleeding-related adverse events. Hepatic Enzyme Elevations In short-term, controlled trials, in alcohol-dependent patients, the incidence of AST elevations associated with naltrexone for extended-release injectable suspension treatment was similar to that observed with oral naltrexone treatment (1.5% each) and slightly higher than observed with placebo treatment (0.9%). In the 6-month controlled trial conducted in opioid-dependent subjects, 89% had a baseline diagnosis of hepatitis C infection, and 41% had a baseline diagnosis of HIV infection. There were frequently observed elevated liver enzyme levels (ALT, AST, and GGT); these were more commonly reported as adverse events in the naltrexone for extended-release injectable suspension 380 mg group than in the placebo group. Patients could not enroll in this trial if they had a baseline ALT or AST value that was more than three times the upper limit of normal. More patients treated with naltrexone for extended-release injectable suspension in this study experienced treatment-emergent elevations in transaminases to more than three times the upper limit of normal than patients treated with placebo. Shifts to more than three times the upper limit of normal occurred in 20% of patients treated with naltrexone for extended-release injectable suspension as compared with 13% of placebo patients. Shifts in values of AST to more than three times the upper limit were also more common in the naltrexone for extended-release injectable suspension (14%) arm compared with the placebo (11%) arm. Opioid-dependent patients treated with naltrexone for extended-release injectable suspension experienced a mean maximal increase from baseline ALT levels of 61 IU/L compared with 48 IU/L in placebo patients. Similarly for AST, opioid-dependent patients treated with naltrexone for extended-release injectable suspension experienced a mean maximal increase from baseline AST levels of 40 IU/L compared with 31 IU/L in placebo patients. Creatinine Phosphokinase In short-term controlled trials in alcohol-dependent patients, more patients treated with naltrexone for extended-release injectable suspension 380 mg (11%) and oral naltrexone (17%) shifted from normal creatinine phosphokinase (CPK) levels before treatment to abnormal CPK levels at the end of the trials, compared to placebo patients (8%). In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. For both the oral naltrexone and naltrexone for extended-release injectable suspension 380 mg groups, CPK abnormalities were most frequently in the range of 1–2 × ULN. However, there were reports of CPK abnormalities as high as 4x ULN for the oral naltrexone group, and 35 × ULN for the naltrexone for extended-release injectable suspension 380 mg group. Overall, there were no differences between the placebo and naltrexone (oral or injectable) groups with respect to the proportions of patients with a CPK value at least three times the upper limit of normal. No factors other than naltrexone exposure were associated with the CPK elevations. More opioid-dependent patients treated with naltrexone for extended-release injectable suspension 380 mg (39%) shifted from normal creatinine phosphokinase (CPK) levels before treatment to abnormal CPK levels during the study as compared to patients treated with placebo (32%). There were reports of CPK abnormalities as high as 41.8 × ULN for the placebo group, and 22.1 × ULN for the naltrexone for extended-release injectable suspension 380 mg group. Other Events Observed During the Naltrexone for Extended-Release Injectable Suspension Clinical Studies The following is a list of treatment-emergent adverse reactions reported by alcohol- and/or opioid-dependent subjects treated with naltrexone for extended-release injectable suspension in all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events that were so general as to be uninformative, and those events reported only once that did not have a substantial probability of being acutely life-threatening. Blood and Lymphatic System Disorders – lymphadenopathy (including cervical adenitis), white blood cell count increased Cardiac Disorders – angina pectoris, angina unstable, atrial fibrillation, cardiac failure congestive, coronary artery atherosclerosis, myocardial infarction, palpitations Eye Disorders – conjunctivitis, vision blurred Gastrointestinal Disorders – abdominal discomfort, colitis, constipation, flatulence, gastroesophageal reflux disease, gastrointestinal hemorrhage, hemorrhoids, pancreatitis acute, paralytic ileus, perirectal abscess General Disorders and Administration Site Conditions – chest pain, chest tightness, chills, face edema, irritability, lethargy, pyrexia, rigors Hepatobiliary Disorders – cholecystitis acute, cholelithiasis Immune System Disorders – seasonal allergy, hypersensitivity reaction (including angioneurotic edema and urticaria) Infections and Infestations – bronchitis, gastroenteritis, laryngitis, pneumonia, sinusitis, tooth abscess, upper respiratory tract infection, urinary tract infection, advanced HIV disease in HIV-infected patients Investigations – weight decreased, weight increased Metabolism and Nutrition Disorders – appetite increased, dehydration, heat exhaustion, hypercholesterolemia Musculoskeletal and Connective Tissue Disorders – joint stiffness, muscle spasms, myalgia, pain in limb Nervous System Disorders – cerebral arterial aneurysm, convulsions, disturbance in attention, dysgeusia, mental impairment, migraine, ischemic stroke, paresthesia Pregnancy, Puerperium, and Perinatal Conditions – abortion missed Psychiatric Disorders – abnormal dreams, agitation, alcohol withdrawal syndrome, euphoric mood, delirium, libido decreased Respiratory, Thoracic, and Mediastinal Disorders – chronic obstructive pulmonary disease, dyspnea, pharyngolaryngeal pain, sinus congestion Skin and Subcutaneous Tissue Disorders – night sweats, pruritus, sweating increased Vascular Disorders – deep venous thrombosis, hot flushes, pulmonary embolism 6.2 Postmarketing Experience Adverse Events Following Patient Self-Administration Adverse events including injection site reactions and precipitated opioid withdrawal resulting in serious outcomes, including hospitalization, have been reported following patient self-administration of naltrexone for extended-release injectable suspension. Naltrexone for extended-release injectable suspension must be prepared and administered by a healthcare provider. Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis have been reported during postmarketing surveillance. Reports From Other Intramuscular Drug Products Containing Polylactide-co-glycolide (PLG) Microspheres Retinal Artery Occlusion Retinal artery occlusion after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres has been reported very rarely during postmarketing surveillance. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during naltrexone for extended-release injectable suspension clinical trials or postmarketing surveillance. Naltrexone for extended-release injectable suspension should be administered by intramuscular (IM) injection into the gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel [see Dosage and Administration ( 2 ) ] .

8 USE IN SPECIFIC POPULATIONS Caution is recommended in administering naltrexone for extended-release injectable suspension to patients with moderate to severe renal impairment (8.6) . Naltrexone for extended-release injectable suspension pharmacokinetics have not been evaluated in subjects with severe hepatic impairment (8.7) . 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). 8.2 Lactation Risk Summary Naltrexone and its major metabolite, 6β-naltrexol, are present in human milk. There are no data on the effects on the breastfed infant or the effects on milk production. The developmental health benefits of breastfeeding should be considered along with the mother’s clinical need for naltrexone and any potential adverse effects on the breastfed infant from naltrexone or the mother’s underlying maternal condition. 8.4 Pediatric Use The safety and efficacy of naltrexone for extended-release injectable suspension have not been established in the pediatric population. The pharmacokinetics of naltrexone for extended-release injectable suspension have not been evaluated in a pediatric population. 8.5 Geriatric Use In trials of alcohol-dependent subjects, 2.6% (n=26) of subjects were >65 years of age, and one patient was >75 years of age. Clinical studies of naltrexone for extended-release injectable suspension did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. No subjects over age 65 were included in studies of opioid-dependent subjects. The pharmacokinetics of naltrexone for extended-release injectable suspension have not been evaluated in the geriatric population. This drug 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, it may be useful to monitor renal function. 8.6 Renal Impairment Pharmacokinetics of naltrexone for extended-release injectable suspension are not altered in subjects with mild renal insufficiency (creatinine clearance of 50-80 mL/min). Dose adjustment is not required in patients with mild renal impairment. Naltrexone for extended-release injectable suspension pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency. Because naltrexone and its primary metabolite are excreted primarily in the urine, caution is recommended in administering naltrexone for extended-release injectable suspension to patients with moderate to severe renal impairment [see Clinical Pharmacology ( 12.3 ) ] . 8.7 Hepatic Impairment The pharmacokinetics of naltrexone for extended-release injectable suspension are not altered in subjects with mild to moderate hepatic impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required in subjects with mild or moderate hepatic impairment. Naltrexone for extended-release injectable suspension pharmacokinetics were not evaluated in subjects with severe hepatic impairment [see Clinical Pharmacology ( 12.3 ) ] .

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).