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)]

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 VIVITROL, more than 1100 patients with alcohol and/or opioid dependence have been treated with VIVITROL. 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 VIVITROL discontinued treatment due to an adverse event, as compared to 7% of the alcohol-dependent patients treated with placebo. Adverse events in the VIVITROL 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 VIVITROL 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 VIVITROL group than in the placebo group. A majority of patients treated with VIVITROL 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 VIVITROL and occurring more frequently in the combined VIVITROL 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
	Diarrheaa)	21	10	3	12	27	13	27	13	57	13
	Abdominal painb)	17	8	4	16	23	11	23	11	50	11
	Dry Mouth	9	4	6	24	10	5	8	4	24	5
Infections & Infestations	Pharyngitisc)	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
	Anxietyd)	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 conditionse)	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 crampsf)	3	1	0	0	16	8	5	2	21	5
Skin & Subcutaneous Tissue Disorders	Rashg)	8	4	3	12	12	6	10	5	25	6
Nervous System Disorders	Headacheh)	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 VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL and occurring more frequently in the VIVITROL group than in the placebo group)
Body System	Adverse Event / Preferred Term	Placebo N=124		VIVITROL 380 mg N=126
Body System	Adverse Event / Preferred Term	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
Infections and Infestations	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 VIVITROL had increases in eosinophil counts relative to subjects on placebo. With continued use of VIVITROL, eosinophil counts returned to normal over a period of several months.

Platelet Count

VIVITROL 380 mg was associated with a decrease in platelet count. In clinical trials, alcohol-dependent patients treated with VIVITROL experienced a mean maximal decrease in platelet count of 17.8 × 103/μL, compared to 2.6 × 103/μL in placebo patients.

After 24 weeks of treatment, opioid-dependent patients treated with VIVITROL experienced a mean maximal decrease in platelet count of 62.8 × 103/μL, compared to 39.9 × 103/μL in placebo patients. In randomized controlled trials, VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL (14%) arm compared with the placebo (11%) arm. Opioid-dependent patients treated with VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL 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 VIVITROL 380 mg group.

Other Events Observed During the VIVITROL Clinical Studies

The following is a list of treatment-emergent adverse reactions reported by alcohol- and/or opioid-dependent subjects treated with VIVITROL 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 VIVITROL. VIVITROL 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 VIVITROL clinical trials or postmarketing surveillance. VIVITROL 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)].