Naltrexone XR Inj

VIVITROL® (naltrexone for extended-release injectable suspension) is supplied as a microsphere formulation of naltrexone for suspension, to be administered by intramuscular injection. Naltrexone is an opioid antagonist with little, if any, opioid agonist activity.

Naltrexone is designated chemically as morphinan-6-one, 17 (cyclopropylmethyl) 4,5-epoxy3,14-dihydroxy-(5α) (CAS Registry # 16590-41-3). The molecular formula is C20H23NO4 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 168170°C (334-338°F). It is insoluble in water and is soluble in ethanol.

VIVITROL is provided as a carton containing a vial each of VIVITROL microspheres and diluent, one 5-mL syringe, one 1-inch 20-gauge preparation needle, two 1 °-inch 20-gauge and two 2-inch 20-gauge administration needles with needle protection device.

VIVITROL 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 is incorporated in 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. The composition of the diluent includes carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection. The microspheres must be suspended in the diluent prior to injection.

Dosage Forms And Strengths

VIVITROL is an injectable suspension for single use. VIVITROL contains 380 mg of naltrexone in a microsphere formulation per vial (337 mg of naltrexone per gram of microspheres) and 4 mL diluent.

VIVITROL (naltrexone for extended-release injectable suspension) is supplied in single-use cartons. Each carton contains one 380-mg vial of VIVITROL microspheres, one vial containing 4 mL (to deliver 3.4 mL) of diluent for the suspension of VIVITROL, one 5-mL prepackaged syringe, one 1-inch 20-gauge needle, two 1 °-inch 20-gauge needles and two 2-inch 20-gauge needles with needle protection devices: NDC 65757-300-01.

Storage And Handling

The entire dose pack should be stored in the refrigerator (2 -8°C, 36 -46°F). Unrefrigerated, VIVITROL can be stored at temperatures not exceeding 25°C (77°F) for no more than 7 days prior to administration. Do not expose the product to temperatures above 25°C (77°F). VIVITROL should not be frozen.

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].

Keep out of Reach of Children.

Manufactured and marketed by: Alkermes, Inc. 852 Winter Street Waltham, MA 02451-1420. Revised: Dec 2015

Included as part of the PRECAUTIONS section.

There is limited experience with overdose of VIVITROL. Single doses up to 784 mg were administered to 5 healthy subjects. There were no serious or severe adverse events. The most common effects were injection site reactions, nausea, abdominal pain, somnolence, and dizziness. There were no significant increases in hepatic enzymes.

In the event of an overdose, appropriate supportive treatment should be initiated.

VIVITROL®

(viv-i-trol)
(naltrexone for extended-release injectable suspension)

Read this Medication Guide before you start receiving VIVITROL injections and each time you receive an injection. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about VIVITROL?

VIVITROL can cause serious side effects, including:

1. Risk of opioid overdose.

You can accidentally overdose in two ways.

• VIVITROL blocks the effects of opioids, such as heroin or opioid pain medicines. Do not take large amounts of opioids, including opioid-containing medicines, such as heroin or prescription pain pills, to try to overcome the opioid-blocking effects of VIVITROL. This can lead to serious injury, coma, or death.
• After you receive a dose of VIVITROL, its blocking effect slowly decreases and completely goes away over time. If you have used opioid street drugs or opioid-containing medicines in the past, using opioids in amounts that you used before treatment with VIVITROL can lead to overdose and death. You may also be more sensitive to the effects of lower amounts of opioids:
  • after you have gone through detoxification
  • when your next VIVITROL dose is due
  • if you miss a dose of VIVITROL
  • after you stop VIVITROL treatment

It is important that you tell your family and the people closest to you of this increased sensitivity to opioids and the risk of overdose.

You or someone close to you should get emergency medical help right away if you:

• have trouble breathing
• become very drowsy with slowed breathing
• have slow, shallow breathing (little chest movement with breathing)
• feel faint, very dizzy, confused, or have unusual symptoms

2. Severe reactions at the site of the injection (injection site reactions).

Some people on VIVITROL have had severe injection site reactions, including tissue death (necrosis). Some of these injection site reactions have required surgery. Call your healthcare provider right away if you notice any of the following at any of your injection sites:

• intense pain
• blisters
• the area feels hard
• an open wound
• large area of swelling
• a dark scab
• lumps

Tell your healthcare provider about any reaction at an injection site that concerns you, gets worse over time, or does not get better by two weeks after the injection.

3. Sudden opioid withdrawal.

Anyone who receives a VIVITROL injection must not use any type of opioid (must be opioid-free) including street drugs, prescription pain medicines, cough,cold, or diarrhea medicines that contain opioids, or opioid dependence treatments, buprenorphine or methadone, for at least 7 to 14 days before starting VIVITROL. Using opioids in the 7 to 14 days before you start receiving VIVITROL may cause you to suddenly have symptoms of opioid withdrawal when you get the VIVITROL injection. Sudden opioid withdrawal can be severe, and you may need to go to the hospital.

You must be opioid-free before receiving VIVITROL unless your healthcare provider decides that you don't need to go through detox first. Instead, your doctor may decide to give your VIVITROL injection in a medical facility that can treat you for sudden opioid withdrawal.

4. Liver damage or hepatitis. Naltrexone, the active ingredient in VIVITROL, can cause liver damage or hepatitis.

Tell your healthcare provider if you have any of the following symptoms of liver problems during treatment with VIVITROL:

• stomach area pain lasting more than a few days
• dark urine
• yellowing of the whites of your eyes
• tiredness

Your healthcare provider may need to stop treating you with VIVITROL if you get signs or symptoms of a serious liver problem.

What is VIVITROL?

VIVITROL is a prescription injectable medicine used to:

• treat alcohol dependence. You should stop drinking before starting VIVITROL.
• prevent relapse to opioid dependence, after opioid detoxification.

This means that if you take opioids or opioid-containing medicines, you must stop taking them before you start receiving VIVITROL. See “What is the most important information I should know about VIVITROL?”

To be effective, treatment with VIVITROL must be used with other alcohol or drug recovery programs such as counseling. VIVITROL may not work for everyone.

It is not known if VIVITROL is safe and effective in children.

Who should not receive VIVITROL?

Do not receive VIVITROL if you:

• are using or have a physical dependence on opioid-containing medicines or opioid street drugs. See “What is the most important information I should know about VIVITROL?”
• To see whether you have a physical dependence on opioid-containing medicines or opioid street drugs, your healthcare provider may give you a small injection of a medicine called naloxone. This is called a naloxone challenge test. If you get symptoms of opioid withdrawal after the naloxone challenge test, do not start treatment with VIVITROL at that time. Your healthcare provider may repeat the test after you have stopped using opioids to see whether it is safe to start VIVITROL.
• are having opioid withdrawal symptoms. Opioid withdrawal symptoms may happen when you have been taking opioid-containing medicines or opioid street drugs regularly and then stop.
  Symptoms of opioid withdrawal may include: anxiety, sleeplessness, yawning, fever, sweating, teary eyes, runny nose, goose bumps, shakiness, hot or cold flushes, muscle aches, muscle twitches, restlessness, nausea and vomiting, diarrhea, or stomach cramps. See “What is the most important information I should know about VIVITROL?” Tell your healthcare provider if you have any of these symptoms before taking VIVITROL.
• are allergic to naltrexone or any of the ingredients in VIVITROL or the liquid used to mix VIVITROL (diluent). See the end of this Medication Guide for a complete list of ingredients in VIVITROL and the diluent.

What should I tell my healthcare provider before receiving VIVITROL?

Before you receive VIVITROL, tell your healthcare provider if you:

• have liver problems
• use or abuse street (illegal) drugs
• have hemophilia or other bleeding problems
• have kidney problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if VIVITROL will harm your unborn baby.
• are breastfeeding. It is not known if VIVITROL passes into your milk, and if it can harm your baby. Naltrexone, the active ingredient in VIVITROL, is the same active ingredient in tablets taken by mouth that contain naltrexone. Naltrexone from tablets passes into breast milk. Talk to your healthcare provider about whether you will breastfeed or take VIVITROL. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take any opioid-containing medicines for pain, cough or colds, or diarrhea. See “What is the most important information I should know about VIVITROL?”

If you are being treated for alcohol dependence but also use or are addicted to opioid-containing medicines or opioid street drugs, it is important that you tell your healthcare provider before starting VIVITROL to avoid having sudden opioid withdrawal symptoms when you start VIVITROL treatment.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How will I receive VIVITROL?

• VIVITROL is injected by a healthcare provider, about 1 time each month.
• VIVITROL is given as an injection into a muscle in your buttocks using a special needle that comes with VIVITROL.
• After VIVITROL is injected, it lasts for a month and it cannot be removed from the body.
• If you miss your appointment for your VIVITROL injection, schedule another appointment as soon as possible. See “What is the most important information I should know about VIVITROL?”
• Whenever you need medical treatment, be sure to tell the treating healthcare provider that you are receiving VIVITROL injections and mention when you got your last dose. This is important because VIVITROL can also block the effects of opioid-containing medicines that might be prescribed for you for pain, cough or colds, or diarrhea.
• Carry written information with you at all times to alert healthcare providers that you are taking VIVITROL, so that they can treat you properly in an emergency. Ask your healthcare provider how you can get a wallet card to carry with you.

What should I avoid while receiving VIVITROL?

Do not drive a car, operate machinery, or do other dangerous activities until you know how VIVITROL affects you. VIVITROL may make you feel dizzy and sleepy. See “What are the possible side effects of VIVITROL?”

What are the possible side effects of VIVITROL?

VIVITROL can cause serious side effects, including:

• See “What is the most important information I should know about VIVITROL?”
• Depressed mood. Sometimes this leads to suicide, or suicidal thoughts, and suicidal behavior. Tell your family members and people closest to you that you are taking VIVITROL.
  You, a family member, or the people closest to you should call your healthcare provider right away if you become depressed or have any of the following symptoms of depression, especially if they are new, worse, or worry you:
  • You feel sad or have crying spells.
  • You are no longer interested in seeing your friends or doing things you used to enjoy.
  • You are sleeping a lot more or a lot less than usual.
  • You feel hopeless or helpless.
  • You are more irritable, angry, or aggressive than usual.
  • You are more or less hungry than usual or notice a big change in your body weight.
  • You have trouble paying attention.
  • You feel tired or sleepy all the time.
  • You have thoughts about hurting yourself or ending your life.
• Pneumonia. Some people receiving VIVITROL treatment have had a certain type of pneumonia that is caused by an allergic reaction. If this happens to you, you may need to be treated in the hospital. Tell your healthcare provider right away if you have any of these symptoms during treatment with VIVITROL:
  • shortness of breath or wheezing
  • coughing that does not go away
• Serious allergic reactions. Serious allergic reactions can happen during or soon after an injection of VIVITROL. Tell your healthcare provider or get medical help right away if you have any of these symptoms of a serious allergic reaction.
  • skin rash
  • swelling of your face, eyes, mouth, or tongue
  • trouble breathing or wheezing
  • chest pain
  • feeling dizzy or faint

Common side effects of VIVITROL may include:

nausea. Nausea may happen after your first VIVITROL injection and usually improves within a few days. Nausea is less likely with future injections of VIVITROL.

• sleepiness
• headache
• dizziness
• vomiting
• decreased appetite
• painful joints
• muscle cramps
• cold symptoms
• trouble sleeping
• toothache

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the side effects of VIVITROL. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about VIVITROL

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about VIVITROL. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about VIVITROL that is written for health professionals.

For more information about VIVITROL call 1-800-848-4876, Option #1 or go to www.vivitrol.com.

What are the ingredients in VIVITROL?

Active ingredient: naltrexone

Inactive ingredients: polylactide-co-glycolide (PLG)

Diluent ingredients: carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Serious adverse reactions that may be associated with VIVITROL therapy in clinical use include: severe injection site reactions, eosinophilic pneumonia, serious allergic reactions, unintended precipitation of opioid withdrawal, accidental opioid overdose and depression and suicidality.

The adverse events seen most frequently in association with VIVITROL therapy for alcohol dependence (ie, those occurring in ≥ 5% and at least twice as frequently with VIVITROL 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.

The adverse events seen most frequently in association with VIVITROL therapy in opioid-dependent patients (ie, those occurring in ≥ 2% and at least twice as frequently with VIVITROL than placebo) were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.

Clinical Studies 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

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.

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

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)

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)

Laboratory Tests

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.

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 x 103/μL, compared to 2.6 x 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 x 103/μL, compared to 39.9 x 103/μL in placebo patients. In randomized controlled trials, VIVITROL was not associated with an increase in bleeding-related adverse events.

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.

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 x ULN. However, there were reports of CPK abnormalities as high as 4x ULN for the oral naltrexone group, and 35 x 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 x ULN for the placebo group, and 22.1 x 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

Postmarketing Reports

Hypersensitivity reactions including anaphylaxis have been reported during postmarketing surveillance.

Retinal Artery Occlusion

Retinal artery occlusion after injection with another drug product containing polylactide-coglycolide (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].

Read the entire FDA prescribing information for Vivitrol (Naltrexone XR Inj)