A comprehensive management program for the treatment of alcohol dependence consists of both pharmacotherapy and psychosocial support such as counseling. Pharmacotherapy along with counseling can affect both the physical and psychosocial components of alcohol dependence. A 2-pronged approach addressing both brain areas is recommended for the treatment of addictive disease, as addictive drives are not primarily conscious.
We know that psychosocial support is an essential component in the treatment of alcohol dependence. However, relapse rates unfortunately remain high when it is used alone. Adding medication to psychosocial support has been recognized as beneficial by the NIAAA. But to date, adherence to oral medications approved for the treatment of alcohol dependence has been poor for a number of reasons. A study of 196 outpatients with alcohol dependence who were given oral naltrexone or placebo found that poor adherence rates were linked to higher relapse rates in a 12 week study. (In this study, patients were considered medication compliant if they took at least 80% of the pills prescribed.)
VIVITROL is administered as a gluteal IM injection once a month, which alleviates the burden of making daily medication decisions on the part of the patient. All other pharmaceutical agents approved in this therapeutic category are administered orally. Disulfiram is dosed at 125 to 500 mg orally in a single daily dose Oral naltrexone is dosed at one 50 mg tablet per day Acamprosate is dosed at 1998 mg per day taken as three doses of two 333 mg tablets each day
An outpatient setting in the VIVITROL phase III clinical trial meant a physician’s office or an outpatient clinic (not a day program). The study population was very similar to that which is seen in real-world treatment settings. VIVITROL is not intended to replace psychosocial support but to complement it. As you will see, when used as part of a program that includes psychosocial support, VIVITROL can significantly improve treatment outcomes in patients who are abstinent at treatment initiation.
VIVITROL has a black box warning for hepatotoxicity. VIVITROL does not appear to be a hepatotoxin at the recommended doses. The warning for oral naltrexone is based on a study that found seriously increased liver enzymes in obese patients who were given 2 to 6 times the recommended dose of daily oral naltrexone. Transient elevations in serum transaminases have been observed with high doses (several times higher; up to 300 mg/day) of oral naltrexone in disorders other than alcohol dependence; these elevations spontaneously reverse over a period of weeks, even with continued treatment. Hepatotoxicity has not been a finding in studies of alcohol-dependent subjects taking the standard recommended dose of oral naltrexone — 50 mg/day. In the VIVITROL phase III clinical trial, researchers specifically studied effects on the liver. They found that mean AST and ALT levels did not change significantly over the course of treatment or with medication. In short-term controlled trials, 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 subjects with mild to moderate hepatic impairment, no changes were noted in liver function after treatment with VIVITROL.
Eosinophilic pneumonia: In clinical trials with VIVITROL, there was one diagnosed case and one suspected case of eosinophilic pneumonia. Both cases required hospitalization and resolved after treatment with antibiotics and corticosteroids. Injection site reactions: In 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. Depression and suicidality: In controlled clinical trials of VIVITROL, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall but were more common in patients treated with VIVITROL than in patients treated with placebo (1% vs 0). Pain management: In an emergency situation in patients receiving VIVITROL, a suggested plan for pain management is regional analgesia, conscious sedation with a benzodiazepine, and use of non-opioid analgesics or general anesthesia. This slide reflects information included in the Contraindications, Warnings, Precautions, and Adverse Reactions sections of the VIVITROL full Prescribing Information.
Data for oral naltrexone beyond day 5 have been extrapolated from a study of normal healthy volunteers (n=14) given oral naltrexone 50 mg daily for 5 days. As you can see, looking at the gray line, daily dosing of oral naltrexone results in fluctuating plasma concentrations of the drug during the day. Naltrexone concentrations peak within the first hour of oral dosing, followed by a steady decline within 8 hours. This pattern recurs each day during treatment. In contrast, VIVITROL provides consistent release of naltrexone Transient initial peak occurs approximately 2 hours after injection Peak concentrations observed in approximately 2 to 3 days Steady state is achieved by the second dose 1 dose of VIVITROL (380 mg) is only ¼ of the cumulative dose of 1 month of oral naltrexone (1,500 mg) Plasma concentrations do not necessarily correlate with clinical efficacy or side effects Early phase Water absorption (hydration) causes the VIVITROL microspheres to swell Small amounts of naltrexone released slowly at or near the surface Extended-release phase—diffusion and erosion Polymer continues to break down Internal structures collapse and erode The polymer used with the Medisorb ® formulation of VIVITROL, PLG, has a history of safe use in humans. It has been used in absorbable sutures, abdominal mesh, bone plates, and other extended-release pharmaceuticals, including an atypical antipsychotic agent. Medisorb is a registered trademark of Alkermes, Inc.
The pharmacokinetic profile of VIVITROL is one feature that differentiates it from oral naltrexone. Due to the route of administration (intramuscular), there is Reduced first-pass hepatic metabolism as compared to oral naltrexone The primary metabolite is generated through reduction of the ketone to produce 6- naltrexol Mediated by dihydrodiol dehydrogenase Reduced total monthly dose Increased exposure VIVITROL is not metabolized by the CYP450 system. Although no clinical trials have been conducted specifically to address drug-drug interactions with VIVITROL, the phase III clinical trial admitted patients with treated depression who were stable on pharmacotherapy for at least 8 weeks. Naltrexone antagonizes the effect of opiate-containing medicines, such as cough and cold remedies, antidiarrheal preparations, and opioid analgesics. Patients should be advised that because VIVITROL can block the effects of opiates and opiate-like drugs, patients will not perceive any effect if they attempt to self administer heroin or any other opioid drug in small doses while on VIVITROL.
Steady state blood levels of VIVITROL are achieved by the second dose. There is minimal accumulation of naltrexone or its primary metabolite with repeat administration of VIVITROL. Elimination of naltrexone and its metabolites takes place via the urine. The half-life of VIVITROL is 5 to 10 days, depending on the erosion of the polymer.
As a once-monthly injection, VIVITROL eliminates the need for patients to make daily adherence decisions. One injection provides a month of medication Adherence to any treatment program is essential for successful outcomes In addition, VIVITROL must be administered by a healthcare provider, which ensures proper administration and dosing.
In the 24-week VIVITROL phase III trial, patients were treated in outpatient settings including physicians’ offices or outpatient clinics (not day programs). The study population was very similar to that which is seen in real-world treatment settings. The psychosocial treatment used in the VIVITROL clinical trial was BRENDA. BRENDA is a low-intensity intervention designed to facilitate direct feedback of addiction-related consequences. It consists of B iopsychosocial assessment R eporting the assessment to the patient (sharing the findings and conclusions) An E mpathetic approach (which might include active listening, encouragement of open discussion, and sympathetic interaction) Identified and stated patient N eeds D irect advice regarding drinking behavior A ssessment of treatment adherence BRENDA sessions were administered by psychologists, nurses, therapists, counselors, and physicians. Patients did not receive an oral naltrexone lead-in. The need for detoxification was determined by the investigator. In the placebo group, 128 patients (61%) completed the trial; in the XR-NTX 190 mg group, 126 patients (60%) completed; and in the VIVITROL 380 mg group, 124 patients (60%) of patients completed the trial. These completion rates are consistent with those seen in other clinical trials in alcohol dependence. Extended-release naltrexone 190 mg IM injection has not been approved by the FDA and will not be made commercially available.
Pretreatment characteristics of the patients in all treatment groups were similar XR-NTX 190 mg refers to the 190 mg dose of extended-release naltrexone microspheres All patients, abstinent at baseline or not, were heavy drinkers in the month before screening; patients were required to have had at least 2 heavy drinking days per week during the month before screening to be included in the trial Completers in the 7-day abstinent group were 15 (88.2%), 10 (55.6%), and 13 (72.2%) for VIVITROL 380 mg, XR-NTX 190 mg, and placebo, respectively
In the 24-week, multicenter, randomized, double-blind, placebo-controlled trial of alcohol-dependent outpatients, patients who were abstinent for a week prior to treatment initiation and received VIVITROL 380 mg in conjunction with psychosocial support had a greater reduction from baseline in the number of any drinking days than abstinent patients treated with placebo ( P =0.02). The patients did not receive oral naltrexone lead-in therapy. All patients received psychosocial support as part of treatment, and all patients received monthly gluteal IM injections.
Among patients who were abstinent for 7 days prior to treatment initiation, more than 40% of the patients receiving VIVITROL plus psychosocial support maintained abstinence throughout the 6-month trial period. The median number of days before patients had a drink was 84 in the VIVITROL 380 mg group and 29 in the placebo group.
Among patients receiving VIVITROL 380 mg or placebo in the 6-month trial, a statistically significant reduction in heavy drinking days was seen in those patients who were abstinent 7 days prior to treatment initiation. 60% of the patients completed the 6-month pivotal study, and 88% of the eligible patients who completed the study entered a 12-month extension study. 60 patients were switched from placebo to VIVITROL for up to 12 additional months while 115 patients continued on VIVITROL in this extension study. It was observed that the effect of VIVITROL continued over the full 18 months. In addition, patients who switched from placebo to VIVITROL at 6 months had a decline in the median number of HDD, ultimately to the same level as those patients who were treated with VIVITROL for the entire course of the study.
Patients treated with VIVITROL 380 mg demonstrated a greater reduction in days of heavy drinking than those treated with placebo. At the end of the trial, patients treated with VIVITROL had 48% fewer heavy drinking days than patients in the placebo group. As noted in the PI, abstinent patients treated with VIVITROL 380 mg had greater reductions in the number of drinking days and heavy drinking days than placebo-treated patients, and were also more likely than placebo-treated patients to maintain complete abstinence throughout treatment. The same treatment effects were not evident among actively drinking patients. At the end of the trial, patients who were switched at 6 months from placebo to VIVITROL 380 mg had a decline in the median number of heavy drinking days similar to those patients who received VIVITROL 380 mg for the duration of the trial. It was observed that the effect of VIVITROL continued over the full 18 months.
In all controlled and uncontrolled trials during the premarketing development of VIVITROL, more than 900 patients with alcohol and/or opioid dependence have been treated with VIVITROL 380 mg and XR-NTX 190 mg and 400 mg. Approximately 400 patients have been treated for 6 months or more, and 230 patients for 1 year or longer. In the phase III clinical trial, the percentage of patients who experienced serious adverse events during treatment was similar among the treatment groups: 11 (5.4%) in the VIVITROL 380 mg group 15 (7.2%) in the placebo group The most common serious adverse event was hospitalization for alcohol detoxification. Adverse events leading to discontinuation in patients treated with VIVITROL were injection site reactions, nausea, pregnancy, headache, and suicide-related events.
The most common adverse events for VIVITROL were based on data from more than 900 patients from all studies, which included VIVITROL 380 mg, and XR-NTX 190 mg and 400 mg. Approximately 400 patients have been treated for 6 months or more, and 230 patients for 1 year or longer. Injection site reaction (ISR) With VIVITROL injection site reaction includes injection site tenderness, induration, pain, and pruritus. The dropout rate attributed to injection site reaction was 3%. Placebo VIVITROL 380 mg Number of injections administered 518 968 No. (%) of injections followed by an ISR Any ISR 115 (22.2) 286 (29.5) Injection site tenderness 91 (17.6) 154 (15.9) Injection site induration 14 (2.7) 114 (11.8) Injection site pain 15 (2.9) 51 (5.3) Injection site ecchymosis 3 (0.6) 17 (1.8) Injection site pruritus 0 27 (2.8) Other 3 (0.6) 32 (3.3) Nausea Nausea was mild in the majority of reports. With VIVITROL, it usually occurred in the first month, and the median duration was a few days. Two percent of patients dropped out of the trial due to nausea.
There were 4 (2.0%) cases of inpatient hospitalization for detoxification in the VIVITROL 380 mg group and 7 cases (3.3%) in the placebo group.
An non-opioid analgesic should be considered for mild to moderate pain management.
If a patient misses a dose, he or she should be instructed to receive the missed dose as soon as possible. It is essential to locate the proper injection site. VIVITROL should be injected into the dorsogluteal site—the upper outer quadrant of the buttock. To locate the dorsogluteal site, draw an imaginary line from the top of the cleft in the buttocks to the greater trochanter. Draw another line vertically midway along the first line. The injection site is in the upper outer quadrant of this imaginary grid. Location of anatomical landmarks is very important for identifying the proper injection site. The sciatic nerve and superior gluteal arteries are located within a couple of centimeters of the intended injection site. Relying on visual estimating can result in an injection that is placed too low, possibly resulting in injury to underlying structures. VIVITROL injections must be given deep into the muscle to ensure optimal drug delivery. VIVITROL must be suspended only in the diluent supplied in the carton, and must be administered with the needle supplied in the carton. Do not make any substitutions for components of the carton.