Vivitrol

General characteristics. Structure:

Powder (active agent): the naltrexone encapsulated in copolymer of lactic and glycolic acid (polymer: 75:25 DL JN1). The bottle contains 430 mg of naltrexone (surplus of 12,9%).

Solvent: a karmelloza of sodium (sodium carboxymethylcellulose), polysorbate 20, sodium chloride, water for injections. The bottle contains 4,0 ml of solvent.

Description.
Sterile powder and sterile solvent for preparation of suspension for intramuscular introduction of the prolonged action.
Powder from white or almost white till light-yellowy-brown color, without visible foreign inclusions; it is easily suspended in solvent without formation of agglomerates.
Solvent: transparent colourless liquid.
The recovered suspension from color, white to white with slightly yellowish-brown shade; has to pass through the needle (which is included in the package) with a small resistance or without resistance. There should not be a solvent exit without suspension.

Pharmacological properties:

Pharmakodinamichesky properties.

Naltrexone represents the antagonist of opioid receptors with the greatest affinity to opioid mu receptors.

In addition to blockade of opioid receptors, drug has no other pharmacological activity. Use of drug for the unknown reasons can cause narrowing of a pupil. Vivitrol's use does not cause accustoming or medicinal dependence. With physical opioid dependence administration of drug causes symptoms of "cancellation" in patients.

The neurobiological mechanisms responsible for decrease in consumption of alcohol observed at the patients who are treated naltrexone with alcohol addiction are clear not to a vpolny measure, but it is supposed that the mechanism of action mentions endogenous opioid system.

Naltrexone blocks effect of opioids, competitively contacting opioid receptors. Blockade of effect of naltrexone can be eliminated with introduction of high doses of opioids that can lead to increase in release of a histamine with a characteristic clinical picture. Linkng with opioid receptors can block effects of endogenous opioid peptides.

Vivitrol is not means of aversivny therapy and does not cause disulfiramopodobny reaction at reception of opiates or alcohol.

Pharmacokinetics.

Absorption. Vivitrol represents the drug of the prolonged action intended for intramuscular injections each 4 weeks or once a month. After intramuscular introduction change of concentration of naltrexone in a blood plasma is characterized by initial peak with a maximum approximately in 2 hours after introduction and the second peak in 2-3 days. Beginning approximately from the 14th day after administration of drug, its concentration in plasma gradually decreases, but measurable concentration remains more than 1 month.

The maximum concentration (Cmax) and the area under a curve "concentration time" of naltrexone and his main metabolite – 6 - beta налтрексола – in a blood plasma are proportional to the entered Vivitrol's dose. The general exposure of naltrexone after single introduction of 380 mg of Vivitrol is 3-4 times higher in comparison with his intake in number of 50 mg within 28 days. After the first injection equilibrium concentration is reached by the end of an interdose interval. After repeated introduction of Vivitrol the minimum cumulation (less than 15%) of naltrexone or a 6-beta naltreksol is observed.

Distribution.

Naltrexone poorly contacts proteins of a blood plasma of in vitro (21%).

Metabolism.

Naltrexone is exposed to active metabolism in an organism. The main metabolite – 6-beta налтрексол – is formed by cytosolic enzyme of digidrodioldegidrogenazy. Enzymes of system of P450 cytochrome do not participate in metabolism of naltrexone. Other metabolites are 2 - hydroxy - 3 - метокси - 6 - beta naltreksol and 2-hydroxy-3-metoksi-naltrexone. Naltrexone and his metabolites form conjugates with a glucuronide. At intramuscular introduction of Vivitrol in comparison with peroral it is formed much less than 6 - beta налтрексола that is caused by reduced presistemny metabolism in a liver.

Removal from an organism.

Naltrexone and his metabolites are removed generally with urine, and in an invariable look the minimum quantity of drug is removed. The elimination half-life of naltrexone makes 5-10 days and depends on extent of degradation of polymer.

The elimination half-life 6 - beta налтрексола makes 5-10 days.

Pharmacokinetics at patients with a renal and liver failure.

Liver failure.

 Vivitrol's pharmacokinetics does not change at patients with a lung or moderately expressed abnormal liver function (classes A and B on Chayld-Pyyu). It is not required to such patients of dose adjustment. At patients with a heavy abnormal liver function Vivitrol's pharmacokinetics was not studied.

Renal failure.

Results of pharmacokinetic analyses specify that the slight renal failure (clearance of creatinine of 50-80 ml/min.) almost does not influence Vivitrol's pharmacokinetics and need for dose adjustment of drug is absent. At patients with moderately expressed and heavy renal failure Vivitrol's pharmacokinetics was not studied.

Influence of a floor.

The research conducted with participation of healthy patients of both sexes (18 women and 18 men) showed that the sex of patients does not influence Vivitrol's pharmacokinetics.

Influence of age and race.

Vivitrol's pharmacokinetics was not studied at elderly patients, children and representatives of different races.

Indications to use:

1. Drug is shown for treatment of alcohol addiction at the patients capable to refrain from alcohol intake before an initiation of treatment. Patients should not consume actively alcohol in an initiation of treatment Vivitrol.

2. Drug is shown for prevention of a recurrence of opioid dependence after an opioid detoxication.

Opioidzavisimy patients, including patients who receive treatment against alcohol addiction, should not accept opioids in an initiation of treatment drug. Treatment by drug has to be a part of the appropriate program of elimination of the dependence including psychosocial support.

Children and elderly patients. Data on safety and efficiency of use of drug for children are absent. Clinical tests of Vivitrol included the insufficient number of patients 65 years are more senior to compare effect of treatment at elderly patients and at younger patients.

Route of administration and doses:

Vivitrol the qualified health workers only with use of the components which are available in packaging have to enter. It is impossible to replace packaging components. The recommended Vivitrol's dose makes 380 mg in oil once in 4 weeks or once a month. The drug should be administered in a gluteus, alternating buttocks. Vivitrol it is impossible to enter intravenously and subcutaneously! If the patient misses introduction of the next dose, the following injection has to be made as soon as possible. Before Vivitrol's use oral administration of naltrexone is not required.

Resuming of treatment after a break.

Data on resuming of treatment after a break are absent. Transfer of patients with alcohol addiction from peroral naltrexone on Vivitrol Net of systematic data on transfer of patients from peroral naltrexone on Vivitrol.

Instructions on suspension preparation.

For preparation of suspension it is necessary to use only the solvent delivered in a set. It is necessary to administer the drug only the needle which is in a set. All components of packaging – a bottle with powder, a bottle with solvent, a needle for preparation of suspension and a needle for an injection with a protective cap – are necessary for administration of drug. In a set there is also a reserve needle for an injection with a protective cap. Do not replace the components which are in a set. To provide exact dosing it is necessary to follow accurately instructions on preparation and administration of drug. Follow rules of an asepsis.

Enter set:

1 bottle with powder;

1 bottle with solvent;

1 one-time syringe;

1 short needle for suspension preparation;

2 needles for an injection with a protective cap;

Instruction on a medical use of drug.

1. Before use get packaging with drug from the refrigerator and let's it heat up to the room temperature (about 45 minutes).

2. For simplification of hashing knock with a bottle bottom with powder on a firm surface to loosen powder.

3. Remove aluminum covers from both bottles. Do not use drug if the cover of bottles is damaged or is absent.

4. Wipe necks of bottles with a spirit napkin.

5. Put on a short needle for preparation of suspension the syringe and select 3,4 ml of solvent from a bottle with solvent. In a bottle there will be a solvent quantity.

Enter 3,4 ml of solvent into a bottle with powder.

Mix solvent and powder, intensively stirring up a bottle within about 1 minute. Before continuing be convinced that suspension is homogeneous. Correctly mixed suspension has to be milky-white color, without lumps and freely flow down on bottle walls.

1. At once after preparation select 4,2 ml of suspension in the syringe, using a needle for suspension preparation.

2. Remove this needle and put on the syringe a needle for an injection.

Before an injection knock on the syringe for release of vials of air, then carefully press on the piston in the syringe so far there will be no 4 ml of suspension left.

Suspension is ready for immediate introduction.

1. The hypodermic needle is entered deeply into a gluteus. After that the podsasyvayushchy movement of the piston check whether the needle got to a vessel (if got, blood is thrown in the syringe). At emergence of blood it is necessary to repeat the procedure, previously having replaced a needle with reserve.

2. The drug is administered the smooth movement deeply in a gluteus. Suspension is entered alternately into different buttocks.

3. Vivitrol it is impossible to enter intravenously and subcutaneously.

After administration of drug close a needle a protective cap, having pressed it one hand to a firm surface and keeping in the direction from itself. Use of the protecting cap prevents spraying of liquid which can remain on a needle after an injection.

Throw out the used and unused components of packaging.

Features of use:

Hepatotoxic.

Reception of overdoses of naltrexone can lead to hepatocellular disturbances. Naltrexone is contraindicated at acute hepatitises and a liver failure. Vivitrol's appointment to patients with acute diseases of a liver has to be thought carefully over and proved, in view of risk of emergence of abnormal liver functions. A ratio between the safe dose of naltrexone and a dose causing disturbances in a liver <5.

At use in the recommended doses Vivitrol is not gepatotoksichny. Patients should be warned about risk of emergence of disturbances of a liver and to advise to ask for medical care in case of symptoms of hepatitis. At emergence of such symptoms treatment by Vivitrol has to be stopped.

Eosinophilic pneumonia.

During clinical trials one case of emergence and one case of suspicion of eosinophilic pneumonia was diagnosed. In both cases patients needed hospitalization, treatment was carried out by means of antibiotics and glucocorticosteroids. It is necessary to consider a possibility of development of eosinophilic pneumonia in the patient receiving Vivitrol and to advise patients at emergence of such symptoms as the progressing asthma and a hypoxia, immediately to ask for medical care. Doctors should consider a possibility of development of eosinophilic pneumonia in patients, resistant to antibiotics.

Hypersensitivity reactions.

At administration of drug Vivitrol such by-effects as a small tortoiseshell, a Quincke's disease, an anaphylaxis can develop. Patients should be warned that in case of development of reactions of hypersensitivity it is necessary to see immediately a doctor and to stop further treatment by drug.

Overdose of opioids after attempt to overcome their blockade.

After an opioid detoxication at patients tolerance to opioids is usually reduced. Vivitrol blocks effects of exogenous opioids within 28 days, however cases of deadly overdose for opioids at patients who accepted opioids before introduction of a new dose of Vivitrol or in case of the admission of the following injection of Vivitrol are known.

The patients who underwent treatment by Vivitrol can be sensitive to smaller doses of opioids, than before treatment. It can cause potentially life-threatening opioid intoxication (respiratory insufficiency or an apnoea, a collapse, etc.). It is necessary to warn patients that after the termination of treatment by Vivitrol they can be sensitive to lower doses of opioids. It is important to remember decrease in tolerance to opioids at the end of a dosing interval, that is approximately in a month after an injection of drug and in case of the admission of the following injection. Patients and members of their families should be warned about hypersensitivity to opioids and about risk of overdose by opioids.

In spite of the fact that Vivitrol is a strong antagonist of opioid receptors with long-term pharmacological effect, the blockade caused by it can be overcome. The patients trying to overcome this blockade by introduction of high doses of exogenous opioids risk to receive a lethal dose of opioids and to endanger the life. Concentration of opioids in plasma right after their reception can be sufficient for overcoming competitive blockade of opioid receptors, and as a result at the patient the life-threatening opioid intoxication which is shown respiratory depression, a collapse can instantly develop. Patients have to realize all gravity of effects of attempt to overcome blockade of opioid receptors.

Influence of drug on duration of pains and childbirth.

Influence of drug on duration of pains and childbirth is unknown.

Influence of drug on laboratory indicators of blood.

At the patients receiving treatment by Vivitrol increase in maintenance of eosinophils in blood was noted, however after several months of treatment the maintenance of eosinophils was normalized.

At the patients receiving high doses of drug decrease in maintenance of thrombocytes on average on 17,8 x 103 мкл was observed. However during the randomized controlled researches Vivitrol's influence on increase in bleedings is not proved.

At the patients with opioid dependence receiving treatment by drug within 24 weeks decrease in maintenance of thrombocytes on average on 62,8 x 103 мкл was observed. At patients, in group of placebo the maintenance of thrombocytes decreased on average on 39,9 x 103 мкл. However during the randomized controlled researches Vivitrol's influence on increase in bleedings is not proved.

Increase in activity of aspartate aminotransferase in blood against the background of treatment by Vivitrol was same as at treatment by peroral naltrexone and made 1,5% in comparison with 0,9% in group of the patients receiving placebo.

In clinical trials lasting up to 6 months with participation of patients with opioid dependence of 89% of patients the diagnosis hepatitis C was made, to 41% of patients - HIV - an infection. In a research increase in activity of "hepatic" enzymes was often observed (alaninaminotranspherases, aspartate aminotransferases and gamma глутамилтрансферазы). These by-effects were more often observed in group of the patients receiving treatment of Vivitroly 380 mg than in group of the patients receiving placebo. Patients, with activity of alaninaminotranspherase or aspartate aminotransferase, exceeding the upper bound of norm more than three times, did not include in a research.

At the patients receiving treatment by Vivitrol, increase in activity of transaminases more than by 3 times in comparison with the upper bound of norm and the demanding immediate treatment it was observed more often than at the patients receiving placebo. Such increase in activity of enzymes was observed at 20% of the patients receiving treatment by Vivitrol in comparison with 13% of patients in group of placebo. Increase in activity of aspartate aminotransferase more than three times in comparison with the upper bound of norm was also more often observed in group of the patients receiving treatment by Vivitrol (14%) in comparison with patients in group of placebo (11%). At the patients with opioid dependence receiving treatment by Vivitrol, activity of alaninaminotranspherase increased on average on 61 ME/l, patients in group have placebo - on average on 48 ME/l.

At the patients with opioid dependence receiving treatment by Vivitrol, activity of aspartate aminotransferase increased on average on 40 ME/l, patients in group have placebo - on average on 31 ME/l.

During clinical trials at the patients receiving Vivitrol increase in activity of a kreatinfosfokinaza, as a rule, in 1 - 2 time in comparison with the upper bound of norm was observed. Similar increase in activity of a kreatinfosfokinaza is observed also at treatment by peroral naltrexone. However cases of 4-fold and even 35-fold increase in activity of this enzyme in group of the patients receiving peroral naltrexone and Vivitrol, respectively are known.

At 39% of the patients with opioid dependence receiving treatment by Vivitrol increase in activity of a kreatinfosfokinaza above normal values, in group of the patients receiving placebo was observed, increase in activity of a kreatinfosfokinaza was observed at 32% of patients.

In certain cases at the patients receiving placebo, activity of a kreatinfosfokinaza raised by 41,8 times in comparison with the upper bound of norm; in group of the patients receiving treatment by Vivitrol cases of increase in activity of a kreatinfosfokinaza by 22,1 times in comparison with the upper bound of norm are known.

When carrying out some enzyme immunoassays of urine emergence of false positive results on a number of drugs, in particular on opioids is possible. Additional information is provided in instructions for carrying out specific analyses.

Impact on ability to drive the car and to work with the equipment. During treatment by drug Vivitrol can arise dizziness. In case of developing of dizziness it is necessary to refrain from driving of transport, and also from work with the equipment.

Side effects:

In clinical trials lasting up to 6 months of 9% of patients with alcohol addiction who were treated Vivitrol stopped treatment because of emergence of side effects. In group of patients to whom entered placebo treatment because of by-effects was stopped by 7% of patients. The most frequent causes of failure from treatment by Vivitrol were reactions in an injection site (3%), nausea (2%), pregnancy (1%), a headache (1%) and suicide behavior (0,3%). In group of the patients receiving placebo injections, treatment was stopped only by 1% of patients on an origin of reactions in an injection site. In clinical trials lasting up to 6 months of 2% of patients with opioid dependence who were treated Vivitrol stopped treatment because of emergence of side effects. In group of patients to whom entered placebo treatment because of by-effects was stopped by 2% of patients. 

By-effects, at patients with alcohol addiction, meeting during clinical trials in more than 5% of cases (frequent) are listed below, degree of manifestation of these by-effects was characterized as easy and moderate.

From digestive tract:

- nausea, vomiting, diarrhea, frequent desires to defecation, gastrointestinal frustration, a frequent liquid chair, an abdominal pain, discomfort in a stomach, dryness in a mouth, anorexia, a loss of appetite, appetite disturbance.

From respiratory system:

- upper respiratory tract infections, laryngitis, sinusitis, pharyngitis (including streptococcal), nasopharyngitis.

The general frustration and reactions in an injection site:

- pain, morbidity, consolidation, swelling, itch, hemorrhages, adynamy, lethargy, slackness.

From a musculoskeletal system:

- arthritis, joint pain, constraint of joints, dorsodynia, extremity pain, spasm of muscles, twitching of muscles, constraint of muscles.

From skin and hypodermic fabrics:

- rash, papular rashes, heat rash.

From a nervous system: Headache, migraine, dizziness, faint, drowsiness, alarm, sedative state.

- patients with opioid dependence had by-effects, generally same, as well as at patients with alcohol addiction.

The by-effects at patients with opioid dependence which are found during clinical trials in more than 2% of cases (frequent) are listed below, degree of manifestation of these by-effects was characterized as easy and moderate.

Laboratory indicators:

- increase in activity of alaninaminotranspherase, aspartate aminotransferase and gamma glutamiltransferaza.

From respiratory system:

- nasopharyngitis, flu.

From a nervous system:

- sleeplessness, headache.

From cardiovascular system:

- increase in arterial pressure.

The general frustration and reactions in an injection site:

- pain.

From digestive tract:

- dentagra.

The by-effects revealed during the preregistration researches of drug:

From digestive tract:

- a food faddism, increase in appetite, a reflux esophagitis, a lock, a meteorism, hemorrhoids, colitis, gastrointestinal bleeding, paralytic impassability of intestines, pararectal abscess, a gastroenteritis, tooth abscess, discomfort in a stomach, acute pancreatitis.

The general frustration and reactions in an injection site:

- temperature increase, a lethargy, a stethalgia, constraint in breasts, increase or a degrowth of a body, a shiver, a fever, a face edema.

Mental disorders:

- irritability, sleep disorder, syndrome of "cancellation" of alcohol, agitation, euphoria, delirium.

From a nervous system:

- disturbance of attention, migraine, decrease in cerebration, spasm, ischemic stroke, aneurisms of brain arteries, paresthesia.

From sense bodys:

- indistinct sight, conjunctivitis.

From a musculoskeletal system:

- extremity pain, spasm of muscles, constraint in joints, mialgiya.

From skin and hypodermic fabrics:

- the strengthened sweating, including at night, an itch.

From respiratory system:

- pharyngalgia, asthma, nose congestion, obstructive bronchitis, bronchitis, pneumonia, laryngitis, sinusitis, upper respiratory tract infections.

From a metabolism:

- heatstroke, dehydration, hypercholesterolemia.

From cardiovascular system:

- "Inflows", deep vein thrombosis, pulmonary thrombosis, cardiopalmus, fibrillation of auricles, myocardial infarction, stenocardia, unstable stenocardia, chronic heart failure, atherosclerosis of coronary arteries.

From blood and lymphatic system:

- a lymphadenopathy, including an inflammation of cervical lymph nodes, increase in maintenance of leukocytes in blood.

From immune system:

- a seasonal allergy, hypersensitivity reactions, including a Quincke's disease and a small tortoiseshell, the HIV infection pogressirovaniye at HIV-positive patients.

From urinogenital system:

- misbirth, decrease in a libido, infection of urinary tract.

From gepatobiliarny system:

- cholelithiasis, increase in activity of alaninaminotranspherase and aspartate aminotransferase, acute cholecystitis.

Interaction with other medicines:

Vivitrol's interaction with other drugs is not studied. Naltrexone is an antagonist of the opiod-containing medicines (for example, drugs for cough, cold, anti-diarrheal drugs and opiodny analgetics). As naltrexone is not substrate of enzymes of system of cytochrome, inductors or inhibitors of these enzymes will hardly affect Vivitrol's clearance. Researches for assessment of the clinical importance of influence of other drugs on Vivitrol's metabolism were not conducted therefore it is necessary to be careful and estimate possible risk and potential advantage at Vivitrol's appointment together with other drugs. Indicators of safety of use of Vivitrol together with antidepressants and without them are identical.

Contraindications:

Vivitrol is contraindicated:

• The patient accepting narcotic analgetics;

• At reception of opioids against the background of treatment by drug;

• The patient in a condition of acute cancellation of opioids (an opioid abstinence syndrome);

• The patient who did not undergo provocative test by Naloxonum or having a positive take of the analysis on availability of opioids in urine;

• The patient with hypersensitivity to active ingredient of drug, or to any of its fillers and solvent components;

• At heavy abnormal liver functions (including an acute hepatitis and a liver failure);

• At pregnancy and a lactation;

• Children's age up to 18 years.

With care:

Use at a liver failure. Dose adjustment is not required to patients with a lung or moderately expressed abnormal liver function (classes A and B on Chayld-Pyyu). At patients with a heavy abnormal liver function Vivitrol's pharmacokinetics was not studied. To such patients Vivitrol, as well as all other intramuscular injections, it is necessary to appoint with care because of the risk connected with an intramuscular injection (for example, in the presence of thrombocytopenia and disturbance of coagulation).

Use at a renal failure. Dose adjustment is not required to patients with a slight renal failure (clearance of creatinine of 50-80 ml/min.). At patients with moderately expressed and heavy renal failure Vivitrol's pharmacokinetics was not studied. In view of the fact that naltrexone and his primary metabolite are brought out of an organism mainly with urine, Vivitrol to patients with a moderate or heavy renal failure is recommended to appoint with care.

Overdose:

Data on overdose are very limited. Single doses of 784 mg entered to 5 healthy volunteers. They noted no serious by-effects. Reactions in the place of an injection, nausea, an abdominal pain, drowsiness and dizziness were the most widespread by-effects. Substantial increase of amount of liver enzymes was not noted.

In case of overdose it is necessary to carry out the corresponding supporting treatment.

Storage conditions:

In the refrigerator at a temperature from 2 °C to 8 °C. At a temperature not above 25 °C no more than 7 days. Not to subject to influence of temperatures above 25 °C. To store in the place, unavailable to children. Not to freeze. 

Issue conditions:

According to the recipe

Packaging:

Powder for preparation of suspension for intramuscular introduction of the prolonged action of 380 mg.

Powder: The amount of powder containing 430 mg of naltrexone (surplus of 12,9%) is placed in the glass bottle with a capacity of 5 ml corked by a rubber bung and supplied with a cap. Solvent: 4 ml of solvent place in the glass bottle with a capacity of 5 ml corked by a rubber bung and supplied with a cap. One bottle with powder, one bottle from 4 ml of solvent, one 5-ml syringe, one short needle for suspension preparation, two needles for an injection with a protective cap, in a pack cardboard together with the instruction on a medical use.