Naltrexona generis

Overdose

Symptoms

- There is limited clinical experience with Naltrexona Generis overdose in patients.

- There was no evidence of toxicity in volunteers receiving 800 mg/day for seven days.

Treatment

- In case of overdose, patients should be monitored and treated symptomatically in a closely supervised environment.

Symptoms

- There is limited clinical experience with naltrexone overdose in patients.

- There was no evidence of toxicity in volunteers receiving 800 mg/day for seven days.

Treatment

- In case of overdose, patients should be monitored and treated symptomatically in a closely supervised environment.

Contraindications

- Severe renal impairment

- Severe hepatic impairment

- Acute hepatitis

- Opioid addicted patients with a current abuse of opioids since an acute withdrawal syndrome may ensue.

- Positive screening result for opioids or after failure of the naloxone provocation test.

- for use in conjunction with an opioid - containing medication

- in combination with methadone.

Pharmaceutical form

Undesirable effects

The following undesirable effects are ranked according to system organ class and to their frequency:

Very common (> 1/10)

Common (>1/100 to < 1/10)

Uncommon (>1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

not known (cannot be estimated from the available data)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system (To be completed nationally).

The following undesirable effects are ranked according to system organ class and to their frequency:

Very common (> 1/10)

Common (>1/100 to < 1/10)

Uncommon (>1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

not known (cannot be estimated from the available data)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system (To be completed nationally).

Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. However, there is some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymes has been found in humans with therapeutic and higher doses.

Naltrexona Generis (100 mg/kg, approximately 140 times the human therapeutic dose) caused a significant increase in pseudo-pregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. The relevance of these observations to human fertility is not known.

Naltrexona Generis has been shown to have an embryocidal effect in the rat and rabbit when given in doses approximately 140 times the human therapeutic dose. This effect was demonstrated in rats dosed with 100 mg/kg of Naltrexona Generis prior to and throughout gestation, and rabbits treated with 60 mg/kg of Naltrexona Generis during the period of organogenesis.

Preclinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. However, there is some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymes has been found in humans with therapeutic and higher doses.

Naltrexone (100 mg/kg, approximately 140 times the human therapeutic dose) caused a significant increase in pseudo-pregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. The relevance of these observations to human fertility is not known.

Naltrexone has been shown to have an embryocidal effect in the rat and rabbit when given in doses approximately 140 times the human therapeutic dose. This effect was demonstrated in rats dosed with 100 mg/kg of naltrexone prior to and throughout gestation, and rabbits treated with 60 mg/kg of naltrexone during the period of organogenesis.

Therapeutic indications

For use as an additional therapy within a comprehensive treatment program including psychological guidance for detoxified patients who have been opioid-dependent & alcohol dependence to support abstinence.

Naltrexona Generis price

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: other nervous system drugs; drugs used in addictive disorders, ATC code: N07BB04

Naltrexona Generis is a specific opioid antagonist with only minimal agonistic activity. It acts by stereospecific competition with receptors which are mainly located in the central and peripheral nervous system. Naltrexona Generis competitively binds to these receptors and blocks the access for exogenously administered opioids.

Naltrexona Generis treatment does not lead to physical or mental dependence. No tolerance for the opioid antagonising effect is seen.

Naltrexona Generis Hydrochloride 50 mg film-coated tablets reduces the risk of relapse and supports abstinence from opioids.

Naltrexona Generis Hydrochloride 50 mg film-coated tablets is a non-aversive therapy and does not cause reactions after opioid intake. Therefore it does not cause a disulfiram-type reaction.

The mechanism of action of Naltrexona Generis in alcoholism is not completely elucidated, however an interaction with the endogenous opioid system is suspected to play an important role. Alcohol consumption in humans has been hypothesised to be reinforcing through an alcohol-induced stimulation of the endogenous opioid system.

Naltrexona Generis is not an aversive therapy and does not cause a disulfiram-like negative reaction when alcohol is ingested.

The prominent effect of Naltrexona Generis treatment of alcohol-addicted patients seems to be a reduction of the risk of a full relapse with uncontrolled binge-drinking after having consumed a limited amount of alcohol.

This gives the patient a “second chance” to escape the otherwise mutually reinforcing mechanisms of a full relapse with complete loss of control. Naltrexona Generis also seems to have an effect on the primary craving as it is non-reinforcing on isolated consumption of limited amounts of alcohol.

Pharmacotherapeutic group: other nervous system drugs; drugs used in addictive disorders, ATC code: N07BB04

Naltrexone is a specific opioid antagonist with only minimal agonistic activity. It acts by stereospecific competition with receptors which are mainly located in the central and peripheral nervous system. Naltrexone competitively binds to these receptors and blocks the access for exogenously administered opioids.

Naltrexone treatment does not lead to physical or mental dependence. No tolerance for the opioid antagonising effect is seen.

Naltrexona Generis 50 mg film-coated tablets reduces the risk of relapse and supports abstinence from opioids.

Naltrexona Generis 50 mg film-coated tablets is a non-aversive therapy and does not cause reactions after opioid intake. Therefore it does not cause a disulfiram-type reaction.

The mechanism of action of naltrexone in alcoholism is not completely elucidated, however an interaction with the endogenous opioid system is suspected to play an important role. Alcohol consumption in humans has been hypothesised to be reinforcing through an alcohol-induced stimulation of the endogenous opioid system.

Naltrexone is not an aversive therapy and does not cause a disulfiram-like negative reaction when alcohol is ingested.

The prominent effect of naltrexone treatment of alcohol-addicted patients seems to be a reduction of the risk of a full relapse with uncontrolled binge-drinking after having consumed a limited amount of alcohol.

This gives the patient a “second chance” to escape the otherwise mutually reinforcing mechanisms of a full relapse with complete loss of control. Naltrexone also seems to have an effect on the primary craving as it is non-reinforcing on isolated consumption of limited amounts of alcohol.

Pharmacokinetic properties

Absorption

Naltrexona Generis is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration.

Biotransformation

It undergoes a liver first-pass effect and peak plasma concentration is reached within approximately one hour.

Naltrexona Generis is hydroxylated in the liver basically to the main active metabolite 6-beta-naltrexol and, to a lesser extent, to 2-hydroxy-3-methoxy-6-beta-naltrexol.

The plasma-half-life of Naltrexona Generis is approximately 4 hours, the average blood level is 8.55 mg/ml, and plasmaprotein-binding is 21%. The plasma-half-life of 6-beta-naltrexol is 13 hours.

Elimination

The medicinal product is excreted primarily renal. About 60% of the peroral dose is excreted within 48 hours as glucuronidised 6-beta-naltrexol and Naltrexona Generis.

Absorption

Naltrexone is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration.

Biotransformation

It undergoes a liver first-pass effect and peak plasma concentration is reached within approximately one hour.

Naltrexone is hydroxylated in the liver basically to the main active metabolite 6-beta-naltrexol and, to a lesser extent, to 2-hydroxy-3-methoxy-6-beta-naltrexol.

The plasma-half-life of naltrexone is approximately 4 hours, the average blood level is 8.55 mg/ml, and plasmaprotein-binding is 21%. The plasma-half-life of 6-beta-naltrexol is 13 hours.

Elimination

The medicinal product is excreted primarily renal. About 60% of the peroral dose is excreted within 48 hours as glucuronidised 6-beta-naltrexol and naltrexone.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

In accordance to national guidance the therapy should be initiated and supervised by a physician experienced in treatment of opioid-addicted and alcohol-addicted patients

High dose opioid intake, concomitant with Naltrexona Generis treatment, can lead to life-threatening opioid poisoning from respiratory and circulatory impairment.

Should Naltrexona Generis be used in opioid-dependent patients a withdrawal syndrome may occur rapidly: the first symptoms can occur within 5 minutes, the last after 48 hours. The treatment of withdrawal symptoms is symptomatic.

It is not uncommon for alcohol abusing individuals to show signs of impaired hepatic function. Abnormal hepatic function test parameters have been reported in obese and elderly patients receiving Naltrexona Generis in dosages higher than recommended (up to 300 mg/day). Hepatic function controls should be made before and during treatment. Special attention should be paid to patients with hepatic enzyme levels in serum exceeding three times the normal value and patients with renal impairment.

Liver function test abnormalities have been reported in obese and elderly patients taking Naltrexona Generis who have no history of drug abuse. Liver function tests should be carried out both before and during treatment.

Patients must be warned against the concomitant use of opioids (e.g. opioids in cough medication, opioids in symptomatic medication for the treatment of common colds, or opioids contained in anti diarrhoeal agents, etc.) during Naltrexona Generis treatment.

Naltrexona Generis treatment must begin only when the opioid has been discontinued for a sufficiently long period (about 5 to 7 days for heroin and at least 10 days for methadone).

If the patient needs opioid treatment, e.g. opioid analgesia or anesthesia in emergency situations, the dose needed may be higher than normal. In these cases, the respiratory depression and circulatory effects will be more profound and longer lasting. Symptoms related to release of histamine (generalized erythema, diaphoresis, itching and other skin and mucocutaneous manifestations) can also be manifested more easily. The patient requires specific attention and care in these situations.

During treatment with Naltrexona Generis, painful conditions should be treated with non-opioid analgesia only.

Patients should be warned that large doses of opioids to overcome the blockade may after the cessation of the Naltrexona Generis result in an acute opioid overdose, with possible fatal outcome.

Patients might be more sensitive to opioid containing medicines after treatment with Naltrexona Generis.

Patients suspected of using or being addicted to opioids must undergo a naloxone provocation test, unless it can be verified that the patient has not taken any opioids for 7-10 days (urine test) prior to the initiation of treatment with Naltrexona Generis.

A withdrawal syndrome precipitated by naloxone will be of shorter duration than withdrawal precipitated by Naltrexona Generis.

The recommended procedure is as follows:

Intravenous provocation

- Intravenous injection of 0.2 mg naloxone

- If after 30 seconds no adverse reactions occur, a further i.v. injection of 0.6 mg naloxone may be administered.

- The patient should be observed continuously for 30 minutes for any detectable sign of withdrawal symptoms.

If any symptoms of withdrawal occur Naltrexona Generis-therapy must not be undertaken. If the test-result is negative the treatment can be initiated. If any doubt exists that the patient is opioid-free, the challenge may be repeated with the dosage of 1.6 mg. If no reaction occurs after this, 25 mg of Naltrexona Generis hydrochloride can be administered to the patient.

A naloxone hydrochloride provocation test should not be made in patients with clinically prominent withdrawal symptoms nor in any case of a positive urine test for opioids.

Naltrexona Generis is extensively metabolised by the liver and excreted predominantly in the urine. Therefore, caution should be observed in administering the medicinal product to patients with impaired hepatic or renal function. Liver function tests should be carried out both before and during treatment.

The risk of suicide is known to increase in substance abusers, with or without concomitant depression. Treatment with Naltrexona Generis tablet does not eliminate this risk.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In accordance to national guidance the therapy should be initiated and supervised by a physician experienced in treatment of opioid-addicted and alcohol-addicted patients

High dose opioid intake, concomitant with Naltrexone treatment, can lead to life-threatening opioid poisoning from respiratory and circulatory impairment.

Should naltrexone be used in opioid-dependent patients a withdrawal syndrome may occur rapidly: the first symptoms can occur within 5 minutes, the last after 48 hours. The treatment of withdrawal symptoms is symptomatic.

It is not uncommon for alcohol abusing individuals to show signs of impaired hepatic function. Abnormal hepatic function test parameters have been reported in obese and elderly patients receiving naltrexone in dosages higher than recommended (up to 300 mg/day). Hepatic function controls should be made before and during treatment. Special attention should be paid to patients with hepatic enzyme levels in serum exceeding three times the normal value and patients with renal impairment.

Liver function test abnormalities have been reported in obese and elderly patients taking naltrexone who have no history of drug abuse. Liver function tests should be carried out both before and during treatment.

Patients must be warned against the concomitant use of opioids (e.g. opioids in cough medication, opioids in symptomatic medication for the treatment of common colds, or opioids contained in anti diarrhoeal agents, etc.) during naltrexone treatment.

Naltrexone treatment must begin only when the opioid has been discontinued for a sufficiently long period (about 5 to 7 days for heroin and at least 10 days for methadone).

If the patient needs opioid treatment, e.g. opioid analgesia or anesthesia in emergency situations, the dose needed may be higher than normal. In these cases, the respiratory depression and circulatory effects will be more profound and longer lasting. Symptoms related to release of histamine (generalized erythema, diaphoresis, itching and other skin and mucocutaneous manifestations) can also be manifested more easily. The patient requires specific attention and care in these situations.

During treatment with naltrexone, painful conditions should be treated with non-opioid analgesia only.

Patients should be warned that large doses of opioids to overcome the blockade may after the cessation of the naltrexone result in an acute opioid overdose, with possible fatal outcome.

Patients might be more sensitive to opioid containing medicines after treatment with naltrexone.

Patients suspected of using or being addicted to opioids must undergo a naloxone provocation test, unless it can be verified that the patient has not taken any opioids for 7-10 days (urine test) prior to the initiation of treatment with naltrexone.

A withdrawal syndrome precipitated by naloxone will be of shorter duration than withdrawal precipitated by naltrexone.

The recommended procedure is as follows:

Intravenous provocation

- Intravenous injection of 0.2 mg naloxone

- If after 30 seconds no adverse reactions occur, a further i.v. injection of 0.6 mg naloxone may be administered.

- The patient should be observed continuously for 30 minutes for any detectable sign of withdrawal symptoms.

If any symptoms of withdrawal occur naltrexone-therapy must not be undertaken. If the test-result is negative the treatment can be initiated. If any doubt exists that the patient is opioid-free, the challenge may be repeated with the dosage of 1.6 mg. If no reaction occurs after this, 25 mg of Naltrexona Generis can be administered to the patient.

A naloxone hydrochloride provocation test should not be made in patients with clinically prominent withdrawal symptoms nor in any case of a positive urine test for opioids.

Naltrexone is extensively metabolised by the liver and excreted predominantly in the urine. Therefore, caution should be observed in administering the medicinal product to patients with impaired hepatic or renal function. Liver function tests should be carried out both before and during treatment.

The risk of suicide is known to increase in substance abusers, with or without concomitant depression. Treatment with Naltrexone tablet does not eliminate this risk.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on ability to drive and use machines

Naltrexona Generis may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery.

Naltrexone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery.

Dosage (Posology) and method of administration

Use in adults

Naltrexona Generis treatment should be initiated and supervised by suitable qualified physicians.

The initial dose of Naltrexona Generis hydrochloride should be 25 mg (half a tablet) for opioid-dependent patient followed by the usual dose of one tablet per day (= 50 mg Naltrexona Generis hydrochloride)

A missed dose can be managed by providing 1 tablet per day each day till the next regular dosage-administration.

Naltrexona Generis administered to opioid-dependent persons can cause life-threatening withdrawal symptoms. Patients suspected of using or being addicted to opioids must undergo a naloxone provocation test , unless it can be verified that the patient has not taken any opioids for 7-10 days (urine test) prior to the initiation of treatment with Naltrexona Generis.

As Naltrexona Generis is an adjunctive therapy and the full recovery process in opioid-dependent patients is individually variable, no standard duration of treatment can be stated; an initial period of three months should be considered. However, prolonged administration may be necessary.

The recommended dose for alcohol dependence to support abstinence is 50 mg per day (1 tablet). A dose of over 150 mg on any single day is not recommended, since this can lead to a higher incidence of side effects.

As Naltrexona Generis hydrochloride is an adjunctive therapy and the full recovery process from alcohol dependence is individually variable, no standard duration of treatment can be stated; an initial period of three months should be considered. However, prolonged administration may be necessary

The dosage-regimen can be modified in order to improve compliance to a three-times-a-week dosing schedule as follows: administration of 2 tablets (=100 mg Naltrexona Generis hydrochloride) on Monday and on Wednesday and 3 tablets (=150 mg Naltrexona Generis hydrochloride) on Friday.

Paediatric population

Naltrexona Generis should not be used in children and adolescents under 18 years of age, since clinical data in this age-group are lacking. Safe use in children has not been established.

Older people

There are insufficient data on the safety and efficacy of Naltrexona Generis for this indication in elderly patients.

Use in adults

Naltrexone treatment should be initiated and supervised by suitable qualified physicians.

The initial dose of Naltrexona Generis should be 25 mg (half a tablet) for opioid-dependent patient followed by the usual dose of one tablet per day (= 50 mg Naltrexona Generis)

A missed dose can be managed by providing 1 tablet per day each day till the next regular dosage-administration.

Naltrexone administered to opioid-dependent persons can cause life-threatening withdrawal symptoms. Patients suspected of using or being addicted to opioids must undergo a naloxone provocation test , unless it can be verified that the patient has not taken any opioids for 7-10 days (urine test) prior to the initiation of treatment with naltrexone.

As Naltrexone is an adjunctive therapy and the full recovery process in opioid-dependent patients is individually variable, no standard duration of treatment can be stated; an initial period of three months should be considered. However, prolonged administration may be necessary.

The recommended dose for alcohol dependence to support abstinence is 50 mg per day (1 tablet). A dose of over 150 mg on any single day is not recommended, since this can lead to a higher incidence of side effects.

As Naltrexona Generis is an adjunctive therapy and the full recovery process from alcohol dependence is individually variable, no standard duration of treatment can be stated; an initial period of three months should be considered. However, prolonged administration may be necessary

The dosage-regimen can be modified in order to improve compliance to a three-times-a-week dosing schedule as follows: administration of 2 tablets (=100 mg Naltrexona Generis) on Monday and on Wednesday and 3 tablets (=150 mg Naltrexona Generis) on Friday.

Paediatric population

Naltrexone should not be used in children and adolescents under 18 years of age, since clinical data in this age-group are lacking. Safe use in children has not been established.

Older people

There are insufficient data on the safety and efficacy of naltrexone for this indication in elderly patients.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.