This information is intended for use by health professionals

1. Name of the medicinal product

Naltrexone Hydrochloride 50 mg film-coated tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 50.00 mg naltrexone hydrochloride

Excipient(s) with known effect: Each film-coated tablet contains 192.85 mg of lactose

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet

Yellow colored, oval, biconvex, film coated tablets with breakline on one side and plain on other side.

The tablet can be divided into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

For use as an additional therapy within a comprehensive treatment program including psychological guidance for detoxified patients who have been opioid-dependent (see section 4.2 and 4.4) & alcohol dependence to support abstinence.

4.2 Posology and method of administration

Use in adults

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

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

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 (see section 4.4), 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 naltrexone 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 naltrexone hydrochloride) on Monday and on Wednesday and 3 tablets (=150 mg naltrexone hydrochloride) 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.

4.3 Contraindications

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

• 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 (see section 4.5).

4.4 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 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 (see section 4.3).

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 naltrexone 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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of naltrexone with an opioid-containing medication should be avoided.

Presently, clinical experience and experimental data on the effect of naltrexone on the pharmacokinetics of other substances are limited. Concomitant treatment with naltrexone and other medicinal products should be conducted with caution and should be followed carefully.

No interaction studies have been performed.

In vitro studies have shown that neither naltrexone nor its main metabolite 6-ß-naltrexol is metabolised via human CYP450 enzymes. Therefore it is unlikely that the pharmacokinetics of naltrexone is affected by cytochrome P450 enzyme inhibiting drugs.

Association not recommended: opioid derivatives (analgesics, antitussives, substitution treatments), Central antihypertensives, (alpha-methyldopa).

Concomitant administration of naltrexone with an opioid-containing medication should be avoided.

Methadone in substitution treatment. There is a risk of onset of withdrawal syndrome.

Association to be taken into account: barbiturates; benzodiazepines, anxiolytics others than benzodiazepines (i.e meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, trimipramine), sedative antihistaminics H1, neuroleptics (droperidol).

Data from a safety and tolerability study of co-administration of naltrexone with acamprosate in non-treatment seeking, alcohol dependent individuals showed that naltrexone administration significantly increased acamprosate plasma level. Interaction with other psychopharmacological agents (e.g. disulfirame, amitryptiline, doxepine, lithium, clozapine, benzodiazepines) have not been investigated

Until now no interaction between cocaine and naltrexone hydrochloride has been described.

There are no known interactions between naltrexone and alcohol.

For interactions with opioid containing drugs please see section 4.4.

4.6 Fertility, pregnancy and lactation

Pregancy

There are no clinical data on naltrexone hydrochloride use in pregnancy. Data from animal studies have shown reproductive toxicity (see section 5.3.). The data are insufficient to establish clinical relevance. The potential risk for humans is unknown. Naltrexone should only be given to pregnant women when, in the judgement of the attending physician the potential benefits outweigh and the possible risk.

The use of naltrexone in pregnant alcoholic patients receiving long-term treatment with opiates or substitution treatment with opiates, or in pregnant patients who are opioid-dependent, creates a risk of acute withdrawal syndrome which could have serious consequences for the mother and the foetus (see section 4.4). Naltrexone administration must be suspended if opiate analgesics are prescribed (see section 4.5).

Lactation:

There are no clinical data on naltrexone HCl use in lactation. It is unknown whether naltrexone or 6-beta-naltrexol is excreted in human breast milk. During treatment breast feeding is not recommended.

4.7 Effects on ability to drive and use machines

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

4.8 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)

MedDRA system organ class

Infections and infestation

Uncommon

Oral herpes

Tinea pedis

Blood and lymphatic system disorders

Uncommon

Lymphadenopathy

Rare

Idiopathic thrombocytopenic purpura

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders:

Very common

Nervousness

Anxiety

Insomnia

Common

Affective disorders

Despondency

Irritability

Mood swings

Uncommon

Hallucination

Confusional state

Depression

Paranoia

Disorientation

Nightmare

Agitation

Libido disorder

Abnormal dreams

Rare

Suicidal ideation

Attempted suicide

Very rare

Euphoria

Nervous system disorder

Very common

Headache

Sleep disorders

Restlessness

Common

Dizziness

Shivering

Vertigo

Uncommon

Tremor

Somnolence

Rare

Speech disorder

Eye disorders

Common

Lacrimation increased

Uncommon

Vision-blurred

Eye irritation

Photophobia

Eye swelling

Eye pain

Asthenopia

Ear and labyrinth disorders

Uncommon

Ear discomfort

Ear pain

Tinnitus

Vertigo

Cardiac disorders

Common

Tachycardia

Palpitations

Electrocardiogram change

Vascular disorders

Uncommon

Blood pressure fluctuation

Flushing

Respiratory, thoracic and mediastinal disorder

Common

Chest pain

Uncommon

Nasal congestion

Nasal discomfort

Rhinorrhea

Sneezing

Oropharyngeal pain

Sputum increased

sinus disorder

Dyspnoea

Dysphonia

Cough

Yawning

Gastrointestinal disorder

Very common

Abdominal pain

Abdominal cramps

Nausea or Inclination to vomit

Vomiting

Common

Diarrhoea

Constipation

Uncommon

Flatulence

Haemorrhoids

Ulcer

Dry mouth

Hepatobiliary disorders

Uncommon

Liver disorder

blood bilirubin increased

hepatitis

During treatment an increase of liver transaminases may occur. After discontinuation of Naltrexone the transaminases decreased to baseline within several weeks.

Skin and subcutaneous tissue disorder

Common

Rash

Uncommon

Seborrhoea

Pruritus

Acne

Alopecia

Very rare

Exanthema

Musculoskeletal and connective tissue disorders :

Very common

Arthralgia

Myalgia

Uncommon

Groin pain

Very Rare

Rhabdomyolysis

Renal and urinary disorders

Common

Urine retention

Uncommon

Pollakiuria

Dysuria

Reproductive system and breast disorders

Common

Delayed ejaculation

Erectile dysfunction

General disorder and administration site conditions

Very common

Feebleness

Asthenia

Common

Lack of appetite

Thirst

Energy increased

Chills

Hyperhidrosis

Uncommon

Increased appetite

weight loss

weight gain

Pyrexia

Pain

Peripheral coldness

Feeling hot

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).

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

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

Naltrexone 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 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.

5.2 Pharmacokinetic properties

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.

5.3 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 (see section 4.4 and 4.8).

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.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Lactose monohydrate

Cellulose Microcrystalline

Crospovidone

Colloidal anhydrous silica

Magnesium stearate

Film Coating:

Hypromellose (E464)

Macrogol 400

Polysorbate 80 (E 433)

Iron Oxide Yellow (E172)

Iron oxide red (E172)

Titanium Dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Naltrexone Hydrochloride 50 mg film-coated tablets are packed in White opaque PVC/PE/Aclar – Alu Blister and Alu-Alu blister packs containing 7, 14, 28, 30, 50 and 56 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex, HA1 4HF

United Kingdom

8. Marketing authorisation number(s)

PL 20075/0144

9. Date of first authorisation/renewal of the authorisation

01/03/2010

10. Date of revision of the text

30/10/2013