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 filmcoated tablet contains 50 mg naltrexone hydrochloride. One filmcoated tablet contains 126.8 mg lactose monohydrate. For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Filmcoated tablet.

Capsule shaped, beige film-coated tablets with a break-score on each 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 4.2 and 4.4)

4.2 Posology and method of administration

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

Naltrexone hydrochloride administered to opioid-dependent persons can cause life- threatening withdrawal symptoms. Administration of Naltrexone hydrochloride must not be started before a naloxone challenge test is performed and a negative result obtained (see section 4.4).

Treatment with Naltrexone hydrochloride should be considered only in patients who have remained opioid-free for a minimum of 7-10 days.

Before starting Naltrexone hydrochloride treatment, this test must be confirmed by urine screening.

Posology

Use in adults

Treatment must begin with low doses of naltrexone, according to the treatment induction schedule.

The recommended initial dose of Naltrexone hydrochloride is 25 mg (half a tablet) followed by 50 mg per day (one tablet).

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.

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

A dose of over 150 mg on any single day is not recommended, since this can lead to a higher incidence of side effects.

Use in children and adolescents

Naltrexone hydrochloride is not recommended in children and adolescents below 18 years old. Safe use in children has not been established.

Use in elderly

Safe use for the treatment of opiate dependence in the elderly has not been established.

Method of administration

Naltrexone hydrochloride 50 mg film-coated tablets should be taken with a liquid.

Duration of administration

As Naltrexone hydrochloride 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.

4.3 Contraindications

Naltrexone hydrochloride is contraindicated:

- in patients who have demonstrated hypersensitivity to the Naltrexone hydrochloride or to any of the excipients listed in section 6.1.

- in patients with acute hepatitis or liver failure

- in patients with severe renal failure

- in patients currently dependent on opioids since an acute withdrawal syndrome may ensue.

- in any patient who has a positive screen for opioids or who has failed 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.

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

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

It is not uncommon for opioid abusing individuals to have impaired liver function. In addition, it is not unusual for alcohol abusers to have altered liver function. Changes in hepatic function tests have been described in obese elderly patients receiving Naltrexone hydrochloride at doses higher than recommended (up to 300 mg/day) for the treatment of alcoholism. Liver function tests should be performed before starting treatment and periodically throughout treatment.

A withdrawal syndrome may be precipitated by Naltrexone hydrochloride in opioid dependent patients; signs and symptoms may develop within 5 minutes and the last up to 48 hours. Treatment should be symptomatic and may include opioid administration.

In an emergency situation in which the administration of opioid analgesics is required in patients receiving Naltrexone, a higher than usual dose of opioid analgesics may be administered to have the same therapeutic effect. The resulting respiratory depression may be deeper and more prolonged and non-receptor mediated effects may also appear (e.g. swelling of the face, pruritus, generalized erythema, diaphoresis, and other dermal and mucosal symptoms presumably due to histamine liberation). In these circumstances, the patient must be carefully monitored by trained personnel in a hospital center.

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

Patients should be warned that attempts to overcome the blockade by administering large doses of opioids may result in an acute opioid intoxication after the end of the Naltrexone hydrochloride effect which may be possibly life threatening. High dose opioid intake, concomitant with Naltrexone hydrochloride treatment, can lead to life-threatening opioid poisoning from respiratory and circulatory impairment.

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 hydrochloride treatment (see section 4.3).

A naloxone challenge test is recommended to screen for presence of opioid use; a withdrawal syndrome precipitated by naloxone hydrochloride will be of shorter duration than one precipitated by Naltrexone.

The naloxone hydrochloride challenge test should not be made in patients with clinically significant withdrawal symptoms nor in patients tested positive for opioids in the urine.

The recommended procedure is as follows:

Naloxone test

- Intravenous:

Administer 0.2 mg naloxone intravenously. If no adverse reactions appear after 30 seconds, administer another dose of 0.6 mg naloxone intravenously. Continue observing the patient over 20 minutes for signs of withdrawal.

- Subcutaneous:

Administer 0.8 mg naloxone subcutaneously. Observe the patient for 20 minutes for signs and symptoms of withdrawal.

If any symptoms of withdrawal occur naltrexone-therapy must not be undertaken. If the test- result is negative the treatment can be initiated.

Confirmation of the test: If there is any doubt that the patient is opioid-free, treatment with Naltrexone hydrochloride should be delayed 24 hours. In this case, the test should be repeated with 1.6 mg naloxone.

If no reaction occurs after this, 25 mg of naltrexone hydrochloride can be administered to the patient.

Naltrexone hydrochloride 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).

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

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

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

4.5 Interaction with other medicinal products and other forms of interaction

Presently, clinical experience and experimental data on the effect of Naltrexone hydrochloride on the pharmacokinetics of other substances are limited. Concomitant treatment with Naltrexone hydrochloride 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 hydrochloride nor its main metabolite 6-ß- naltrexol is metabolised via human CYP450 enzymes. Therefore it is unlikely that the pharmacokinetics of Naltrexone hydrochloride 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 hydrochloride 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).

There have been reports of cases of lethargy and somnolence following concomitant administration of Naltrexone hydrochloride and thioridazine.

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

Data from a safety and tolerability study of the co-administration of Naltrexone hydrochloride with acamprosate in non-treatment seeking, alcohol dependent individuals showed that Naltrexone hydrochloride administration significantly increased acamprosate plasma level.

Interaction with other psychopharmacological agents (e.g. disulfirame, amitryptiline, doxepine, lithium, clozapine, benzodiazepines) have not been investigated.

There are no known interactions between Naltrexone hydrochloride and alcohol.

Concomitant use with opioid containing medicines is contraindicated (see sections 4.3 and 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy:

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 hydrochloride 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 hydrochloride 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 hydrochloride administration must be suspended if opiate analgesics are prescribed (see section 4.5).

Lactation:

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

4.7 Effects on ability to drive and use machines

Naltrexone hydrochloride 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 known data)

The side effects observed with Naltrexone hydrochloride appear to be similar in both alcoholics and patients dependent on opioids. Serious adverse reactions are unusual.

Blood and lymphatic system disorders

Uncommon: lymphadenopathy

Rare: idiopathic thrombocytopenic purpura

Psychiatric disorders

Very common: nervousness, anxiety, insomnia

Common: irritability, affective disorders

Uncommon: hallucination, confusional state, depression, paranoia, disorientation, nightmare, agitation, libido disorder, abnormal dreams

Rare: suicidal ideation, attempted suicide

Nervous system disorders

Very common: headache, restlessness

Common: dizziness

Uncommon: tremor, somnolence

Eye disorders

Common: lacrimation increased

Uncommon: vision-blurred, eye irritation, photophobia, eye swelling, eye pain or asthenopia

Cardiac disorders

Common: tachycardia, palpitations, electrocardiogram change

Vascular disorders

Uncommon: blood pressure fluctuation, flushing

Respiratory disorders

Common: chest pain

Uncommon: nasal congestion, nasal discomfort, rhinorrhea, sneezing, oropharyngeal pain, sputum increased, sinus disorder, dyspnoea, dysphonia, cough, yawning

Gastrointestinal disorders

Very common: abdominal pain, nausea and/ or 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 hydrochloride the transaminases decreased to baseline within several weeks.)

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: seborrhoea, pruritus, acne, alopecia

Musculoskeletal and connective tissue disorders

Very common: arthralgia and myalgia

Uncommon: groin pain

Very rare: rhabdomyolysis

Reproductive system and breast disorders

Common: ejaculation delayed, erectile dysfunction

Renal and urinary tract disorders

Uncommon: pollakiuria, dysuria

Ear and labyrinth disorders

Uncommon: ear discomfort, ear pain, tinnitus, vertigo

Infections and infestations

Uncommon: oral herpes, tinea pedis

Metabolism and nutrition disorders

Common: decreased appetite

General disorders

Very common: asthenia

Common: 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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Symptoms

There is limited clinical experience with Naltrexone hydrochloride 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: Drugs used in alcohol dependence

ATC code: N07BB04

Naltrexone hydrochloride 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 hydrochloride competitively binds to these receptors and blocks the access for exogenously administered opioids.

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

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

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

5.2 Pharmacokinetic properties

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

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

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

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 hydrochloride.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. However, there is some evidence on hepatotoxicity with increasing dose, since reversible increases of liver enzymes have been found in humans with therapeutic and higher doses (see section 4.4 and 4.8).

Naltrexone hydrochloride (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 hydrochloride 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 hydrochloride prior to and throughout gestation, and rabbits treated with 60 mg/kg of Naltrexone hydrochloride during the period of organogenesis.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Lactose monohydrate

Powdered cellulose

Microcrystalline cellulose

Silica, colloidal anhydrous

Crosprovidone

Magnesium stearate

Film-coat: Opadry 31 F 27245 Beige

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Macrogol 4000

Black ferric oxide (E172)

Red ferric oxide (E172)

Yellow ferric oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Pack size: 7, 14, 28, 30 and 56 tablets in PCV/PVDC Aluminium blister.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

AOP Orphan Pharmaceuticals AG

Wilhelminenstrasse 91/II f

1160 Wien

Austria

8. Marketing authorisation number(s)

PL 21344/0002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 14.08.2006

Date of latest renewal: 13.07.2010

10. Date of revision of the text

23/02/2021