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 filmcoated tablets with a break-score on each side.

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

Use in adults

Route of administration – orally with small amounts of liquid.

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

The initial dose of Naltrexone hydrochloride should be 25 mg (half a tablet) followed by the usual dose of one tablet per day (= 50 mg naltrexone hydrochloride).

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.

Naltrexone hydrochloride 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 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 hydrochloride.

No standard duration of treatment is stated as Naltrexone hydrochloride is an adjunctive therapy and the full recovery process in opioid-dependent patients, receiving psychological guidance as well, is individually variable. An initial period of three months should be considered, but prolonged administration may be necessary.

Naltrexone hydrochloride does not cause psychological or physical dependency. There is no attenuation in its opioid-antagonising activity in long term treatment.

Use in children and adolescents (< 18 years)

Naltrexone hydrochloride 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.

Use in Elderly

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

4.3 Contraindications

- Hypersensitivity to the active substance naltrexone hydrochloride or to any of the excipients listed in section 6.1.

- Severe renal impairment

- Severe hepatic impairment

- Acute hepatitis

- Opioid –dependent patients who failed detoxification because an acute withdrawal syndrome may ensue.

- Patients currently abusing opioids and with acute symptoms of withdrawal.

- Patients with withdrawal symptoms after naloxone hydrochloride administration.

- Patients with a positive urine test for opioids.

4.4 Special warnings and precautions for use

High dose opioid intake, concomitant with Naltrexone hydrochloride treatment, can lead to life-threatening opioid poisoning from respiratory and circulatory impairment. Such reactions to opioids can be greater after treatment with Naltrexone hydrochloride.

Therefore a naloxone provocation test is recommended to detect the presence of any opioid use; a withdrawal syndrome precipitated by naloxone will be of shorter duration than withdrawal precipitated by Naltrexone hydrochloride.

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 hydrochloride -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.

Hepatic impairment is not uncommon in opioid-dependent patients. Liver function test abnormalities have also been reported in obese and elderly patients taking Naltrexone hydrochloride who have no history of drug abuse. Naltrexone hydrochloride is extensively metabolized 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.

Should Naltrexone hydrochloride 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.

Non-opioid analgesia should be administered in case of emergent need for analgesics.

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). If a patient needs opioid treatment, e. g. opioid analgesia or anaesthesia in emergency situations, the opioid does needed to achieve the desired therapeutic effect may be larger than normal. In these cases, respiratory depression and circulatory effets will be more profound and longer lasting. Symptoms related to release of histamine (diaphoresis, itching and other skin and mucocutaneous manifestations) can also be manifested more easily. The patient requires specific attention and care in these situations.

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

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

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

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. It is not known whether Naltrexone hydrochloride affects the metabolism of other substances. Co- administration of substances with a narrow therapeutic index must be made cautiously. In vitro studies have shown that neither Naltrexone Hydrochloride nor its main metabolite 6-β-naltrexol are metabolized via human CYP450 enzymes. It is therefore unlikely that the pharmacokinetics of Naltrexone hydrochloride is affected by substances inhibiting and/or inducing CYP450 enzymes. Case reports of lethargy and somnolence have been reported after the concomitant administration of Naltrexone Hydrochloride and thioridazine.

Patients must be warned about the use of opioids during Naltrexone hydrochloride treatment (see section 4.4).

Currently there are no known interactions between Naltrexone hydrochloride and alcohol.

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 the possible risk.

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. During treatment breast feeding is not recommended.

4.7 Effects on ability to drive and use machines

Opizone 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)

MedDRA system organ class

Symptom

Nervous system disorder

Very common

Headache

Sleep disorders

Restlessness

Nervousness

Common

Thirst

Dizziness

Shivering

Increased transpiration

Vertigo

Rare

Speech disorder

Very rare

Tremor

Gastrointestinal disorder

Very common

Abdominal pain

Abdominal cramps

Nausea

Inclination to vomit

Common

Diarrhoea

Constipation

Hepatobiliary disorders

Rare

Hepatic disorders

Musculoskeletal and connective tissue disorders

Very common

Joint and muscle pain

General disorder and administration site conditions

Very common

Feebleness

Common

Lack of appetite

Eye disorders

Common

Increased lacrimation

Respiratory, thoracic and mediastinal disorder

Common

Pain in the chest

Renal and urinary disorders

Common

Urine retention

Skin and subcutaneous tissue disorder

Common

Rash

Very rare

Exanthema

Reproductive system and breast disorders

Common

Delayed ejaculation

Decreased potency

Psychiatric disorders

Common

Anxiety

Increased energy

Despondency

Irritability

Mood swings

Rare

Depression

Suicidal ideation

Attempted suicide

Very rare

Agitation

Euphoria

Hallucination

Blood and lymphatic system disorders

Very rare

Idiopathic thrombocytopenic purpurea

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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: Opioid antagonist

ATC code: N07BB04

Naltrexone hydrochloride is an orally effective, long-acting 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 filmcoated tablet reduces the risk of relapse and supports abstinence from opioids.

Naltrexone hydrochloride 50 mg filmcoated 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 50 mg filmcoated tablet's active ingredient, naltrexone hydrochloride, is a specific opioid-antagonist. After oral administration Naltrexone hydrochloride is rapidly and completely absorbed from the gastro-intestinal tract. Metabolism occurs in the liver to a large extent (first-pass effect) and the peak plasma concentration is reached within approximately one hour. It has a large apparent volume of distribution and 21 % of the absorbed dose is bound to plasma proteins.

Naltrexone hydrochloride is hydroxylated 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 about 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 renally. About 60% of the peroral dose is excreted within 48 hours as glucuronidised 6-beta-naltrexol and Naltrexone hydrochloride.

Five to ten times higher plasma concentrations of Naltrexone hydrochloride have been reported in cirrhotic patients.

No data are available on the pharmacokinetics of Naltrexone hydrochloride in special patients groups (children, elderly and renal impairment). Caution is advised when using Naltrexone hydrochloride in these patients (see also 4.2).

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 have been found in humans with therapeutic and higher doses (see section 4.4 and 4.8).

Naltrexone Hydrochloride (100 mg/kg) caused a significant increase in pseudo-pregnancy in the rat. A decrease in the pregnanca 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

Crosprovidone

Microcrystalline cellulose

Silica colloidal anhydrous

Magnesium stearate

Film-coat: Opadry 31 F 27245 Beige

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Macrogol 4000 oxide

Black iron oxide (E172)

Red iron oxide (E172)

Yellow iron 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.

6.5 Nature and contents of container

Pack size: 7, 14, 28, 30 and 56 tablets in PCV/PVDC blister coated with aluminium foil stored in outer carton.

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: 14.06.2010

10. Date of revision of the text

08/11/2017