Opizone 50 mg film-coated tablets

Each film-coated tablet contains 50 mg naltrexone hydrochloride.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Capsule shaped, beige film-coated tablets with a break-score on each side.

The tablet can be divided into equal halves.

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)

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

Use in adults

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.

Opizone 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.

As Opizone 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.

Use in children and adolescents

Opizone is not recommended for use in children and adolescents below 18 due to a lack of data on safety and efficacy.

Use in elderly

The experience in elderly patients is limited.

- Hypersensitivity to naltrexone hydrochloride or to any of the excipients

- Acute hepatitis

- Severe hepatic impairment

- Severe renal impairment

- 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.

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

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

Should Opizone 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.

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 Opizone treatment (see section 4.3).

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

If a patient needs opioid treatment, e.g. opioid analgesia or anaesthesia in emergency situations, the opioid dose needed to achieve the desired therapeutic effect may be larger than normal. In these cases, respiratory depression and circulatory effects 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 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 Opizone-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.

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

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

Naltrexone hydrochloride 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.

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

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.

One case of lethargy and somnolence has been reported after concomitant use of naltrexone and thioridazine.

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 4.4.

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 should only be given to pregnant women when, in the judgement of the attending physician the potential benefits outweigh and the possible risk.

Lactation:

There are no clinical data on naltrexone hydrochloride 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.

Opizone has minor or moderate influence on the ability to drive and use machines.

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)

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.

Pharmacotherapeutic group: Opioid antagonist

ATC code: V03A B30

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.

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

Opizone 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.

Naltrexone 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 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.

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.

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 (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.

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)

Not applicable.

3 years.

Do not store above 25°C

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

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

Not all pack sizes may be marketed.

No special requirements.

AOP Orphan Pharmaceuticals AG

Wilhelminenstrasse 91/II f

1160 Vienna

Austria

PL Number: 21344/0002

14.08.2006

23.09.2009