NALOREX 50 mg Film-Coated Tablets

Naltrexone hydrochloride 50 mg per tablet.

Pale yellow, film coated, capsule-shaped tablet debossed on one side with 'R11' and scored and debossed with '50' on the other side.

Nalorex is indicated as an adjunctive prophylactic therapy in the maintenance of detoxified, formerly opioid-dependent patients.

Route of administration - oral.

Administration of Nalorex must not be started before a naloxone challenge test is performed and a negative result obtained.

Naloxone test

- Intravenous: Administer 0.2 mg naloxone IV. If no adverse reactions appear after 30 seconds, administer another dose of 0.6 mg naloxone iv. 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.

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

If there is no evidence of a reaction, Nalorex administration may be initiated with 25 mg by mouth (half a tablet).

Before starting Nalorex treatment, this test must be confirmed by urine screening. Treatment must begin with low doses of naltrexone, according to the treatment induction schedule.

The initial dose of Nalorex should be 25 mg (half a tablet) followed by 50 mg (one tablet) daily.

A three-times-a-week dosing schedule may be considered if it is likely to result in better compliance e.g. 100 mg on Monday, 100 mg on Wednesday and 150 mg on Friday.

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

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

Naloxone hydrochloride challenge is recommended to minimise the chance of a prolonged withdrawal syndrome precipitated by Nalorex (see section 4.4).

As Nalorex is an adjunctive therapy and full recovery from opioid dependence is variable, no standard duration of treatment can be recommended; an initial period of three months should be considered. However, prolonged administration may be necessary.

Use in Children

Nalorex is not recommended in patients below 18 years old.

Safe use in children has not been established.

Use in Elderly

There is no experience of use in the elderly.

Nalorex should not be given to patients with acute hepatitis or liver failure.

Nalorex should not be given to patients currently dependent on opioids since an acute withdrawal syndrome may ensue.

Nalorex should not be used in conjunction with an opioid-containing medication.

Nalorex is contraindicated in any patient who has a positive screen for opioids or who has failed the Narcan Challenge.

Nalorex should not be given to patients who are hypersensitive to naltrexone hydrochloride or any of the excipients.

Nalorex is contraindicated in patients with severe renal failure.

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.

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 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.

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.

Since Nalorex is extensively metabolised 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.

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

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

The naloxonechallenge test should neither be performed in patients with clinically significant withdrawal symptoms nor in patients tested positive for opioids in the urine.

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

In an emergency situation in which the administration of opioid analgesics is required in patients receiving Nalorex 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.

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

Lactose: Patients with the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Nalorex.

Concomitant administration of Nalorex with an opioid-containing medication should be avoided. Patients should be warned that attempts to overcome the blockade may result in acute opioid intoxication which may be life threatening. In an emergency requiring opioid analgesia an increased dose of opioid may be required to control pain. The patient should be closely monitored for evidence of respiratory depression or other adverse symptoms and signs.

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-β-naltrexol is metabolised via human CYP450 enzymes. Therefore it is unlikely that the pharmacokinetics of naltrexone is affected by cytochrome P450 enzyme inhibiting drugs.

Sedative products: opioid derivatives (analgesics, antitussives, substitution treatments), neuroleptics, barbiturates, benzodiazepins, anxiolytics others than benzodiazepins (i.e meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, trimipramine), sedative antihistaminics H1, central antihypertensives, baclofen, thalidomide.

Association not recommended: agonist opioid analgesics; agonist-antagonist opioids; opioids in substitution treatment.

Association to be taken into account: barbiturates; benzodiazepines.

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 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.

There are no known interactions between naltrexone and alcohol.

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

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 judgment 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. Breast feeding is not recommended during naltrexone treatment.

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

The following adverse reactions have been reported before and during naltrexone medication: Frequency is defined using the following convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1,000); very rare (<1/10,000).

The side effects observed with naltrexone 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, headache

Eye disorders

Common: lacrimation increased

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

Cardiac disorders

Common: tachycardia, palpitations, electrocardiogram change

Uncommon: palpitation

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 Nalorex the transaminases decreased to baseline within several weeks.)

Occasional liver function abnormalities have also been reported. One case of reversible idiopathic thrombocytopenic purpura has occurred in a patient taking Nalorex.

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: seborrhoea, pruritus, acne, alopecia

Musculoskeletal and connective tissue disorders

Very common: arthralgia and myalgia

Very rare: rhabdomyolysis

Uncommon: groin pain

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

There is no clinical experience with Nalorex overdose in patients. There was no evidence of toxicity in volunteers receiving 800 mg/day for seven days, however, in case of overdose, patients should be monitored and treated symptomatically in a closely supervised environment.

Naltrexone is a specific, high affinity, long acting competitive antagonist at opioid receptors. It has negligible opioid agonist activity. Tolerance does not develop with prolonged use.

Naltrexone is rapidly absorbed after oral administration. It is metabolised by the liver and excreted primarily in the urine, less than 5% is excreted in the faeces. Naltrexone has an elimination half-life of four hours. The major metabolite 6-β- naltrexol has an elimination half-life of 12.9 hours.

Nalorex is well established in medical use. Preclinical data is broadly consistent with clinical experience.

Not applicable.

36 months.

Do not store above 25°C.

White opaque PVC/PE/Aclar blister or white opaque PVC/Aclar/PVC blister with aluminium foil in packs of 28 tablets.

Not applicable.

PL 11184/0104

31 July 1992 / 10 October 2005

December 2011

POM