NALOREX

Nalorex 50mg Film Coated Tablets

Naltrexone hydrochloride 50 mg per tablet.

Excipients with known effect:

lactose monohydrate, 204mg per tablet.

For a full list of excipients, see section 6.1.

Film-coated tablet. (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.

Treatment should be considered only in patients who have remained opioid free for a minimum of 7 – 10 days and are not showing signs or symptoms of withdrawal. Self reported abstinence should be verfied by urinalysis.

Administration of Nalorex must not be started before a naloxone challenge test is performed and a negative result obtained. The naloxone test is positive if signs or symptoms of withdrawal appear.

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

NALOREX is contraindicated

• in patients with acute hepatitis or liver failure.

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

• in patients in acute opioid withdrawal

• for use in conjunction with an opioid-containing medication.

• in combination with methadone (see section 4.5).

• in any patient who has a positive urine screen for opioids or who has failed the Naloxone Challenge.

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

• 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.

Hepatic & renal impairment

Since Nalorex is extensively metabolised by the liver and because Nalorex and it’s primary metabolites are 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 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 at doses higher than recommended (up to 300 mg/day) for the treatment of alcoholism. Liver function tests should be carried out both before and during treatment.

Nalorex has the capacity to cause hepatocellular injury when given in excessive doses. Nalorex does not appear to be a hepatotoxin at the recommended doses.

Use in patients with active liver disease must be carefully considered in light of its potential hepatotoxic effects. The margin of separation between the apparently safe and potentially hepatotoxic dose of Nalorex appears to be only five-fold or less. Patients should be warned of the risk of hepatic injury and advised to stop the use of Nalorex and seek medical attention if they experience symptoms of acute hepatitis.

Withdrawal syndrome

Naltrexone treatment must begin only when the opioid has been discontinued for a sufficiently long period (about 5 7 days for heroin and at least 10 days for methadone) to prevent the occurrence of an acute withdrawal syndrome or exacerbation of a pre existing subclinical withdrawal syndrome (see secion 4.2 and 4.3).

Use of Nalorex does not eliminate or diminish withdrawal symptoms. If Nalorex is initiated early in the withdrawal process, it will not preclude the patient’s experience of the full range of signs and symptoms that would be experienced if Nalorex had not been started. Numerous adverse events are known to be associated with withdrawal

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

Specific patient warnings

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

Patients must be cautioned about the concomitant use of opioids (eg opioids in cough preparations, opioids for symptomatic treatment of colds or opioids in antidiarrhoeal preparations etc) during treatment with naltrexone (see section 4.3 and 4.5)

Patients should be warned that after naltrexone treatment is discontinued they may be more sensitive to lower doses of opioids than previously tolerated. This decreased tolerance to opioids may result in life-threatening opioid intoxication and fatal overdose from a relatively low dose of opioids should a patient decide to return to opioid use.

Emergency analgesics

In an emergency situation in which the administration of opioid analgesics is required in patients receiving Nalorex a suggested plan of management is regional analgesia, conscious sedation with a benzodiazepine, use of non opioid analgesics or general anaesthesics. 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. A rapidly acting opioid analgesic that minimizes the duration of respiratory depression is preferred. As naltrexone does not block the histamine releasing effects of certain opioids short acting opioids that are not potent histamine releasers should be used to reduce non-receptor mediated effects (e.g. swelling of the face, pruritus, generalized erythema, diaphoresis, bronchoconstriction 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.

Suicide

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 naltrexone with an opioid-containing medication should be avoided. (see section 4.3 and 4.4)

Patients should be warned that attempts to overcome the blockade by administering large doses of opioids may result in acute opioid intoxication which may be 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 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-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: treatment opioid derivatives (analgesics, antitussives, substitution treatments), Central antihypertensives, (alpha-methyldopa).

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).

Until now 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 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).

Breast feeding 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. Nalorex has a minor or moderate influence on the ability to drive and use machines.

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, <1/1,000); 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

Respiratory disorders

Common: chest pain

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

Cardiac disorders

Common: tachycardia, palpitations, electrocardiogram change

Vascular disorders

Uncommon: blood pressure fluctuation, flushing

Gastrointestinal disorders

Very common: abdominal pain, nausea and/or vomiting

Common: diarrhoea, constipation

Uncommon: flatulence, haemorrhoids, ulcer, dry mouth

Musculoskeletal and connective tissue disorders

Very common: arthralgia and myalgia

Uncommon: painful shoulders, legs or knees, twitching, groin pain

Very rare: rhabdomyolysis

Reproductive system and breast disorders

Common: ejaculation delayed, erectile dysfunction

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: seborrhoea, pruritus, acne, alopecia.

Psychiatric disorders

Very common: Insomnia anxiety, nervousness

Common: affective disorders, irritability

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

Rare: suicidal ideation, attempted suicide

Eye disorders

Common: lacrimation increased

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

Ear and labyrinth disorders

Uncommon: Ear discomfort, ear pain, tinnitus, vertigo

Nervous system disorders

Very common: headache, restlessness

Common: dizziness

Uncommon: tremor, somnolence

Renal and urinary tract disorders

Uncommon: pollakiuria, dysuria

Unknown: Renal failure

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, hyperhidriosis.

Uncommon: increased appetite, weight loss, weight gain, pyrexia, swollen glands, pain, peripheral coldness, feeling hot

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.)

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2. Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; email: medsafety@hpra.ie.

There is limited 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.

Pharmacotherapeutic group: antidotes, ATC code: V03A B30

Naltrexone is a specific opiate antagonist. 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 antagonises the actions of exogenously administered opioids.

Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties.

Naltrexone is rapidly and almost completely absorbed after oral administration.

It undergoes a liver first-pass effect and 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 is hydroxylated in the liver basically to 6-beta-naltrexol and, to a lesser extent, to 2-hydroxy-3-methoxy-6-beta-naltrexol. Both naltrexone and 6-beta-naltrexol contribute to the observed pharmacological activity. Naltrexone is excreted mainly in the urine as the conjugated form.

The plasma half-life is approximately 4 hours for naltrexone and 13 hours for 6-beta-naltrexol.

Acute, subacute and chronic toxicity studies of naltrexone have been conducted on a number of rodents and non-rodents. No unusual observations were made.

Carcinogenicity studies have been conducted on rats and mice. The results of these studies show that naltrexone is not carcinogenic under the applied conditions.

An extensive in-vitro and in-vivo trial yielded no relevant mutagenic potential.

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 (see section 4.6). 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.

Lactose monohydrate

Microcrystalline Cellulose

Crospovidone

Silica, colloidal, anhydrous

Magnesium stearate

Tablet Coat:

Pale Yellow Opadry containing:

Hypromellose

Macrogol

Polysorbate 80

Titanium Dioxide (E171)

Yellow and Red Oxides (E172)

Not applicable.

3 years.

Do not store above 25^ºC.

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

Not all pack sizes may be marketed.

No special requirements.

Bristol-Myers Squibb Pharmaceuticals Limited

Swords

Co. Dublin

Ireland

PA0002/070/001

Date of first authorisation:15 October 1991

Date of last renewal:15 October 2006