Bristol-Myers Squibb Pharmaceutical Limited

Nalorex 50 mg Film Coated Tablets

Naltrexone hydrochloride 50 mg per tablet.

Also contains lactose monohydrate, 204 mg per tablet.

For a full list of excipients, see section 6.1.

Film-coated 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.

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).

Nalorex treatment should be initiated in a drug addiction centre and supervised by suitably qualified physicians.

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.

Narcan^® (Naloxone hydrochloride) challenge is recommended to minimise the chance of a prolonged withdrawal syndrome precipitated by Nalorex (see also Warnings).

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 and Adolescents

Nalorex is not recommended in patients 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.

Nalorex is contraindicated in patients with acute hepatitis or liver failure.

Nalorex is contraindicated in patients currently dependent on opioids since an acute withdrawal syndrome may ensue.

Nalorex is contraindicated in patients in acute opioid withdrawal.

Nalorex is contraindicated for use 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 is contraindicated in patients who have demonstrated hypersensitivity to Naltrexone hydrochloride or any of the excipients.

Nalorex is contraindicated in patients with severe renal failure.

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.

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

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

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 centre.

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.

Patients taking naltrexone may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrhoeal preparations, and opioid analgesics.

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. 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-beta-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. Interactions 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.

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.

Animal studies do not suggest a teratogenic effect, but there is no experience of use during human pregnancy. The drug should only be used in pregnancy or lactation if considered essential by the physician.

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 duing 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.

Respiratory disorders

Common: chest pain

Uncommon: nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath, yawning

Cardiovascular disorders

Common: tachycardia, palpitations, electrocardiogram change

Uncommon: nose bleeds, phlebitis, edema, increased blood pressure

Gastrointestinal disorders

Very common: abdominal pain/cramps, nausea and/or vomiting

Common: diarrhoea, constipation

Uncommon: excessive gas, hemorrhoids, diarrhoea, ulcer, dry mouth

Musculoskeletal disorders

Very common: joint and muscle pain

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

Very rare: rhabdomyolysis

Genitourinary disorders

Common: delayed ejaculation, decreased potency

Uncommon: increased frequency of or discomfort during urination, increased or decreased sexual interest

Skin and subcutaneous disorders

Common: skin rash

Uncommon: oily skin, purities, acne, athlete's foot, cold sores, alopecia.

Psychiatric disorders

Very common: Difficulty sleeping, anxiety, nervousness, head ache

Common: feeling down, irritability, dizziness

Uncommon: depression, paranoia, fatigue, restlessness, confusion, disorientation, hallucinations, nightmares, bad dreams

Eye disorders

Common: increased lacrimation

Uncommon: eyes-blurred, burning, light sensitive, swollen, aching or strained

Ear and labyrinth disorders

Uncommon: ears- clogged, aching, tinnitus,vertigo

Nervous system disorders

Very common: headache, restlessness

Common: dizziness

Uncommon: tremor, somnolence, headache

Renal and urinary tract disorders

Uncommon: pollakiuria, dysuria

Infections and infestations

Uncommon: oral herpes, tinea pedis

Metabolism and nutrition disorders

Common: decreased appetite

General disorders

Very common: low energy

Common: loss of appetite, increased thirst, increased energy, chills, increased sweating.

Uncommon: increased appetite, weight loss, weight gain, yawning, somnolence, fever, dry mouth, head “pounding”, inguinal pain, swollen glands, side pains, cold feet, hot spells.

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.

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.

Pharmacotherapuetic group: antidote, ATC Code: V03A B30.

Naltrexone is a specific opiate antagonist. It acts by stereo specific 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, sub acute 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 (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.

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 Iron oxides (E172)

Not applicable

3 years.

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.

No special requirements.

Bristol-Myers Squibb Pharmaceuticals Limited

Swords

Co. Dublin

Ireland

PA 0002/070/001

March 2011