ADEPEND Film-coated tablet Ref.[7824] Active ingredients: Naltrexone

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

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

In opioid-dependent patients, withdrawal symptoms may be caused by Adepend 50 mg film-coated tablets. These may manifest after 5 minutes and least up to 48 hours. The treatment should be symptomatic and may include administration of opioids.

Liver function test

Due to its hepatotoxic effect, special caution should be taken with the administration of Adepend in patients with acute liver disease or liver impairment.

Naltrexone hydrochloride is metabolised mainly by the liver and mainly eliminated by urine. Therefore patients with liver or renal impairment should be supervised carefully during treatment (see section 4.3). Liver function tests should be conducted before and during therapy.

It is not uncommon that the liver function of alcohol addicts is impaired. In elderly, obese alcohol addicted patients, liver function tests have demonstrated abnormal results after administration of higher doses of naltrexone (up to 300 mg/day).

Liver function tests should be carried out both before and during treatment.

Screen for presence of opioid use

In case of the suspicion of opioid dependence it is recommended to screen for the presence of opioid use:

• Urine test: If the suspicion of opioid use is aroused despite a negative urine test result and the lack of visible clinical withdrawal symptoms, it is recommended to confirm the result of the urine test with a naloxone challenge test.
• Naloxone challenge test: Withdrawal symptoms caused by naloxone hydrochloride are of shorter duration than those precipitated by Adepend 50 mg film-coated tablets.

A naloxone challenge test should neither be performed in patients with clinically significant withdrawal symptoms nor in patients tested positive for opioids in the urine. If withdrawal symptoms should occur during this test the treatment with Adepend 50 mg film-coated tablets must not be initiated. The treatment may be initiated following a negative test result.

Recommended administration scheme:

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 30 minutes for signs of withdrawal.

Subcutaneous: Administer 0.8 mg naloxone sc. Observe the patient for 30 minutes for signs of withdrawal.

Confirmation of the test: If there is any doubt that the patient is opioid-free, treatment with Adepend 50 mg film-coated tablets should be delayed 24 hours. In this case, the test should be repeated with 1.6 mg naloxone.

Naltrexone treatment must begin only when the opioid has been discontinued for sufficiently long period (about 5 to 7 days for heroin and at least 10 days for methadone).

Patients must be warned against the use of high doses of opioids to neutralize the blockade as this might result in acute and possibly fatal opioid intoxication as soon as the effect of naltrexone has ceased. High-dose opioid intake, concomitant with naltrexone treatment, can lead to life-threatening opioid poisoning from respiratory and circulatory impairment.

Patients might be more sensitive to opioid containing medicines after treatment with Adepend 50 mg film-coated tablets.

Naltrexone may cause a transient increase in the diastolic blood pressure followed by decrease in body temperature and heart rate.

Patients must be warned against concomitant use of opioids (e.g. opioid containing cough medication, opioid containing medication for symptomatic treatment of common cold or opioid containing medication for diarrhea etc.) during treatment with Adepend 50 mg film-coated tablets.

If the patient treated with Adepend 50 mg film-coated tablets needs opioid treatment, e.g. opioid analgesia or anesthesia in emergency situations, the dose needed may be higher than normal to reach the same therapeutic effect. In these cases, respiratory depression and circulatory disturbance will be more profound and longer lasting. Symptoms related to release of histamine (e.g. face swelling, itching, erythema, diaphoresis and other skin and mucocutaneous manifestations) can occur more easily. The patient requires specific attention and supervision by health care personnel in a medical unit.

The increased suicidal risk in drug addicts with or without accompanying depression is not reduced by the intake of Adepend 50 mg film-coated tablets.

Special attention should be paid to patients with hepatic enzyme levels in serum exceeding three times the normal value and patients with renal impairment.

Lactose

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

At the moment, there is only limited clinical experience and experimental data on the effect of naltrexone on the pharmacokinetics of other substances. Concomitant treatment with naltrexone and other medicinal products should be conducted with caution and should be followed carefully. No studies for interactions have been performed.

Cases of lethargy and somnolence have been reported after concomitant use of naltrexone and thioridazine.

In vitro studies have shown that neither naltrexone hydrochloride nor its active metabolite 6-beta-naltrexol is metabolised by human cytochrom P450 enzymes. Therefore it is unlikely that the pharmacokinetics of Adepend 50 mg film-coated tablets is affected by cytochrom P450 enzyme inhibiting or inducing drugs:

Patients might be more sensitive to opioid containing medicines after treatment with Adepend 50 mg film-coated tablets.

Contraindicated combinations: Concomitant use of naltrexone with opioid derivates (analgesics, antitussives, substitution treatments) is contraindicated (see section 4.3 and 4.4).

Methadone in substitution treatment: There is a risk of onset of withdrawal symptoms.

Combinations not recommended: Concomitant use of naltrexone with central antihypertensives (alpha-methyldopa) is not recommended.

Combinations where caution is advised: Concomitant use of naltrexone with barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (e.g. meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, trimipramine), sedative antihistamines H1 and neuroleptics (droperidol) may be considered with caution.

So far, no interaction between cocaine and naltrexone hydrochloride has been described.

Data from a safety and tolerability study of co-administration of naltrexone with acamprosate in non-treatment seeking, alcohol dependent individuals showed that naltrexone administration significantly increased the acamprosate plasma level.

Interaction with other psychopharmacological agents (e.g. disulfirame, amitryptiline, doxepine, lithium, clozapine, benzodiazepines) has not been investigated.

Currently, interactions between naltrexone and alcohol are not known.

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 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 fetus (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 hydrochloride use in lactation. It is unknown whether naltrexone or 6-beta-naltexol is excreted in human breast milk. Breast feeding is not recommended during naltrexone treatment.

Adepend 50 mg film-coated tablets may influence psychological and physical abilities and, therefore, conduction of potentially dangerous tasks like driving vehicles or using machines should be avoided.

The following undesirable effects are classified according to system organ class and frequency: Very Common (1/10), Common (1/100 to 1/10), Uncommon (1/1000 to 1/100), Rare (1/10000 to 1/1000), Very Rare (1/10000), Not known (cannot be estimated from the available data).

The side effects observed with naltrexone appear to be similar in both alcoholics and patients dependent on opioids. Serious adverse reactions are unusual.

Infections and infestations

Uncommon: oral herpes, tinea pedis

Blood and lymphatic system disorders

Uncommon: lymphadenopathy

Rare: idiopathic thrombocytopenic purpura

Metabolism and nutrition disorders

Common: decrease of appetite

Psychiatric disorders

Very common: nervousness, anxiety, insomnia

Common: irritability, affective disorder

Uncommon: hallucination, confusion, despondency, depression, paranoia, disorientation, nightmares, agitation, libido disorder, abnormal dreams

Rare: suicidal ideation, attempted suicide

Nervous system disorders

Very common: headache, restlessness

Common: dizziness

Uncommon: tremor, somnolence

Eye disorders

Common: increased lacrimation

Uncommon: blurred vision, irritation and swelling of the eye, photophobia, eye pain or tiredness, colour asthenopia

Ear and labyrinth disorders

Uncommon: ear discomfort, ear pain, tinnitus, vertigo

Cardiac disorders

Common: tachycardia, heart palpitation, anomalies in the ECG

Vascular disorders

Uncommon: blood pressure changes, flushing

Respiratory, thoracic and mediastinal disorders

Common: pain in the chest

Uncommon: nasal congestion, nasal discomfort, rhinorrhoea, sneezing, oropharyngeal disorders, increased sputum, sinus disorders, dyspnoea, dysphonia, coughing, yawning

Gastrointestinal disorders

Very common: abdominal pain, nausea, emesis

Common: diarrhoea, constipation

Uncommon: flatulence, haemorrhoids, ulcus, mouth dryness

Hepatobiliary disorders

Uncommon: hepatic disorders, increased bilirubin levels, hepatitis (During treatment, increase of transaminases is possible. After discontinuing the intake of Adepend, transaminases decrease to the original levels within some weeks.)

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: seborrhea, pruritus, acne, alopecia

Musculoskeletal and connective tissue disorders

Very common: arthralgia and myalgia

Uncommon: groin pain

Very rare: rhabdomyolysis

Renal and urinary disorders

Uncommon: pollakisuria, dysuria

Reproductive system and breast disorders

Common: delayed ejaculation, erectile dysfunction, libido disorders

General disorders and administration site conditions

Very common: asthenia

Common: thirst, increased energy, chills, hyperhidrosis

Uncommon: increased appetite, weight loss, weight gain, fever, pain, sensation of cold in extremities, hot flushes

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

Not applicable.