4.1. Therapeutic indications

Selincro is indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL) [see section 5.1], without physical withdrawal symptoms and who do not require immediate detoxification.

Selincro should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption.

Selincro should be initiated only in patients who continue to have a high DRL two weeks after initial assessment.

4.2. Posology and method of administration

Posology

At an initial visit, the patient's clinical status, alcohol dependence, and level of alcohol consumption (based on patient reporting) should be evaluated. Thereafter, the patient should be asked to record his or her alcohol consumption for approximately two weeks.

At the next visit, Selincro may be initiated in patients who continued to have a high DRL (see section 5.1) over this two-week period, in conjunction with psychosocial intervention focused on treatment adherence and reducing alcohol consumption.

Selincro is to be taken as-needed: On each day the patient perceives a risk of drinking alcohol, one tablet should be taken, preferably 1-2 hours prior to the anticipated time of drinking. If the patient has started drinking alcohol without taking Selincro, the patient should take one tablet as soon as possible.

The maximum dose of Selincro is one tablet per day. Selincro can be taken with or without food (see section 5.2).

During pivotal trials the greatest improvement was observed within the first 4 weeks. The patient's response to treatment and the need for continued pharmacotherapy should be evaluated on a regular (for example, monthly) basis (see section 5.1). The physician should continue to assess the patient's progress in reducing alcohol consumption, overall functioning, treatment adherence, and any potential side effects. Clinical data for the use of Selincro under randomised controlled conditions are available for a period of 6 to 12 months. Caution is advised if Selincro is prescribed for more than 1 year.

Special populations

Elderly (≥65 years of age)

No dose adjustment is recommended for this patient population (see sections 4.4 and 5.2).

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Selincro in children and adolescents <18 years of age have not been established. No data are available (see section 5.1).

Method of administration

Selincro is for oral use.

The film-coated tablet should be swallowed whole.

The film-coated tablet should not be divided or crushed because nalmefene may cause skin sensitisation when in direct contact with the skin (see section 5.3).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients taking opioid agonists (such as opioid analgesics, opioids for substitution therapy with opioid agonists (e.g. methadone) or partial agonists (e.g. buprenorphine)) (see section 4.4).

Patients with current or recent opioid addiction.

Patients with acute symptoms of opioid withdrawal.

Patients for whom recent use of opioids is suspected.

Patients with severe hepatic impairment (Child-Pugh classification).

Patients with severe renal impairment (eGFR <30 ml/min per 1.73 m2).

Patients with a recent history of acute alcohol withdrawal syndrome (including hallucinations, seizures, and delirium tremens).

4.4. Special warnings and precautions for use

Selincro is not for patients for whom the treatment goal is immediate abstinence. Reduction of alcohol consumption is an intermediate goal on the way to abstinence.

Opioid administration

In an emergency situation when opioids must be administered to a patient taking Selincro, the amount of opioid required to obtain the desired effect may be greater than usual. The patient should be closely monitored for symptoms of respiratory depression as a result of the opioid administration and for other adverse reactions.

If opioids are needed in an emergency, the dose must always be titrated individually. If unusually large doses are required, close observation is necessary.

Selincro should be temporarily discontinued for 1 week prior to the anticipated use of opioids, for example, if opioid analgesics might be used during elective surgery.

The prescriber should advise patients that it is important to inform their health care professional of last Selincro intake if opioid use becomes necessary.

Caution should be exercised when using medicinal products containing opioids (for example, cough medicines, opioid analgesics (see section 4.5)).

Comorbidity

Psychiatric disorders

Psychiatric effects were reported in clinical studies (see section 4.8). If patients develop psychiatric symptoms that are not associated with treatment initiation with Selincro, and/or that are not transient, the prescriber should consider alternative causes of the symptoms and assess the need for continuing treatment with Selincro.

Selincro has not been investigated in patients with unstable psychiatric disease. Caution should be exercised if Selincro is prescribed to patients with current psychiatric comorbidity such as major depressive disorder.

The increased suicidal risk in alcohol and substances abusers, with or without accompanying depression, is not reduced by the intake of nalmefene.

Seizure disorders

There is limited experience in patients with a history of seizure disorders, including alcohol withdrawal seizures.

Caution is advised if treatment aimed at reduction of alcohol consumption is started in such patients.

Renal or hepatic impairment

Selincro is extensively metabolised by the liver and excreted predominantly in the urine. Therefore, caution should be exercised when prescribing Selincro to patients with mild or moderate hepatic or mild or moderate renal impairment, for example, by more frequent monitoring.

Caution should be exercised when prescribing Selincro to patients with elevated ALAT or ASAT (>3 times ULN) as these patients were excluded from the clinical development programme.

Elderly patients (≥65 years of age)

Limited clinical data are available on the use of Selincro in patients ≥65 years of age with alcohol dependence.

Caution should be exercised when prescribing Selincro to patients ≥65 years of age (see sections 4.2 and 5.2).

Others

Caution is advised if Selincro is co-administered with a potent UGT2B7 inhibitor (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

No in vivo drug-drug interaction studies have been conducted.

Based on in vitro studies, no clinically relevant interactions between nalmefene, or its metabolites, and concomitantly administered medicinal products metabolised by the most common CYP450 and UGT enzymes or membrane transporters are anticipated. Co-administration with medicinal products that are potent inhibitors of the UGT2B7 enzyme (for example, diclofenac, fluconazole, medroxyprogesterone acetate, meclofenamic acid) may significantly increase the exposure to nalmefene. This is unlikely to present a problem with occasional use, but if long-term concurrent treatment with a potent UGT2B7 inhibitor is initiated, a potential for an increase in nalmefene exposure cannot be excluded (see section 4.4). Conversely, concomitant administration with a UGT inducer (for example, dexamethasone, phenobarbital, rifampicin, omeprazole) may potentially lead to subtherapeutic nalmefene plasma concentrations.

If Selincro is taken concomitantly with opioid agonists (for example, certain types of cough and cold medicinal products, certain antidiarrhoeal medicinal products, and opioid analgesics), the patient may not benefit from the opioid agonist.

There is no clinically relevant pharmacokinetic drug-drug interaction between nalmefene and alcohol. There seems to be a small impairment in cognitive and psychomotor performance after administration of nalmefene. However, the effect of nalmefene and alcohol in combination did not exceed the sum of the effects of each substance when taken alone.

Simultaneous intake of alcohol and Selincro does not prevent the intoxicating effects of alcohol.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited data (fewer than 300 pregnancy outcomes) from the use of nalmefene in pregnant women.

Animal studies have shown reproductive toxicity (see section 5.3).

Selincro is not recommended during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of nalmefene/metabolites in milk (see section 5.3). It is unknown whether nalmefene is excreted in human milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Selincro therapy, taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman.

Fertility

In fertility studies in rats, no effects were observed for nalmefene on fertility, mating, pregnancy, or sperm parameters.

4.7. Effects on ability to drive and use machines

Adverse reactions such as disturbance in attention, visual impairment, feeling abnormal, nausea, dizziness, somnolence, insomnia, and headache may occur following administration of nalmefene (see section 4.8). The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.

Consequently, Selincro may have minor to moderate influence on the ability to drive and use machines and patients should exercise caution particular when starting treatment with Selincro.

4.8. Undesirable effects

Summary of the safety profile

The frequencies of the adverse reactions in Table 1 were calculated based on three randomised, double-blind, placebo-controlled studies in patients with alcohol dependence.

The most common adverse reactions were nausea, dizziness, insomnia, and headache. The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.

Confusional state and, rarely, hallucinations and dissociation were reported in the clinical studies. The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration (a few hours to a few days). Most of these adverse reactions resolved during continued treatment and did not recur upon repeated administration. While these events were generally short-lasting, they could represent alcoholic psychosis, alcohol withdrawal syndrome, or comorbid psychiatric disease.

Tabulated list of adverse reactions

Frequencies are defined as: 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), or not known (cannot be estimated from the available data).

Table 1 Frequencies of adverse reactions

System Organ Class

Frequency

Adverse Reaction

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Very common

Insomnia

Common

Sleep disorder

Confusional state

Restlessness

Libido decreased (including loss of libido)

Uncommon

Hallucination (including hallucination auditory, hallucination tactile, hallucination visual, and somatic hallucination)

Dissociation

Nervous system disorders

Very Common

Dizziness

Headache

Common

Somnolence

Tremor

Disturbance in attention

Paraesthesia

Hypoaesthesia

Eye disorders

Not known

Visual impairment (mostly transient)

Cardiac disorders

Common

Tachycardia

Palpitations

Gastrointestinal disorders

Very Common

Nausea

Common

Vomiting

Dry mouth

Diarrhoea

Skin and subcutaneous tissue disorders

Common

Hyperhidrosis

Not known

Angioedema

Urticaria

Pruritus

Rash

Erythema

Musculoskeletal and connective tissue disorders

Common

Muscle spasms

Not known

Myalgia

Reproductive system and breast disorder

Not known

Priapism

General disorders and administration site conditions

Common

Fatigue

Asthenia

Malaise

Feeling abnormal

Investigations

Common

Weight decreased

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

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In a study in patients diagnosed with pathological gambling, doses of nalmefene up to 90 mg/day for 16 weeks were investigated. In a study in patients with interstitial cystitis, 20 patients received 108 mg/day of nalmefene for more than 2 years. Intake of a single dose of 450 mg nalmefene has been reported without changes in blood pressure, heart rate, respiration rate, or body temperature.

No unusual pattern of adverse reactions was observed in these settings, but experience is limited.

Management of an overdose should be observational and symptomatic.