4.1. Therapeutic indications

Symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults.

4.2. Posology and method of administration

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Posology

Amifampridine should be given in divided doses, three or four times a day. The recommended starting dose is 15 mg amifampridine a day, which can be increased in 5 mg increments every 4 to 5 days, to a maximum of 60 mg per day. No single dose should exceed 20 mg.

Tablets are to be taken with food. Please see section 5.2 for further information about bioavailability of amifampridine in the fed and fasted state.

If treatment is discontinued, patients may experience some of the symptoms of LEMS.

Renal or hepatic impairment

Amifampridine should be used with caution in patients with renal or hepatic impairment. A starting dose of 5 mg amifampridine (half tablet) once per day is recommended in patients with moderate or severe impairment of renal or hepatic function. For patients with mild impairment of renal or hepatic function, a starting dose of 10 mg amifampridine (5 mg twice a day) per day is recommended. Patients should be titrated more slowly than those without renal or hepatic impairment with doses increased in 5 mg increments every 7 days. If any adverse reaction occurs, upward dose titration should be discontinued (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Amifampridine in children aged 0 to 17 years has not been established. No data are available.

Method of administration

For oral use only.

4.3. Contraindications

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

Epilepsy

Uncontrolled asthma

Concomitant use with sultopride (see sections 4.5 and 5.1)

Concomitant use with medicinal products with a narrow therapeutic window (see section 4.5)

Concomitant use with medicinal products with a known potential to cause QTc prolongation

In patients with congenital QT syndromes (see section 4.4)

4.4. Special warnings and precautions for use

Renal and hepatic impairment

The pharmacokinetics of amifampridine has been assessed in a single dose Phase I study in patients with renal impairment (see section 5.2).

No studies have been conducted in patients with hepatic impairment. In view of the risk of markedly increased exposure to medicinal product, patients with renal or hepatic impairment must be carefully monitored. The dose of amifampridine should be titrated more slowly in patients with renal and hepatic impairment than those with normal renal and hepatic function. Upward dose titration should be discontinued if any adverse reaction occurs (see section 4.2).

Seizures

Exposure to amifampridine is associated with an increased risk for epileptic seizures. The risk of seizures is dose-dependent and is increased in patients with risk factors which lower the epileptic threshold; including use in combination with other medicinal products known to lower the epileptic threshold (see section 4.5). In the event of a seizure, treatment should be discontinued.

Carcinogenicity risk

In a 2-year dietary carcinogenicity study, benign and malignant Schwannomas have been observed in rats treated with amifampridine (see section 5.3). Amifampridine was not genotoxic in a standard battery of in vitro and in vivo tests. The correlation between the use of amifampridine and the development of tumours in humans is unknown at this time.

Most Schwannomas are benign and asymptomatic. They can present in many locations, therefore the clinical presentation can be varied. A diagnosis of Schwannoma should be considered for patients who present with symptoms such as a mass that is painful on palpation or symptoms similar to a compressive neuropathy. Schwannomas are generally slow-growing and can exist for months to years without producing symptoms. The benefit of continuing treatment with amifampridine should be reviewed for any patient who develops a Schwannoma.

Amifampridine should be used with caution in patients with an increased risk of Schwannomas, such as patients with past medical history of such tumours, neurofibromatosis Type 2 or schwannomatosis.

Cardiac effects

Clinical and electrocardiogram (ECG) monitoring are indicated at the initiation of the treatment and yearly thereafter. In case of signs and symptoms indicative of cardiac arrhythmias, ECG should be performed immediately.

Concomitant diseases

Patients must be told to inform any physician they consult that they are taking this medicinal product, since close monitoring of a concomitant disease, particularly asthma, may be necessary.

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

Pharmacokinetic interactions

Medicinal products eliminated through metabolism or active secretion

There are no data on the effects of amifampridine on the metabolism or active secretion of other medicinal products. Thus, special care should be taken in patients undergoing concomitant treatment with medicinal products eliminated through metabolism or active secretion. Monitoring is advised when possible. The dose of the concomitantly given medicinal product should be adjusted if necessary. Concomitant use of medicinal products with a narrow therapeutic window is contraindicated (see section 4.3).

Substances which are potent inhibitors of enzymes that metabolise medicinal products (see section 5.2)

Potent cytochrome P450 (CYP450) enzyme inhibitors e.g. cimetidine, ketoconazole are not likely to inhibit the metabolism of amifampridine by human N-acetyl-transferase enzymes (NATs) giving rise to increased amifampridine exposure. The results from the in vitro CYP450 inhibition study indicate amifampridine is unlikely to play a role in metabolic-based clinical drug-drug interactions related to inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 metabolism of co-administered medicinal products. Regardless, patients should be closely monitored for adverse reactions when initiating treatment with a potent enzyme or renal transporter inhibitor. If treatment with a potent inhibitor is discontinued, patients should be monitored for efficacy as an increase of amifampridine dose may be necessary.

Substances which are potent inducers of enzymes that metabolise medicinal products (see section 5.2)

The results from in vitro studies suggest there is low potential for drug-drug interactions due to enzyme induction of CYP1A2, CYP2B6, and CYP3A4 enzymes by amifampridine.

Pharmacodynamic interactions

Based on the pharmacodynamic properties of amifampridine, the concomitant use with sultopride or other medicinal products known to cause QT prolongation (e.g., disopyramide, cisapride, domperidone, rifampicin and ketoconazole) is contraindicated as this combination may lead to an enhanced risk of ventricular tachycardia, notably torsade de pointes (see sections 4.3 and 5.1).

Combinations requiring precautions for use

Medicinal products known to lower the epileptic threshold

The concomitant use of amifampridine and substances known to lower the epileptic threshold may lead to an increased risk of seizures. The decision to administer proconvulsant or epileptic-threshold lowering substances concomitantly should be carefully considered in the light of the severity of the associated risks. These substances include most anti-depressants (tricyclic antidepressants, selective serotonin uptake inhibitors), neuroleptics (phenothiazines and butyrophenones), mefloquine, bupropion and tramadol (see sections 4.4 and 5.1).

Combinations to be taken into consideration

Medicinal products with atropinic effects

The concomitant use of amifampridine and medicinal products with atropinic effects may reduce the effect of both active substances and should be taken into consideration. Medicinal products with atropinic effects include tricyclic anti-depressants, most H1 atropinic anti-histamines, anticholinergic, anti-Parkinson medicinal products, atropinic antispasmodics, disopyramide, phenothiazine neuroleptics and clozapine.

Medicinal products with cholinergic effects

The concomitant use of amifampridine and medicinal products with cholinergic effects (e.g. direct or indirect cholinesterase inhibitors) may lead to an increased effect of both products and should be taken into consideration.

Non depolarising muscle relaxant acting medicinal products

The concomitant use of amifampridine and medicinal products with non-depolarising muscle relaxant effects (e.g. mivacurium, pipercurium) may lead to a decreased effect of both products and should be taken into consideration.

Depolarising muscle relaxant acting medicinal products

The concomitant use of amifampridine and medicinal products with depolarising muscle relaxant effects (e.g. suxamethonium) may lead to a decreased effect of both products and should be taken into consideration.

4.6. Fertility, pregnancy and lactation

Pregnancy

Amifampridine should not be used during pregnancy. Women of childbearing potential must use effective contraception during Amifampridine treatment. No adequate clinical data on exposed pregnancies are available for amifampridine. Amifampridine has shown no effect on embryo-foetal viability and development in rabbits; however, in rats, an increase in the number of mothers delivering still-born offspring was observed (see section 5.3).

Breast-feeding

It is unknown whether amifampridine is excreted in human breast milk. Available reproductive data in animals have shown presence of amifampridine in milk of breast-feeding mothers. Assessment of breast-feeding neo-natal animals showed no indication of adverse reactions when exposed to amifampridine through breast-milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Amifampridine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Non-clinical safety data are available regarding the effects of amifampridine on reproductive function.

No impairment of fertility has been observed in non-clinical studies with amifampridine (see section 5.3).

4.7. Effects on ability to drive and use machines

Due to adverse reactions such as drowsiness, dizziness, seizures and blurred vision, amifampridine may have minor or moderate influence on the ability to drive or use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are paraesthesias (such as peripheral and peribucal paraesthesias) and gastro-intestinal disorders (such as epigastralgia, diarrhoea, nausea and abdominal pain). The intensity and incidence of most adverse reactions is dose-dependent.

Table 1 below lists the adverse reactions reported with amifampridine.

Tabulated list of adverse reactions

Frequencies are defined as: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000) and Unknown (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Frequencies were estimated based on a clinical study to evaluate the effects of amifampridine on cardiac repolarization at a single dose of 30 mg or 60 mg in healthy volunteers.

Table 1: Adverse Reactions Reported with Amifampridine

MedDRA

System organ class

MedDRA

Preferred term

Frequency

Psychiatric disorders

Sleep disorders, anxiety

Unknown

Nervous system disorders

Convulsions, chorea, myoclonia drowsiness, weakness, fatigue, headache

Unknown

Dizziness1, hypoaesthesia1, paraesthesia1

Very common

Eye disorders

Blurred vision

Unknown

Cardiac disorders

Cardiac rhythm disorders, palpitations

Unknown

Vascular disorders

Raynaud's syndrome

Unknown

Cold extremities1

Common

Respiratory, thoracic and mediastinal disorders

Bronchial hypersecretion, asthma attack in asthmatic patients or patients with a history of asthma, cough

Unknown

Gastrointestinal disorders

Hypoaesthasia oral1, paraesthesia oral1, peripheral and peribucal paraesthesias, nausea1

Very common

Abdominal pain

Common

Diarrhoea, epigastralgia

Unknown

Hepatobiliary disorders

Elevated liver enzyme levels (transaminases)

Unknown

Skin and subcutaneous disorders

Hyperhidrosis1, cold sweat1

Very common

1 Adverse reactions reported in a clinical study to evaluate the effects of amifampridine on cardiac repolarization at a single dose of 30 mg or 60 mg in healthy volunteers.

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 the 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

There is little experience with overdose. The manifestations of acute overdose include vomiting and abdominal pain. Patient should discontinue the treatment in the event of overdose. No specific antidote is known. Supportive care should be given as clinically indicated, including close monitoring of vital signs.