4.1. Therapeutic indications

Fampyra is indicated for the improvement of walking in adult patients with multiple sclerosis with walking disability (EDSS 4-7).

4.2. Posology and method of administration

Treatment with fampridine is restricted to prescription and supervision by physicians experienced in the management of MS.

Posology

The recommended dose is one 10 mg tablet, twice daily, taken 12 hours apart (one tablet in the morning and one tablet in the evening). Fampridine should not be administered more frequently or at higher doses than recommended (see section 4.4). The tablets should be taken without food (see section 5.2).

Missed dose

The usual dosing regimen should always be followed. A double dose should not be taken if a dose is missed.

Starting and evaluating Fampyra treatment

• Initial prescription should be limited to two to four weeks of therapy as clinical benefits should generally be identified within two to four weeks after starting Fampyra

• An assessment of walking ability, e.g. the Timed 25 Foot Walk (T25FW) or Twelve Item Multiple Sclerosis Walking Scale (MSWS-12), is recommended to evaluate improvement within two to four weeks. If no improvement is observed, the treatment should be discontinued

• This medicinal product should be discontinued if benefit is not reported by patients.

Re-evaluating Fampyra treatment

If decline in walking ability is observed, physicians should consider an interruption to treatment in order to reassess the benefits of frampridine (see above). The re-evaluation should include withdrawal of this medicinal product and performing an assessment of walking ability. Fampridine should be discontinued if patients no longer receive walking benefit.

Special populations

Elderly

Renal function should be checked in the elderly before starting treatment with this medicinal product. Monitoring renal function to detect any renal impairment is recommended in the elderly (see section 4.4).

Patients with renal impairment

Fampridine is contraindicated in patients with moderate and severe renal impairment (creatinine clearance <50 mL/min) (see sections 4.3 and 4.4).

Patients with hepatic impairment

No dose adjustment is required for patients with hepatic impairment.

Paediatric population

The safety and efficacy of this medicinal product in children aged 0 to 18 years have not been established. No data are available.

Method of administration

Fampyra is for oral use.

The tablet must be swallowed whole. It must not be divided, crushed, dissolved, sucked or chewed.

4.3. Contraindications

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

Concurrent treatment with other medicinal products containing fampridine (4-aminopyridine).

Patients with prior history or current presentation of seizure.

Patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).

Concomitant use of Fampyra with medicinal products that are inhibitors of Organic Cation Transporter 2 (OCT2) for example, cimetidine.

4.4. Special warnings and precautions for use

Seizure risk

Treatment with fampridine increases seizure risk (see section 4.8).

This medicinal product should be administered with caution in the presence of any factors which may lower seizure threshold.

Fampridine should be discontinued in patients who experience a seizure while on treatment.

Renal impairment

Fampridine is primarily excreted unchanged by the kidneys. Patients with renal impairment have higher plasma concentrations which are associated with increased adverse reactions, in particular neurological effects. Determining renal function before treatment and its regular monitoring during treatment is recommended in all patients (particularly in the elderly in whom renal function might be reduced). Creatinine clearance can be estimated using the Cockroft-Gault formula.

Caution is required when Fampyra is prescribed in patients with mild renal impairment or in patients using medicinal products that are substrates of OCT2 for example, carvedilol, propranolol and metformin.

Hypersensitivity reactions

In post-marketing experience, serious hypersensitivity reactions (including anaphylactic reaction) have been reported, the majority of these cases occurred within the first week of treatment. Particular attention should be given to patients with a previous history of allergic reactions. If an anaphylactic or other serious allergic reaction occurs, this medicinal product should be discontinued and not restarted.

Other warnings and precautions

Fampridine should be administered with caution to patients with cardiovascular symptoms of rhythm and sinoatrial or atrioventricular conduction cardiac disorders (these effects are seen in overdose). There is limited safety information in these patients.

The increased incidence of dizziness and balance disorder seen with fampridine may result in an increased risk of falls. Therefore, patients should use walking aids as needed.

In clinical studies low white blood cell counts were seen in 2.1% of Fampyra patients versus 1.9% of patients on placebo. Infections were seen in the clinical studies (see section 4.8) and increased infection rate and impairment of the immune response cannot be excluded.

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

Interaction studies have only been performed in adults.

Concurrent treatment with other medicinal products containing fampridine (4-aminopyridine) is contraindicated (see section 4.3).

Fampridine is eliminated mainly via the kidneys with active renal secretion accounting for about 60% (see section 5.2). OCT2 is the transporter responsible for the active secretion of fampridine. Thus, the concomitant use of fampridine with medicinal products that are inhibitors of OCT2 for example, cimetidine are contraindicated (see section 4.3) and concomitant use of fampridine with medicinal products that are substrates of OCT2 for example, carvedilol, propranolol and metformin is cautioned (see section 4.4.)

Interferon: fampridine has been administered concomitantly with interferon-beta and no pharmacokinetic medicinal product interactions were observed.

Baclofen: fampridine has been administered concomitantly with baclofen and no pharmacokinetic medicinal product interactions were observed.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data from the use of fampridine in pregnant women.

Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure it is preferable to avoid the use of fampridine in pregnancy.

Breast-feeding

It is unknown whether fampridine is excreted in human or animal milk. Fampyra is not recommended during breast-feeding.

Fertility

In animal studies no effects on fertility were seen.

4.7. Effects on ability to drive and use machines

Fampyra has a moderate influence on the ability to drive and use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The safety of Fampyra has been evaluated in randomised controlled clinical studies, in open label long term studies and in the post marketing setting.

Adverse reactions identified are mostly neurological and include seizure, insomnia, anxiety, balance disorder, dizziness, paraesthesia, tremor, headache and asthenia. This is consistent with fampridine's pharmacological activity. The highest incidence of adverse reactions identified from placebo-controlled trials in multiple sclerosis patients with fampridine given at the recommended dose, are reported as urinary tract infection (in approximately 12 % of patients).

Tabulated list of adverse reactions

Adverse reactions are presented below by system organ class and absolute frequency. 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); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1: Tabulated list of adverse reactions

MedDRA System Organ Class (SOC)

Adverse reaction

Frequency category

Infections and infestations

Urinary tract infection1

Influenza1

Nasopharyngitis1

Viral infection1

Very Common

Common

Common

Common

Immune system disorders

Anaphylaxis

Angioedema

Hypersensitivity

Uncommon

Uncommon

Uncommon

Psychiatric disorders

Insomnia

Anxiety

Common

Common

Nervous system disorders

Dizziness

Headache

Balance disorder

Vertigo

Paraesthesia

Tremor

Seizure 2

Trigeminal neuralgia 3

Common

Common

Common

Common

Common

Common

Uncommon

Uncommon

Cardiac disorders

Palpitations

Tachycardia

Common

Uncommon

Vascular disorders

Hypotension4

Uncommon

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Pharyngolaryngeal pain

Common

Common

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Dyspepsia

Common

Common

Common

Common

Skin and subcutaneous tissue disorders

Rash

Urticaria

Uncommon

Uncommon

Musculoskeletal and connective tissue disorders

Back pain

Common

General disorders and administration site conditions

Asthenia

Chest discomfort4

Common

Uncommon

1 See section 4.4

2 See sections 4.3 and 4.4

3 includes both de novo symptoms and exacerbation of existing trigeminal neuralgia

4 These symptoms were observed in the context of hypersensitivity

Description of selected adverse reactions

Hypersensitivity

In post-marketing experience, there have been reports of hypersensitivity reactions (including anaphylaxis) which have occurred with one or more of the following: dyspnoea, chest discomfort, hypotension, angioedema, rash and urticaria. For further information on hypersensitivity reactions, please refer to sections 4.3 and 4.4.

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

Symptoms

Acute symptoms of overdose with fampridine were consistent with central nervous system excitation and included confusion, tremulousness, diaphoresis, seizure, and amnesia.

Central nervous system adverse reactions at high doses of 4-aminopyridine include dizziness, confusion, seizures, status epilepticus, involuntary and choreoathetoid movements. Other side effects at high doses include cases of cardiac arrhythmias (for example, supraventricular tachycardia and bradycardia) and ventricular tachycardia as a consequence of potential QT prolongation. Reports of hypertension have also been received.

Management

Patients who overdose should be provided supportive care. Repeated seizure activity should be treated with benzodiazepine, phenytoin, or other appropriate acute anti-seizure therapy.