fampridine: prescribing information – dosing, contraindications, interactions, side effects

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

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 fampridine (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.

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.

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
Seizure2
Trigeminal neuralgia3
Common
Common
Common
Common
Common
Common
Uncommon
Uncommon

MedDRA System Organ
Class (SOC)
Adverse reaction
Frequency category
Cardiac disorders
Palpitations
Common

Tachycardia
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 national reporting system listed in Appendix V.

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.

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.

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.

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

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX07.

Pharmacodynamic effects

Fampyra is a potassium channel blocker. By blocking potassium channels, fampridine reduces the leakage of ionic current through these channels, thereby prolonging repolarization and thus enhancing action potential formation in demyelinated axons and neurological function. Presumably, by enhancing action potential formation, more impulses might be conducted in the central nervous system.

Clinical efficacy and safety

Three phase III, randomised, double-blind, placebo controlled confirmatory studies, (MS-F203 and MS-F204 and 218MS305) have been performed. The proportion of responders was independent of concomitant immunomodulatory therapy (including interferons, glatiramer acetate, fingolimod and natalizumab). The Fampyra dose was 10 mg twice a day (BID).

Studies MS-F203 and MS-F204

The primary endpoint in studies MS-F203 and MS-F204 was the responder rate in walking speed as measured by the Timed 25-foot Walk (T25FW). A responder was defined as a patient who consistently had a faster walking speed for at least three visits out of a possible four during the double blind period as compared to the maximum value among five off-treatment visits.

A significantly greater proportion of Fampyra treated patients were responders as compared to placebo (MS-F203: 34.8% vs. 8.3%, p< 0.001; MS-F204: 42.9% vs. 9.3%, p< 0.001).

Patients who responded to Fampyra increased their walking speed on average by 26.3% vs 5.3% on placebo (p< 0.001) (MS-F203) and 25.3% vs 7.8% (p< 0.001) (MS-F204). The improvement appeared rapidly (within weeks) after starting the treatment.

Statistically and clinically meaningful improvements in walking were seen, as measured by the 12-item Multiple Sclerosis Walking Scale.

Table 2: Studies MS-F203 and MS-F204

STUDY *
MS-F203
MS-F204

Placebo
Fampyra
10 mg BID
Placebo
Fampyra
10 mg BID n of subjects

Consistent improvement
8.3%
34.8%
9.3%
42.9%
Difference

26.5%

33.5%
CI95%
P-value

17.6%, 35.4%
< 0.001

23.2%, 43.9%
< 0.001

STUDY *
MS-F203
MS-F204

Placebo
Fampyra
10 mg BID
Placebo
Fampyra
10 mg BID
≥ 20% improvement
11.1%
31.7%
15.3%
34.5%
Difference

20.6%

19.2%
CI95%
P-value

11.1%,30.1%
< 0.001

8.5%,29.9%
< 0.001
Walking speed
Feet/sec
Ft per sec
Ft per sec
Ft per sec
Ft per sec
Baseline

Absorption

Orally administered fampridine is rapidly and completely absorbed from the gastrointestinal tract.
Fampridine has a narrow therapeutic index. Absolute bioavailability of Fampyra prolonged-release tablets has not been assessed, but relative bioavailability (as compared to an aqueous oral solution) is 95%. The Fampyra prolonged-release tablet has a delay in the absorption of fampridine manifested by slower rise to a lower peak concentration, without any effect on the extent of absorption.

When Fampyra prolonged-release tablets are taken with food, the reduction in the area under the plasma concentration-time curve (AUC0-∞) of fampridine is approximately 2-7% (10 mg dose). The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. However, Cmax increases by 15-23%. Since there is a clear relationship between Cmax and dose related adverse reactions, it is recommended to take Fampyra without food (see section 4.2).

Distribution

Fampridine is a lipid-soluble active substance which readily crosses the blood-brain barrier.
Fampridine is largely unbound to plasma proteins (bound fraction varied between 3-7% in human plasma). Fampridine has a volume of distribution of approximately 2.6 L/kg.
Fampridine is not a substrate for P-glycoprotein.

Biotransformation

Fampridine is metabolised in humans by oxidation to 3-hydroxy-4-aminopyridine and further conjugated to the 3-hydroxy-4-aminopyridine sulfate. No pharmacological activity was found for the fampridine metabolites against selected potassium channels in vitro.

The 3-hydroxylation of fampridine to 3-hydroxy-4-aminopyridine by human liver microsomes appeared to be catalysed by Cytochrome P450 2E1 (CYP2E1).

There was evidence of direct inhibition of CYP2E1 by fampridine at 30 μM (approximately 12% inhibition) which is approximately 100 times the average plasma fampridine concentration measured for the 10 mg tablet.