FAMPYRA 10mg prolonged-release tablets medication leaflet

Fampyra 10 mg prolonged-release tablets

Each prolonged-release tablet contains 10 mg of fampridine.

For the full list of excipients, see section 6.1.

Prolonged-release tablet.

An off-white, film coated, oval biconvex 13 x 8 mm tablet with flat edge debossed with A10 on oneside.

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

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

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

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

Starting and evaluating Fampyra treatment

* Initial prescription should be limited to two to four weeks of therapy as clinical benefits shouldgenerally 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 improvementwithin 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 inorder to reassess the benefits of fampridine (see above). The re-evaluation should include withdrawalof this medicinal product and performing an assessment of walking ability. Fampridine should bediscontinued if patients no longer receive walking benefit.

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 section4.4).

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

No dose adjustment is required for patients with hepatic impairment.

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

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.

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 maylower seizure threshold.

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

Fampridine is primarily excreted unchanged by the kidneys. Patients with renal impairment havehigher plasma concentrations which are associated with increased adverse reactions, in particularneurological effects. Determining renal function before treatment and its regular monitoring duringtreatment is recommended in all patients (particularly in the elderly in whom renal function might bereduced). 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 patientsusing medicinal products that are substrates of OCT2 for example, carvedilol, propranolol andmetformin.

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

Fampridine should be administered with caution to patients with cardiovascular symptoms of rhythmand 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 anincreased 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% ofpatients on placebo. Infections were seen in the clinical studies (see section 4.8) and increasedinfection 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) iscontraindicated (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, theconcomitant 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 medicinalproducts 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 nopharmacokinetic medicinal product interactions were observed.

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

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 ispreferable to avoid the use of fampridine in pregnancy.

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

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).

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

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

Adverse reactions are presented below by system organ class and absolute frequency. Frequencies aredefined 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 theavailable data).

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

Table 1: Tabulated list of adverse reactions

MedDRA System Organ Adverse reaction Frequency category

Class (SOC)

Infections and infestations Urinary tract infection1 Very Common

Influenza1 Common

Nasopharyngitis1 Common

Viral infection1 Common

Immune system disorders Anaphylaxis Uncommon

Angioedema Uncommon

Hypersensitivity Uncommon

Psychiatric disorders Insomnia Common

Anxiety Common

Nervous system disorders Dizziness Common

Headache Common

Balance disorder Common

Vertigo Common

Paraesthesia Common

Tremor Common

Seizure2 Uncommon

Trigeminal neuralgia3 Uncommon

MedDRA System Organ Adverse reaction Frequency category

Class (SOC)

Cardiac disorders Palpitations Common

Tachycardia Uncommon

Vascular disorders Hypotension4 Uncommon

Respiratory, thoracic and Dyspnoea Commonmediastinal disorders Pharyngolaryngeal pain Common

Gastrointestinal disorders Nausea Common

Vomiting Common

Constipation Common

Dyspepsia Common

Skin and subcutaneous tissue Rash Uncommondisorders Urticaria Uncommon

Musculoskeletal and connective Back pain Commontissue disorders

General disorders and Asthenia Commonadministration site conditions Chest discomfort4 Uncommon1 See section 4.42 See sections 4.3 and 4.43 Includes both de novo symptoms and exacerbation of existing trigeminal neuralgia4 These symptoms were observed in the context of hypersensitivity

In post-marketing experience, there have been reports of hypersensitivity reactions (includinganaphylaxis) 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Acute symptoms of overdose with fampridine were consistent with central nervous system excitationand 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 effectsat high doses include cases of cardiac arrhythmias (for example, supraventricular tachycardia andbradycardia) and ventricular tachycardia as a consequence of potential QT prolongation. Reports ofhypertension have also been received.

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

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

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

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 ofconcomitant immunomodulatory therapy (including interferons, glatiramer acetate, fingolimod andnatalizumab). 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 asmeasured by the Timed 25-foot Walk (T25FW). A responder was defined as a patient whoconsistently had a faster walking speed for at least three visits out of a possible four during the doubleblind 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% onplacebo (p< 0.001) (MS-F203) and 25.3% vs 7.8% (p< 0.001) (MS-F204). The improvement appearedrapidly (within weeks) after starting the treatment.

Statistically and clinically meaningful improvements in walking were seen, as measured by the12-item Multiple Sclerosis Walking Scale.

Table 2: Studies MS-F203 and MS-F204

STUDY * MS-F203 MS-F204

Placebo Fampyra Placebo Fampyra10 mg BID 10 mg BIDn of subjects 72 224 118 119

Consistent 8.3% 34.8% 9.3% 42.9%improvement

Difference 26.5% 33.5%

CI95% 17.6%, 35.4% 23.2%, 43.9%

P-value < 0.001 < 0.001

STUDY * MS-F203 MS-F204

Placebo Fampyra Placebo Fampyra10 mg BID 10 mg BID≥ 20% improvement 11.1% 31.7% 15.3% 34.5%

Difference 20.6% 19.2%

CI95% 11.1%,30.1% 8.5%,29.9%

P-value < 0.001 < 0.001

Walking speed Ft per sec Ft per sec Ft per sec Ft per sec

Feet/sec

Baseline 2.04 2.02 2.21 2.12

Endpoint 2.15 2.32 2.39 2.43

Change 0.11 0.30 0.18 0.31

Difference 0.19 0.12p-value 0.010 0.038

Average % Change 5.24 13.88 7.74 14.36

Difference 8.65 6.62p-value < 0.001 0.007

MSWS-12-score(mean, sem)

Baseline 69.27 (2.22) 71.06 (1.34) 67.03 (1.90) 73.81 (1.87)

Average change -0.01 (1.46) -2.84 (0.878) 0.87 (1.22) -2.77 (1.20)

Difference 2.83 3.65p-value 0.084 0.021

LEMMT (mean, sem)(Lower Extremity

Manual Muscle Test)

Baseline 3.92 (0.070) 4.01 (0.042) 4.01 (0.054) 3.95 (0.053)

Average change 0.05 (0.024) 0.13 (0.014) 0.05 (0.024) 0.10 (0.024)

Difference 0.08 0.05p-value 0.003 0.106

Ashworth Score(A test for musclespasticity)

Baseline 0.98 (0.078) 0.95 (0.047) 0.79 (0.058) 0.87 (0.057)

Average change -0.09 (0.037) -0.18 (0.022) -0.07 (0.033) -0.17 (0.032)

Difference 0.10 0.10p-value 0.021 0.015

BID = twice a day

Study 218MS305

Study 218MS305 was conducted in 636 subjects with multiple sclerosis and walking disability.

Duration of double-blind treatment was 24 weeks with a 2 week post-treatment follow-up. Theprimary endpoint was improvement in walking ability, measured as the proportion of patientsachieving a mean improvement of ≥ 8 points from baseline MSWS-12 score over 24 weeks. In thisstudy there was a statistically significant treatment difference, with a greater proportion of Fampyratreated patients demonstrating an improvement in walking ability, compared to placebo-controlledpatients (relative risk of 1.38 (95% CI: [1.06, 1.70]). Improvements generally appeared within 2 to 4weeks of initiation of treatment, and disappeared within 2 weeks of treatment cessation.

Fampridine treated patients also demonstrated a statistically significant improvement in the Timed Upand Go (TUG) test, a measure of static and dynamic balance and physical mobility. In this secondaryendpoint, a greater proportion of fampridine treated patients achieved ≥ 15% mean improvement frombaseline TUG speed over a 24 week period, compared to placebo. The difference in the Berg Balance

Scale (BBS; a measure of static balance), was not statistically significant.

In addition, patients treated with Fampyra demonstrated a statistically significant mean improvementfrom baseline compared to placebo in the Multiple Sclerosis Impact Scale (MSIS-29) physical score(LSM difference -3.31, p<0.001).

Table 3: Study 218MS305

Over 24 weeks Placebo Fampyra 10 mg Difference (95% CI)

N = 318* BID p - value

N = 315*

Proportion of patients with 34% 43% Risk difference: 10.4%mean improvement of ≥ 8 (3% ; 17.8%)points from baseline 0.006

MSWS-12 score

MSWS-12 score LSM: -4.14

Baseline 65.4 63.6 (-6.22 ; -2.06)

Improvement from -2.59 -6.73 < 0.001baseline

TUG 35% 43% Risk difference: 9.2%

Proportion of patients with (0.9% ; 17.5%)mean improvement of ≥ 15% 0.03in TUG speed

TUG LSM: -1.36

Baseline 27.1 24.9 (-2.85 ; 0.12)

Improvement from -1.94 -3.3 0.07baseline (sec)

MSIS-29 physical score 55.3 52.4 LSM: -3.31

Baseline -4.68 -8.00 (-5.13 ; -1.50)

Improvement from < 0.001baseline

BBS score LSM: 0.41

Baseline 40.2 40.6 (-0.13 ; 0.95)

Improvement from 1.34 1.75 0.141baseline

*Intent to treat population = 633; LSM = Least square mean, BID = twice a day

The European Medicines Agency has waived the obligation to submit the results of studies with

Fampyra in all subsets of the paediatric population in treatment of multiple sclerosis with walkingdisability (see section 4.2 for information on paediatric use).

Orally administered fampridine is rapidly and completely absorbed from the gastrointestinal tract.

Fampridine has a narrow therapeutic index. Absolute bioavailability of Fampyra prolonged-releasetablets has not been assessed, but relative bioavailability (as compared to an aqueous oral solution) is95%. The Fampyra prolonged-release tablet has a delay in the absorption of fampridine manifested byslower 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 theplasma concentration-time curve (AUC0-∞) of fampridine is approximately 2-7% (10 mg dose). Thesmall reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. However, Cmaxincreases by 15-23%. Since there is a clear relationship between Cmax and dose related adversereactions, it is recommended to take Fampyra without food (see section 4.2).

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 humanplasma). Fampridine has a volume of distribution of approximately 2.6 L/kg.

Fampridine is not a substrate for P-glycoprotein.

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

The 3-hydroxylation of fampridine to 3-hydroxy-4-aminopyridine by human liver microsomesappeared 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 measuredfor the 10 mg tablet.

Treatment of cultured human hepatocytes with fampridine had little or no effect on induction of

CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5 enzyme activities.

The major route of elimination for fampridine is renal excretion, with approximately 90% of the doserecovered in urine as parent active substance within 24 hours. Renal clearance (CLR 370 mL/min) issubstantially greater than glomerular filtration rate due to combined glomerular filtration and activeexcretion by the renal OCT2 transporter. Faecal excretion accounts for less than 1% of theadministered dose.

Fampridine is characterized by linear (dose-proportional) pharmacokinetics with a terminalelimination half-life of approximately 6 hours. The maximum plasma concentration (Cmax) and, to asmaller extent, area under the plasma concentration-time curve (AUC) increase proportionately withdose. There is no evidence of clinically relevant accumulation of fampridine taken at therecommended dose in patients with full renal function. In patients with renal impairment,accumulation occurs relative to the degree of impairment.

Fampridine is primarily excreted unchanged by the kidneys, and with creatinine clearance known todecrease with age, monitoring of renal function in elderly patients is recommended (see section 4.2).

No data are available.

Fampridine is eliminated primarily by the kidneys as unchanged active substance and therefore renalfunction should be checked in patients where renal function might be compromised. Patients with mildrenal impairment can be expected to have approximately 1.7 to 1.9 times the fampridineconcentrations achieved by patients with normal renal function. Fampyra must not be administered topatients with moderate and severe renal impairment (see sections 4.3 and 4.4).

Fampridine was studied in oral repeat dose toxicity studies in several animal species.

Adverse responses to orally administered fampridine were rapid in onset, most often occurring withinthe first 2 hours post-dose. Clinical signs evident after large single doses or repeated lower doses weresimilar in all species studied and included tremors, convulsions, ataxia, dyspnoea, dilated pupils,prostration, abnormal vocalization, increased respiration, and excess salivation. Gait abnormalities andhyper-excitability were also observed. These clinical signs were not unexpected and representexaggerated pharmacology of fampridine. In addition, single cases of fatal urinary tract obstructionswere observed in rats. The clinical relevance of these findings remains to be elucidated, but a causalrelationship with fampridine treatment cannot be excluded.

In reproduction toxicity studies in rats and rabbits, decreased weight and viability of foetuses andoffspring were observed at maternally toxic doses. However, no increased risk for malformations oradverse effects on fertility was noted.

In a battery of in vitro and in vivo studies fampridine did not show any potential to be mutagenic,clastogenic or carcinogenic.

Hypromellose

Microcrystalline cellulose

Silica, colloidal anhydrous

Magnesium stearate

Film-coat

Hypromellose

Titanium dioxide (E-171)

Polyethylene glycol 400

Not applicable.

3 years.

After first opening a bottle, use within 7 days.

Store below 25 °C. Store the tablets in the original packaging in order to protect from light andmoisture.

Fampyra is supplied in either bottles or blister packs.

HDPE (high-density polyethylene) bottle with polypropylene caps, each bottle contains 14 tablets anda silica gel desiccant.

Pack size of 28 (2 bottles of 14) tablets.

Pack size of 56 (4 bottles of 14) tablets.

Aluminium/aluminium (oPA/Alu/HDPE/PE+CaO desiccant layer/Alu/PE) blisters, each blister traycontains 14 tablets.

Pack size of 28 (2 blisters of 14) tablets.

Pack size of 56 (4 blisters of 14) tablets.

Not all pack sizes may be marketed.

No special requirements.

Merz Therapeutics GmbH

Eckenheimer Landstraße 10060318 Frankfurt am Main

Germany

EU/1/11/699/001

EU/1/11/699/002

EU/1/11/699/003

EU/1/11/699/004

Date of first authorisation: 20 July 2011

Date of latest renewal: 25 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu