Consumer medicine information

Fampyra

Fampridine

BRAND INFORMATION

Brand name

Fampyra

Active ingredient

Fampridine

Schedule

SUMMARY CMI

FAMPYRA^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using FAMPYRA?

FAMPYRA contains the active ingredient fampridine. FAMPYRA is used in adult patients with Multiple Sclerosis (MS) to improve walking.

For more information, see Section 1. Why am I using FAMPYRA? in the full CMI.

2. What should I know before I use FAMPYRA?

Do not use if you have ever had an allergic reaction to FAMPYRA or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use FAMPYRA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with FAMPYRA and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use FAMPYRA?

One tablet taken in the morning and one tablet taken in the evening (12 hours apart). It is important to take the tablets 12 hours apart.
Swallow each tablet whole, with a drink of water.
Do not divide, crush, dissolve, suck or chew the tablet, as this may increase your risk of side-effects.

More instructions can be found in Section 4. How do I use FAMPYRA? in the full CMI.

5. What should I know while using FAMPYRA?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using FAMPYRA. Keep all your doctor's appointments so your progress can be checked.
Things you should not do	Do not stop using this medicine suddenly. Do not take more than the recommended dose.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how FAMPYRA affects you.
Drinking alcohol	Tell your doctor if you drink alcohol.
Looking after your medicine	Keep your tablets in their container until it is time to take them. If you take the tablets out of their container they may not keep well. Use within 7 days after first opening a bottle. Keep FAMPYRA in a cool, dry place where it stays below 25°C.

For more information, see Section 5. What should I know while using FAMPYRA? in the full CMI.

6. Are there any side effects?

Common side effects may include: digestion system symptoms such as vomiting and nausea, constipation or upset stomach, unsteadiness, anxiety, numbness of the skin, tremor, facial nerve pain, urinary tract infection, headache, weakness, difficulty sleeping, sore throat or back pain.

Side effects that require seeking urgent medical help include: seizures and allergic reaction.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

FAMPYRA^® (fam-peer-a)

Active ingredient: fampridine (fam-pri-deen) 10 mg modified release (MR) tablet

Consumer Medicine Information (CMI)

This leaflet provides important information about using FAMPYRA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FAMPYRA.

Where to find information in this leaflet:

1. Why am I using FAMPYRA?
2. What should I know before I use FAMPYRA?
3. What if I am taking other medicines?
4. How do I use FAMPYRA?
5. What should I know while using FAMPYRA?
6. Are there any side effects?
7. Product details

1. Why am I using FAMPYRA?

FAMPYRA contains the active ingredient fampridine. FAMPYRA is belongs to a group of medicines called potassium channel blockers. They work by stopping potassium leaving the nerve cells which have been damaged by MS.

This medicine is thought to work by letting signals pass down the nerve more normally, which allows you to walk better.

FAMPYRA is used in adult patients with Multiple Sclerosis (MS) to improve walking.

Your doctor may prescribe FAMPYRA for another purpose. Ask your doctor if you have any questions about why FAMPYRA has been prescribed for you.

There is no information on the use of this medicine in those below 18 years of age.

This medicine is available only with a doctor's prescription.

2. What should I know before I use FAMPYRA?

Warnings

Do not use FAMPYRA if:

you are allergic to fampridine, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
Some of the symptoms of an allergic reaction may include:
- shortness of breath;
- wheezing or difficulty breathing;
- swelling of the face, lips, tongue or other parts of the body;
- rash, itching or hives on the skin.
you are currently taking other forms of fampridine (4-amino pyridine).
Taking FAMPYRA with other forms of fampridine may increase the risk of seizures, fits or convulsions.
Ask your doctor or pharmacist if you are not sure if you have been taking one of these medicines.
you have ever had a seizure, or you have been told by your doctor you have a high risk of seizure (also referred to as a fit or convulsion)
FAMPYRA may increase the risk of seizures, fits or convulsions.
Some patients may be at a higher risk of seizure than others, due to other ongoing medical conditions. Your doctor will discuss your full medical history to advise on your seizure risk.
you have serious problems with your kidneys.
In patients with serious kidney disease FAMPYRA may increase the risk of side effects.
Your doctor will be especially careful if fampridine is given at the same time as any medicine which may affect how your kidneys eliminate medicines for example carvedilol, propranolol, and metformin.
Do not take FAMPYRA if the packaging is torn or shows signs of tampering.
Do not take FAMPYRA if the expiry date (EXP) printed on the pack has passed.
If you take this medicine after the expiry date has passed, it may not work as well.

Check with your doctor if:

you are allergic to any other medicines, foods, dyes, or preservatives take any medicines for any other condition
you have or have had any other health problems or medical conditions, including:
- Problems with your kidneys
- History of a seizure (also referred to as a fit or convulsion)
- Sudden, repeated attacks of facial nerve pain known as trigeminal neuralgia

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss the benefits and risks of using FAMPYRA when pregnant or breastfeeding.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FAMPYRA.

4. How do I use FAMPYRA?

How much to take

The dose is one tablet taken 12 hours apart.
Continue taking your medicine for as long as your doctor tells you.
This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.
Your doctor will assess whether FAMPYRA is working for you with a walk test after an initial 8 weeks of treatment. If a response isn't seen, your doctor will stop treatment.
Follow the instructions provided and use FAMPYRA until your doctor tells you to stop.

When to take FAMPYRA

The dose is one tablet taken in the morning and one tablet taken in the evening (12 hours apart).
You must always leave 12 hours between tablets.
Follow all directions given to you by your doctor, pharmacist, or MS education nurse carefully. They may differ from the information contained in this leaflet.

How to take FAMPYRA

Take FAMPYRA exactly as your doctor has prescribed.
Swallow each tablet whole, with a drink of water.
Do not divide, crush, dissolve, suck or chew the tablet, as this may increase your risk of side-effects.

If you forget to use FAMPYRA

FAMPYRA should be used regularly at the same time each day. If you miss your dose at the usual time, do not take a double dose to make up for the dose you missed.

You must always leave 12 hours between each tablet.

If you use too much FAMPYRA

If you think that you have used too much FAMPYRA, you may need urgent medical attention.

You should immediately:

phone the Australian Poisons Information Centre
(by calling 13 11 26) or the New Zealand National Poisons Information Centre, (by calling 0800 POISON or 0800 764 766), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too much FAMPYRA, you may:

Feel dizzy
Become confused
Feel agitated with trembling or shaking
Notice increased sweating
Have a seizure, fit or convulsion
Temporarily lose your memory

5. What should I know while using FAMPYRA?

Things you should do

Keep all your doctor's appointments so your progress can be checked.

Your doctor may do some tests from time to time to prevent unwanted side effects.

Call your doctor straight away if you:

are about to be started on any new medicines, remind your doctor or pharmacist that you are taking FAMPYRA.
are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
It may affect other medicines used during the surgery.
If you become pregnant while taking this medicine, tell your doctor immediately.
If you are about to have any blood tests, tell your doctor that you are taking this medicine.
It may interfere with the results of some tests.

Remind any doctor, dentist or pharmacist you visit that you are using FAMPYRA.

Things you should not do

Do not take FAMPYRA to treat any other complaints unless your doctor tells you to.
Do not give your medicine to anyone else, even if they have the same condition as you.
Do not take more than the recommended dose.
Do not stop taking your medicine or lower the dosage without checking with your doctor.
If you stop taking it suddenly, your condition may worsen, or you may have unwanted side-effects.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how FAMPYRA affects you.

This medicine may cause dizziness or a feeling of unsteadiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep your tablets in their container until it is time to take them.
If you take the tablets out of their container they may not keep well.
Use within 7 days after first opening a bottle.
Keep FAMPYRA in a cool, dry place where it stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

FAMPYRA helps most people with MS, but it may have unwanted side effects in some people.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Digestion system-related:

Feeling sick (nausea)
Being sick (vomiting)
Constipation
Upset stomach

Nervous system-related:

Dizziness
Feeling unsteady
Anxiety
Numbness or tingling of the skin
Tremor (minor shaking)
Nerve pain in the face occurring for the first time
Worsening of facial nerve pain in people with trigeminal neuralgia
Spinning sensation (vertigo)

Urinary tract-related:

Urinary tract infection

Nonspecific side effects:

Headache
Feeling weak
Difficulty sleeping
Sore throat
Back pain

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Nervous system-related:

Seizure (also known as a fit or convulsion)

This is a serious side effect. You may need urgent medical attention.
Allergic reaction-related:

Difficulty breathing (shortness of breath)
Swelling of the face, mouth, lips, throat, or tongue
Reddening or itching of the skin

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What FAMPYRA contains

Active ingredient (main ingredient)	fampridine
Other ingredients (inactive ingredients)	hypromellose microcrystalline cellulose silicon dioxide magnesium stearate the film coat (Opadry White Y-1-7000 E171) contains: titanium dioxide macrogol 400
Potential allergens	None

FAMPYRA does not contain lactose, sucrose, gluten, tartrazine, or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What FAMPYRA looks like

FAMPYRA tablet is an off-white oval tablet with A10 on one side.

FAMPYRA - AUST R 170002.

Further information

You can obtain more information from your doctor, pharmacist or nurse or by telephoning 1800 852 289 in Australia or 0800 852 289 in New Zealand.

Who distributes FAMPYRA

FAMPYRA is supplied in Australia by:

Biogen Australia Pty Ltd
Level 4, 2 Banfield Road
Macquarie Park NSW 2113
Australia

FAMPYRA is supplied in New Zealand by:

Biogen NZ Biopharma Limited
Auckland, New Zealand

This leaflet was prepared in September 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Fampyra

Active ingredient

Fampridine

Schedule

1 Name of Medicine

Fampridine, also known by its chemical name, 4-aminopyridine.

2 Qualitative and Quantitative Composition

Fampyra is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet contains 10 mg fampridine, formulated as a modified release tablet for twice-daily oral administration. Each tablet also contains hypromellose, microcrystalline cellulose, silicon dioxide, magnesium stearate and the film coat (Opadry White Y-1-7000) contains hypromellose, titanium dioxide and macrogol 400.

3 Pharmaceutical Form

Modified release tablet.
Fampyra (fampridine) is a 10 mg modified release white to off-white, film coated, oval shaped, biconvex, non-scored tablet with flat edge, debossed with "A10" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Fampyra modified release tablets are indicated for the symptomatic improvement of walking ability in adult patients with Multiple Sclerosis (MS) who have shown improvement after 8 weeks of treatment.

4.2 Dose and Method of Administration

The recommended dosage of Fampyra for adults is one 10 mg tablet, twice daily, taken approximately 12 hours apart.
Tablets must be swallowed whole. As the tablets are modified release tablets, doses cannot be divided, crushed, dissolved, sucked or chewed. The tablets can be taken with or without food.
The usual dosing regime of one tablet in the morning and one tablet in the evening taken 12 hours apart should always be followed. A double dose should not be taken if a dose is missed.
Patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min or eGFR less than 59 mL/min/1.73 m²) should be excluded from treatment (see Section 4.3 Contraindications).
As with all medicines, physicians should review the individual benefit/ risk of Fampyra treatment with the individual patient to ensure continuing positive benefit/ risk. Prescribers should re-evaluate the patient 8 weeks after the first treatment. Continued therapy should not be considered unless a walk test demonstrates response.

4.3 Contraindications

Fampyra is contraindicated in patients with known hypersensitivity to fampridine or any excipients in this product.
Fampyra should not be administered to patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min or eGFR less than 59 mL/min/1.73 m²).
Fampyra should not be administered to patients with prior history of seizure.
Prior to starting Fampyra all patients should be assessed for their risk of seizure, by taking a full patient history. Patients who are considered by the physician to be at high risk of seizure should be excluded from treatment.
Fampyra should not be administered to patients currently on treatment with other forms of fampridine/ 4-aminopyridine.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Fampyra should not be administered at doses higher than the recommended dose of 10 mg, twice daily, 12 hours apart.

Seizures.

A dose-dependent increase in risk of seizures has been observed in clinical studies with Fampyra at doses above the recommended 10 mg taken twice daily. The recommended daily dose of Fampyra, 10 mg, twice daily, taken 12 hours apart should not be exceeded.
Fampyra should be administered with caution in the presence of any factors, which may lower seizure threshold.
Fampyra should be discontinued in patients who experience a seizure while on treatment.

Use in hepatic impairment.

Fampyra has not been studied in patients with hepatic impairment in clinical trials. Since fampridine is primarily excreted unchanged in the urine, hepatic insufficiency is not expected to significantly affect fampridine pharmacokinetics. No dose adjustment is required for patients with hepatic impairment.

Use in renal impairment.

Fampridine is primarily excreted unchanged through the kidneys. Patients with renal impairment may have higher plasma concentrations, which are associated with increased adverse drug reactions, in particular, neurological effects. Therefore, Fampyra should be used with caution, and monitoring of renal function considered in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min or eGFR 60-89 mL/min/1.73 m²).
Particular caution is required when Fampyra is prescribed concurrently with drugs or medicinal products that can significantly impact renal function.
Fampyra is eliminated through the kidneys primarily as unchanged drug and therefore, caution should be taken in prescribing Fampyra in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min or eGFR 60-89 mL/min/1.73 m²). Renal function in these patients should be closely monitored as the clinical situation warrants.
Patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min or eGFR less than 59 mL/min/1.73 m²) should be excluded from treatment (see Section 4.3 Contraindications).

Use in the elderly.

Population pharmacokinetics showed that fampridine clearance modestly decreased with increased age, but not sufficiently to necessitate a dose adjustment with increasing age.

Paediatric use.

Safety and effectiveness of Fampyra in patients younger than 18 years of age have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Fampridine is actively secreted unchanged by the kidneys; there is a theoretical possibility of an interaction with other drugs that are renally secreted (see Section 5.2 Pharmacokinetic Properties).
Organic Cation Transporter-2 (OCT2) is a renal transporter involved in the active secretion of fampridine.

Cimetidine.

In a single-dose clinical study, the OCT2 inhibitor cimetidine 400 mg every 6 hours and fampridine 10 mg single dose were concurrently administered to 23 healthy volunteers. The test-reference ratio for AUC_0-∞ was 125.1% (90% CI: 120.5%, 129.8%) due to a reduction in apparent clearance of Fampyra (CL/F). This increase in systemic exposure is not expected to be clinically meaningful.
In human liver microsomes in vitro, there was little evidence of a direct or metabolism-dependent inhibition of activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 by fampridine at concentrations up to 30 microM (approximately 100 times the C_max at the MRHD). Fampridine is therefore unlikely to inhibit CYP enzymes, or affect the pharmacokinetics of drugs that are substrates of these enzymes, at therapeutic concentrations.
Treatment of cultured human hepatocytes with fampridine at concentrations up to 25 microM (nearly 100 times the C_max at the MRHD) for 3 days had little or no effect on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5 enzyme activities. Thus, there is little potential for induction of these enzymes at therapeutic concentrations.
Fampridine is not a substrate or an inhibitor for the p-glycoprotein transporter in vitro. Thus, fampridine is unlikely to affect the pharmacokinetics of drugs that are substrates of p-glycoprotein and the pharmacokinetics of fampridine are unlikely to be affected by drugs that inhibit p-glycoprotein.

Interferon.

Fampridine has been administered concomitantly with interferon-beta and no pharmacokinetic drug interactions were observed.

Baclofen.

Fampridine has been administered concomitantly with baclofen and no pharmacokinetic drug interactions were observed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in rats following oral doses of fampridine up to 9 mg/kg/day in males and females treated prior to and during mating, continuing in females to late gestation or weaning. Exposure at this dose was equivalent to 8 fold the human exposure at the maximum recommended human dose (MRHD), based on plasma AUC, and maternal toxicity was observed.
(Category C)
Adequate and well-controlled studies in pregnant women have not been conducted. Fampyra should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
In reproductive studies in rats and rabbits, when fampridine was administered orally at doses up to 10 mg/kg/day and 5 mg/kg/day, respectively, during the period of organogenesis, there was no evidence of embryotoxicity or teratogenicity, even at doses that were maternally toxic. In a study in which rats were dosed from early gestation to weaning, there were no effects on the offspring at a dose of 1 mg/kg/day, giving a systemic exposure (plasma AUC) about 1.5 fold human exposure at the MRHD. Pup survival and weight gains were reduced at higher doses.
It is not known whether fampridine is excreted in human milk and the excretion of fampridine in milk has not been studied in animals. Lipophilic drugs pass easily into milk because of the high percentage of fat content in milk. Fampridine, being a lipophilic drug, may be excreted in human milk. Because of the potential for serious adverse reactions from fampridine in the breast-fed infant, a decision on whether to discontinue breast-feeding or to discontinue therapy with Fampyra should be made, taking into account the importance of Fampyra to the woman.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Central nervous system-related adverse reactions such as dizziness, vertigo and seizures associated with the use of Fampyra might influence the ability to drive and use machines, therefore caution should be advised.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

Clinical trial data.

Adverse drug reactions are defined as those adverse events occurring at ≥ 1% higher frequency in the active treatment period with Fampyra than with placebo and considered with other fampridine data.
The highest incidence of adverse reactions identified from placebo-controlled trials in MS patients with Fampyra given at the recommended dose relate to nervous system excitation, as expected with the mechanism of action of Fampyra. These include insomnia, balance disorder, dizziness, headache and asthenia. Urinary tract infection (UTI) is also reported more frequently, although infection was often not proven. It is thought that this effect may be in part due to an effect of Fampyra to produce neuronal stimulation in the bladder mimicking symptoms of UTI. See Table 1.

The safety profile of Fampyra 10 mg b.i.d. was also assessed in study 218MS305, a placebo-controlled study with 635 patients included in the safety population (placebo: N=319; Fampyra: N=316). The safety profile observed in this study was consistent with the known safety profile of Fampyra and no new safety concerns were identified.

Post-marketing data.

Suspected adverse reactions reported in post-marketing experience that are not already included under Clinical trial data are described below. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Seizure.

In post-marketing experience, there have been reports of seizure. Confounding factors may have contributed to the occurrence of seizure in some patients.

Hypersensitivity reactions.

Hypersensitivity reactions (including anaphylaxis) have been reported from post-marketing experience with fampridine.

Trigeminal neuralgia.

De novo symptoms or exacerbations of trigeminal neuralgia.

Vertigo.

4.9 Overdose

Symptoms.

Acute symptoms of overdose were consistent with central nervous system excitation and included dizziness, confusion, tremulousness, diaphoresis, seizure, and amnesia. The severity of symptoms is usually closely related to the pharmacokinetic exposure.

Treatment.

Patients should be provided supportive care. Repeated seizure activity should be treated with benzodiazepine, phenytoin, or other appropriate acute anti-seizure therapy.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fampridine is a non-selective potassium channel blocker and is a lipid-soluble drug which readily crosses the blood-brain barrier. Multiple Sclerosis (MS) is characterised by demyelination, and although the exact mechanism of action of fampridine is not known, fampridine is believed to act mainly by blocking the potassium channels in demyelinated nerves, which reduces the leakage of current from the axons, restoring neuronal conduction and action potential formation.
Fampyra does not prolong the QTc interval and does not have a clinically important effect on QRS duration.

Clinical trials.

The efficacy of Fampyra prolonged release tablets, (10 mg b.i.d) in improving walking ability in patients with ambulatory impairment, in all relapsing remitting and progressive forms of MS, was demonstrated in three phase III, randomised, double-blind, placebo controlled confirmatory studies, (MS-F203, MS-F204 and 218MS305) The proportion of patients displaying improvement in walking ability was independent of concomitant immunomodulatory therapy (including interferons, glatiramer acetate, fingolimod and natalizumab). No differences in effectiveness based on degree of impairment, age, gender or body mass index were detected.
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 quantitative test of walking ability that has been demonstrated to be a useful and reliable measure of the complex neurological process of walking. This responder rate analysis was performed to determine the number of patients who showed consistent improvement in walking speed during double-blind treatment, i.e. Timed Walk Responders. 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 open off-treatment visits.
The clinical meaningfulness of the primary endpoint (timed walk response) was validated by demonstrating significant association between improvements in walking speed with improvements on a patient self-assessment of walking disability, the 12- item Multiple Sclerosis Walking Scale (MSWS12).
The clinical meaningfulness of the improvement in T25FW in studies MS-F203 and MS-F204 was further validated by results from confirmatory study 218MS305. In this study, the primary endpoint was the proportion of patients demonstrating improvements on a patient self-assessment of walking disability, the 12-item Multiple Sclerosis Walking Scale (MSWS12). The MSWS12 questionnaire is a reliable and validated measurement of a patient's impression of the effect of their MS related walking disability over the previous two weeks on their ability to perform a range of activities of daily life, such as standing, climbing stairs, moving around the home and walking distances outside.

Studies MS-F203 and MS-F204.

In studies MS-F203 and MS-F204 a significantly greater proportion of patients taking Fampyra 10 mg b.i.d had a consistent improvement in walking speed compared to patients taking placebo as measured by the T25FW, (MS-F203: 34.8% vs 8.3%, p < 0.001; MS-F204: 42.9% vs 9.3%, p < 0.001). The increased responder rate in the Fampyra cohort was observed across all types of MS disease included in the studies, independent of whether they were on DMT treatment or not. The Timed Walk Responders also demonstrated statistically significant mean improvement in walking speed (i.e. magnitude of timed walk response) compared to placebo (pooled results: 25.3% vs. 5.8%; p < 0.001) as reported by % change from baseline T25FW score. The improvement appeared rapidly (within weeks) after starting treatment.
Changes from baseline MSWS-12 scores in studies MS-F203 and MS-F204, indicated that Timed Walk Responders taking Fampyra also demonstrated statistically and clinically significant, improvement in their ability to perform a range of activities of daily life, such as standing, climbing stairs, moving around the home and walking distances outside. Similarly, the SGI (Subject Global Impression) and CGI (Clinician Global Impression) scores showed responders had significantly greater improvement than non-responders. Pooled results from studies MS-F203 and MS-F204 also indicated a significant reduction in the Ashworth Score (p < 0.001), which measures the degree of muscle spasticity, in the Fampyra cohort compared to placebo.
In study MS-F203, Fampyra also demonstrated significant improvements in leg strength compared to placebo, as measured by the Lower Extremity Manual Muscle Test (LEMMT), (p < 0.003).

Study 218MS305.

Study 218MS305 was a 24-week randomised, double-blind, placebo-controlled study. The Intent to Treat (ITT) population included 633 patients (315 on Fampyra) with Expanded Disability Status Scale (EDSS) scores ranging from 4 to 7. Patients included in the study were predominantly female (58%). The mean age was 49 years, the median disease duration was 10 years (mean 6.4 years) and the mean EDSS at screening was 5.48.
The primary endpoint in study 218MS305 was improvement in walking ability, measured as the proportion of patients achieving a mean improvement of ≥ 8 points from baseline MSWS-12 score over 24 weeks. In this study there was a statistically significant treatment difference, with a greater proportion of Fampyra treated patients demonstrating an improvement in walking ability, compared to placebo-controlled patients (0.432 vs. 0.336; odds ratio: 1.61; p=0.006). Fampyra treated patients also demonstrated a statistically significant improvement in the Timed Up and Go (TUG) test, a measure of static and dynamic balance and physical mobility. In this secondary endpoint, a greater proportion of Fampyra treated patients achieved ≥ 15% mean improvement from baseline TUG speed over a 24-week period, compared to placebo (0.434 vs. 0.347; odds ratio: 1.46; p=0.030).
The Multiple Sclerosis Impact Scale (MSIS-29), a patient reported outcome (PRO) measure to assess the change from baseline in a patient's physical well-being over 24 weeks, was an additional secondary endpoint in study 218MS305. In this measure, patients treated with Fampyra prolonged release tablets demonstrated a statistically significant mean improvement from baseline compared to placebo (Least Squares (LS) mean difference -3.31, p < 0.001).
In addition, positive and sustained treatment effects were observed in the Berg Balance Scale (a measure of static balance) and ABILHAND questionnaire (a patient reported outcome measuring improvement in upper limb mobility), in both placebo and Fampyra treated patients although neither were statistically significant for Fampyra (p=0.141 and p=0.197, respectively).
See Table 2.

Observational study 218MS401.

Study 218MS401 was a Phase IV, multinational, observational study of Fampyra's safety and efficacy in routine medical practice. The study population included 4646 MS patients, predominantly female (65.75) with a median age of 52.6 years.
Analysis conducted using data from 589 MS patients ≥ 65 years old treated with Fampyra (representing 392.1 patient years) showed that the most commonly reported treatment emergent adverse events (TEAEs) among patients < 65 years and patients ≥ 65 years were similar to the most commonly reported TEAEs for the overall safety population treated with (dal)fampridine.
Review of events in patients with a history of seizures, or at increased seizure risk due to other seizure lowering medication, or antiepileptic/anticonvulsant medications showed that the nature and types of safety events in these subpopulations were consistent with the overall safety population treated with (dal)fampridine. 32 patients (0.7%) had 33 seizure-related AEs (incident rate 0.9/100 patient years). The incidence of seizure in Study 218MS401 was similar to the incidence of seizure in previous studies with Fampyra and the background incidence of seizure among patients with MS.
A safety evaluation in patients with 12 months exposure to Fampyra (long-term safety) were consistent with the known safety profile of (dal)fampridine.
Overall, the safety profile observed in this study was consistent with the known safety profile of Fampyra and no new safety concerns were identified.
Post marketing analysis of efficacy data in Study 218MS401 showed that long-term treatment with Fampyra (for up to 12 months) consistently provided improvements in patient-reported physical and psychological scores as assessed by MSIS-29 and in physician-reported CGI-I assessment on walking ability.

5.2 Pharmacokinetic Properties

Absorption.

Orally administered fampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of Fampyra has not been assessed, but relative bioavailability (as compared to an aqueous oral solution) is 95%. Fampyra tablets have a prolonged release of fampridine characterised by a slower rise to and a lower peak concentration when compared to an immediate release formulation, without any effect on the extent of absorption.
When Fampyra is taken with food, the reduction in the area under the plasma concentration-time curve (AUC_0-∞) 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.

Distribution.

Fampridine is largely unbound to plasma proteins (greater than 90%) and has a volume of distribution of 2.6 L/kg.

Metabolism.

Fampridine is metabolised by oxidation to 3-hydroxy-4-aminopyridine and further conjugated to the 3-hydroxy-4-aminopyridine sulfate. Negligible pharmacological activity was found for these 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 two or more kinetically distinct enzymes. CYP2E1 appeared to be the major enzyme responsible for the 3-hydroxylation of fampridine, based on correlation analysis, chemical inhibition studies and incubations with recombinant human CYP enzymes.

Elimination.

The major route of elimination for fampridine is renal excretion, with approximately 90% of the dose recovered in urine as parent drug within 24 hours. Renal clearance (CLR 370 mL/min) is substantially greater than glomerular filtration rate. Faecal excretion accounts for less than 1% of the administered dose.
Fampyra is characterised by linear (dose-proportional) pharmacokinetics with a terminal elimination half-life of approximately 6 hours. The maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) increase proportionately over a dose range of 5 to 40 mg. There is no evidence of clinically relevant accumulation of fampridine taken at the recommended dose in patients with full renal function. In patients with increasing amounts of renal impairment accumulation occurs in line with the degree of impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Fampridine was not genotoxic in in vitro assays (bacterial reverse mutation assay, mouse lymphoma tk assay, and chromosomal aberration test in Chinese hamster ovary cells), or in in vivo mouse and rat micronucleus tests.

Carcinogenicity.

Fampridine did not cause any increase in tumours in lifetime dietary carcinogenicity studies in mice and rats. The highest dose used in mice was approximately 80 mg/kg/day, which produced an exposure (based on plasma AUC) that was 11 fold human exposure at the MRHD. The highest dose in rats was approximately 18 mg/kg/day, which produced an exposure (based on plasma AUC) that was 10 fold human exposure at the MRHD. There was a significant increase in uterine polyps in high dose female rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Do not store above 25°C. Store the tablets in the original bottle.
Do not use after the expiry date printed on the pack. After first opening a bottle, use within 7 days.

6.5 Nature and Contents of Container

Fampyra (fampridine) 10 mg modified release tablets are off white, oval bi-convex, film coated, modified release tablets with a flat edge, debossed with A10 on one side and plain on the other, each containing fampridine 10 mg.
Each pack contains 4 HDPE bottles with a polypropylene child-resistant closure. Each bottle contains 14 tablets and a silica gel desiccant (in total there are 56 tablets in each pack).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The structural formula of fampridine, also known by its chemical name, 4-aminopyridine, is shown below:
Fampridine is also known by its chemical name, 4-aminopyridine with the following structure:

Fampridine is a fine white powder with a molecular weight of 94.1, CAS 504-24-5 a molecular formula of C₅H₆N₂, an octanol/water partition coefficient (log P) of -0.76 and pKa of 9.17. At ambient conditions, fampridine is soluble in water (unbuffered ≥ 49 mg/mL, pH 7.0 buffered ≥ 57 mg/mL), methanol ≥ 53 mg/mL, acetone ≥ 52 mg/mL, tetrahydrofuran ≥ 52 mg/mL, isopropanol ≥ 52 mg/mL, acetonitrile ≥ 62 mg/mL, N, N-dimethylformamide ≥ 83 mg/mL, dimethylsulfoxide ≥ 78 mg/mL, and ethanol ≥ 77 mg/mL.

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