Consumer medicine information

Ruzurgi

Amifampridine

BRAND INFORMATION

Brand name

Ruzurgi

Active ingredient

Amifampridine

Schedule

SUMMARY CMI

RUZURGI^®

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.

▼ This medicine is new. Please report side effects. See the full CMI for further details.

1. Why am I taking RUZURGI?

RUZURGI contains the active ingredient amifampridine. RUZURGI is used to treat Lambert-Eaton myasthenic syndrome (LEMS) in adults and children aged 6 years and above.

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

2. What should I know before I take RUZURGI?

Do not take if you have ever had an allergic reaction to amifampridine, fampridine or other aminopyridines, or any of the ingredients listed at the end of the CMI. Do not take if you have a history of seizures, fits or convulsions.

Talk to your doctor if you have any other medical conditions, including problems with your kidneys or liver, heart, 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 take RUZURGI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with RUZURGI and increase the side effects of RUZURGI when taken together.

See Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take RUZURGI?

Follow the instructions provided and use until your doctor tells you to stop.
How much RUZURGI you should take will depend upon your weight and whether you have any other medical conditions such as problems with your liver or kidneys. Your doctor will determine the right dose for you and how often you should take it.
You may need to split the tablets or prepare an oral suspension of RUZURGI tablets to get the right dose for you.
If you have problems taking tablets or require a feeding tube, you may need to prepare an oral suspension of RUZURGI tablets.

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

5. What should I know while taking RUZURGI?

Things you should do	Tell your doctor straight away if you are pregnant or planning to become pregnant. Take RUZURGI exactly as prescribed by your doctor. Remind any doctor, dentist, or pharmacist you visit that you are taking RUZURGI.
Things you should not do	Do not stop taking this medicine or change the dose without first checking with your doctor.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how RUZURGI affects you.
Looking after your medicine	Store RUZURGI tablets below 25°C for up to 3 months. Do not refrigerate. Keep your tablets in the bottle and tightly closed until you're ready to take them.

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

6. Are there any side effects?

Less serious side effects include, numbness, burning, prickling, or tingling sensations on any part of the body, stomach or gut pain, indigestion, dizziness, nausea, back pain, muscle spasms. Serious side effects include seizures, fits or convulsions, or an allergic reaction to the medicine.

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.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

RUZURGI^® (rew-ZUR-jee)

Active ingredient: amifampridine (a-mee-fam-pri-deen)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking RUZURGI?

RUZURGI contains the active ingredient amifampridine. RUZURGI is a potassium channel blocker. It is thought to help restore the normal connection between nerves and muscles, which may help to reduce muscle weakness.

RUZURGI is used to treat Lambert-Eaton myasthenic syndrome (LEMS) in adults and children aged 6 years and above.

2. What should I know before I take RUZURGI?

Warnings

Do not take RUZURGI if:

you are allergic to amifampridine, fampridine or other aminopyridines, or any of the ingredients listed at the end of this leaflet.
you are taking other forms of amifampridine or other aminopyridines
Always check the ingredients to make sure you can use this medicine.
you have a history of seizures, fits or convulsions.

Check with your doctor if you:

have any other medical conditions including
- a history of seizures, fits, or convulsions
- problems with your liver
- problems with your kidneys
- problems with your heart such as torsades de pointes
take any medicines for any other condition

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.

Effective birth control (contraception) should be used if you are taking RUZURGI.

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

Children

RUZURGI should not be taken by children less than 6 years of age.

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.

Some medicines may lead to an increased risk of seizures or other side effects when taken with RUZURGI.

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

4. How do I take RUZURGI?

How much to take

Follow the instructions provided and use until your doctor tells you to stop.
How much RUZURGI you should take will depend upon your weight and whether you have any other medical conditions such as problems with your liver or kidneys.
Your doctor will determine the right dose for you and how often you should take it.
Your doctor may tell you to split the tablets in half, or prepare an oral suspension of the tablets, to get the right dose for you. Information on how to prepare an oral suspension of RUZURGI is provided below.
Patients who have difficulty swallowing tablets, require feeding tubes or require a dose that cannot be achieved by taking the tablet can prepare an oral suspension of the tablets.
If the patient weighs less than 45 kg, the maximum daily dose is 4 whole tablets (40 mg) in divided doses.
If the patient weighs 45 kg or more, the maximum daily dose is 10 whole tablets (100 mg) in divided doses

How to take RUZURGI

RUZURGI should be taken with a glass of water.
RUZURGI can be taken with or without food.

How to prepare a 1 mg per 1 mL of oral suspension of RUZURGI for patients requiring 10 mg or less per dose

You will need:

one 30 mL bottle,
one 10 mL syringe, and
10 mL of sterile water.

You can get all these supplies from your local pharmacy.

Follow the steps below to make up the suspension:

Place one (1) 10 mg RUZURGI (amifampridine) tablet in the 30 mL bottle.

Add 10 mL of sterile water to the bottle using the syringe. Do not use any food or other liquids.

Secure the cap on the bottle and shake well for 30 seconds.

Using the syringe withdraw the prescribed dose from the bottle.

Take the prescribed dose by injecting the suspension into your mouth.

Refrigerate the suspension between doses and discard any unused suspension after 24 hours.

How to prepare a 1 mg per 1 mL of oral suspension of RUZURGI for patients requiring 10 mg or more per dose

You will need:

one 30 mL bottle,
one 10 mL syringe, and
30 mL of sterile water.

You can get all these supplies from your local pharmacy.

Follow the steps below to make up the suspension:

Place three (3) 10 mg RUZURGI tablets in the 30 mL bottle.

Add 30 mL of sterile water to the bottle using the syringe. You will need to fill the syringe 3 times to create a volume of 30 mL. Do not use any food or other liquids.

Secure the cap on the bottle and shake well for 30 seconds.

Using the syringe withdraw the prescribed dose from the bottle.

Take the dose by injecting the suspension into your mouth.

Repeat steps 4 and 5 until you have taken the prescribed dose.
Refrigerate the suspension between doses and discard any unused suspension after 24 hours.

How to prepare a 1 mg per 1 mL of oral suspension of RUZURGI for patients who require a feeding tube

You will need:

one 30 mL bottle,
one 10 mL syringe with a catheter tip, and
30 mL of sterile water and extra to flush the feeding tube.

You can get all these supplies from your local pharmacy.

Follow the steps below to make up the suspension:

Follow one of the procedures above for preparing a 1 mg per 1 mL oral suspension of RUZURGI for, 10 mg or less per dose, or 10 mg or more per dose.
Using the syringe with the catheter tip withdraw the prescribed dose from the bottle.

Connect the syringe to the feeding tube and immediately inject the suspension into the stomach.

If the prescribed dose is more than 10 mg, repeat steps 2 and 3 until you have taken the prescribed dose.

Flush the feeding tube

Disconnect the syringe from the feeding tube.
Refill the syringe with 10 mL of sterile water and shake the syringe.

Connect the syringe to the feeding tube and flush any remaining suspension into the stomach.
Refrigerate the suspension between doses and discard any unused suspension after 24 hours.

If you forget to take RUZURGI

RUZURGI should be taken according to the directions provided by your doctor. If you miss your dose at the usual time, and it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you take too much RUZURGI

If you think that you have taken too much RUZURGI, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), 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.

5. What should I know while taking RUZURGI?

Things you should do

Take RUZURGI exactly as prescribed by your doctor.

Remind any doctor, dentist, or pharmacist you visit that you are taking RUZURGI.

Call your doctor straight away if you:

are pregnant or planning to become pregnant.

Things you should not do

Do not stop taking this medicine or change the dose without first checking with your doctor.
Do not give RUZURGI to anyone else even if they have the same condition as you.
Do not take RUZURGI for any other conditions unless your doctor tells you to.

Driving or using machines

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

RUZURGI may cause dizziness in some people.

Looking after your medicine

RUZURGI tablets

Store below 25°C for up to 3 months. Do not refrigerate.
Keep your tablets in the bottle and tightly closed until you are ready to take them.

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
do not store it in the car or on windowsills.

Keep it where young children cannot reach it.

Oral suspension of RUZURGI tablets

Refrigerate the oral suspension between doses.

Keep it where young children cannot reach it.

When to discard your medicine

RUZURGI tablets have a 3 month expiry from the date of first use.

The oral suspension has an expiry of 24 hours from when it is prepared. Discard any unused suspension.

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.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them should be 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
Numbness, burning, prickling, or tingling sensation in the arms, hands, legs, feet, mouth, or other parts of the body. Muscle spasms Back pain Stomach or gut pain Indigestion Dizziness Nausea (feeling sick)	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

Seizures, fits or convulsions

Allergy-related:

Shortness of breath
Wheezing or difficulty breathing
Swelling of the face, lips, tongue, or other parts of the body
Rash, itching, hives on the skin

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.

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 RUZURGI tablets contain

Active ingredient (main ingredient)	Each tablet contains 10 mg of amifampridine
Other ingredients (inactive ingredients)	colloidal anhydrous silica calcium hydrogen phosphate dihydrate magnesium stearate microcrystalline cellulose sodium starch glycollate
Potential allergens	Not applicable

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

RUZURGI does not contain gluten.

What RUZURGI looks like

RUZURGI is a white to off-white oval-shaped tablet. On one side it is scored and debossed with “10” on the left of the score line and “110” on the right of the score line. On the other side it is debossed with “LACUNA” (Aust R 352630).

RUZURGI is available in bottles of 100 tablets.

Who distributes RUZURGI

Lacuna Pharma Pty Ltd
21/21 Kangoo Road,
Somersby
NSW 2250

This leaflet was updated in September 2024.

RUZURGI^® v3.0

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Ruzurgi

Active ingredient

Amifampridine

Schedule

1 Name of Medicine

Amifampridine.

2 Qualitative and Quantitative Composition

Each Ruzurgi tablet contains 10 mg of amifampridine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Each tablet is functionally scored, oval, white to off-white, and debossed with "10/110" on one side and "LACUNA" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ruzurgi is indicated for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and children aged 6 years and above.

4.2 Dose and Method of Administration

Dose.

Dosing should be individualised based on clinical circumstances, patient response, and patient population. The dose should be gradually titrated to the optimal effective dose with the minimum of side effects. Once achieved, this optimal dose should be maintained, and dosing frequency should be adjusted, as needed.
The recommended oral dose is based on body weight (see Table 1).
Safety and effectiveness in paediatric patients below the age of 6 years have not been established.
If a dose is missed by a few hours, patients who experience weakness should take their usual dose as soon as possible. If it is close to their next dose, they should take their medication at the next regular interval. Patients should not take double or extra doses.

Method of administration.

Ruzurgi can be taken without regard to food. Swallow tablets with a glass of water.
The tablets have a functional score to facilitate splitting when increments of 5 mg are required.

Preparation of 1 mg/mL oral suspension.

When patients require a dosage in less than 5 mg increments, have difficulty swallowing tablets, or require feeding tubes, a 1 mg/mL oral suspension can be prepared (e.g. by placing three 10 mg tablets in a 30 mL container, adding 30 mL of sterile water, and shaking well for 30 seconds).
Crushing the tablets prior to making the suspension is not necessary. After preparation of the suspension, an oral syringe can be used to draw up and administer the correct dose by mouth or by feeding tube. Refrigerate the suspension between doses and shake well before drawing up each dose. The suspension can be stored under refrigeration for up to 24 hours. Discard any unused portion of the suspension after 24 hours.

Dosage adjustment.

Renal impairment.

Ruzurgi has not been studied in controlled trials of patients or volunteers with any degree of renal impairment. Renal clearance is an elimination pathway for amifampridine and the inactive metabolite, 3-N-acetyl amifampridine. Ruzurgi should be titrated more slowly, using the lowest dose in patients with moderate or severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use).
Consider dose reduction or discontinuation of Ruzurgi for patients with renal impairment, based on clinical effect and tolerability.

Hepatic impairment.

Ruzurgi has not been studied in controlled clinical trials of patients or volunteers with any degree of hepatic impairment. Ruzurgi is extensively metabolised and hepatic impairment can slow its metabolism, resulting in higher plasma drug levels.
Initiation and titration of Ruzurgi in patients with mild and moderate hepatic impairment should be done cautiously, using the lowest recommended initial single and total daily doses. See Section 4.4 Special Warnings and Precautions for Use.

Known N-acetyltransferase 2 (NAT2) poor metabolisers.

Exposure of Ruzurgi is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolisers, see Section 5.2 Pharmacokinetic Properties, Pharmacogenomics. The recommended starting dosage of Ruzurgi in patients weighing 45 kg or more who are known N-acetyltransferase 2 (NAT2) poor metabolisers is 10 mg daily taken orally in divided doses (2 to 3 times per day). The recommended starting dosage in patients weighing less than 45 kg who are known NAT2 poor metabolisers is 5 mg daily taken orally in divided doses (2 to 3 times daily). This is consistent with initiating Ruzurgi in patients with hepatic impairment using the lowest recommended initial dosing. Consider dosage modification of Ruzurgi for patients who are known NAT2 poor metabolisers as needed based on clinical effect and tolerability.

4.3 Contraindications

Ruzurgi is contraindicated in patients with:
A history of seizures, see Section 4.4 Special Warnings and Precautions for Use.
Are taking other forms of amifampridine or other aminopyridines.
Hypersensitivity to amifampridine or another aminopyridine, see Section 4.4 Special Warnings and Precautions for Use.

4.4 Special Warnings and Precautions for Use

Seizures.

Ruzurgi can cause seizures. Seizures have been observed in patients with and without a history of seizures taking Ruzurgi at the recommended doses, and at various times after initiation of treatment. Many of the patients were taking medications or had comorbid medical conditions that may have lowered the seizure threshold. Ruzurgi should be used with caution when used concomitantly with drugs that are known to lower the seizure threshold, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions. Seizures may be dose-dependent. Because seizure events were captured retrospectively from expanded access programs, it is not possible to reliably estimate their frequency with use of Ruzurgi. Consider discontinuation or dose-reduction of Ruzurgi in patients who have a seizure while on treatment. Ruzurgi is contraindicated in patients with a history of seizures, see Section 4.3 Contraindications.

QT prolongation.

QTc interval prolongation has been observed at supratherapeutic doses (120 mg Ruzurgi in 4 equal doses of 30 mg at 4-hour intervals) in a thorough QT study, see Section 5.1 Pharmacodynamic Properties. Drugs that prolong the QTc increase the risk of torsade de pointes, a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by a drug. Torsade de pointes can be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death. Caution should be observed if Ruzurgi is administered to patients who have risk factors for torsade de pointes and particularly in patients with the slow acetylator phenotype, see Section 5.1 Pharmacodynamic Properties.

Hypersensitivity.

In clinical trials, hypersensitivity reactions and anaphylaxis associated with Ruzurgi administration have not been reported. Anaphylaxis has been reported in patients taking another aminopyridine; therefore, it may occur with Ruzurgi. If anaphylaxis occurs, administration of Ruzurgi should be discontinued and appropriate therapy initiated.

NAT2 poor metabolisers.

Exposure of Ruzurgi is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolisers, see Section 5.2 Pharmacokinetic Properties, Pharmacogenomics. See Section 4.2 Dose and Method of Administration, for dosing recommendations in patients who are NAT2 poor metabolisers.

Use in hepatic impairment.

The effects of Ruzurgi have not been studied in patients with hepatic impairment. Ruzurgi is extensively metabolised by N-acetyltransferase 2 (NAT2), and hepatic impairment may cause an increase in exposure. Therefore, initiate Ruzurgi in patients with mild and moderate hepatic impairment using the lowest recommended initial single and total daily doses. Additional caution and monitoring of adverse reactions is recommended for patients with severe hepatic impairment.

Use in renal impairment.

Ruzurgi has not been studied in controlled trials of patients or volunteers with any degree of renal impairment. Renal clearance is an elimination pathway for amifampridine and the inactive metabolite, 3-N-acetyl amifampridine. Therefore, in patients with mild or moderate renal impairment, Ruzurgi should be initiated at the lowest recommended starting dosage and patients should be closely monitored for adverse reactions. In patients with severe renal impairment, extra caution should be exercised and patients should be monitored for tolerability and adverse reactions.

Use in the elderly.

Based on data from two controlled studies of patients with LEMS and the Expanded Access Programs, a total of 106 patients, 65 years of age and older, received treatment with Ruzurgi. No overall differences in safety and efficacy were observed between the elderly and younger adult patients.
Ruzurgi is known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in individual dose selection and titration to effect. It may also be useful to monitor renal function.

Paediatric use.

There is no controlled experience for the safety and efficacy of Ruzurgi in paediatric LEMS patients. Seven patients, 9 to 16 years of age, have received Ruzurgi in clinical practice.
There are no actual pharmacokinetic/exposure data in paediatric LEMS patients 6 to 17 years of age. Use of Ruzurgi in this population is supported by evidence from controlled studies of Ruzurgi in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modelling and simulation to identify the dosing regimen in paediatric patients, and some safety data (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties).
Safety and efficacy in paediatric patients below the age of 6 years have not been studied.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs that lower seizure threshold.

The concomitant use of Ruzurgi and drugs that lower seizure threshold may lead to an increased risk of seizures, see Section 4.4 Special Warnings and Precautions for Use. The decision to administer Ruzurgi concomitantly with drugs that lower the seizure threshold should be carefully considered in light of the associated risks.

Drugs with cholinergic effects.

The concomitant use of Ruzurgi and drugs with cholinergic effects (e.g. direct or indirect cholinesterase inhibitors) may increase the cholinergic effects of Ruzurgi and of those drugs and increase the risk of adverse reactions.

Drug interaction studies.

In vitro studies.

Amifampridine is not metabolised by cytochrome P450 (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
In vitro studies with human liver microsomes indicated that amifampridine and 3-N-acetyl amifampridine were not direct or time-dependent inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.
In vitro studies in cryopreserved human hepatocytes indicated that amifampridine did not induce CYP isoforms CYP1A2, CYP2B6, or CYP3A4.
Based on in vitro studies with Caco-2 cells amifampridine is unlikely to act as a substrate or inhibitor of the P glycoprotein transporter. Amifampridine is not an inhibitor of the BCRP transporter.
In vitro studies with Chinese hamster ovary cells expressing human OATP1B1, OATP1B3, OAT1, and OCT2 and Madin-Darby canine kidney cells expressing human OAT3 indicated that amifampridine is not an inhibitor of OCT2, OAT1, OAT3, OATP1B1, or OATP1B3 at clinically-relevant concentrations. The studies also indicated that amifampridine is not a substrate for OAT1, OAT3, or OCT2 transporters.

In vivo studies.

Controlled clinical drug interaction studies have not been performed with Ruzurgi.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal studies to assess the potential adverse effects of Ruzurgi (amifampridine) on fertility have not been conducted.
(Category C)
There are no adequate and well-controlled studies of Ruzurgi (amifampridine) in pregnant women. No adverse outcomes were reported in the 6 known completed pregnancies involving 3 patients with LEMS receiving compassionate use amifampridine. Two pregnancies have been reported in female partners of male LEMS patients with no reported adverse outcomes. Ruzurgi should be used during pregnancy only if the potential benefits to the mother justifies the potential risk to the fetus.
Animal studies to assess the potential adverse effects of Ruzurgi (amifampridine) on embryofetal development have not been conducted. However, potassium channels play a role in uterine smooth muscle function during gestation and parturition.
Women of childbearing potential should use effective contraception during treatment with Ruzurgi.
There are no data on the presence of amifampridine or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ruzurgi, any potential adverse effects on the breastfed infant from Ruzurgi, or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, some patients have experienced dizziness when being treated with Ruzurgi. The effect of Ruzurgi on the individual patient should be considered prior to driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The following serious adverse reactions are described elsewhere in the labeling:
Seizures, see Section 4.4 Special Warnings and Precautions for Use.
Hypersensitivity, see Section 4.4 Special Warnings and Precautions for Use.

Clinical trials experience.

In a double-blind, 3-way crossover, pharmacology study to assess the effects of Ruzurgi on QTc interval prolongation, Ruzurgi was administered at doses greater than the usual recommended dose (120 mg administered as 4 equal doses of 30 mg at 4-hour intervals) to 52 healthy adult volunteers, see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology. Treatment-emergent adverse events (TEAE) that occurred in at least 1% of subjects during Ruzurgi treatment and with incidence at least 2% greater than during placebo treatment are displayed in Table 2.

Study participants classified as poor metabolisers (inferred using seven human NAT2 and four human NAT1-specific single nucleotide polymorphisms), were more likely to experience adverse reactions during Ruzurgi treatment than intermediate or normal metabolisers, see Section 5.2 Pharmacokinetic Properties, Pharmacogenomics.

Expanded access experience.

In expanded access programs, 162 patients with LEMS (54% female) were treated with Ruzurgi. Among patients with available exposure data, the median duration of treatment was 1.7 years (range 1 day to 27.6 years) for a total of 766.4 person years. Patient age at the time Ruzurgi was initiated ranged from 21 to 84 years (mean 58.7 years). The median of the maximum total daily dosage was 75 mg/day.
In general, the most frequent adverse reactions observed in the expanded access programs were similar to those observed in the Thorough QT study (TQT) study. Additionally, the following adverse events were reported in ≥ 5% of patients during exposures ranging from 1 day to > 27 years: paraesthesia, oral paraesthesia, falls, diarrhoea, pneumonia, small cell lung cancer, nausea, muscle spasms, dyspnoea, arthralgia, asthenia, depression, dysphagia, headache, hypoaesthesia, metastases to the central nervous system, abdominal pain, abdominal discomfort, dyspepsia, vomiting, cerebrovascular accident, pulmonary mass, Herpes Zoster, dizziness, sleep apnoea syndrome, hypertension, hyperlipidaemia, insomnia, vision blurred, diplopia (double vision), anaemia, anxiety, constipation, feeling cold, gastrooesophageal reflux disease, pain in extremity, chest pain, and pain. Because these reactions were captured retrospectively from expanded access programs, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Paediatric patients (6 to less than 18 years of age).

The safety of Ruzurgi was evaluated in 7 paediatric LEMS patients 6 to less than 18 years of age who were treated with Ruzurgi in the Expanded Access Programs for at least one year. Adverse reactions reported in these patients were similar to those seen in adult LEMS patients and included one patient with palpitations.

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.

4.9 Overdose

Events reported after inadvertent overdose of repeated single doses of Ruzurgi 20 mg in patients on stable chronic doses included diffuse muscle spasm and chest, abdominal or back pain. In case reports, events reported after intake of Ruzurgi at doses of 300 mg per day or greater (more than three times the maximum recommended daily dosage) include vomiting, nystagmus, seizures and status epilepticus, rhabdomyolysis, chest pain, diaphoresis, palpitations, paroxysmal supraventricular tachycardia, transient QTc prolongation, aspiration with acute respiratory failure, and cardiac arrest.
Patients with suspected overdose with Ruzurgi should be monitored for signs or symptoms of exaggerated Ruzurgi adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
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.

The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has not been fully elucidated. Amifampridine is a broad-spectrum potassium channel blocker.

Clinical trials.

The efficacy of Ruzurgi for the treatment of LEMS was established in a randomised, double-blind, placebo-controlled, withdrawal study (DAPPER) in patients with an established clinical diagnosis of LEMS. The mean age of patients was 56 years (range: 23 to 83 years).
Two thirds of patients were female and primarily Caucasian. Ninety-seven percent of patients had a diagnosis of autoimmune LEMS, and 3% of patients had a diagnosis of paraneoplastic LEMS. Patients were allowed to use stable dosages of peripherally-acting cholinesterase inhibitors or oral immunosuppressants. Seventy-nine percent of patients randomised to Ruzurgi were receiving cholinesterase inhibitors, versus 83% in the placebo group, and 29% of patients randomised to Ruzurgi were receiving an immunosuppressant therapy, versus 39% in the placebo group.
The primary measure of efficacy was the categorisation of the degree of change (e.g. greater than 30% deterioration) in the Triple Timed Up and Go test (3TUG) upon withdrawal of Ruzurgi, when compared with the time-matched average of the 3TUG assessments at baseline. The 3TUG is a measure of the time it takes a person to rise from a chair, walk 3 meters, and return to the chair for 3 consecutive laps without pause. Higher 3TUG scores represent greater impairment.
The secondary efficacy endpoint was the self-assessment scale for LEMS-related weakness (W-SAS), a scale from -3 to 3 assessing a person's feeling of weakening or strengthening from baseline. A higher positive W-SAS score indicates a perceived greater improvement of strength. A more negative score indicates perceived greater weakening.
Patients were required to be on an adequate and stable dose of Ruzurgi (30 mg to 100 mg daily for at least 3 months) prior to screening.
After an initial open-label run-in phase, 32 patients were randomised in a double-blind fashion to either continue treatment with Ruzurgi (n = 14) or switch to placebo over a 3-day downward titration (n = 18) period. Following the downward titration period, patients remained on blinded Ruzurgi or placebo for up to 16 more hours. Efficacy was assessed 2 hours after the last dose of the downward titration period.
None of the patients randomised to continue Ruzurgi experienced a greater than 30% deterioration in the final post-dose 3TUG test. In contrast, 72% of patients (13/18) randomised to placebo experienced a greater than 30% deterioration in the final 3TUG test. See Table 3. Patients who were randomised to placebo returned to baseline after restarting Ruzurgi. Figure 1 shows the time course of the mean percent change from baseline on the 3TUG during the double-blind phase and with re-initiation of Ruzurgi.

The W-SAS score showed a significantly greater decrease in patients randomised to placebo (-2.4) than in those who continued treatment with Ruzurgi (-0.2; p < 0.0001), indicating that patients who were randomised to placebo perceived a worsening of weakness compared to those who remained on Ruzurgi.

Cardiac electrophysiology.

The effect of Ruzurgi on QTc interval prolongation was studied in a double-blind, randomised, placebo- and positive-controlled study in 52 healthy subjects (including 23 subjects with poor inferred metaboliser phenotype based on NAT2 genotyping). Study participants were administered 120 mg Ruzurgi in 4 equal doses of 30 mg at 4-hour intervals (Dose 1, 2, 3, and 4), see Section 5.2 Pharmacokinetic Properties, Pharmacogenomics. The upper bound of the two sided 90% CIs of the LS mean estimate of the placebo-subtracted differences in QTcF between amifampridine and placebo, were below 10 ms for all post-baseline time points. The LS mean estimates of the placebo-subtracted differences in QTcF between amifampridine and placebo exceeded 5 ms at 13.5 hours postdose (5.20) and 15 hours post-dose (6.14).
In the same thorough QT study, the LS mean estimates of the placebo-subtracted differences in QTcF between amifampridine and placebo in slow acetylators, exceeded 5 ms in 15 out of 23 post-baseline time points. The upper bound of the two-sided 90% CIs of the mean baseline corrected differences in QTcF between amifampridine and placebo were above 10 ms at three post-baseline time points (13.5, 14 and 15 hours). The greatest mean baseline corrected difference for in QTcF between amifampridine and placebo was 8.29 ms (90% CI 5.10, 11.49). In vitro, Ruzurgi did not inhibit the human ether-a-go-go-related gene ion channel.

5.2 Pharmacokinetic Properties

The pharmacokinetics of amifampridine free-base form, Ruzurgi, are approximately dose proportional. Steady state was generally reached within 1 day of dosing. With multiple dosing the mean RC_max and RAUC_(0-tau) of 3,4-DAP were 0.902 and 1.12, respectively, and the mean RC_max and RAUC_(0-tau) of the major metabolite N-acetyl amifampridine were 1.44 and 1.75, respectively, see Section 5.2 Pharmacokinetic Properties, Pharmacogenomics.

Absorption.

The absolute bioavailability of Ruzurgi has not been assessed. Amifampridine is absorbed in an approximately dose-proportional manner under fasting conditions with a median time to maximum concentration (t_max) of 0.5 hours post administration.

Effect of food.

Compared to administration of Ruzurgi in the fasting state, administration of the 20 and 30 mg dose levels of Ruzurgi with a standard high fat meal resulted in decreased C_max (41% and 52%, respectively) and increased median t_max to 1.0 hour; AUC_0-last was only reduced for the 30 mg dose (23%), see Section 4.2 Dose and Method of Administration.

Distribution.

In healthy volunteers, amifampridine demonstrates moderate to high volume of distribution.
In vitro human plasma protein binding of amifampridine and 3-N-acetyl amifampridine was 25.3% and 43.3%, respectively.

Metabolism.

In vitro studies with recombinant human N-acetyltransferase (NAT) enzyme preparations indicate that amifampridine is rapidly metabolised by the N-acetyltransferase 2 (NAT2) enzyme to the 3-N-acetyl amifampridine metabolite. Metabolism of amifampridine by N-acetyltransferase 1 (NAT1) may also occur but at a much slower rate.
Amifampridine does not undergo glucuronidation or sulfonation.

Excretion.

Following oral administration of a single 20 or 30 mg dose of Ruzurgi to healthy volunteers, the apparent oral clearance (CL/F) of amifampridine was 149 to 214 L/h, the average elimination half-life (t_1/2) was 3.6 to 4.2 hours. The average t_1/2 of the 3-N-acetyl amifampridine metabolite was 4.1 to 4.8 hours.
The combined median (range) total percent recovery of amifampridine and 3-N-acetyl amifampridine in urine after a 20 mg dose under fasting and fed conditions was 90.3% (45.0%-106.0%) and 85.8% (55.4%-101.2%), respectively. After a 30 mg dose, the total percent recovery of amifampridine and 3-N-acetyl amifampridine metabolite in the urine following under fasting and fed conditions was 82.6% (32.8%-95.8%) and 67.1% (26.2%-91.1%), respectively.

Specific populations.

Paediatric patients (6 to less than 18 years of age).

A population pharmacokinetic analysis showed that body weight significantly correlates with the clearance of amifampridine; clearance increased with an increase in body weight. A weight-based dosing regimen is necessary to achieve amifampridine exposures in paediatric patients 6 to less than 18 years of age similar to those observed in adults at effective doses of Ruzurgi, see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials.

Hepatic impairment.

The pharmacokinetics of amifampridine in patients or volunteers with any degree of hepatic impairment has not been studied in controlled clinical trials. Hepatic impairment can slow the metabolism of amifampridine, leading to higher plasma drug levels. See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

Renal impairment.

Treatment with Ruzurgi in patients with any degree of renal impairment has not been studied in controlled clinical trials. Both amifampridine and its metabolite, 3-N-acetylamifampridine, are cleared through the renal system. The metabolite is likely to accumulate in patients with renal impairment. See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.

Pharmacogenomics.

Genetic variants in the N-acetyltransferase gene 2 (NAT2) affect the rate and extent of Ruzurgi metabolism. In normal healthy volunteers, poor metabolisers, also referred to as "slow acetylators" (i.e. carriers of two reduced function alleles) had higher average plasma amifampridine concentrations than intermediate metabolisers, also referred to as "intermediate acetylators" (i.e. carriers of one reduced and one normal function alleles), and normal metabolisers, also referred to as "fast/rapid acetylators" (i.e. carriers of two normal function alleles).
In the Thorough QT (TQT) study, see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology, poor metabolisers (N = 23) had 1.1 to 3.7 times higher AUC_0-4h than intermediate metabolisers (N = 25) and 1.3 to 3.7 times higher C_max than intermediate metabolisers (N = 26), following the first dose. Poor metabolisers had 6.0 to 8.5 times higher AUC_0-4h and 6.1 to 7.6 times higher C_max than normal metabolisers (N = 3), following the first dose.

5.3 Preclinical Safety Data

Genotoxicity.

Amifampridine was negative for mutagenicity in an in vitro bacterial reverse mutation (Ames) assay and for clastogenicity in in vivo mouse micronucleus and chromosomal aberration assays at oral doses up to 20 mg/kg. Amifampridine was positive for clastogenicity in an in vitro mouse lymphoma assay in the absence of metabolic activation. The metabolite was negative in both Ames test and in the in vitro mouse lymphoma assay.

Carcinogenicity.

Carcinogenicity studies with amifampridine indicated an increased incidence of endometrial carcinomas in female rats treated with amifampridine at subclinical exposures.

6 Pharmaceutical Particulars

6.1 List of Excipients

Colloidal anhydrous silica, calcium hydrogen phosphate dihydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycollate.
Ruzurgi does not contain gluten.

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. See Section 6.4 Special Precautions for Storage, for the shelf life after dispensing and the shelf life of the oral suspension.

6.4 Special Precautions for Storage

Prior to dispensing.

Store tablets in a refrigerator between 2°C and 8°C. Do not freeze. Keep container tightly closed with desiccant canister inside after opening. Protect from moisture and light.

After dispensing.

Store below 25°C for up to 3 months in the original container. Protect from moisture and light.

1 mg/mL oral suspension.

The suspension can be stored under refrigeration for up to 24 hours. Discard any unused portion of the suspension after 24 hours.

6.5 Nature and Contents of Container

Ruzurgi is supplied in HDPE bottles of 100 tablets with child-resistant cap and desiccant canister.

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

Amifampridine is a potassium channel blocker.
The chemical name of amifampridine is 3,4-diaminopyridine.
It is a white to off-white, crystalline solid with a molecular formula of C₅H₇N₃ and a molecular weight of 109.13 g/mol. It is sparingly soluble in water. A 1% aqueous solution of amifampridine has a pH of 10.8 at 25°C.

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