Consumer medicine information

Fintepla

Fenfluramine

BRAND INFORMATION

Brand name

Fintepla

Active ingredient

Fenfluramine

Schedule

SUMMARY CMI

Fintepla^®

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 or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Fintepla^®?

Fintepla^® contains the active ingredient fenfluramine. Fenfluramine is used to treat seizures associated with 2 forms of childhood epilepsy: Dravet syndrome and Lennox-Gastaut syndrome.

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

2. What should I know before I use Fintepla^®?

Do not use Fintepla^® if you or your child have ever had an allergic reaction to fenfluramine or any of the ingredients listed at the end of the CMI, or if you or your child have a heart problem such as valve disease or pulmonary arterial hypertension, or if you or your child have taken medicines called monoamine oxidase inhibitors in the last 2 weeks.

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 Fintepla^®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fintepla^® 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 Fintepla^®?

Fintepla^® is an oral solution that is taken twice a day. The required dose will be calculated by your doctor based on your or your child's body weight. Starting at a low dose which may be gradually increased.

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

5. What should I know while using Fintepla^®?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Fintepla^®. If you or your child take more Fintepla^® than you or your child should, talk to a doctor or go to a hospital straight away, taking the medicine bottle with you.
Things you should not do	Do not use this medicine after the expiry date which is stated on the label and carton after EXP.
Looking after your medicine	Keep this medicine out of the sight and reach of children. Store below 30°C. Do not refrigerate or freeze. Keep in the original carton to protect from light.

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

6. Are there any side effects?

Side effects that need serious medical attention include being agitated, having hallucinations or passing out, fast heartbeat, fever, twitching muscles and being uncoordinated, sleepy or confused, being flushed or hot, shivering or sweating, feeling sick or being sick and diarrhoea. These are symptoms of serotonin syndrome or of taking too much Fintepla^®.

Common side effects include falling, diarrhoea, vomiting, weight loss, constipation, loss of appetite, high temperature, feeling tired, sleepy or weak, chest infection, bronchitis, influenza, ear infection, pneumonia, trembling of the hands, arms or legs, long-lasting seizures, irritability, lethargy, producing a lot of saliva, abnormal behaviour, rapid mood changes, aggression, agitation, insomnia, having problem with coordination of movements, walking and balance and decreased muscle tone.

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.

WARNING: VALVULAR HEART DISEASE AND PULMONARY ARTERIAL HYPERTENSION
• There is an association between some serotonergic drugs including fenfluramine (the active ingredient in Fintepla), and problems with the valves in the heart (valvular heart disease) and high blood pressure in the arteries of the lungs (pulmonary arterial hypertension).
• Echocardiogram assessments are required before, during and after treatment with Fintepla.

FULL CMI

Fintepla^®

Active ingredient(s): fenfluramine

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fintepla^®. 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 Fintepla^®.

Where to find information in this leaflet:

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

1. Why am I using Fintepla^®?

Fintepla^® contains the active ingredient fenfluramine. Fenfluramine is thought to work by increasing the activity in the brain of a natural substance called serotonin and the sigma-1 receptor.

Fintepla^® is used to treat seizures (fits) in patients aged 2 years and older who have either a type of epilepsy called Dravet syndrome, or a type of epilepsy called Lennox-Gastaut syndrome. It can help to reduce the severity and the number of seizures.

2. What should I know before I use Fintepla^®?

Warnings

Do not use Fintepla^® if:

You or your child are allergic to fenfluramine or any of the other ingredients listed at the end of this leaflet.
You or your child have problems with the valves in the heart (valvular heart disease) and high blood pressure in the arteries in the lungs (pulmonary arterial hypertension)..
You or your child have taken medicines called monoamine oxidase inhibitors (MAOIs) in the last 2 weeks.

If any of the above applies to you or your child (or you are not sure), talk to your doctor or pharmacist before taking Fintepla.

Check with your doctor if you or your child:

have glaucoma,
have had thoughts about harming or killing yourself,
are taking a medicine called cyproheptadine, which is used to treat allergies or improve appetites.
have heart problems.
have or have had weight loss.
have or have had depression or mood problems.
have kidney problems, have liver problems.

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?

Tests and Checks

Before you or your child start taking Fintepla^® your doctor must check the heart with an echocardiogram. The doctor will check that the valves in the heart work properly and the pressure in the artery between the heart and lungs is not too high. Once you or your child has started taking Fintepla^®, you will have an echocardiogram check every 6 months for the first 2 years and then once a year. If Fintepla treatment is stopped, you or your child will need to have an echocardiogram 6 months after the last dose.

Your doctor should also check your weight before and during your treatment as Fintepla^® can cause you to lose weight.

Serotonin syndrome

Tell your doctor or pharmacist before taking Fintepla^® if you or your child are taking medicines which can increase the levels of serotonin in your brain. This is because taking these medicines and Fintepla^® can cause serotonin syndrome, which is a life-threatening condition. Medicines that can increase serotonin levels include:

‘triptans’ (such as sumatriptan) – used for migraine,
MAOI medicines (such as phenelzine and tranylcypromine) – used for depression,
Medicines called selective serotonin uptake inhibitors (SSRI) e.g., sertraline, citalopram, fluoxetine etc. or serotonin-noradrenaline reuptake inhibitors (SNRI) e.g., venlafaxine, desvenlafaxine and duloxetine – used for depression and anxiety.

Look out for the signs of serotonin syndrome which include:

being agitated, seeing things which are not there (hallucinations) or passing out,
heart and circulation problems such as fast heartbeat, blood pressure going up and down, high body temperature, sweating,
twitching muscles and being uncoordinated,
feeling or being sick and diarrhoea.

Tell your doctor straight away if you notice any of the serious side effects above.

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.

Fintepla is not recommended for use during pregnancy.

Children

Fintepla^® is not recommended for children under 2 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.

Other Medicines

Tell your doctor or pharmacist if you or your child are taking, have recently taken, or might take any other medicines. This is because Fintepla^® can affect the way some other medicines work. Also, some other medicines can affect the way Fintepla^® works.

Fintepla^® can make you or your child feel sleepy. You or your child may be even more sleepy if you take other medicines such as anti-depressants or alcohol at the same time as Fintepla^®.

In particular, tell your doctor or pharmacist if you or your child are taking, have recently taken, or might take:

stiripentol, a medicine for epilepsy, as your dose of Fintepla^® may need to be reduced,
‘triptans’, MAOI, SNRI or SSRI medicines – see above under ‘Serotonin syndrome’,
carbamazepine, primidone, rifampicin, phenobarbital and other barbiturates, phenytoin, and efavirenz, as your dose of Fintepla^® may need to be increased.

Also speak with your doctor or pharmacist if you or your child smoke as the dose of Fintepla may need to be increased.

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

4. How do I use Fintepla^®?

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with them if you are not sure.

How much to take

You will be told how many milliliters (mL) to take for each dose.
Take the medicine twice a day.
Your doctor will start you or your child on a low dose. This can then be gradually increased depending on how well the medicine works and how it affects you or your child.
The maximum amount you can take is 6 mL twice a day.
If you are taking stiripentol, the maximum amount you can take is 4 mL twice a day.
Do not take more than the prescribed dose as it may cause serious side effects.

How to take Fintepla^®

Take this medicine by mouth.
Take the medicine with food or between meals.
Fintepla oral solution is compatible with a ketogenic diet.
The medicine is a liquid. Use the oral syringes provided to measure your dose, as explained below.
Use the green 3 mL syringe for doses up to 3.0 mL.
Use the purple 6 mL syringe for doses between 3.2 mL and 6.0 mL.
Fintepla oral solution is compatible with most enteral feeding tubes.
To flush the feeding tube, fill the syringe used for dosing with water and flush the tube. Do this 3 times.

Write on the carton the date you first opened the bottle.

You must attach the bottle adaptor the first time you open the bottle. The following instructions tell you how to attach the adaptor.

Inserting the bottle adaptor:

When the bottle is first opened the bottle adaptor must be pushed into the bottle.

Wash and dry your hands.

Remove the bottle adaptor from its packaging.

Place the bottle on a flat, firm surface.

Open the bottle.

Hold the bottle firmly.

Line up the bottle adapter with the open top of the bottle.

Push the bottle adaptor into the bottle with your palm until the adaptor is flush with the top of the bottle.

Leave in the bottle adaptor after using the medicine.

Screw the bottle cap onto the bottle with the bottle adaptor left in.

Taking the medicine:

Before you measure out the dose, make sure the plunger is pushed all the way into the oral syringe.

Hold the bottle of medicine firmly on a hard, flat surface.

Push the tip of the oral syringe into the bottle adaptor until it cannot be pushed further.

Hold the oral syringe and bottle together and turn upside down.

Slowly pull the plunger to draw up the right dose.

Hold the oral syringe and bottle together and then turn over.

Holding the bottle firmly, gently pull the oral syringe out of the bottle adaptor.

Place the tip of the oral syringe against the inside of the patient's cheek.

Gently push the plunger until it is fully pressed. There will be a small volume left in the tip of the syringe. This is normal.

Do not squirt the medicine into the back of the throat as this may cause choking.

Place the cap back on the bottle and turn until it stops.

Always leave the adaptor in place in the bottle.

Cleaning the syringe:

Rinse the oral syringe with cold water and allow it to air dry after each use.

Rinse the inside of the syringe and the plunger.
Cold water can be pulled into the syringe with the plunger and pushed out several times to clean the syringe.
It is okay to separate the plunger from the syringe to rinse each part.
Do not use detergent to clean the syringe and plunger
Do not clean the syringe and plunger in a dishwasher.

The syringe and plunger must be completely dry before the next use.

If you forget to take Fintepla^®

Take it as soon as you remember it. However, if it is nearly time for the next dose, skip the missed dose.

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

If you or your child take more Fintepla^® than you or your child should

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. Take the medicine bottle with you.

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

The following effects may happen being agitated, sleepy or confused, being flushed or hot, shivering and sweating.

If you or your child stop taking Fintepla

Do not stop taking Fintepla without talking to your doctor. If your doctor decides to stop this medicine, the doctor will ask you or your child to slowly lower the amount taken each day. Slowly lowering the dose will reduce the risk of having a seizure and status epilepticus.

Six months after the last dose of Fintepla, you or your child will need to have an echocardiogram.

5. What should I know while using Fintepla^®?

Remind any doctor, dentist or pharmacist you visit that you or your child is taking Fintepla^®.

Things you should not do:

Use the medicine if:

the expiration date on the packaging has passed (the expiry date refers to the last day of that month),
the carton seals have been broken, or
it is more than 3 months since the bottle was first opened.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Fintepla^® affects you.

Talk to your doctor about driving, using machines, or if you or your child undertake activities such as cycling or other sports, because you or your child may feel sleepy after taking this medicine.

Looking after your medicine

Store Fintepla below 30°C. Do not refrigerate or freeze.
Keep the bottle in the outer carton in order to protect it from light.
Wash the syringe after each use.
If you lose or damage a syringe, or cannot read the dose markings on a syringe, use another oral syringe provided in your pack, or speak to your pharmacist.

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

Keep it where young children cannot reach it.

When to discard your medicine

Discard after the expiry date, or if it is more than 3 months since the bottle was first opened.

Getting rid of any unwanted medicine

Do not use this medicine after the expiry date.

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 are mild 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

Infection:

High temperature (fever)
Chest infection
Bronchitis
Influenza
Ear infection (otitis media)
Pneumonia

Stomach and gut:

Diarrhoea
Vomiting
Loss of appetite
Weight loss
Constipation

General:

Falling
Feeling tired, sleepy or weak
Trembling of the hands, arms or legs
Long-lasting seizures (status epilepticus)
Irritability
Lethargy
Producing a lot of saliva
Abnormal behaviour
Rapid mood changes
Aggression
Agitation
Insomnia
Having problem with coordination of movements, walking and balance
Decreased muscle tone

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

Serotonin syndrome:

being agitated, seeing things which are not there (hallucinations) or passing out
heart and circulation problems such as fast heartbeat, blood pressure going up and down, high body temperature, sweating
twitching muscles and being uncoordinated
feeling or being sick and diarrhoea

Allergic reaction:

difficulty breathing or swallowing
low blood pressure, which can make you dizzy or light-headed
swelling of the face, lips, tongue or throat
severe itching of the skin, with a red rash or raised bumps.

Valvular heart disease or pulmonary arterial hypertension:

shortness of breath
tiredness or weakness, especially with increased activity
lightheadedness or fainting
swollen ankles or feet
chest pain
sensations of a rapid, fluttering heartbeat (palpitations)
irregular pulse
bluish colour to your lips and skin (cyanosis)

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 that 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 Fintepla^® contains

Active ingredient
(main ingredient)

Fenfluramine (as hydrochloride)

Other ingredients
(Inactive ingredients)

Sodium ethyl hydroxybenzoate (E 215)
Sodium methyl hydroxybenzoate (E 219)
Sucralose (E 955)
Hyetellose (E 1525)
Monosodium phosphate (E 339)
Disodium phosphate (E 339)
Cherry flavouring powder:
- Acacia (E 414)
- Glucose (maize)
- Ethyl benzoate
- Natural flavouring preparations
- Natural flavouring substances
- Flavouring substances
- Maltodextrin (maize)
- Sulphur dioxide (E 220)
- Potassium citrate (E 332)
- Citric acid monohydrate (E 330)
Water

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

What Fintepla^® looks like

Fintepla^® oral solution is a clear, colourless, cherry-flavored slightly viscous liquid. The solution is provided in a white bottle with a child-resistant and tamper evident cap.

Each pack contains a bottle adapter, two green 3 mL oral syringes with 0.1 mL graduations, and two purple 6 mL syringes with 0.2 mL graduations and the medicine bottle, either:

A bottle containing 60 mL oral solution (Aust R 429413),
A bottle containing 120 mL oral solution (Aust R 429413),
A bottle containing 250 mL oral solution (Aust R 429413), or
A bottle containing 360 mL oral solution (Aust R 429413).

Who distributes Fintepla^®

UCB Pharma
A division of UCB Australia Pty Ltd
Level 1, 1155 Malvern Road
Malvern VIC 3144, Australia
Phone: +61 3 9828 1800
Website: www.ucbaustralia.com.au
E‐mail: [email protected]

This leaflet was prepared in November 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Fintepla

Active ingredient

Fenfluramine

Schedule

1 Name of Medicine

Fenfluramine hydrochloride.

2 Qualitative and Quantitative Composition

Fintepla oral solution contains 2.2 mg of fenfluramine (as hydrochloride) per mL.

Excipients with known effect.

Sucralose, hydroxybenzoates, benzoates, sulfites. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Oral solution.

The solution is a clear, colourless, slightly viscous liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Fintepla is indicated as add-on therapy in the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older.

4.2 Dose and Method of Administration

Fintepla should be initiated and supervised by physicians with experience in the treatment of epilepsy.
All patients are started at 0.1 mg/kg Fintepla taken twice daily (BD) and may be titrated every 7 days based on clinical response and tolerability, to an appropriate maintenance dose. The maximum daily maintenance dosage of Fintepla is based on whether patients are taking stiripentol concomitantly. Dosage recommendations and titration schedule for paediatric (children aged 2 years and older) and adult populations are provided in Table 1.

Method of administration.

Fintepla is to be administered orally and may be taken with or without food.
Fintepla contains a very limited amount of digestible carbohydrate and is compatible with a ketogenic diet.
Graduated syringes are supplied with each bottle of Fintepla oral solution.
If the calculated dose is 3.0 mL or less, the green printed 3 mL syringe should be used;
If the calculated dose is more than 3.0 mL, the purple printed 6 mL syringe should be used.
The calculated dose should be rounded to the nearest graduated increment.
Fintepla oral solution is compatible with most enteral feeding tubes. To flush the feeding tube, fill the syringe used for dosing with water and flush the tube. Do this 3 times.

Discontinuation of treatment.

When discontinuing treatment, the dose should be decreased gradually. As with all anti-epileptic medicines, abrupt discontinuation should be avoided, when possible, to minimize the risk of increased seizure frequency and status epilepticus.

Dose adjustment.

No dose adjustment is required based on age, gender, race or ethnicity, or in patients with mild to moderate renal impairment.
A dose reduction for Fintepla is recommended when it is co-administered with strong CYP1A2 or CYP2D6 inhibitors, in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m²), in patients with mild hepatic impairment (Child-Pugh class A), moderate hepatic impairment (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C).

Mild, moderate and severe hepatic impairment.

See Table 2 for dosage adjustments and recommendations for patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). A maximum dosage of 0.2 mg/kg twice daily (maximum 17 mg/day) is recommended in patients with severe hepatic impairment (Child-Pugh class C).

Severe renal impairment.

For patients with severe renal impairment (estimated glomerular filtration rate (eGFR) 15 to 29 mL/min/1.73 m²), a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol is recommended (see Section 4.4 Special Warnings and Precautions for Use).

Concomitant use of strong CYP1A2 or CYP2D6 inhibitors.

For patients with concomitant use of Fintepla with a strong CYP1A2 or CYP2D6 inhibitor, a maximum total daily dosage of 20 mg without concomitant stiripentol and 17 mg with concomitant stiripentol is recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).
Aortic or mitral valvular heart disease (see Section 4.4 Special Warnings and Precautions for Use).
Pulmonary arterial hypertension (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use, or within 14 days of the administration, of monoamine oxidase inhibitors (MAOIs) because of an increased risk of serotonin (5-HT) syndrome (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Valvular heart disease (VHD) and pulmonary arterial hypertension (PAH).

Because of the association between serotonergic drugs with 5-HT_2B receptor agonist activity, including fenfluramine (the active ingredient in Fintepla), and VHD and PAH, as well as reported cases of valvular heart disease and pulmonary arterial hypertension that may have been caused by fenfluramine with past use at higher doses to treat adult obesity, cardiac monitoring using echocardiography is required. Patients with VHD or PAH were excluded from the controlled clinical studies of fenfluramine for the treatment of Dravet syndrome and Lennox-Gastaut syndrome. In clinical trials of up to 3 years in duration, no patient receiving Fintepla developed VHD or PAH. However, VHD and PAH have been reported from post-marketing surveillance of Fintepla used at the doses recommended for patients with Dravet syndrome and Lennox-Gastaut syndrome.
Monitoring.

Prior to starting treatment.

Prior to starting treatment, patients must undergo an echocardiogram to assess the patient for the risk of VHD and PAH to establish a baseline prior to initiating treatment and exclude any pre-existing valvular heart disease or pulmonary hypertension.

Ongoing monitoring.

Echocardiograms should be conducted every 6 months for the first 2 years and then annually. A final echocardiogram should be done 6 months after the last dose of treatment with Fintepla.
Important echocardiogram findings to monitor for include:
valvular abnormality or new abnormality via echocardiogram;
VHD as indicated by mild or greater aortic regurgitation or moderate or greater mitral regurgitation, with additional characteristics of VHD (e.g. valve thickening or restrictive valve motion);
PAH as indicated by elevated right heart/pulmonary artery pressure (PASP > 35 mm Hg).
If echocardiogram findings are suggestive of VHD a follow-up echocardiogram should be considered at an earlier timeframe to evaluate whether the abnormality is persistent. If pathological abnormalities on the echocardiogram are observed, it is recommended to evaluate the benefit versus risk of continuing fenfluramine treatment with the prescriber, caregiver, and cardiologist.
If echocardiogram findings are suggestive of PAH, a repeat echocardiogram should be performed as soon as possible and within 3 months to confirm these findings. If the echocardiogram finding is confirmed and suggestive of an increased probability of PAH it should lead to a benefit-risk evaluation of continuation of Fintepla by the prescriber, carer, and cardiologist. If the echocardiogram finding, after confirmation, suggests a high probability of PAH, it is recommended fenfluramine treatment should be stopped.
If treatment is stopped because of VHD or PAH, appropriate monitoring and follow-up should be provided in accordance with local guidelines for treatment.

Decreased appetite and weight loss.

Fenfluramine can cause decreased appetite and weight loss. An additive effect on decreased appetite can occur when fenfluramine is combined with other anti-epileptic medicines, for example stiripentol. The decrease in weight appears to be dose related. Most subjects resumed weight gain over time while continuing treatment. The patient's weight should be monitored. A benefit risk evaluation should be undertaken prior to commencing treatment with fenfluramine in patients with a history of anorexia nervosa or bulimia nervosa or who are significantly underweight or likely to be adversely impacted by further weight loss.

Fintepla controlled access program.

A controlled access program has been created to 1) prevent off-label use in weight management in obese patients and 2) confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring in patients taking Fintepla.

Somnolence.

Fenfluramine can cause somnolence. Other central nervous system (CNS) depressants, including alcohol, could potentiate the somnolence effect of fenfluramine.

Suicidal behaviour and ideation.

Suicidal behaviour and ideation have been reported in patients treated with anti-epileptic drugs (AEDs) in several indications. A meta-analysis of randomised placebo-controlled trials with anti-epileptic medicines that did not include fenfluramine has shown a small increased risk of suicidal behaviour and ideation. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for fenfluramine. Patients and caregivers of patients should be advised to seek medical advice should any signs of suicidal behaviour and ideation emerge.

Serotonin syndrome.

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with fenfluramine treatment, particularly with concomitant use of other serotonergic agents; with agents that impair metabolism of serotonin such as MAOIs; or with antipsychotics that may affect serotonergic neurotransmitter systems (including SSRIs, SNRIs, tricyclic antidepressants (TCAs), or triptans).
Symptoms of serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
If concomitant treatment with fenfluramine and other serotonergic agents that may affect the serotonergic systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy with Fintepla and/or other serotonergic agents should be considered.

Increased seizure frequency.

As with other anti-epileptic medicines, a clinically relevant increase in seizure frequency may occur during treatment with fenfluramine, which may require adjustment in the dose of fenfluramine and/or concomitant anti-epileptic medicines, or discontinuation of fenfluramine, to optimise the benefit-risk balance.

Glaucoma.

Fenfluramine can cause mydriasis and can precipitate angle closure glaucoma. Discontinue therapy in patients with acute decreases in visual acuity. Consider discontinuation if there is ocular pain and another cause cannot be determined.

Use in hepatic impairment.

Exposure to fenfluramine is increased in subjects with various degrees of hepatic impairment (Child-Pugh class A, B, and C), necessitating a dosage adjustment in these patients (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Exposure to fenfluramine is increased in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²), necessitating a dose adjustment in these patients (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

A study to evaluate the PK and safety of Fintepla in elderly subjects has not been conducted. Clinical studies of Fintepla for the treatment of Dravet syndrome or LGS did not include patients 65 years of age and over.

Paediatric use.

The safety and efficacy of Fintepla in children below the age of 2 years have not been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cyproheptadine.

Cyproheptadine is a potent serotonin receptor antagonist and may therefore decrease the efficacy of fenfluramine. If cyproheptadine is added to treatment with fenfluramine, patients should be monitored for worsening of seizures. If fenfluramine treatment is initiated in a patient taking cyproheptadine, fenfluramine's efficacy may be reduced.

Serotonergic drugs.

Concomitant administration of Fintepla and drugs (e.g. SSRIs, SNRIs, TCAs, MAO inhibitors, trazodone, etc.), over-the-counter medications (e.g. dextromethorphan), or herbal supplements (e.g. St. John's wort) that increase serotonin may increase the risk of serotonin syndrome (see Section 4.4 Special Warnings and Precautions for Use). Concomitant use of Fintepla is contraindicated within 14 days of taking MAOIs. Use Fintepla with caution in patients taking other medications that increase serotonin.

Drug interaction studies.

Effect of steady state stiripentol plus clobazam and/or valproate on fenfluramine.

At steady state in the Phase 3 studies, the co-administration of 0.2 mg/kg BD (0.4 mg/kg/day), maximum 17 mg/day, fenfluramine with a standard AED regimen of stiripentol plus clobazam and/or valproate, resulted in a 130% increase in fenfluramine AUC_0-24 and a 60% decrease in norfenfluramine AUC_0-24, as compared to 0.35 mg/kg twice daily (0.7 mg/kg/day), maximum 26 mg/day, fenfluramine without stiripentol.

Effect of steady state cannabidiol on fenfluramine.

Co-administration of a single 0.35 mg/kg dose of fenfluramine with repeated doses of cannabidiol increased the AUC_0-inf of fenfluramine by 59% and the C_max by 10% and decreased the AUC_0-inf of norfenfluramine by 22% and the C_max by 33%, as compared to fenfluramine administered alone. Co-administration of a single 0.35 mg/kg dose of fenfluramine, with repeated doses of cannabidiol, did not affect the PK of cannabidiol, as compared to cannabidiol alone. No dose adjustment is necessary when fenfluramine is co-administered with cannabidiol.

Effect of fenfluramine on other medicinal products.

Co-administration of a single 0.7 mg/kg dose of fenfluramine, with a single dose of a stiripentol, clobazam, and valproic acid combination, did not affect the PK of stiripentol, nor the PK of clobazam or its N-desmethyl-metabolite norclobazam, nor the PK of valproic acid, as compared to the stiripentol, clobazam, and valproic acid combination alone.

Effect of fenfluramine on CYP2D6 substrates.

In vitro studies indicate that fenfluramine may inhibit CYP2D6. It has been reported that steady-state desipramine concentrations increase approximately 2-fold with concomitant administration of fenfluramine. Co-administration of fenfluramine with CYP2D6 substrates may increase their plasma concentrations.

Effect of fenfluramine on CYP2B6 and CYP3A4 substrates.

In vitro studies indicate that fenfluramine may induce CYP2B6 and may induce intestinal CYP3A4. Co-administration of fenfluramine with CYP2B6 substrates or CYP3A4 substrates may decrease their plasma concentrations.

Effect of fenfluramine on MATE1 substrates.

In vitro studies indicate that norfenfluramine (major and pharmacologically active metabolite) may inhibit the multidrug and toxin extrusion protein 1 (MATE1) transporter at clinically relevant concentrations. Co-administration of fenfluramine with MATE1 substrates may increase their plasma concentrations.

Effect of strong CYP1A2, CYP2B6 or CYP3A inducers.

Coadministration of a single 0.35 mg/kg dose of Fintepla with rifampin (a CYP1A2, CYP2B6, and CYP3A inducer) at steady state (600 mg once daily) in healthy volunteers decreased the AUC_0-inf of fenfluramine by 58% and the C_max by 40% and decreased the AUC_0-inf of norfenfluramine by 50%, and increased the C_max of norfenfluramine by 13%, as compared to Fintepla administered alone. An increase in Fintepla dosage should be considered when coadministered with a strong CYP1A2 or CYP2B6 inducer; however, do not exceed twice the maximum daily dosage of Fintepla (maximum of 52 mg/day).

Effect of strong CYP1A2 or CYP2D6 Inhibitors.

Coadministration of a single 0.35 mg/kg dose of Fintepla with fluvoxamine (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC_0-inf of fenfluramine by 102% and the C_max by 22% and decreased the AUC_0-inf of norfenfluramine by 22% and the C_max by 44%, as compared to Fintepla administered alone.
Coadministration of a single 0.35 mg/kg dose of Fintepla with paroxetine (a strong CYP2D6 inhibitor) at steady state (30 mg once daily) in healthy volunteers increased the AUC_0-inf of fenfluramine by 81% and the C_max by 13% and decreased the AUC_0-inf of norfenfluramine by 13% and the C_max by 29%, as compared to Fintepla administered alone.

Transporters.

Fenfluramine and norfenfluramine were not in vitro substrates of P-glycoprotein, BCRP, OATP1B1, OATP1B3, OATP1A2, OATP2B1, OCT1, OAT1, OAT3, OCT2, MATE1 and MATE2-K.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects of fenfluramine on human fertility up to clinical doses of 104 mg/day were noted. However, animal studies suggest that Fintepla may possibly affect male and female fertility. Oral administration of fenfluramine to male and female rats prior to and throughout mating and continuing in females to implantation resulted in a decrease in fertility and increases in abnormal sperm and epithelial vacuolation of the epididymis at 17.3 mg/kg/day and altered oestrous cyclicity, decreased corpora lutea and implantations, and increased embryolethality at ≥ 6.9 mg/kg/day. These doses were associated with parental toxicity as seen by effects on body weight and lower food consumption. The no-effect doses for adverse effects on fertility and reproductive performance in rats (6.9 and 3 mg/kg/day in males and females, respectively) were associated with subclinical plasma fenfluramine exposures (AUC), and norfenfluramine exposures approximately 4 and 2 times, respectively, those in humans at the maximum recommended human dose (MRHD) of 26 mg/day fenfluramine hydrochloride.
(Category D)
There is limited data in pregnant women who have taken fenfluramine and therefore it is difficult to draw conclusions on the use of fenfluramine in pregnant women.
Fenfluramine and norfenfluramine crossed placenta in pregnant rats and rabbits with fetal levels 2 to 5-fold higher than maternal plasma levels.
Oral administration of fenfluramine to pregnant rats and rabbits during organogenesis resulted in embryofetal death in both species, lower fetal body weights with correlating effects on ossification and marked increases in fetal malformations (cleft palate and malrotated hindlimb) were seen in rats. While these effects occurred with maternotoxicity, a direct effect of fenfluramine on embryofetal death and malformations cannot be dismissed. At the no effect dose for adverse effects on embryofetal development in rats (8.6 mg/kg/day), maternal plasma exposures (AUC) of fenfluramine and norfenfluramine were approximately 5 and 8 times, respectively, those in humans at the MRHD of 26 mg/day. A no adverse effect level was not established in rabbits with exposures (AUC) of fenfluramine and norfenfluramine subclinical at the lowest tested dose.
Oral administration of fenfluramine to female rats throughout gestation and lactation resulted in marked increases in stillborn pups and neonatal offspring deaths at 34.6 mg/kg/day. While maternal body weight gain was lower at this dose, a direct drug-related effect cannot be excluded. At the no effect dose for stillbirths and neonatal survival in rats (8.6 mg/kg/day), maternal plasma exposures (AUC) of fenfluramine and norfenfluramine were approximately 5 and 8 times, respectively, those in humans at the MRHD of 26 mg/day.
There are no or limited amount of data from the use of Fintepla in pregnant women. Studies in animals have shown reproductive toxicity. Fintepla is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is not known whether Fintepla is excreted in human breast milk.
In a lactation study with dexfenfluramine, both dexfenfluramine and nordexfenfluramine were found in milk. Milk concentrations were up to 12-fold plasma concentrations.
In a pre- and postnatal study in rats in which fenfluramine was given orally daily throughout gestation and lactation, delayed growth and reflex development of breast-fed pups was seen at all doses during the preweaning period. At the lowest dose tested in rats (4.3 mg/kg/day), maternal plasma exposures of fenfluramine and norfenfluramine were approximately 2 and 3.5 times, respectively, those in humans at the MRHD.
A risk to the breastfed child cannot be excluded. Breastfeeding is contraindicated whilst on Fintepla.

4.7 Effects on Ability to Drive and Use Machines

Fintepla may cause somnolence and fatigue, which may influence the ability to drive and use machines. Patients should be advised not to drive or operate machinery until they have gained sufficient experience to gauge whether it adversely affects their abilities.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Dravet syndrome. The most commonly reported adverse reactions are decreased appetite, diarrhoea, upper respiratory tract infection, echocardiogram abnormal*, fatigue, pyrexia, blood glucose decreased and somnolence. Table 3 lists the TEAEs that were reported in Fintepla and at an incidence of at least 1% with a higher incidence than placebo in Study 1 and 2, and Study 3.
*Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation.

Lennox-Gastaut syndrome. The most commonly reported adverse reactions are decreased appetite, fatigue, upper respiratory tract infection, somnolence, diarrhoea and vomiting. Table 4 lists the TEAEs that were reported in Fintepla at an incidence of at least 1% with a higher incidence than placebo during the titration and maintenance phases of Study 4.

Description of selected adverse reactions.

Decreased appetite and weight loss.

Fenfluramine can cause decreased appetite and weight loss. In the controlled trials of children and young adults with DS (Study 1 and Study 2) 34.7% of Fintepla-treated patients had an adverse reaction of decreased appetite, compared with 7.6% of patients on placebo. Additional analyses were conducted on body weight changes of ≥ 7% from baseline at one or more visits. In the DS double-blind studies (Study 1, Study 2 and Study 3), more subjects randomized to any Fintepla treatment group compared to placebo had weight decrease of ≥ 7% from baseline (18.9% vs 2.4%) at the end of the double-blind treatment period. In the placebo-controlled study for LGS, approximately 27.8% of patients treated with Fintepla reported decreased appetite compared with 11.5% of patients on placebo. During the placebo-controlled studies, weight loss from baseline of ≥ 7% was recorded in 6.3% of subjects in any Fintepla treatment group, and 0% in the placebo group at the end of double-blind period. The decreases in appetite and weight appeared to be dose related. Most subjects resumed weight gain over time while continuing Fintepla treatment.

Echocardiographic safety assessments of VHD and PAH.

VHD and PAH were evaluated in the placebo-controlled and open-label extension (OLE) studies via echocardiogram for up to 3 years in duration for 341 DS patients and 263 LGS patients. Screening for VHD assessed for mild or greater aortic regurgitation (AR) or moderate or greater mitral regurgitation and assessed for additional characteristics of VHD (e.g. valve thickening or restrictive valve motion). In these clinical studies, 2 patients with LGS exhibited mild AR but neither patient had any cardiac signs or symptoms or evidence of valvular structural changes. Neither patient had VHD. The rates of mild AR are consistent with those seen in the screening period prior to treatment (3 patients in LGS and 1 patient in DS clinical trials).

Lethargy, somnolence and fatigue.

In the controlled trials in patients with DS, lethargy was commonly reported in 9.7% and somnolence and fatigue/asthenia were very commonly reported in 13.0% and 18.1%, respectively in the Fintepla treatment groups combined. In the controlled study with LGS, lethargy was commonly reported in 4% of subjects. Fatigue/asthenia and somnolence were very commonly reported in 18.8% and 13.6% subjects, respectively. The majority of the adverse reactions of lethargy, somnolence, and fatigue were reported in the first 2 weeks of treatment with Fintepla and were mild or moderate in severity. Discontinuation due to lethargy, somnolence, and fatigue was rare and, in most cases, these adverse events resolved or improved with ongoing treatment. In the controlled trials with DS, 0.8% and 1.6% of subjects in the combined Fintepla treatment groups discontinued due to lethargy and somnolence, respectively. In the LGS study, 1.7% subjects in the Fintepla treatment group discontinued due to somnolence.

Seizures.

In the controlled trials in patients with DS seizures were reported less frequently in the Fintepla treated patients (5.1%) and patients on placebo (9.8%). However, seizures assessed as related to the study drug were more commonly reported in Fintepla treated patients (2.8%) than placebo treated patients (1.5%). In the LGS trial, seizures were reported with a similar frequency in the Fintepla treated patients (6.8%) and patients on placebo (6.9%). However, seizures assessed as related to the study drug were more commonly reported in Fintepla treated patients (6.3%) than placebo treated patients (1.1%).

Gastrointestinal disorders.

In the Phase 3 LGS controlled trial in children and young adults, diarrhoea (11.9%) and vomiting (10.8%) were observed more frequently in the combined fenfluramine groups than in the placebo group (4.6% and 5.7%, respectively) during the 14 week titration and maintenance periods. In the LGS controlled trial through the open-label trial, diarrhoea and constipation were observed more frequently in the higher dose groups.
All events reported for diarrhoea and constipation were mild or moderate in severity.

Infections and infestations disorders.

In the Phase 3 LGS controlled trial in children and young adults, upper respiratory tract infection (7.4%) was observed more frequently in the combined fenfluramine groups than in the placebo group (3.4%) during the 14 week titration and maintenance periods.
A higher frequency of infections was reported in the active arm among 2-6-year-old age group in the LGS controlled study. The combined incidences of upper respiratory tract infections (including streptococcal pharyngitis, pharyngotonsillitis, rhinitis, sinusitis and viral upper respiratory tract infection) was most commonly reported in 14.2% of subjects in the fenfluramine treatment group. Bronchitis (2.3%), influenza (2.3%), otitis media (1.1%), and pneumonia (2.3%) were commonly reported. Most of these infections were reported for 2 or more subjects in the fenfluramine treatment group and were not reported in the placebo group. In the LGS controlled trial through the open-label trial, nasopharyngitis, upper respiratory tract infection, gastroenteritis viral, and pneumonia were observed more frequently in the higher dose groups.
All events reported for nasopharyngitis, upper respiratory tract infection, gastroenteritis viral, were mild or moderate in severity. Two cases of severe pneumonia were reported in the 0.4 - < 0.6 mg/kg/day mean daily dose group during the open-label part of the trial.

Post-marketing experience.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported in post-marketing experience. It is not always possible to reliably estimate the frequency of their incidence in the population to be treated.

Nervous system disorders.

Serotonin syndrome.

Psychiatric disorders.

Aggression.

Abnormal behaviour.

Irritability, insomnia.

Cardiac disorders.

VHD.

Respiratory, thoracic and mediastinal disorders.

PAH.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Only limited data have been reported concerning clinical effects and management of overdose of fenfluramine. Agitation, drowsiness, confusion, flushing, tremor (or shivering), fever, sweating, abdominal pain, hyperventilation, and dilated non-reactive pupils were reported at much higher doses of fenfluramine than those included in the clinical trial program.
Vital functions should be monitored closely, and supportive treatment administered in case of convulsions, arrhythmias, or respiratory difficulties.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fenfluramine is a serotonin releasing agent, and thereby stimulates multiple 5 HT receptor sub-types through the release of serotonin. Fenfluramine may reduce seizures by acting as an agonist at specific serotonin receptors in the brain, including the 5 HT_1D, 5 HT_2A, and 5 HT_2C receptors, and also by acting as a positive modulator of the sigma-1 receptor. The precise mode of action of fenfluramine in DS and LGS is not known.

Pharmacodynamics.

Pharmacodynamic interactions with other CNS depressants increase the risk of aggravated CNS depression (see Section 4.4 Special Warnings and Precautions for Use, Somnolence).

Cardiac electrophysiology.

The effect of multiple oral administrations of therapeutic (26 mg/day, i.e. 13 mg BD) and supratherapeutic (103.7 mg/day, i.e. 51.8 mg BD) doses of Fintepla on the heart rate-corrected QT interval using Fridericia's correction formula (QTcF) was studied in a placebo- and positive-controlled study in healthy adult male and female volunteers. The supratherapeutic Fintepla dose of 103.7 mg/day provided a 4-fold higher dose than the maximum recommended daily dose for clinical use. Steady-state systemic exposures (C_max and AUC) of fenfluramine and norfenfluramine were slightly greater than dose proportional over the dose range of 13 to 51.8 mg BD. No clinically relevant changes in the mean QTc (Fridericia) interval from baseline were observed.
Fintepla did not prolong the QT interval following multiple doses up to 4 times the maximum recommended dose.

Clinical trials.

Dravet syndrome. The effectiveness of Fintepla in children and young adults with DS was evaluated in 3 randomised, multicentre, placebo-controlled studies (ZX008-1501, ZX008-1502 and ZX008-1504).
Study 1 (n=119) and Study 3 (n=143) are the prospective, merged analyses of the first 119 patients enrolled (Study 1) and the remaining subsequently enrolled patients (Study 3) from 2 identical double-blind, placebo-controlled studies, ZX008-1501 and ZX008-1502, to assess the efficacy, safety, and pharmacokinetics of Fintepla when used as adjunctive therapy in paediatric and young adult subjects with Dravet syndrome. Study ZX008-1501 and Study ZX008-1502 were conducted in parallel and the design was identical: 3-arm, multicentre, randomised, double-blind, parallel group, placebo-controlled studies consisting of a 6-week baseline period followed by a 2-week titration period and a 12-week maintenance period for a total of 14-weeks treatment. Eligible patients were randomised 1:1:1 to 1 of 2 doses of fenfluramine (0.7 mg/kg/day or 0.2 mg/kg/day, maximum 26 mg/day) or placebo. The mean (standard deviation [SD]) age of patients enrolled was 9.0 (4.7) years in Study 1 and was 9.3 (4.7) years in Study 3, with a range of 2 to 18 years. The majority of patients were ≥ 6 years of age (73.9% in Study 1 and 74.6% in Study 3), male (53.8% in Study 1 and 51.4% in Study 3), and white (82.4% in Study 1 and 74.6% in Study 3). All enrolled patients were inadequately controlled on at least 1 AED, with or without vagal nerve stimulation and/or ketogenic diet. Patients were taking between 1 and 5 AEDs at study entry.
The most frequently used concomitant AEDs (≥ 25% overall) were valproate (59.6% in Study 1 and 57.7% in Study 3), clobazam (58.8% in Study 1 and 56.3% in Study 3), topiramate (25.2% in Study 1 and 26.8% in Study 3) and levetiracetam (28.2% in Study 3). Stiripentol was excluded as a concomitant AED from Study 1 and 3.
The results of primary and selected secondary endpoints from Study 1 and Study 3 are provided in Table 5.
At the end of the T+M period, the median CSF (per 28 days) in Study 1 was 26.0, 14.3, and 5.4 in the placebo, 0.2 mg/kg/day, and 0.7 mg/kg/day groups, respectively and in Study 3 was 12.0, 6.6, and 3.1 in treatment groups, respectively. This resulted in a mean reduction in monthly CS compared with placebo, of 32.4% and 49.9% in the 0.2 mg/kg/day dose groups (p = 0.016 and p < 0.001 respectively) for Study 1 and Study 3 respectively and 62.3% and 64.8% in the 0.7 mg/kg/day dose groups (both p < 0.001) for Study 1 and Study 3 respectively.
Patients achieving ≥ 50% reduction in monthly CS from baseline were considered responders. Patients in the placebo groups of both studies achieved responder status (7.5% and 6.3% in Study 1 and Study 3 respectively). However, statistically significantly higher levels of response were observed in the Fintepla treated groups. In both studies over 40% of patients were responders after 0.2 mg/kg/day (41.0% Study 1 and 45.7% Study 3) and more than 70% of patients achieved at least a 50% reduction after 0.7 mg/kg/day. At least 20.5% of patients achieved ≥ 75% reduction (both dose groups in each study) and more than 7.5% achieved ≥ 100% reduction (both dose groups in Study 1 and the higher dose group in Study 3).
The longest (median) seizure free interval in Study 1 was 9.0, 14.0, and 20.5 days in the placebo, 0.2 mg/kg/day, and 0.7 mg/kg/day groups, respectively and in Study 3 was 10, 18.5 and 30 days in the treatment groups, respectively.

Study 2 (previously known as Study ZX008-1504) (N=87) was a 2-arm, multicentre, randomised, double-blind, parallel group, placebo-controlled study consisting of a 6-week baseline period, a 3-week titration period and a 12-week maintenance period for a total of 15 weeks treatment. Eligible patients were randomised 1:1 to Fintepla 0.4 mg/kg/day (maximum 17 mg/day) or placebo added to their stable standard of care regimen of stiripentol (plus clobazam and/or valproate) and possibly other anti-epileptic medicines. The mean (SD) age of patients enrolled in Study 2 was 9.1 (4.80) years, with a range of 2 to 19 years. The majority of patients were ≥ 6 years of age (72.4%) and the minority < 6 years (27.6%), male (57.5%) and, where reported, white (59.8%). All enrolled subjects were inadequately controlled on at least 1 AED, which included stiripentol, with or without vagal nerve stimulation and/or ketogenic diet. The median baseline convulsive seizure frequency per 28 days was 10.7 and 14.0 in the placebo and fenfluramine 0.4 mg/kg/day groups, respectively.
The results of primary and selected secondary endpoints from Study 2 are provided in Table 6.
At the end of the maintenance period, the median CSF (per 28 days) was 11.4 in the placebo group and 5.2 in the Fintepla group, a 54.0% reduction (p < 0.001).
Responders (achieving ≥ 50% reduction in monthly CS from baseline) were reported in both treatment groups, 4.5% in the placebo group and 53.5% in the Fintepla group. In the Fintepla group 34.9% of patients reported ≥ 75% reduction in monthly CS from baseline and 2.3% reported ≥75% reduction in monthly CS from baseline in the placebo group.
The longest (median) seizure free interval in Study 2 was 13 days in the placebo and 22.0 days in the 0.4 mg/kg/day group.

Adults.

The DS population in Study 1, Study 2 and Study 3 was predominantly paediatric patients, with only 11 adult subjects (3.2%) who were 18-19 years old, and therefore limited efficacy and safety data were obtained in the adult DS population.

Open-label data.

DS patients who participated in Study 1, Study 2 and Study 3 could participate in an open-label extension (OLE) study (Study ZX008-1503). The primary objective of the OLE study was long-term effectiveness and safety of Fintepla, whereby the dose could be titrated to optimise treatment. Data are reported for 330 patients who participated in the OLE study and received Fintepla for up to 3 years (median treatment period: 631 days; range: 7-1086). A total of 23% of subjects discontinued study participation during the OLE treatment period, including 15% due to lack of efficacy and 1% due to adverse events.
Lennox-Gastaut syndrome.

Children and adults.

Study 4 Part 1 (ZX008-1601 Part 1) was a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of 2 fixed doses of Fintepla. The primary analysis cohort (Cohort A) and included subjects from North America, Europe, and Australia.
Study 4 compared a 0.7 mg/kg/day (N=87) and a 0.2 mg/kg/day (N=89) dose (up to a maximum daily dose of 26 mg/kg) of Fintepla with placebo. Patients with a diagnosis of LGS and were inadequately controlled on at least 1 AED, with or without vagal nerve stimulation and/or ketogenic diet. The study had a 4-week baseline period, followed by randomization into a 2-week titration period and a subsequent 12-week maintenance period, where the dose of Fintepla remained stable.
The most frequently used concomitant AEDs (in at least 25% of patients) were clobazam (45.2%), lamotrigine (33.5%), and valproate (55.9%).
The primary efficacy endpoint in Study 4 was the percentage change from baseline in the frequency of drop seizures per 28 days (DSF) during the combined 14-week titration and maintenance periods (i.e. treatment period) in the fenfluramine 0.7 mg/kg/day group compared with the placebo group. Key secondary endpoints included the proportion of patients who achieve a ≥ 50% reduction from baseline in DSF for the fenfluramine 0.7 mg/kg/day group compared with the placebo group. Results are presented in Table 7.

The seizure type with the greatest median percentage change from Baseline in the fenfluramine 0.7 mg/kg/day group relative to the placebo group was generalised tonic-clonic seizures (-45.7% fenfluramine 0.7 mg/kg/day [n=38] versus -3.7% placebo [n=38]).

Open-label data.

LGS patients who completed Study 4 Part 1 could participate in Part 2, a 52-week, flexible-dose OLE study. The primary objective of the OLE was to assess the long-term safety and tolerability of fenfluramine at doses of 0.2 mg/kg/day to 0.7 mg/kg/day. All patients received fenfluramine 0.2 mg/kg/day for 1 month, then the dose was titrated to optimize treatment.
Among the 172 LGS subjects treated with Fintepla for ≥ 12 months, 46.5% had received a mean daily dose of 0.4 to < 0.6 mg/kg/day, 33.7% received a mean daily dose ≥ 0.6 mg/kg/day, 19.8% received a mean daily dose of > 0 to < 0.4 mg/kg/day.
The most common reason for discontinuation was lack of efficacy (55 [22.3%]), adverse event (13 [5.3%]), and withdrawal by subject (13 [5.3%]).

5.2 Pharmacokinetic Properties

The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy adult subjects, in paediatric patients with DS, and in paediatric and adult patients with LGS.

Absorption.

Fenfluramine has a time to maximum plasma concentration (T_max) in the range of 3 to 5 hours at steady state. The absolute bioavailability of fenfluramine is approximately 68%-83%. There was no effect of food on the pharmacokinetics of fenfluramine or norfenfluramine.
The plasma half-lives of fenfluramine and norfenfluramine indicate that approximately 94% of steady state would be reached in approximately 4 days for fenfluramine and 5 days for norfenfluramine (4 half-lives).

Distribution.

Fenfluramine is 50% bound to human plasma proteins in vitro and binding is independent of fenfluramine concentrations up to 100 nanogram/mL. The geometric mean (CV%) volume of distribution (Vz/F) of fenfluramine is 11.9 L/kg (16.5%) following oral administration of fenfluramine in healthy subjects.

Metabolism.

Over 75% of fenfluramine is metabolised to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. Other CYP enzymes CYP2C9, CYP2C19, and CYP3A4/5 are involved to a minor extent. Norfenfluramine is then deaminated and oxidised to form additional metabolites. The extent to which these additional metabolites are present in plasma and urine is unknown. The involvement of enzymes other than CYPs (e.g. UDP-glucuronosyltransferases) in the metabolism of norfenfluramine is unknown.

Excretion.

Most of an orally administered dose of fenfluramine (> 90%) is excreted in the urine mainly as metabolites; less than 5% is found in faeces. The geometric mean (CV%) clearance (CL/F) of fenfluramine is 6.9 L/h (29%) and the half-life is 20 hours following oral administration of fenfluramine in healthy subjects. The elimination half-life of norfenfluramine is 30 h.

Special populations.

Genetic polymorphisms.

No impact of genotype in CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 on fenfluramine or norfenfluramine PK was observed.

Renal impairment.

The effects of renal impairment on the PK of a single oral dose of Fintepla 0.35 mg/kg has been evaluated in 8 subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m²) and 8 healthy subjects as controls. The geometric mean value of total exposure (AUC_0-inf) of fenfluramine was increased by 88% in the severe renal impairment group compared with healthy matched controls, with a smaller increase (20%) in C_max in subjects with severe renal impairment. Increase in norfenfluramine AUC in subjects with severe renal impairment was small (approximately 13%), with a decrease in C_max (21%). Fintepla has not been studied in patients with end-stage renal disease. It is not known if fenfluramine or its active metabolite, norfenfluramine, are dialyzable.

Hepatic impairment.

The PK and safety of a single oral dose of Fintepla 0.35 mg/kg has been evaluated in adult subjects with various degrees of hepatic impairment (7-8 per group) and matching healthy subjects as controls. The geometric mean AUC_0-t, AUC_0-inf, and C_max of fenfluramine were 95%, 98%, and 19% higher, respectively, in the mild hepatic impairment group; 113%, 113%, and 16% higher, respectively, in the moderate hepatic impairment group; and 185%, 177%, and 29% higher, respectively, in the severe hepatic impairment group, compared with the healthy controls. Fintepla is titrated gradually based on tolerability and response (Section 4.2).

Racial and ethnic groups.

The evaluation in subjects with DS and LGS was limited by the small sample size of non-white subjects such that no conclusion on the effect of race on the PK of Fintepla can be made. The PK profile of fenfluramine and norfenfluramine following a single oral dose of Fintepla 0.35 mg/kg alone and in combination with multiple doses of stiripentol and clobazam has been studied in healthy adult Japanese and Caucasian subjects. Fenfluramine and norfenfluramine exposures were similar between Caucasian and Japanese subjects with and without the combination of stiripentol and clobazam.

Gender.

The PK of fenfluramine and norfenfluramine were consistent between males and females.

Body weight.

Drug clearance and PK exposure of fenfluramine and norfenfluramine are consistent across a broad range of BMI (12.3 to 35 kg/m²).

5.3 Preclinical Safety Data

Genotoxicity.

Fenfluramine was not genotoxic when tested in the in vitro bacterial reverse mutation test (Ames) and an in vivo micronucleus and comet assay in rats.

Carcinogenicity.

Once daily oral administration of fenfluramine to Tg.rasH2 mice (up to 51.8 mg/kg/day) for 26 weeks and to male and female rats (up to 6.9 mg/kg/day) for up to 89 and 97 weeks, respectively, resulted in no evidence of drug-induced tumours in either species. In rats, plasma exposures (AUC) of fenfluramine and norfenfluramine (the major metabolite) at the highest dose tested were approximately 5 and 11 times, respectively, those in humans at the MRHD of 26 mg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients are: sodium ethyl hydroxybenzoate: 0.23 mg/mL, sodium methyl hydroxybenzoate: 2.3 mg/mL, sucralose, hyetellose, monosodium phosphate, disodium phosphates, cherry flavour SN932130 (proprietary ingredient ID: 147573), potassium citrate, citric acid monohydrate, water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

4 years.
This product should be used within 3 months of first opening the bottle.

6.4 Special Precautions for Storage

Store below 30°C. Do not refrigerate or freeze. Store the bottle and syringe together.

6.5 Nature and Contents of Container

Fintepla is presented in a white High-Density Polyethylene (HDPE) bottle with a child-resistant, tamper-evident cap packaged in a carton, a Low-Density Polyethylene (LDPE) press-in bottle adaptor, and 4 Polypropylene (PP)/HDPE oral syringes. The oral syringe included in the pack should be used to administer the prescribed dose.

Presentations.

Bottle containing 60 mL oral solution, a bottle adaptor, 2x 3 mL oral syringes with 0.1 mL graduations, and 2x 6 mL syringes with 0.2 mL graduations.
Bottle containing 120 mL oral solution, a bottle adaptor, 2x 3 mL oral syringes with 0.1 mL graduations, and 2x 6 mL syringes with 0.2 mL graduations.
Bottle containing 250 mL oral solution, a bottle adaptor, 2x 3 mL oral syringes with 0.1 mL graduations, and 2x 6 mL syringes with 0.2 mL graduations.
Bottle containing 360 mL oral solution, a bottle adaptor, 2x 3 mL oral syringes with 0.1 mL graduations, and 2x 6 mL syringes with 0.2 mL graduations.
Not all pack sizes may be marketed.

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 name: fenfluramine hydrochloride.

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Fintepla

Fenfluramine

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