Consumer medicine information

Fycompa

Perampanel

BRAND INFORMATION

Brand name

Fycompa Tablets

Active ingredient

Perampanel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fycompa.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Fycompa.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

WHAT FYCOMPA IS USED FOR

Fycompa is used to treat certain forms of epilepsy in people aged 12 years and older.

  • It is used to treat fits that affect one part of your brain (called a “partial seizure”). These partial seizures may or may not then be followed by a fit affecting all of your brain (called a “secondary generalisation”).
  • It is also used to treat certain fits that affect all of your brain from the start and cause convulsions (called “primary generalised tonic-clonc seizures).

It contains the active ingredient perampanel. Perampanel belongs to a group of medicines called anti epileptics.

It works by reducing the number of fits that you have.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

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

Fycompa has some potential for abuse and misuse and should be used with caution in patients with a history of drug abuse.

There is not enough information to know whether Fycompa would be addictive if abused.

Fycompa should be used with caution in patients aged 65 years or older due to the high rates of dizziness and falls in those patients.

Fycompa should be used with caution in patients with a history of severe mental conditions or aggression.

There is not enough information to recommend the use of this medicine for children under the age of 12 years.

BEFORE YOU TAKE FYCOMPA

When you must not take it

Do not take this medicine if you have an allergy to:

  • Perampanel, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description

Fycompa contains lactose.

If you have been told by your doctor that you have intolerance to some sugars, tell your doctor before taking it.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not give this medicine to a child under the age of 12 years.

Safety and effectiveness in children younger than 12 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver problems
  • moderate or severe kidney problems
  • history of alcoholism, drug dependence or other psychiatric illness

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Fycompa is not recommended in pregnancy.

You must use a reliable method of contraception to avoid becoming pregnant while you are being treated with Fycompa.

You should continue doing this for one month after stopping treatment.

Tell your doctor if you are taking hormonal contraceptives.

Fycompa may make certain hormonal contraceptives such as levonorgestrel less effective.

You should use other forms of safe and effective contraception (such as a condom or coil) when taking Fycompa. You should also do this for one month after stopping treatment. Discuss with your doctor what may be appropriate contraception for you.

It is not known whether the ingredients of Fycompa can pass into breast milk.

The doctor will weigh up the benefit and risks to your baby of taking Fycompa while you are breastfeeding.

If you have not told your doctor about any of the above, tell him/her before you start taking Fycompa.

Taking other medicines

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

Some medicines and Fycompa may interfere with each other. These include:

  • Carbamazepine, phenytoin, oxcarbazepine
  • Rifampicin,
  • Hypericum (St. John’s wort),
  • Felbamate
  • Ketoconazole
  • Oral contraceptives

These medicines may be affected by Fycompa or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE FYCOMPA

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

The usual starting dose for this medicine is 2 mg once a day before you go to bed.

Your doctor may increase the dose in 2 mg steps to a maintenance dose between 4 and 12 mg depending on your response.

If you have mild or moderate liver problems, your dose should not be more than 8 mg each day and your dose increases should be at least 2 weeks apart.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Fycompa may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

You can take Fycompa with or without food.

Do not chew, crush or split the tablet. The tablets cannot be split accurately as there is no break line. To ensure you get the entire dose, the tablets should be swallowed whole without chewing or crushing.

When to take Fycompa

Take your medicine at about the same time each day before going to bed.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take Fycompa

Continue taking your medicine for as long as your doctor tells you.

Do not stop unless your doctor advises you to.

Your doctor may reduce your dose slowly to avoid your fits (seizures) coming back or getting worse.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

If you forget to take it

Wait until your next dose, and then continue to take it as you would normally.

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

This may increase the chance of you getting an unwanted side effect.

If you have missed less than 7 days of treatment with Fycompa, continue taking your daily tablet as originally instructed by your doctor.

If you have missed more than 7 days of treatment with Fycompa, talk to your doctor immediately.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Fycompa. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

WHILE YOU ARE TAKING FYCOMPA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Fycompa.

Tell any other doctors, dentists and pharmacists who treat you that you are taking Fycompa.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking Fycompa.

It may affect other medicines used during surgery.

If you become pregnant while taking Fycompa, tell your doctor immediately.

Do not stop treatment without first discussing it with your doctor.

If you are about to have any blood tests, tell your doctor that you are taking Fycompa.

It may interfere with the results of some tests.

Keep all of your doctor’s appointments so that your progress can be checked.

Things you must not do

Do not take Fycompa to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Serious or life-threatening psychiatric and behavioural adverse reactions including aggression, hostility, irritability, anger, suicidal ideation and homicidal ideation and threats have been reported in patients taking Fycompa.

Patients and caregivers should contact a healthcare provider immediately if any of these reactions or changes in mood, behaviour, or personality that are not typical for the patient are seen while they are taking Fycompa or after stopping Fycompa.

If changes in behaviour or personality are seen notify your doctor immediately. They may reduce your dose of Fycompa or stop treatment with Fycompa.

Patients starting Fycompa should be carefully observed especially when starting treatment and if the dose is increased.

Do not drive or operating machinery until you know how Fycompa affects you.

You must talk to your doctor about the effect of your epilepsy on driving and using machines.

Fycompa may make you feel dizzy or sleepy, particularly at the beginning of treatment. If this happens to you, do not drive or use any tools or machines.

Fycompa may make you more likely to fall over, particularly if you are an older person; this might be due to your illness.

Avoid alcohol while taking Fycompa as it may make these effects worse.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Fycompa

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

A small number of people being treated with anti-epileptics have had thoughts of harming or killing themselves. If at any time you have these thoughts, contact your doctor or go to accident & emergency straight away.

If you get a skin rash, or fever, and/or enlarged lymph nodes, these could be signs of an allergic reaction. See your doctor immediately as very occasionally this may become serious.

Very common (may affect more than 1 user in 10) side effects are:

  • feeling dizzy
  • feeling sleepy (drowsiness or somnolence).

Common (may affect more than 1 user in 100) side effects are:

  • increased or decreased appetite, weight gain
  • feeling aggressive, angry, irritable, anxious or confused
  • difficulty with walking or other balance problems (ataxia, gait disturbance, balance disorder)
  • slow speech (dysarthria)
  • blurred vision or double vision (diplopia)
  • spinning sensation (vertigo)
  • feeling sick (nausea)
  • back pain
  • feeling very tired (fatigue)
  • falling down.

Not known (the frequency of this side effect cannot be estimated from the available data) are:

  • thoughts about harming yourself or ending your own life (suicidal thoughts), tried to end your own life (attempted suicide)
  • skin rash
  • fever
  • enlarged lymph nodes

If you get any side effects, talk to your doctor or pharmacist.

This includes any possible side effects not listed in this leaflet.

Ask your doctor or pharmacist to answer any questions you may have.

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

Other side effects not listed above may also occur in some people.

AFTER TAKING FYCOMPA

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store Fycompa or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Fycompa 2 mg film coated tablet is an orange, round, biconvex film-coated tablet, engraved with E275 on one side and 2 on other side. Available in packs of 7.

Fycompa 4 mg film coated tablet is a red, round, biconvex film-coated tablet, engraved with E277 on one side and 4 on other side. Available in packs of 28.

Fycompa 6 mg film coated tablet is a pink, round, biconvex film-coated tablet, engraved with E294 on one side and 6 on other side. Available in packs of 28.

Fycompa 8 mg film coated tablet is a purple, round, biconvex film-coated tablet, engraved with E295 on one side and 8 on other side. Available in packs of 28.

Fycompa 10 mg film coated tablet is a green, round, biconvex film-coated tablet, engraved with E296 on one side and 10 on other side. Available in packs of 28.

Fycompa 12 mg film coated tablet is a blue, round, biconvex film-coated tablet, engraved with E297 on one side and 12 on other side. Available in packs of 28.

Ingredients

Active ingredient:

  • Perampanel (as hemisesquihydrate)

Excipient Ingredients:

  • lactose,
  • hypromellose,
  • povidone,
  • purified talc,
  • magnesium stearate,
  • microcrystalline cellulose (6 mg, 8 mg, 10 mg and 12 mg only)
  • macrogol 8000,
  • titanium dioxide,
  • iron oxide yellow (2 mg, 10 mg),
  • iron oxide red (2mg, 4 mg, 6 mg, and 8 mg only),
  • iron oxide black (8 mg only) and
  • Indigo carmine aluminium lake (10 mg & 12 mg only).

This medicine does not contain gluten, tartrazine or any other azo dyes.

BRAND INFORMATION

Brand name

Fycompa Tablets

Active ingredient

Perampanel

Schedule

S4

 

1 Name of Medicine

Perampanel (as hemisesquihydrate).

6.7 Physicochemical Properties

Perampanel hemisesquihydrate is a crystalline solid and is obtained as a white to yellowish white powder. The pKa value of perampanel hemisesquihydrate is 3.24 and the partition coefficient is 2.86 at 25°C. Perampanel hemisesquihydrate is freely soluble in N-methyl-2-pyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether and practically insoluble in heptane and water. In aqueous solutions, perampanel hemisesquihydrate is very slightly soluble in 0.1 M HCl at 37°C and practically insoluble in pH 2-11 Britton-Robinson buffers at 25°C, pH 4.5 USP acetate buffer and pH 7.5 USP phosphate buffer at 37°C.

Chemical structure.

The chemical name of perampanel hemisesquihydrate is 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1, 2-dihydropyridin-3-yl) benzonitrile hydrate (4:3). It has a molecular weight of 362.9.
The empirical formula of perampanel hemisesquihydrate is C23H15N3O.3/4 H2O.
Perampanel hemisesquihydrate has the following structural formula:

CAS number.

CAS Number: 380917-97-5.

2 Qualitative and Quantitative Composition

Fycompa 2 mg film-coated tablets.

Each 2 mg Fycompa film-coated tablet contains 2 mg of perampanel (as hemisesquihydrate).

Excipient with known effect.

Each 2 mg tablet contains 78.5 mg of lactose (as monohydrate).

Fycompa 4 mg film-coated tablets.

Each 4 mg Fycompa film-coated tablet contains 4 mg of perampanel (as hemisesquihydrate).

Excipient with known effect.

Each 4 mg tablet contains 157 mg of lactose (as monohydrate).

Fycompa 6 mg film-coated tablets.

Each 6 mg Fycompa film-coated tablet contains 6 mg of perampanel (as hemisesquihydrate).

Excipient with known effect.

Each 6 mg tablet contains 151 mg of lactose (as monohydrate).

Fycompa 8 mg film-coated tablets.

Each 8 mg Fycompa film-coated tablet contains 8 mg of perampanel (as hemisesquihydrate).

Excipient with known effect.

Each 8 mg tablet contains 149 mg of lactose (as monohydrate).

Fycompa 10 mg film-coated tablets.

Each 10 mg Fycompa film-coated tablet contains 10 mg of perampanel (as hemisesquihydrate).

Excipient with known effect.

Each 10 mg tablet contains 147 mg of lactose (as monohydrate).

Fycompa 12 mg film-coated tablets.

Each 12 mg Fycompa film-coated tablet contains 12 mg of perampanel (as hemisesquihydrate).

Excipient with known effect.

Each 12 mg tablet contains 145 mg of lactose (as monohydrate).

All film-coated tablets.

Excipients with known effect.

Sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablet.
Fycompa 2 mg film-coated tablets are orange, round, biconvex tablets, engraved with E275 on one side and '2' on other side.
Fycompa 4 mg film-coated tablets are red, round, biconvex tablets, engraved with E277 on one side and '4' on other side.
Fycompa 6 mg film-coated tablets are pink, round, biconvex tablets, engraved with E294 on one side and '6' on other side.
Fycompa 8 mg film-coated tablets are purple, round, biconvex tablets, engraved with E295 on one side and '8' on other side.
Fycompa 10 mg film-coated tablets are green, round, biconvex tablets, engraved with E296 on one side and '10' on other side.
Fycompa 12 mg film-coated tablets are blue, round, biconvex tablets, engraved with E297 on one side and '12' on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Perampanel is a first in class selective, non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal overexcitation. Several perampanel metabolites are also AMPA antagonists, although weaker than the parent compound. In vitro, perampanel inhibited AMPA-induced (but not NMDA-induced) increase in intracellular calcium in rat cortical neurons. In vivo, perampanel displayed anticonvulsant activity in several animal models.
The precise mechanism by which perampanel exerts its antiepileptic effects in humans remains to be fully elucidated.

Pharmacodynamic effects.

Pharmacokinetic-pharmacodynamic (efficacy) analyses have shown that within the recommended dose range there is a positive correlation between serum levels of Fycompa and seizure frequency for partial-onset seizures and primary generalised tonic-clonic seizures.

Psychomotor performance.

Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in healthy volunteers in a dose-related manner. The effects of perampanel on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. Psychomotor performance testing returned to baseline within 2 weeks of cessation of perampanel dosing.

Cognitive function.

In a healthy volunteer study to assess the effects of perampanel on alertness, and memory using a standard battery of assessments, no effects of perampanel were found following single and multiple doses of perampanel up to 12 mg/day.

Cardiac electrophysiology.

Perampanel did not prolong the QTc interval when administered in daily doses up to 12 mg/day, and did not have a dose related or clinically important effect on QRS duration.

Clinical trials.

Partial-onset seizures.

The efficacy of Fycompa in partial-onset seizures was established in three adjunctive therapy 19 week, randomised, double-blind, placebo-controlled, multicentre trials in adult and adolescent patients. Subjects had partial-onset seizures with or without secondary generalisation and were not adequately controlled with one to three concomitant AEDs. During a 6-week baseline period, subjects were required to have more than five seizures with no seizure-free period exceeding 25 days. In these three trials, subjects had a mean duration of epilepsy of approximately 21.06 years. Between 85.3% and 89.1% of patients were taking two to three concomitant AEDs with or without concurrent vagal nerve stimulation.
Two studies (studies 304 and 305) compared doses of Fycompa 8 and 12 mg/day with placebo and the third study (study 306) compared doses of Fycompa 2, 4 and 8 mg/day with placebo. In all three trials, following a 6-week Baseline Phase to establish baseline seizure frequency prior to randomisation, subjects were randomised and titrated to the randomised dose. During the Titration Phase in all three trials, treatment was initiated at 2 mg/day and increased in weekly increments of 2 mg/day to the target dose. Subjects experiencing intolerable adverse events could remain on the same dose or have their dose decreased to the previously tolerated dose. In all three trials, the Titration Phase was followed by a Maintenance Phase that lasted 13 weeks, during which patients were to remain on a stable dose of Fycompa.
The pooled 50% responder rates were placebo 19%, 4 mg 29%, 8 mg 35% and 12 mg 35%. A statistically significant effect on the reduction in 28 day seizure frequency (Baseline to Treatment Phase) as compared to the placebo group was observed with Fycompa treatment at doses of 4 mg/day (Study 306), 8 mg/day (Studies 304, 305 and 306), and 12 mg/day (Studies 304 and 305). The 50% responder rates in the 4 mg, 8 mg and 12 mg groups were respectively 23.0%, 31.5%, and 30.0% in combination with enzyme inducing anti-epileptic medicinal products and were 33.3%, 46.5% and 50.0% when Fycompa was given in combination with non-enzyme inducing anti-epileptic medicinal products. These studies show that once-daily administration of Fycompa at doses of 4 mg to 12 mg was significantly more efficacious than placebo as adjunctive treatment in this population. See Table 4.
Therefore the number needed to treat (NNT) with any dose of Fycompa for 4 mg to 12 mg to achieve a 50% reduction in seizure frequency was 6.25 to 10.9.
Data from placebo-controlled studies demonstrate that improvement in seizure control is observed with a once-daily Fycompa dose of 4 mg and this benefit is enhanced as the dose is increased to 8 mg/day. No efficacy benefit was observed at the dose of 12 mg as compared to the dose of 8 mg in the overall population. Benefit at the dose of 12 mg was observed in some patients who tolerate the dose of 8 mg and when the clinical response to that dose was insufficient. A clinically meaningful reduction in seizure frequency relative to placebo was achieved as early as the second week of dosing when patients reached a daily dose of 4 mg.

Open label extension study for partial onset seizures.

Ninety-seven percent of the patients who completed the randomised trials were enrolled in the open label extension study (n = 1186). Patients from the randomised trial were converted to perampanel over 16 weeks followed by a long-term maintenance period (≥ 1 year). The mean average daily dose was 10.05 mg.

Elderly patients in clinical trials for partial onset seizures.

In these studies, 31 patients aged 65 and over received perampanel. Due to high rates of dizziness and falls in these patients, Fycompa should be used with caution in the elderly.

Primary generalised tonic-clonic seizures.

Fycompa as adjunctive therapy in patients 12 years of age and older with idiopathic generalised epilepsy experiencing primary generalised tonic-clonic seizures was established in a multicentre, randomised, double-blind, placebo-controlled study (Study 332). Eligible patients on a stable dose of 1 to 3 AEDs experiencing at least 3 primary generalised tonic-clonic seizures during the 8-week baseline period were randomised to either Fycompa or placebo. The population included 164 patients (Fycompa N = 82, placebo N = 82). Patients were titrated over four weeks to a target dose of 8 mg per day or the highest tolerated dose and treated for an additional 13 weeks on the last dose level achieved at the end of the titration period. The total treatment period was 17 weeks. Study drug was given once per day.
The primary endpoint was the percent change from baseline in primary generalised tonic-clonic seizure frequency per 28 days during the treatment period (titration + maintenance) as compared to the baseline period. The median percent change in primary generalised tonic-clonic seizure frequency per 28 days during the Titration and Maintenance Periods (combined) relative to Prerandomization was greater with Fycompa (-76.5%) than with placebo (-38.4%), P < 0.0001. The 50% primary generalised tonic-clonic seizures responder rate during the Maintenance Period was significantly higher in the Fycompa group (64.2%) than in the placebo group (39.5%), P = 0.0019. The 50% responder rates were 58.0% for the Fycompa group and 35.8% for the placebo group (P = 0.0059) when discontinued patients were considered non-responders. The 50% responder rate was 22.2% when Fycompa was used in combination with enzyme inducing anti-epileptic medicinal products and 69.4% when Fycompa was given in combination with non-enzyme inducing anti-epileptic medicinal products. The number of Fycompa subjects taking enzyme inducing anti-epileptic medicinal products was small (n = 9).
During the 3 month maintenance period, 30.9% of the patients on Fycompa in the clinical studies became free of PGTC seizures compared with 12.3% on placebo. Freedom from all seizures was achieved in 23.5% of patients on Fycompa compared to 4.9% of patients on placebo. There are no data regarding the effects of withdrawal of concomitant anti-epileptic medicinal products to achieve monotherapy with Fycompa. The efficacy of Fycompa in the treatment of absence and myoclonic seizures has not been demonstrated.

Paediatric population.

The three pivotal double-blind placebo-controlled phase 3 studies included 143 adolescents between the ages of 12 and 18. The results in these adolescents were similar to those seen in the adult population.
Study 332 included 22 adolescents between the ages of 12 and 18. The results in these adolescents were similar to those seen in the adult population.
The safety and efficacy of Fycompa in children below 12 years of age have not been established yet. No data are available.

5.2 Pharmacokinetic Properties

The pharmacokinetics of perampanel have been studied in healthy adult subjects (age range 18 to 79) and subjects with hepatic impairment.

Absorption.

Perampanel is around 100% bioavailable. Median Tmax range from 0.5 to 2.5 hours under fasted conditions.
Perampanel is readily absorbed after oral administration with no evidence of marked first pass metabolism. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food, peak plasma concentrations are reduced and delayed by 2 hours compared with dosing in a fasted state.

Distribution.

Data from in vitro studies indicate that perampanel is approximately 95% bound to plasma proteins.
In vitro studies show that perampanel is not a substrate or significant inhibitor of organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT) 1, 2, 3, and 4, organic cation transporters (OCT) 1, 2, and 3, and the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein (BCRP).

Metabolism.

Perampanel is extensively metabolised via primary oxidation and sequential glucuronidation. Primary oxidative metabolism is mediated by CYP3A based on results of in vitro studies using recombinant human CYPs and human liver microsomes. However, the metabolism has not been completely elucidated and other pathways cannot be excluded.
Following administration of radiolabeled perampanel, only trace amounts of perampanel metabolites were observed in plasma.

Excretion.

Following administration of a radiolabeled perampanel dose to 8 healthy elderly subjects, 30% of recovered radioactivity was found in the urine and 70% in the faeces. In urine and faeces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. In a population pharmacokinetic analysis of pooled data from 19 Phase 1 studies, the average t1/2 of perampanel was 105 hours. When dosed in combination with the strong CYP3A inducer carbamazepine, the average t1/2 was 25 hours.

Linearity/non-linearity.

The pharmacokinetics of perampanel are linear within the dose range 2 to 12 mg daily.

Special populations.

Hepatic impairment.

The pharmacokinetics of perampanel following a single 1 mg dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 healthy, demographically matched subjects. The mean apparent clearance of unbound perampanel in mildly impaired subjects was 188 mL/min vs. 338 mL/min in matched controls, and in moderately impaired subjects was 120 mL/min vs. 392 mL/min in matched controls. The t1/2 was longer in mildly impaired (306 h vs. 125 h) and moderately impaired (295 h vs. 139 h) subjects compared to matched healthy subjects.

Renal impairment.

The pharmacokinetics of perampanel have not been formally evaluated in patients with renal impairment. Perampanel is eliminated almost exclusively by metabolism followed by rapid excretion of metabolites; only trace amounts of perampanel metabolites are observed in plasma. Apparent clearance of perampanel was decreased by 27% in patients with mild renal impairment (creatinine clearance 50-80 mL/min) compared to patients with normal renal function (creatinine clearance > 80 mL/min), with corresponding 37% increase in AUC. Considering the substantial overlap in the exposure between normal and mildly impaired patients, no dosage adjustment is necessary for patients with mild renal impairment. Fycompa has not been studied in patients with severe renal impairment and patients undergoing haemodialysis (see Section 4.2 Dose and Method of Administration).

Gender.

In a population pharmacokinetic analysis of patients with partial onset seizures receiving perampanel up to 12 mg/day and patients with primary generalised tonic-clonic seizures receiving perampanel up to 8 mg/day in placebo-controlled clinical trials, perampanel clearance in females (0.54 L/h) was 18% lower than in males (0.66 L/h).

Elderly (65 years of age and above).

Perampanel was given to 31 patients with epilepsy aged 65 years or older. While large differences in the pharmacokinetics of perampanel were not apparent, due to the adverse events experienced by these patients perampanel should be used with caution in the elderly.

Paediatric population.

In a population pharmacokinetic analysis of the adolescent patients in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.

5.3 Preclinical Safety Data

Carcinogenicity.

Perampanel was administered orally to mice (1, 3, 10 or 30 mg/kg/day) and rats (10, 30 or 100 mg/kg/day in males; 3, 10 or 30 mg/kg/day in females) for up to 104 weeks. There was no evidence of treatment-related tumours in either species. Estimated exposures (plasma AUC) to perampanel at the highest doses tested were less than anticipated clinical exposure at the MRHD of 12 mg/day.

Genotoxicity.

Perampanel was negative in the bacterial reverse mutation and mouse lymphoma tk assays in vitro, and in the micronucleus test in rats in vivo.

Juvenile animal data.

Oral administration of perampanel to juvenile rats for 12 weeks from postnatal day 7 of life at doses of 1, 3 and 3/10/30 mg/kg/day (high-dose escalations after 4 and 8 weeks) was associated with CNS clinical signs and decreased hindlimb grip strength/foot splay (all doses), reduced growth and neurobehavioural impairment (mid/high doses), and delayed sexual maturation (high dose). A no-effect dose was not determined. Oral administration of perampanel to juvenile dogs for 33 weeks from postnatal day 42 of life at doses of 1, 5 and 5/10 mg/kg/day (high dose escalation after 2 weeks) was associated with CNS clinical signs at all dose. The CNS clinical signs were due to exaggerated pharmacologic effects of perampanel.

4 Clinical Particulars

4.1 Therapeutic Indications

Fycompa is indicated for the adjunctive treatment of partial onset seizures with or without secondarily generalised seizures in adult and adolescent patients from 12 years of age with epilepsy.
Fycompa is indicated for the adjunctive treatment of primary generalised tonic-clonic seizures in adult and adolescent patients from 12 years of age with idiopathic generalised epilepsy.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Paediatric use.

There is no experience with Fycompa in children < 12 years. Fycompa is not recommended children aged less than 12 years.

Use in the elderly.

Twenty patients aged 65 and over received perampanel in the double blind phase 3 epilepsy studies. Dizziness and falls were particularly frequent in these patients and the incidence of falls was increased in elderly patients taking perampanel (see Section 4.4 Special Warnings and Precautions for Use, Falls). Dizziness occurred in 55.6% of elderly patients given the 8 mg dose and falls occurred in 57.1% given the 12 mg dose. Fycompa should be used with caution in the elderly.

Suicidal ideation and behaviour.

Antiepileptic drugs (AED), including Fycompa, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED-treatment patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in the placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analyses. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other indications, but the absolute risk differences were similar for epilepsy and psychiatric conditions.
Anyone considering prescribing Fycompa or any other AED must balance the risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self-harm. Behaviours of concern should be reported immediately to the treating doctor.

Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Fycompa. DRESS may be fatal or life-threatening. If signs or symptoms of DRESS are present, the patient should be evaluated immediately and Fycompa should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Nervous system disorders.

Dizziness and gait disturbance.

Fycompa caused dose-related increases in events related to dizziness and disturbance in gait or coordination (see Section 4.8 Adverse Effects (Undesirable Effects)). In the controlled Phase 3 epilepsy clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomised to receive Fycompa at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were reported in 12% and 16% of patients randomised to receive Fycompa at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients.
These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of Fycompa-treated subjects compared to 1% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.

Somnolence and fatigue.

Fycompa caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy).
In the controlled Phase 3 epilepsy clinical trials, 16% and 18% of patients randomised to receive Fycompa at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12% and 15% of patients randomised to receive Fycompa at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of Fycompa-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.

Falls.

An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with Fycompa (with and without concurrent seizures). In the controlled Phase 3 epilepsy clinical trials, falls were reported in 5% and 10% of patients randomised to receive Fycompa at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in Fycompa-treated patients than placebo-treated patients.
Twenty patients aged 65 and over years received perampanel in the double blind phase 3 epilepsy studies, Dizziness and falls were particularly frequent in these patients. Dizziness occurred in 55.6% of elderly patients given the 8 mg dose and 42.9% given the 12 mg dose. Falls occurred in 11.1% of elderly patients given the 8 mg dose and 57.1% given the 12 mg dose. Fycompa should be used with caution in the elderly.

End of treatment.

It is recommended that discontinuation be undertaken gradually to minimise the potential for rebound seizures (see Section 4.2 Dose and Method of Administration). However, due to its long half-life and subsequent slow decline in plasma concentrations, Fycompa can be discontinued abruptly if absolutely needed.

Serious psychiatric and behavioural reactions.

Serious or life-threatening psychiatric and behavioural adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking Fycompa. Aggression was observed more frequently in adolescents than adults. Monitor patients for these reactions as well as for changes in mood, behaviour, or personality that are not typical for the patient, particularly during the titration period and at higher doses. Fycompa should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening.
In controlled Phase 3 epilepsy clinical trials, hostility and aggression related adverse reactions occurred in 12% and 20% of patients randomised to receive Fycompa at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were dose related and generally appeared within the first 6 weeks of treatment although new events continued to be observed through more than 37 weeks. Fycompa-treated patients experienced more hostility and aggression related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients.
In general, in the placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more frequently in patients being treated with Fycompa than in patients taking placebo. These events included irritability, aggression, anger and anxiety which occurred in 2% or greater of Fycompa treated patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with Fycompa treatment and more common than with placebo, included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening, Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 Fycompa treated patients in controlled and open label studies, including non-epilepsy studies.
In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history, prior aggressive behaviour, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and Fycompa significantly worsened mood and increased anger. Patients taking Fycompa should avoid the use of alcohol.
In healthy volunteers taking Fycompa, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes and disorientation confusional state.
In the non-epilepsy trials, psychiatric events that occurred in Fycompa-treated subjects more often than placebo-treated subjects included disorientation, delusion and paranoia.
Patients, their caregivers, and families should be informed that Fycompa may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of Fycompa, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period), or at others times of dose increases. The dose of Fycompa should be reduced if these symptoms occur. Permanently discontinue Fycompa for persistent severe or worsening psychiatric symptoms or behaviours and refer for psychiatric evaluation.

Abuse potential.

Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of Fycompa abuse.
In a clinical trial of 40 volunteers with a history of polydrug use supra-therapeutic doses of Fycompa (24 mg and 36 mg) produced responses for "Euphoria" that were similar to alprazolam 3 mg, and lower than ketamine 100 mg. The incidence of euphoria reported as an adverse event in this study following Fycompa administration 8 mg, 24 mg and 36 mg was 37%, 46%, 46%, respectively, which was higher than alprazolam 3 mg (13%) but lower than ketamine 100 mg (89%).
"Drug Liking", "Overall Drug Liking", and "Take Drug Again" for Fycompa were each statistically lower than for ketamine 100 mg. In addition, for "Bad Drug Effects", Fycompa 24 mg and 36 mg produced responses significantly higher than ketamine 100 mg. For "Sedation", Fycompa 24 and 36 mg produced responses similar to alprazolam 3 mg and higher than ketamine 100 mg. On the "Take Drug Again" scale all doses of Fycompa produced lower scores than 1.5 mg and 3 mg alprazolam, and most of the differences were statistically significant.
The potential for Fycompa to produce withdrawal symptoms has not been adequately evaluated.

Monotherapy.

Fycompa has not been assessed as monotherapy in patients with epilepsy. Monotherapy is not recommended.

Galactose intolerance.

Fycompa contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Patients with hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Renal impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment.

Effect on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Fycompa is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes (see Section 5.2 Pharmacokinetic Properties).

Drug interaction studies.

In vitro assessment of drug interactions.

Drug metabolising enzyme.

In human liver microsomes, perampanel (30 micromol/L) had a weak inhibitory effect on CYP2C8 and UGT1A9 among major hepatic CYPs and UGTs.
Compared with positive controls (including phenobarbital, rifampicin), perampanel was found to weakly induce only CYP3A4/5 (≥ 3 micromol/L) and CYP2B6 (30 micromol/L) among major hepatic CYPs and UGTs in cultured human hepatocytes.

Transporters.

Perampanel was not a substrate or significant inhibitor of several influx or efflux transporters in vitro (organic anion transporting polypeptides 1B1 and 1B3; organic anion transporters 1, 2, 3 and 4; organic cation transporters 1, 2 and 3; efflux transporters P-glycoprotein and Breast Cancer Resistance Protein).

Oral contraceptives.

In healthy women receiving 12 mg (but not 4 or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive, Fycompa was shown to decrease the levonorgestrel exposure (mean Cmax and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by Fycompa 12 mg whereas Cmax was decreased by 18%. Therefore, the possibility of decreased efficacy of progestative containing oral contraceptives should be considered for women needing Fycompa 12 mg/day and an additional reliable non-hormonal method (for example intra-uterine device (IUD), condom) form of contraceptive is to be used (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Interactions between Fycompa and other anti-epileptic medicinal products.

Potential interactions between Fycompa (up to 12 mg once daily) and other anti-epileptic drugs (AEDs) were assessed in clinical studies and evaluated in the population PK analysis of four pooled Phase 3 studies including patients with partial-onset seizures and primary generalised tonic-clonic seizures. The effect of these interactions on average steady-state concentration is summarised in Table 2.
Some AEDs known as enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to increase perampanel clearance and consequently to decrease plasma concentrations of perampanel reducing its half-life.
Carbamazepine, a known potent enzyme inducer, reduced perampanel levels by two-thirds in a study performed on healthy subjects.
A similar result was seen in a population pharmacokinetic analysis of patients with partial-onset seizures receiving Fycompa up to 12 mg/day and patients with primary generalised tonic-clonic seizures receiving Fycompa up to 8 mg/day in placebo-controlled clinical trials. The total clearance of Fycompa was increased when administered with carbamazepine (2.8-fold), phenytoin (1.7-fold) and oxcarbazepine (1.9-fold), which are known inducers of enzymes of metabolism (see Section 5.2 Pharmacokinetic Properties).
This effect should be taken into account and managed when adding or withdrawing these AEDs from a patient's treatment regimen.
In a population pharmacokinetic analysis of patients with partial-onset seizures receiving Fycompa up to 12 mg/day in placebo-controlled clinical trials, Fycompa did not affect to a clinically relevant manner the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest Fycompa dose evaluated (12 mg/day).
In the epilepsy population pharmacokinetic analysis, perampanel was found to decrease the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolised by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of Fycompa on monohydroxycarbazepine concentrations is not known.
Fycompa is dosed to clinical effect regardless of other AEDs (see Section 4.2 Dose and Method of Administration).

Effect of perampanel on CYP3A substrates.

Concomitant CYP3A inducing AEDs.

Partial-onset seizures.

Response rates after addition of perampanel at fixed doses were less when patients received concomitant CYP3A enzyme-inducing anti-epileptic medicinal products (carbamazepine, phenytoin, oxcarbazepine) as compared to response rates in patient who received concomitant non-enzyme inducing AEDs (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients' response should be monitored when they are switching from concomitant non-inducer anti-epileptic medicinal products to enzyme inducing medicinal products and vice versa. Depending upon individual clinical response and tolerability, the dose may be increased or decreased 2 mg at a time (see Section 4.2 Dose and Method of Administration).

Primary generalised tonic-clonic seizures.

Response rates after addition of perampanel at a fixed dose of 8 mg were less when patients received concomitant CYP3A enzyme-inducing AEDs (carbamazepine, phenytoin, oxcarbazepine) as compared to response rates in patients who received concomitant non-enzyme inducing AEDs (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients' response should be monitored when they are switching from concomitant non-inducer AEDs to enzyme-inducing AEDs, and vice versa. Depending upon individual clinical response and tolerability, the dose may be increased by increments of 2 mg up to 12 mg/day.

Effect of cytochrome P450 inducing or inhibiting medicinal products on perampanel pharmacokinetics.

Patients should be closely monitored for tolerability and clinical response when adding or removing cytochrome P450 inducers or inhibitors, since perampanel plasma levels can be decreased or increased; the dose of Fycompa may need to be adjusted accordingly.

Effect of cytochrome P450 inducers on perampanel pharmacokinetics.

Strong inducers of cytochrome P450, such as rifampicin and hypericum, are expected to decrease perampanel concentrations. Felbamate has been shown to decrease the concentrations of some drugs and may also reduce perampanel concentrations.

Effect of cytochrome P450 inhibitors on perampanel pharmacokinetics.

In healthy subjects, the CYP3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased perampanel AUC by 20% and prolonged perampanel half-life by 15% (67.8 h vs 58.4 h). Larger effects cannot be excluded when Fycompa is combined with a CYP3A inhibitor with longer half-life than ketoconazole or when the inhibitor is given for a longer treatment duration. Strong inhibitors of other cytochrome P450 isoforms could potentially also increase perampanel concentrations.

Levodopa.

In healthy subjects, Fycompa (4 mg once daily for 19 days) had no effect on Cmax or AUC of levodopa.

Alcohol.

The effects of perampanel on tasks involving alertness and vigilance such as driving ability were additive or supra-additive to the effects of alcohol itself, as found in a pharmacodynamic interaction study in healthy subjects. Multiple dosing of perampanel 12 mg/day increased levels of anger, confusion, and depression as assessed using the Profile of Mood State 5-point rating scale (see Section 5.1 Pharmacodynamic Properties). These effects may also be seen when Fycompa is used in combination with other central nervous system (CNS) depressants.
Interaction studies have only been performed in adults. In a population pharmacokinetic analysis of the adolescent patients in the Phase 3 clinical studies, there were no notable differences between this population and the overall population.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no clear effects on fertility or early embryonic development in male or female rats treated with perampanel at oral doses of 1, 10, or 30 mg/kg/day (0.8, 8 and 23 times respectively the MRHD of 12 mg/day based on body surface area). Prolonged and/or irregular estrous cycles were observed at all doses but particularly at the high dose. The effect of Fycompa on human fertility has not been established.
(Category B3)
Fycompa is not recommended during pregnancy. There are limited amounts of data (less than 300 pregnancy outcomes) from the use of Fycompa in pregnant women.
Perampanel and/or its metabolites cross the placenta in rats. Oral administration of perampanel to pregnant rats throughout organogenesis at doses of 1, 3 and 10 mg/kg/day was associated with a dose-related increase in diverticulum of the intestine; a no effect dose was not established. These doses are 0.8, 2 and 8 times respectively the MRHD of 12 mg/day based on body surface area.
There were no effects on embryofetal development following oral administration of perampanel to pregnant rabbits throughout organogenesis at doses of 1, 3 and 10 mg/kg/day (1.4, 4 and 14 times respectively the MRHD of 12 mg/day based on body surface area). Exposure (plasma AUC) at all doses was less than anticipated clinical exposure.
Oral administration of perampanel to rats from early gestation to weaning at doses of 1, 3 or 10 mg/kg/day (0.8, 2 and 8 times the MRHD of 12 mg/day based on body surface area) was associated with increased stillbirths and abnormal delivery and nursing behaviour at the mid- and high-doses; the no-effect dose was 1 mg/kg/day. Behavioural development and reproductive function of the offspring were not affected.

Women of childbearing potential.

Fycompa is not recommended in women of childbearing potential not using contraception unless clearly necessary.
Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk. The excretion into breast milk was measured in rats at 10 days post-partum. Levels peaked at one hour and were about 4 times the levels in plasma. Studies in rats with perampanel administration from early gestation to weaning have shown adverse effects (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
It is not known whether perampanel is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Fycompa therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Summary of safety profile.

In all controlled and uncontrolled trials in patients with partial onset seizures, 1,639 subjects have received perampanel of whom 1,174 have been treated for 6 months and 703 for longer than 12 months.
In the controlled and uncontrolled trial in patients with primary generalised tonic-clonic seizures, 114 subjects have received perampanel of whom 68 have been treated for 6 months and 34 for longer than 12 months.

Partial-onset seizures.

A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies in patients with partial-onset seizures. Approximately 51% of patients were female and the mean age was 35 years.

Adverse reactions leading to discontinuation.

In controlled Phase 3 clinical trials the rate of discontinuation as a result of an adverse reaction was 3%, 8% and 19% in patients randomised to receive Fycompa at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5% in patients randomised to receive placebo. The adverse events most commonly leading to discontinuation (≥ 1% in the 8 mg or 12 mg Fycompa group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria.

Most common adverse reactions.

Table 3 gives the incidence in the Phase 3 controlled trials of the adverse reactions that occurred in ≥ 2% of patients with partial-onset seizures in any Fycompa dose group. Overall, the most frequently reported dose-related adverse reactions in patients receiving Fycompa at doses of 8 mg or 12 mg (≥ 4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation.

Weight gain.

In controlled clinical trials in patients with partial onset seizures clinically significant weight gain (i.e. > 7% BW) occurred in 14%, 15.3% and 15.4% of patients given perampanel 4 mg, 8 mg and 12 mg respectively compared to 7.1% given placebo.
Across the entire perampanel treatment duration in the open label extension study for partial onset seizures, 43.9% of subjects had an increase in body weight of > 7%, and 15.3% had a decrease in body weight of > 7%. The mean change from baseline in body weight at the end of treatment was 2.54 kg. The mean duration of perampanel exposure was 115.41 weeks.
In subjects with primary generalised tonic-clonic seizures who completed the controlled clinical trial and subsequently entered the open label extension phase, 27.9% had a clinically notable increase (> 7%) in body weight across the entire perampanel treatment duration. The mean duration of perampanel exposure was 40.3 weeks.

Other adverse reactions.

The following adverse reactions are discussed in more detail in the precautions section of the prescribing information: psychiatric reactions including aggression; suicidal ideation and behaviour; abuse potential; dizziness and gait disturbance; falls; somnolence and fatigue.

Paediatric population.

Based on the clinical trial database of 143 adolescents, the frequency, type and severity of adverse reactions in adolescents are expected to be the same as in adults.

Primary generalised tonic-clonic seizures.

A total of 81 patients on perampanel constituted the safety population in the Phase 3 placebo-controlled trial in patients with primary generalised tonic-clonic seizures. Approximately 57% of patients were female, and the mean age was 27 years.
In the controlled Phase 3 primary generalised tonic-clonic seizures clinical trial, the adverse event profile was similar to that noted for the controlled Phase 3 partial-onset seizures trials.
The most frequently reported adverse reactions in patients receiving Fycompa (≥ 10% and higher than in the placebo group) included dizziness (32.1%), fatigue (14.8%), headache (12.3%), somnolence (11.1%), and irritability (11.1%). The adverse reactions most commonly leading to discontinuation (≥ 2% in the Fycompa group and greater than placebo) were vomiting and dizziness.

Post-marketing experience.

Skin and subcutaneous tissue disorders.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

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.

4.2 Dose and Method of Administration

Adults and adolescents.

Fycompa must be titrated, according to individual patient response, in order to optimise the balance between efficacy and tolerability. Fycompa should be taken orally once daily at bedtime.

Partial-onset seizures.

Fycompa at doses of 4 mg/day to 12 mg/day has been shown to be effective therapy in partial onset seizures.
Treatment with Fycompa should be initiated with a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg (either weekly or every 2 weeks as per half-life considerations described below) to a maintenance dose of 4 mg/day to 8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased by increments of 2 mg/day to 12 mg/day. It is recommended that Fycompa is maintained at the lowest dose that controls symptoms in order to reduce potential adverse events.
Patients who are taking concomitant medicinal products that do not shorten the half-life of perampanel (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) should be titrated no more frequently than at 2-week intervals. Patients who are taking concomitant medicinal products that shorten the half-life of perampanel (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) should be titrated no more frequently than at 1-week intervals.

Primary generalised tonic-clonic seizures.

Fycompa at a dose up to 8 mg/day has been shown to be effective in primary generalised tonic-clonic seizures.
Treatment with Fycompa should be initiated at a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg (either weekly or every 2 weeks, as per half-life considerations described below) to a maintenance dose of up to 8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased up to 12 mg/day, which may be effective in some patients (see Section 4.4 Special Warnings and Precautions for Use). It is recommended that Fycompa is maintained at the lowest dose that controls symptoms in order to reduce potential adverse events.
Patients who are taking concomitant medicinal products that do not shorten the half-life of perampanel (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) should be titrated no more frequently than at 2 week intervals. Patients who are taking concomitant medicinal products that shorten the half-life of perampanel (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) should be titrated no more frequently than at 1-week intervals.

Treatment withdrawal and missed doses.

When withdrawing Fycompa, the dose should be gradually reduced (see Section 4.4 Special Warnings and Precautions for Use).
Single missed dose: As perampanel has a long half-life, the patient should wait and take their next dose as scheduled.
If more than 1 dose has been missed, for a continuous period of less than 5 half-lives (3 weeks for patients not taking perampanel metabolism-inducing AEDs, 1 week for patients taking perampanel metabolism-inducing AEDs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), consideration should be given to restart treatment from the last dose level.
If a patient has discontinued perampanel for a continuous period of more than 5 half-lives, it is recommended that initial dosing recommendations given above should be followed.

Special populations.

Renal impairment.

Dose adjustment is not required in patients with mild renal impairment. Use in patients with moderate or severe renal impairment or patients undergoing haemodialysis is not recommended.

Patients with hepatic impairment.

Dose increases in patients with mild and moderate hepatic impairment should be based on clinical response and tolerability. For patients with mild or moderate hepatic impairment, dosing can be initiated at 2 mg. Patients should be up-titrated using 2 mg doses no faster than every 2 weeks based on tolerability and effectiveness. Fycompa dosing for patients with mild and moderate impairment should not exceed 8 mg. Use in patients with severe hepatic impairment is not recommended.

Elderly patients.

Fycompa should be used with caution in the elderly (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric patients.

The safety and efficacy of Fycompa in children below 12 years of age have not been established yet. No data are available.

Method of administration.

Fycompa should be taken as single oral dose at bedtime. It may be taken with or without food (see Section 5.2 Pharmacokinetic Properties). The tablet should be swallowed whole with a glass of water. It should not be chewed, crushed or split. The tablets cannot be split accurately as there is no break line. To ensure the patient receives the entire dose the tablets should be swallowed whole without chewing or crushing.

4.7 Effects on Ability to Drive and Use Machines

Fycompa has moderate influence on the ability to drive and use machines.
Fycompa may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities until it is known whether Fycompa affects their ability to perform these tasks.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
There is limited clinical experience with perampanel overdose in humans. In a report of an intentional overdose that could have resulted in a dose up to 264 mg, the patient experienced events of altered mental status, agitation and aggressive behaviour and recovered without sequelae. There is no available specific antidote to the effects of perampanel. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. In view of its long half-life, the effects caused by perampanel could be prolonged. Because of low renal clearance special interventions such as forced diuresis, dialysis or haemoperfusion are unlikely to be of value.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The film-coated tablets contain the excipients lactose monohydrate, hypromellose, povidone, magnesium stearate, purified talc, microcrystalline cellulose (6 mg, 8 mg, 10 mg and 12 mg only), macrogol 8000, titanium dioxide, iron oxide yellow (2 mg, 10 mg), iron oxide red (2 mg, 4 mg, 6 mg, and 8 mg only), iron oxide black (8 mg only) and indigo carmine aluminium lake (10 mg and 12 mg only).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.
Store in original container.

6.5 Nature and Contents of Container

Fycompa 2 mg film coated tablet is available in PVC/aluminium blisters of 7.
Fycompa 4 mg film coated tablet is available in PVC/aluminium blisters of 28.
Fycompa 6 mg film coated tablet is available in PVC/aluminium blisters of 28.
Fycompa 8 mg film coated tablet is available in PVC/aluminium blisters of 28.
Fycompa 10 mg film coated tablet is available in PVC/aluminium blisters of 28.
Fycompa 12 mg film coated tablet is available in PVC/aluminium blisters of 28.

6.6 Special Precautions for Disposal

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

Summary Table of Changes