Consumer medicine information

Xadago

Safinamide

BRAND INFORMATION

Brand name

Xadago

Active ingredient

Safinamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xadago.

What is in this leaflet

This leaflet answers some common questions about Xadago®.

It does not contain all of 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 Xadago® against the benefits they expect it will have for you.

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

Read this leaflet carefully and keep it with the medicine. You may need to read it again.

What Xadago® is used for

Xadago® is used to treat Parkinson’s disease. It is taken when levodopa on its own (or with other medicines) does not control the symptoms of Parkinson’s Disease.

Xadago® belongs to a group of medicines called monoamine oxidase inhibitors (MAOIs). It contains an active ingredient called safinamide.

Parkinson's disease is a condition of the brain that mainly affects movement. The three main symptoms of Parkinson's disease are:

  • Shaking (tremor)
  • Muscle stiffness
  • Slow and unsteady movement.

The symptoms of Parkinson's disease are caused by a lack of dopamine. Dopamine is a natural substance that is made in the brain and helps with movement. Xadago® works by increasing the level of dopamine in the brain. This decreases the symptoms of Parkinson's disease.

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 only available with a doctor’s prescription. Xadago® is not addictive.

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you take Xadago®

When you must not take it

Do not take Xadago® if you have an allergy, or have ever had an allergic reaction to safinamide or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • asthma, wheezing or coughing, shortness of breath
  • swelling of the face, lips, tongue which may cause difficulty in swallowing or breathing
  • hives, itching or skin rash
  • stomach ache, fever, chills, nausea and vomiting, fainting.

Do not take Xadago® if you are taking, or have recently taken, any of the following:

  • a monoamine oxidase inhibitor (MAOI),which are a group of medicines that can be used to treat Parkinson’s Disease, depression and some other conditions.
  • Pethidine, a strong pain killer.

If you are not sure, ask your doctor or pharmacist

Do not take Xadago® if you have:

  • a serious liver problem or disease
  • a condition which may affect your eyes such as:
    -albinism: a lack of pigment in your skin and eyes
    -retinal degeneration: a loss of cells from the light sensitive layer at the back of the eye
    -uveitis: inflammation inside of the eye
    -an inherited vision disorder
    -severe, progressive vision loss due to diabetes

Do not take Xadago® after the expiry date (EXP) printed on the carton and blister foil.

Do not take Xadago® if the packaging is torn or shows signs of tampering or if the tablets do not look quite right. If you notice any of these things return the tablets to your pharmacist.

If you are not sure whether you should take Xadago®, talk to your doctor.

Before you take it

Tell your doctor if you:

  • Have allergies to any medicines or other substances such as, foods, preservatives or dyes.
  • Are pregnant or intend to become pregnant.
    Xadago® should not be used if you are pregnant or planning to become pregnant.
  • Are breast-feeding or planning to breast-feed.
    Xadago® should not be used while breast-feeding.
  • Have a liver problem or disease
  • Have or have had problems with your eyes or have a family history of retinal disease

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

Taking other medicines

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

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

  • a monoamine oxidase inhibitor (MAOI), which are a group of medicines that can be used to treat Parkinson’s Disease, depression and some other conditions.
  • pethidine, a strong pain killer
  • medicines used to treat depression, anxiety, panic disorders, obsessive compulsive disorder or pre-menstrual dysphoric disorders such as selective serotonin reuptake inhibitors (SSRIs), selective-norepinephrine reuptake inhibitors (SNRIs) or tricyclic and tetracyclic antidepressants.
  • nasal and oral decongestants or ‘cold and flu’ medicines that contain ephedrine or pseudoephedrine
  • cough medicines that contain dextromethorphan
  • medicines to lower blood cholesterol such as pitavastatin, pravastatin or rosuvastatin
  • antibiotics such as ciprofloxacin
  • some pain medications such as diclofenac
  • medicines used to treat diabetes such as glyburide or metformin
  • medicines used to treat cancer such as topotecan
  • methotrexate a medicine used to treat cancer, arthritis and autoimmune diseases.
  • medicines to treat virus infections such as aciclovir or ganciclovir
  • medicines that are breast cancer resistance protein (BCRP) substrates such as pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan, diclofenac, glyburide or rosuvastatin
  • medicines that are substrates of the liver protein OCT1 such as metformin, aciclovir, ganciclovir

These medicines may be affected by Xadago® 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 will advise you.

Your doctor has more information on medicines to be careful with or to avoid while you are taking Xadago®.

How to take Xadago®

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

These directions 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

Your doctor will tell you how much Xadago® to take.

The usual starting dose is one 50 mg tablet each day. After two weeks, the dose will usually be increased to one 100 mg tablet each day.

Your doctor will tell you the dose that you should take.

Only take the amount that your doctor tells you to.

How to take it

Xadago® tablets should be swallowed whole with a glass of water. Xadago® may be taken before, after or with food.

When to take it

Take your Xadago® tablet at about the same time every day.

Take it at the same time that you take your other Parkinson’s medication.

Ask your doctor or pharmacist if you are not sure.

How long to take it

Do not stop taking this medicine without first checking with your doctor.

Talk with your doctor about how long you should take Xadago®. You may need to take it for a long time.

If you forget to take it

Skip the dose that you missed. Take the next dose at the usual time the next day.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much Xadago®, immediately:

  • Telephone your doctor or the Poisons Information Centre on 13 11 26 or
  • Go to accident and emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning.

While you are taking Xadago®

Things you must do

Tell your doctor immediately if you become pregnant.

Tell any doctors, dentists and pharmacists who treat you that you are taking Xadago®.

Things you must not do

Do not start taking any other medicine including any that you can buy without a prescription from your pharmacy, supermarket, health food shop, naturopath or herbalist, without first talking to your doctor.

Do not stop taking this medicine without checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping completely.

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

Things to be careful of

Be careful driving or operating machinery until you know how Xadago® affects you. As with some other Parkinson’s disease medications, Xadago® may make you feel sleepy, dizzy or lightheaded.

If you have any of symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

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

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

This medicine helps most people with Parkinson’s disease but it may have unwanted side effects in a few people.

Tell your doctor if you notice any of the following and they worry you:

  • dizziness on standing up, especially when getting up from a sitting or lying position
  • dizziness or light-headedness
  • nausea (feeling sick)
  • accidental injury (e.g. falls)
  • sleepiness
  • trouble sleeping (insomnia)
  • headache
  • uncontrolled, sudden movements (dyskinesia)
  • cough
  • an uncomfortable feeling in the stomach or belching after eating (indigestion)
  • nervousness or feeling anxious.

These are mild side effects of Xadago®.

Tell your doctor as soon as possible if you notice any of the following:

  • cloudiness in your eye or vision changes
  • unusual urges or behaviours for example a strong urge to gamble, increased sexual drive, compulsive spending or buying, impulsive behaviour or binge eating
  • obsessive thoughts

These may be serious side effects that may require medical attention. Serious side effects are uncommon.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • asthma, wheezing, breathlessness, sudden or severe itching, skin rash, hives
  • Serotonin syndrome – this can sometimes happen when medicines like Xadago® are taken with other medicines that are used to treat depression, anxiety, panic disorders, obsessive compulsive disorder or pre-menstrual dysphoric disorders. Symptoms may include: agitation, hallucinations, severe confusion; rapid heart rate, dizziness, sweating, or flushing; high or low blood pressure and seizures and/or problems controlling your movements, muscle twitching stiffness or tightness might get worse.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor or nurse 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 Xadago®

Storage

Keep Xadago® tablets in the blister pack until it is time to take them.

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

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

Keep Xadago® where children cannot reach it. A locked cupboard at least one-and-a-half meters above ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Xadago® or the expiry date has passed, take the left over tablets to your pharmacist.

Product description

What it looks like

Xadago® tablets are available in two (2) different strengths:

Xadago® 50 mg Tablets

Orange to copper, round, biconcave, immediate release, film-coated tablets (7 mm diameter) with metallic gloss and “50” embossed on one side.

Xadago® 100 mg Tablets

Orange to copper, round, biconcave, immediate release, film-coated tablets (9 mm diameter) with metallic gloss and “100” embossed on one side.

Xadago® tablets are supplied in a blister tray packaged in a cardboard box.

Xadago® tablets are supplied in boxes of 10 and 30 tablets. Not all pack sizes may be available.

Ingredients

Active ingredients:

Xadago® 50 mg Tablets

Each tablet contains 50 mg safinamide (as mesilate)

Xadago® 100 mg Tablets

Each tablet contains 100 mg safinamide (as mesilate)

Inactive ingredients:

Xadago® tablets also contain the following inactive ingredients:

  • microcrystalline cellulose
  • crospovidone
  • magnesium stearate
  • colloidal anhydrous silica
  • Opadry complete film coating system 02F59058 Clear
  • Candurin Orange amber
  • Candurin Gold sheen

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

Ask your doctor, nurse or pharmacist if you are unsure about anything or want more information about Xadago®.

Sponsor

Seqirus Pty Ltd
ABN 26 160 735 035
63 Poplar Road,
Parkville, VIC, 3052
Australia

This leaflet was prepared in March 2022.

Australian Registration Numbers:

Xadago® 50 mg: AUST R 292145

Xadago® 100 mg: AUST R 292144

Xadago is a registered trademark of Zambon S.p.A. Under Licence from Newron Pharmaceutical S.p.A

Published by MIMS May 2022

BRAND INFORMATION

Brand name

Xadago

Active ingredient

Safinamide

Schedule

S4

 

1 Name of Medicine

Safinamide (as mesilate).

2 Qualitative and Quantitative Composition

Xadago tablets contain 50 or 100 mg safinamide (as mesilate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Xadago 50 mg tablets.

Orange to copper, round, biconcave, immediate release, film-coated tablets (7 mm diameter) with metallic gloss and "50" embossed on one side. Each tablet contains 50 mg safinamide (as mesilate).

Xadago 100 mg tablets.

Orange to copper, round, biconcave, immediate release, film-coated tablets (9 mm diameter) with metallic gloss and "100" embossed on one side. Each tablet contains 100 mg safinamide (as mesilate).

4 Clinical Particulars

4.1 Therapeutic Indications

Xadago is indicated for the treatment of adult patients with fluctuating idiopathic Parkinson's disease (PD) as add-on therapy to a regimen that includes levodopa (L-Dopa).

4.2 Dose and Method of Administration

Xadago treatment should be started at 50 mg/day. The dose may be increased to 100 mg/day after two weeks on the basis of individual clinical need.
Xadago tablets are for oral use. Xadago should be taken with water. Xadago may be taken with or without food. If a dose is missed, the next dose should be taken at the usual time the next day.

Discontinuation.

Xadago 50 mg can be discontinued without down titration.
Xadago 100 mg should be tapered by decreasing the dose to 50 mg for one week prior to discontinuation.

Paediatric patients.

The safety and efficacy of safinamide in children and adolescents under 18 years of age have not been established. No data are available.

Elderly patients.

No dosage adjustment is required for patients over 75 years of age.

Renal impairment.

No dosage adjustment is required for patients with renal impairment.

Hepatic impairment.

No dose adjustment is required for patients with mild hepatic impairment. For patients with moderate hepatic impairment, the lower dose of 50 mg/day is recommended. If patients progress from moderate to severe hepatic impairment, treatment with Xadago should be stopped. Safinamide is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Tyramine-containing foods.

Xadago can be used without any dietary tyramine restrictions (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to the active substance (safinamide) or to any of the tablet excipients (see Section 6.1 List of Excipients);
Concomitant treatment with other monoamine oxidase (MAO) inhibitors. At least 7 days must elapse between discontinuation of safinamide and initiation of treatment with another MAO inhibitor;
Concomitant treatment with pethidine. At least 7 days must elapse between discontinuation of safinamide and initiation of treatment with pethidine;
Severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use);
Albinism, retinal degeneration, uveitis, inherited retinopathy or severe progressive diabetic retinopathy.

4.4 Special Warnings and Precautions for Use

Serotonin syndrome.

The development of serotonin syndrome has been reported in patients on concomitant treatment with MAO inhibitors (including selective MAO-B inhibitors), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs and methylphenidate, amphetamine and their derivatives (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, delirium, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g. tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea).

Hepatic impairment.

Exercise caution when initiating treatment in patients with moderate hepatic impairment. If patients progress from moderate to severe hepatic impairment, treatment with Xadago should be stopped. Safinamide is contraindicated in patients with severe hepatic impairment. (See Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties.)

Retinal pathology.

Xadago should not be administered to patients with ophthalmological history that would put them at increased risk for potential retinal effects (e.g. family history of hereditary retinal disease or history of uveitis) (see Section 4.3 Contraindications; Section 5.3 Preclinical Safety Data). In clinical trials no retinal degeneration was noted in patients at the maximum human dose.

Impulse control disorders.

Impulse control disorders (ICDs) can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Safinamide treatment has not been associated with any increase in the appearance of ICDs. However some reports of ICDs have been observed with other MAO-inhibitors.
Patients and carers should be made aware of the behavioural symptoms of ICDs that were observed in patients treated with other MAO-inhibitors including cases of compulsions, obsessive thoughts, pathological gambling, increased libido, hyper-sexuality, impulsive behaviour and compulsive spending or buying. Patients may not recognise these behaviours as abnormal. It is therefore important for prescribers to specifically ask patients or their caregivers about the development of new or increased ICD behavioural symptoms.

Dopaminergic side effects.

Safinamide may potentiate the side effects of levodopa and/or other dopaminergic drugs. Pre-existing dyskinesia may be exacerbated. This effect was not seen when safinamide was used as an adjunct to a dopamine agonist in non-fluctuating PD patients. In clinical studies, dyskinesia was generally mild to moderate in intensity, with very few patients reporting severe dyskinesia. There was no increase in troublesome dyskinesias. Reducing the patient's daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.

Tyramine/safinamide interaction.

Safinamide potentiation of the tyramine pressor effect was investigated in one intravenous and two short term oral tyramine challenge studies. Results of these studies and home monitoring of blood pressure after meals during chronic dosing in two therapeutic trials in PD patients, did not detect any clinically important increases in blood pressure. In addition, three therapeutic studies performed in PD patients without any tyramine restriction, did not detect any evidence of tyramine potentiation. Xadago can be used without any dietary tyramine restrictions.

Add-on therapy to a single dopamine-agonist.

Limited data are available for safinamide as add-on therapy to a single dopamine-agonist.
Randomised, controlled studies have been performed; however while safinamide was found to be safe and well tolerated, efficacy results were inconclusive.

Paediatric use.

The safety and efficacy of safinamide in children and adolescents under 18 years of age have not been established.

Effect on laboratory tests.

Xadago has no known effect on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Monoamine oxidase (MAO) inhibitors and products with MAO inhibition activity.

Xadago must not be administered concomitantly with other MAO inhibitors or products which have MAO inhibition activity as there is a risk of non-selective MAO inhibition that may lead to a hypertensive crisis (see Section 4.3 Contraindications). At least 7 days must elapse between discontinuation of safinamide and initiation of treatment with another MAO inhibitor.

Pethidine.

Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors. As this may be a class-effect, the concomitant administration of Xadago and pethidine is contraindicated (see Section 4.3 Contraindications). At least 7 days must elapse between discontinuation of safinamide and initiation of treatment with pethidine.

Sympathomimetic medications.

There have been reports of medicinal product interactions with the concomitant use of MAO inhibitors and sympathomimetic medicinal products. In view of the MAO inhibitory activity of safinamide, concomitant administration of Xadago and sympathomimetics such as those present in nasal and oral decongestants or cold medicinal products containing ephedrine or pseudoephedrine, requires caution.

Dextromethorphan.

There have been reports of medicinal product interactions with the concomitant use of dextromethorphan and non-selective MAO inhibitors. In view of the MAO inhibitory activity of safinamide, concomitant administration of Xadago and dextromethorphan is not recommended. Use caution if concomitant treatment is necessary.

Serotonergic medications.

Serious adverse reactions have been reported with the concomitant use of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic/tetracyclic antidepressants and MAO inhibitors, such as hypertensive crisis (high blood pressure, collapse), neuroleptic malignant syndrome (confusion, sweating, muscle rigidity, hyperthermia, CPK increase), serotonin syndrome (confusion, hypertension, muscle stiffness, hallucinations), and hypotension.
In view of the selective and reversible MAO-B inhibitory activity of safinamide, if concomitant treatment is necessary these medicinal products should be used at the lowest doses necessary, with caution for serotoninergic symptoms.
A washout period corresponding to five (5) half-lives of the SSRI used previously should be considered prior to initiating treatment with Xadago.

Substrates of breast cancer resistance protein (BCRP).

Safinamide may transiently inhibit BCRP in vitro. In drug-drug interaction studies in humans, a weak interaction was observed with rosuvastatin (increases in rosuvastatin AUC between 1.25 and 2.00 fold were reported) but no significant interaction was found with diclofenac. It is recommended to monitor patients when safinamide is taken with medicinal products that are BCRP substrates (e.g. rosuvastatin, pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan, diclofenac or glyburide).

OCT1 substrates.

Safinamide inhibits OCT1 in vitro at clinically relevant portal vein concentrations. Therefore, caution is necessary when safinamide is taken concomitantly with medicinal products that are OCT1 substrates and have a Tmax similar to safinamide (2 hours) (e.g. metformin, aciclovir, ganciclovir) as exposure to these substrates might be increased as a consequence.

OAT3 inhibitors.

The primary safinamide metabolite, 'safinamide acid' (NW-1153), is a substrate for OAT3 at clinically relevant concentrations. Medicinal products that are inhibitors of OAT3 given concomitantly with safinamide may reduce clearance of NW-1153, i.e. and thus may increase its systemic exposure. The systemic exposure of NW-1153 is low (1/10 of parent safinamide). This potential increase is most likely of no clinical relevance as NW-1153, the first product in the metabolic pathway, is further transformed to secondary and tertiary metabolites.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies in female rats showed reduced number of implantations and corpora lutea at exposures in excess of 3 times the anticipated human exposure. Male rats showed minor abnormal morphology and reduced speed of sperm cells at exposures in excess of 1.4 times the anticipated human exposure. Male rat fertility was not affected. The clinical relevance of these findings is unknown.
(Category B3)
Xadago should not be given during pregnancy. Women of childbearing potential should be advised not to become pregnant during safinamide therapy. Limited or no clinical data for safinamide on exposed pregnancies is available. Animal studies have shown reproductive toxicity when exposed to safinamide during pregnancy or lactation (see Section 5.3 Preclinical Safety Data).
 Xadago should not be used during breast feeding. Available pharmacodynamic/toxicological data in animals have shown excretion of safinamide in milk. In rat pups indirectly exposed to safinamide during the lactation period, skin discoloration, presumed to be caused by hyperbilirubinemia resulting from hepatobiliary toxicity, was observed. It is not known if safinamide is excreted in human milk. The potential relevance to humans in unknown; however risk to the breast-fed child cannot be excluded.

4.7 Effects on Ability to Drive and Use Machines

Somnolence and dizziness may occur during safinamide treatment. Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.
Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with safinamide. If affected, patients must refrain from driving and using machines.

4.8 Adverse Effects (Undesirable Effects)

The overall safety profile of Xadago is based on the clinical development program performed in over 3000 subjects, of whom over 500 were treated for more than 2 years.
Treatment Emergent Adverse Events (TEAEs) with an incidence of at least 2% in the Xadago 100 mg/day and greater than placebo from the two pivotal, Phase III, randomised, double-blind, placebo-controlled, 26 week safinamide clinical trials (NW-016 and 27919 [SETTLE]) are presented in Table 1. The most common TEAEs associated with Xadago treatment were dyskinesia, fall, nausea, and insomnia.
The following adverse effects were reported from clinical trials performed with Xadago and considered related to safinamide treatment.
Adverse effects are listed by MedDRA system organ class (SOC) and frequency very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Infections and infestations.

Uncommon: Urinary Tract Infection.
Rare: Bronchopneumonia, furuncle, nasopharyngitis, pyoderma, rhinitis, tooth infection, viral infection.

Neoplasms benign, malignant and unspecified (incl cysts and polyps).

Uncommon: Basal Cell Carcinoma.
Rare: Acrochordon, melanocytic naevus, seborrhoeic keratosis, skin papilloma.

Blood and lymphatic system disorders.

Uncommon: Anaemia, leukopenia, red blood cell abnormality.
Rare: Eosinophilia, lymphopenia.

Metabolism and nutrition disorders.

Uncommon: Decreased appetite, hypertriglyceridaemia, increased appetite, hypercholesterolaemia, hyperglycaemia.
Rare: Cachexia, hyperkalaemia.

Psychiatric disorders.

Common: Insomnia.
Uncommon: Hallucination, depression, abnormal dreams, anxiety, confusional state, affect lability, libido increased, psychotic disorder, restlessness, sleep disorder.
Rare: Compulsions, delirium, disorientation, illusion, impulsive behaviour, loss of libido, obsessive thoughts, paranoia, premature ejaculation, sleep attacks, social phobia, suicidal ideation.

Nervous system disorders.

Common: Dyskinesia, somnolence, dizziness, headache, Parkinson's disease.
Uncommon: Paraesthesia, balance disorder, hypoaesthesia, dystonia, head discomfort, dysarthria, syncope, cognitive disorder.
Rare: Coordination abnormal, disturbance in attention, dysgeusia, hyporeflexia, radicular pain, Restless Legs Syndrome, sedation.

Eye disorders.

Common: Cataract.
Uncommon: Vision blurred, scotoma, diplopia, photophobia, retinal disorder, conjunctivitis, glaucoma.
Rare: Amblyopia, chromatopsia, diabetic retinopathy, erythropsia, eye haemorrhage, eye pain, eyelid oedema, hypermetropia, keratitis, lacrimation increased, night blindness, papilloedema, presbyopia, strabismus.

Ear and labyrinth disorders.

Uncommon: Vertigo.

Cardiac disorders.

Uncommon: Palpitations, tachycardia, sinus bradycardia, arrhythmia.
Rare: Myocardial infarction.

Vascular disorders.

Common: Orthostatic hypotension.
Uncommon: Hypertension, hypotension, varicose vein.
Rare: Arterial spasm, arteriosclerosis, hypertensive crisis.

Respiratory, thoracic, and mediastinal disorders.

Uncommon: Cough, dyspnoea, rhinorrhoea.
Rare: Bronchospasm, dysphonia, oropharyngeal pain, oropharyngeal spasm.

Gastrointestinal disorders.

Common: Nausea.
Uncommon: Constipation, dyspepsia, vomiting, dry mouth, diarrhoea, abdominal pain, gastritis, flatulence, abdominal distension, salivary hypersecretion, gastrooesophageal reflux disease, aphthous stomatitis.
Rare: Peptic ulcer, retching, upper gastrointestinal haemorrhage.

Hepatobiliary disorders.

Rare: Hyperbilirubinaemia.

Skin and subcutaneous tissue disorders.

Uncommon: Hyperhidrosis, pruritus generalised, photosensitivity reaction, erythema.
Rare: Alopecia, blister, dermatitis contact, dermatosis, ecchymosis, lichenoid keratosis, night sweats, pain of skin, pigmentation disorder, psoriasis, seborrhoeic dermatitis.

Musculoskeletal and connective tissue disorders.

Uncommon: Back pain, arthralgia, muscle spasms, muscle rigidity, pain in extremity, muscular weakness, sensation of heaviness.
Rare: Ankylosing spondylitis, flank pain, joint swelling, musculoskeletal pain, myalgia, neck pain, osteoarthritis, synovial cyst.

Renal and urinary disorders.

Uncommon: Nocturia, dysuria.
Rare: Micturition urgency, polyuria, pyuria, urinary hesitation.

Reproductive system and breast disorders.

Uncommon: Erectile dysfunction.
Rare: Benign prostatic hyperplasia, breast disorder, breast pain.

General disorders and administration site conditions.

Uncommon: Fatigue, asthenia, gait disturbance, oedema peripheral, pain, feeling hot.
Rare: Drug effect decreased, drug intolerance, feeling cold, malaise, pyrexia, xerosis.

Investigations.

Uncommon: Weight decreased, weight increased, blood creatine phosphokinase increased, blood triglycerides increased, blood glucose increased, blood urea increased, blood alkaline phosphatase increased, blood bicarbonate increased, blood creatinine increased, electrocardiogram QT prolonged, liver function test abnormal, urine analysis abnormal, blood pressure increased, blood pressure decreased, ophthalmic diagnostic procedures abnormal.
Rare: Blood calcium decreased, blood potassium decreased, blood cholesterol decreased, body temperature increased, cardiac murmur, cardiac stress test abnormal, haematocrit decreased, haemoglobin decreased, international normalised ratio decreased, lymphocyte count decreased, platelet count decreased, very low density lipoprotein increased.

Injury, poisoning and procedural complications.

Common: Fall.
Uncommon: Foot Fracture.
Rare: Contusion, fat embolism, head injury, mouth injury, skeletal injury.

Social circumstances.

Rare: Gambling.

Post-marketing data.

In addition to adverse events reported in clinical trials, the following adverse reactions have been identified during post-approval of use of Xadago. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
A post-marketing report describes a patient who developed a hypersensitivity reaction consisting of swelling of the tongue and gingiva, dyspnoea and skin rash. The symptoms resolved shortly after Xadago was discontinued, but reappeared following rechallenge a month later.

Adverse event reporting.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The expected pattern of events or symptoms following intentional or accidental overdose with Xadago would be those related to its pharmacodynamic profile: MAO-B inhibition with activity-dependent inhibition of Na+ channels. The symptoms of an excessive MAO-B inhibition (increase in dopamine level) could include hypertension, postural hypotension, hallucinations, agitation, nausea, vomiting, and dyskinesia.
There is no known antidote to safinamide or any specific treatment for a safinamide overdose. If an important overdose should occur, Xadago treatment should be discontinued and supportive treatment should be administered as clinically indicated.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Safinamide is an α-aminoamide derivative that acts through both dopaminergic and non-dopaminergic mechanisms of action. Safinamide is a highly selective and reversible monoamine oxidase B (MAO-B) inhibitor that causes an increase in extracellular levels of dopamine in the striatum. MAO-B is inhibited with more than 1000-fold selectivity over MAO-A. In clinical studies, complete inhibition (> 90%) of MAO-B was measured at doses > 20 mg. Safinamide is also associated with state- and use-dependent inhibition of voltage-gated sodium (Na+) channels, calcium (Ca2+) channel modulation and inhibition of glutamate release. An excess of glutamate has been identified to contribute to neuronal death in the substantia nigra as well as to the genesis of motor fluctuations in Parkinson's disease. In in-vivo rat models, safinamide reduced striatal glutamatergic hyperactivity. It is unknown whether these mechanisms are relevant to use in humans.

Clinical trials.

The efficacy of Xadago as an add-on therapy to a stable dose of levodopa (L-dopa), alone or in combination with other PD medications, was established in two pivotal, Phase III, randomised, double-blind, placebo-controlled, multi-centre clinical trials conducted over 26 weeks (NW-016 and 27919 [SETTLE]). Long term efficacy was established in a Phase III, double-blind, placebo-controlled, 18-month (78-week) extension to NW-016 (NW-018). Clinical trials of safinamide as add-on therapy to a single dopamine agonist have also been performed, however efficacy results were inconclusive.
In NW-016 and SETTLE, the primary efficacy measure was the change (increase) in daily ON time without troublesome dyskinesia from baseline to endpoint, based on 18-hour diaries that were completed for at least 3 days before assessment. ON time was defined as time when PD medication was providing benefit with regard to mobility, slowness and stiffness. Secondary efficacy parameters included change in OFF time; Unified Parkinson's Disease Rating Scale (UPDRS) section III - Motor Examination.
Changes in non-motor symptoms, including UPDRS section II - Activities of Daily Living and PD Questionnaire (PDQ-39), which measures eight dimensions of health: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication and bodily pain were also assessed.
In NW-016 patients were randomly assigned to receive safinamide, 50 mg (n=223) or 100 mg per day, (n=224), or placebo (n=222). At baseline the patients' mean duration of PD was approximately 8 years (range 0 to 27.3 years), Hoehn and Yahr stage was similar in both the safinamide and placebo groups (mean 2.8, range 1.0 to 4.0) and average daily OFF time was approximately 5 hours (range 0 to 13 hours). Patients were taking 4-10 levodopa doses per day and the mean daily dose was 605 mg. Other PD medicinal products were concomitantly taken by the following percentage of patients: DA-Agonists (60.8%), COMT-inhibitors (24.4%), Anticholinergic (37.1%) and Amantadine (13.9%).
In SETTLE patients were randomly assigned to receive safinamide, (n=274) or placebo (n=275). Treatment in the safinamide group started at 50 mg/day; in the majority of patients the daily dose was increased to 100 mg/day after two weeks. At baseline the patients' mean duration of PD was approximately 9 years (range 0 to 31 years), Hoehn and Yahr stage was similar in the both the safinamide and placebo groups (mean 2.5, range 1.0 to 4.0). Average daily OFF time was approximately 5.3 hours (range 0 to 12.5 hours). Patients were taking 3-10 levodopa doses per day and the mean daily dose of L-dopa was 777 mg. Other PD medicinal products were concomitantly taken by the following percentage of patients: DA-Agonists (74.3%), COMT-inhibitors (17.9%), Anticholinergic (17.3%) and Amantadine (30.2%).
In both studies, safinamide treatment significantly increased ON time without troublesome dyskinesia compared to placebo treatment (Table 2). The time course of improvement in mean daily ON time showed greater improvement with Xadago compared to baseline at all post-baseline time-points (Figures 1 and 2). In addition data from NW-018, the 18-month (78-week) extension to NW-016, show that improvement in ON time was maintained long-term (Figure 1).
In NW-016, mean (SD) change in daily ON time without troublesome dyskinesia after 24 weeks (6 months) was +1.37 (SD: 2.745) hours for safinamide 50 mg/day, +1.36 (2.625) hours for safinamide 100 mg/day and +0.97 (2.375) hours for placebo (least-squares mean difference: 50 mg/day safinamide: +0.51 hours, 95% CI, 0.07-0.94 hours; p=0.0223; 100 mg/day safinamide: +0.55 hours, 95% CI, 0.12-0.99, p=0.0130). The increase in daily ON time without troublesome dyskinesia for both safinamide doses compared to placebo was maintained at the end of NW-018, the 18-month extension to NW-016; compared to baseline, the mean (SD) daily change in ON time after 2 years was +1.15 (SD: 2.75) hours for safinamide 50 mg/day; +1.19 (2.88) hours for safinamide 100 mg/day, and +0.56 (2.51) hours for placebo (least-squares mean difference: 50 mg/day safinamide: +0.67 hour, 95% CI, 0.23-1.11 hours; p=0.0031; 100 mg/day safinamide: +0.83 hour, 95% CI, 0.39-1.27, p=0.0002).
In SETTLE, mean (SD) change in daily ON time without troublesome dyskinesia after 24 weeks (6 months) was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, compared to +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; p < 0.001). In both NW-016 and SETTLE the increase in ON time was accompanied by a similar significant reduction in OFF time and a reduction in UPDRS section III - Motor Examination score assessed during ON time (Table 2).
Assessment of non-motor symptoms in clinical studies demonstrated a reduction (improvement) in UPDRS section II - Activities of daily living; the difference was statistically significant compared to placebo in NW-016 and NW-018 (100 mg/day safinamide group) (p=0.0060 and p=0.0068) (Table 2).
The PDQ-39 questionnaire summary index score showed a greater improvement for safinamide compared with placebo. This difference was statistically significant compared to placebo in SETTLE (p=0.006) and for the 100 mg/day safinamide group in NW-016 (p=0.0360) and NW-018 (p=0.0195) (Table 2).

5.2 Pharmacokinetic Properties

Absorption.

Safinamide is rapidly absorbed after single and multiple oral dosing under fasting conditions; Tmax is reached 1.8-2.8 h after dosing. Absolute bioavailability is high (95%), showing that safinamide is almost completely absorbed after oral administration and first pass metabolism is negligible. The high absorption classifies safinamide as a highly permeable substance.

Food effect.

A slight delay in Tmax was observed in the fed state relative to the fasted condition, but there was no effect on safinamide AUC0-∞ or Cmax. Xadago may be administered with or without food.

Patients with hepatic impairment.

Safinamide exposure in patients with mild hepatic impairment increased marginally (30% in AUC). In patients with moderate hepatic impairment, safinamide exposure increased by approximately 80% (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Patients with renal impairment.

Safinamide exposure was comparable in patients with moderate or severe renal impairment and patients with normal renal function. The pharmacokinetics of safinamide are not affected by impaired renal function.

Distribution.

The volume of distribution (Vss) is approximately 165 L which is 2.5-fold of body volume indicating extensive extravascular distribution of safinamide. Total clearance was determined to be 4.6 L/h classifying safinamide as a low clearance substance. Plasma protein binding of safinamide is 88-90%.

Metabolism.

In humans, safinamide is almost exclusively eliminated via metabolism (~5% of the drug is eliminated unchanged, mainly in urine), through three main metabolic pathways. One pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite 'safinamide acid' (NW-1153). Another pathway is oxidative cleavage of the ether bond forming 'Odebenzylated safinamide' (NW-1199). Finally, the 'N-dealkylated acid' (NW-1689) is formed by oxidative cleavage of the amine bond of either safinamide or the primary safinamide acid metabolite (NW-1153). The 'N-dealkylated acid' (NW-1689) undergoes further conjugation with glucuronic acid yielding its acyl glucuronide. NW-1689 is the main circulating metabolite in human plasma, exceeding the exposure of the parent (161% of parent). NW-1689 AG and NW-1153 account for about 18% and 11% of the parent drug exposure, respectively. None of the metabolites has pharmacological activity.
Safinamide is predominantly metabolised by non-microsomal enzymes (cytosolic amidases/MAOA); CYP3A4 and other CYP iso-enzymes play only a minor role in its overall biotransformation.
Safinamide does not appear to significantly induce or inhibit enzymes at clinically relevant systemic concentrations. In vitro metabolism studies have indicated that there is no meaningful induction or inhibition of cytochrome P450, CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A3/5 at concentrations which are relevant (Cmax of free safinamide 0.4 micromolar at 100 mg/day) in man. Dedicated drug-drug interaction studies performed with ketoconazole, L-dopa and CYP1A2 and CYP3A4 substrates (caffeine and midazolam), did not detect any clinically significant effects on the pharmacokinetics of safinamide, or L-dopa, caffeine and midazolam.

Excretion.

Safinamide undergoes almost complete metabolic transformation and the primary route of excretion is through the kidney. After oral administration of 14C-labelled safinamide, substance-related radioactivity was excreted in urine (76%) and to a low extent in faeces (1.5%) after 192 hours. The terminal elimination half-life of total radioactivity was approximately 80 hours.
The elimination half-life of safinamide is 20-30 hours. Steady-state is reached within one week.
There was no effect on the clearance of safinamide in patients with Parkinson's disease (PD) receiving safinamide as add on therapy to chronic levodopa (L-Dopa) and/or Dopamine Agonists (DA-Agonists).

Linearity/non-linearity.

The pharmacokinetics of safinamide are linear after single and repeated doses. No time-dependency was observed.

5.3 Preclinical Safety Data

Genotoxicity.

Safinamide was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (mouse micronucleus) assays.

Carcinogenicity.

Carcinogenicity studies were conducted for up to two years in mice and rats, at doses of 50, 100 and 200 mg/kg/day and 25, 50 and 100 mg/kg/day, respectively. Study results showed no evidence of tumorigenic potential related to safinamide at systemic exposures up to 2.8 to 3.5 times respectively, the anticipated systemic exposure (based on AUC) in patients given the maximal therapeutic dose.

Retinal degeneration.

Retinal degeneration and loss of photoreceptor cells were observed in albino and pigmented rats administered safinamide orally in toxicity studies of between 2 weeks and 6 months duration. In albino rats administered safinamide orally for two years, retinal scarring and cataracts were observed at all doses tested. No retinal degeneration was noted in monkeys, despite higher systemic exposure than in rodents.

Embryofoetal studies.

Foetal abnormalities have been observed in rats following oral administration of safinamide (0, 50, 100 or 150 mg/kg/day) throughout organogenesis. The lowest dose tested is approximately twice that of the maximum recommended human dose (MRHD) on an AUC basis. When safinamide was administered to pregnant rats in combination with levodopa/carbidopa (80/20 mg/kg/day), the dose causing developmental toxicity was lower than when safinamide was administered by itself (25 mg/kg/day).
No development toxicity was observed in rabbits up to the highest oral dose of safinamide tested (100 mg/kg/day). However, when safinamide was administered in combination with levodopa/carbidopa there was an increased incidence of embryofoetal death and cardiac and skeletal malformations.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silica, Opadry complete film coating system 02F59058 Clear (PING # 111420), Candurin Orange amber (PING # 106848) and Candurin Gold sheen (PING # 106846).
Safinamide mesilate is a white to off-white crystalline powder. Safinamide mesilate is freely soluble in water, methanol and dimethyl sulfoxide. Safinamide mesilate is sparingly soluble in ethanol and is practically insoluble in ethyl acetate. In aqueous buffers that span a pH range of 1.2 to 7.5, safinamide mesilate is highly soluble at pH 1.2 and 4.5, but shows low solubility (< 0.4 mg/mL) at pH 6.8 and 7.5.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Four (4) years.
The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Xadago tablets are supplied in PVC/PVDC/Aluminium blister packs containing 30 tablets. A starter pack containing 10 tablets may also be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

The molecular formula of safinamide mesilate is C17H19FN2O2.CH4O3S, the molecular weight is 398.45 g/mol and the chemical structure is:

CAS number.

The chemical abstracts service (CAS) registry number of safinamide mesilate is 202825-46-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (S4): Prescription Only Medicine.

Summary Table of Changes