4.1. Therapeutic indications

Safinamide is indicated for the treatment of adult patients with idiopathic Parkinson's disease (PD) as add on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients.

4.2. Posology and method of administration

Posology

Treatment with safinamide should be started at 50 mg per day. This daily dose may be increased to 100 mg/day on the basis of individual clinical need.

If a dose is missed the next dose should be taken at the usual time the next day.

Elderly

No change in dose is required for elderly patients.

Experience of use of safinamide in patients over 75 years of age is limited.

Hepatic impairment

Safinamide use in patients with severe hepatic impairment is contraindicated (see section 4.3). No dose adjustment is required in patients with mild hepatic impairment. The lower dose of 50 mg/day is recommended for patients with moderate hepatic impairment. If patients progress from moderate to severe hepatic impairment safinamide should be stopped (see section 4.4).

Renal impairment

No change in dose is required for patients with renal impairment.

Paediatric population

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

Method of administration

For oral use.

Safinamide should be taken with water.

Safinamide may be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Concomitant treatment with other monoamine oxidase (MAO) inhibitors (see sections 4.4 and 4.5).

Concomitant treatment with pethidine (see sections 4.4 and 4.5).

Use in patients with severe hepatic impairment (see section 4.2).

Use in patients with albinism, retinal degeneration, uveitis, inherited retinopathy or severe progressive diabetic retinopathy (see sections 4.4 and 5.3).

4.4. Special warnings and precautions for use

General warning

In general, safinamide may be used with selective serotonin re-uptake inhibitors (SSRIs) at the lowest effective dose, with caution for serotoninergic symptoms. In particular, the concomitant use of safinamide and fluoxetine or fluvoxamine should be avoided, or if concomitant treatment is necessary these medicinal products should be used at low doses (see section 4.5). A washout period corresponding to 5 half-lives of the SSRI used previously should be considered prior to initiating treatment with safinamide.

At least 7 days must elapse between discontinuation of safinamide and initiation of treatment with MAO inhibitors or pethidine (see section 4.3 and 4.5).

When safinamide is co-administered with products that are BCRP substrates, please refer to the SmPC for that particular medicinal product.

Hepatic impairment

Caution should be exercised when initiating treatment with safinamide in patients with moderate hepatic impairment. In case patients progress from moderate to severe hepatic impairment, treatment with safinamide should be stopped (see sections 4.2, 4.3 and 5.2).

Potential for retinal degeneration in patients with prior history of retinal disease

Safinamide 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 sections 4.3 and 5.3.

Impulse control disorders (ICDs)

Impulse control disorders can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Some reports of ICDs have also been observed with other MAO-inhibitors. Safinamide treatment has not been associated with any increase in the appearance of ICDs.

Patients and carers should be made aware of the behavioural symptoms of ICDs that were observed in patients treated with MAO-inhibitors, including cases of compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviour and compulsive spending or buying.

Dopaminergic side effects

Safinamide used as an adjunct to levodopa may potentiate the side effects of levodopa, and pre-existing dyskinesia may be exacerbated, requiring a decrease of levodopa. This effect was not seen when safinamide was used as an adjunct to dopamine agonists in early stage PD patients.

4.5. Interaction with other medicinal products and other forms of interaction

In vivo and in vitro pharmacodynamic drug interactions

MAO inhibitors and pethidine

Safinamide must not be administered along with other MAO inhibitors (including moclobemide) as there may be a risk of non-selective MAO inhibition that may lead to a hypertensive crisis (see section 4.3).

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 safinamide and pethidine is contraindicated (see section 4.3).

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 safinamide and sympathomimetics, such as those present in nasal and oral decongestants or cold medicinal products containing ephedrine or pseudoephedrine, requires caution (see section 4.4).

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, the concomitant administration of safinamide and dextromethorphan is not recommended, or if concomitant treatment is necessary, it should be used with caution (see section 4.4).

Antidepressants

The concomitant use of safinamide and fluoxetine or fluvoxamine should be avoided (see section 4.4), this precaution is based on the occurrence of serious adverse reactions (e.g. serotonin syndrome), although rare, that have occurred when SSRIs and dextromethorphan have been used with MAO inhibitors. If necessary, the concomitant use of these medicinal products should be at the lowest effective dose. A washout period corresponding to 5 half-lives of the SSRI used previously should be considered prior to initiating treatment with safinamide.

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 (see section 4.4). In view of the selective and reversible MAO-B inhibitory activity of safinamide, antidepressants may be administered but used at the lowest doses necessary.

In vivo and in vitro pharmacokinetic drug interactions

Safinamide may transiently inhibit BCRP in vitro. In drug-drug-interaction studies in human, a weak interaction was observed with rosuvastatin (AUC increase between 1.25 and 2.00 fold) 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) and to refer to their SmPCs to determine if a dose adjustment is needed.

Safinamide is almost exclusively eliminated via metabolism, largely by high capacity amidases that have not yet been characterized. safinamide is eliminated mainly in the urine. In human liver microsomes (HLM), the N-dealkylation step appears to be catalysed by CYP3A4, as safinamide clearance in HLM was inhibited by ketoconazole by 90%.

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.

The metabolite 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.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Safinamide should not be given to women of childbearing potential unless adequate contraception is practiced.

Pregnancy

There are no or limited amount of data from the use of safinamide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). safinamide is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of safinamide in milk (for details see 5.3).

A risk for the breast-fed child cannot be excluded. safinamide should not be used during breast feeding.

Fertility

Animal studies indicate that safinamide treatment is associated with adverse reactions on female rat reproductive performance and sperm quality. Male rat fertility is not affected (see section 5.3).

4.7. Effects on ability to drive and use machines

Somnolence and dizziness may occur during safinamide treatment, therefore patients should be cautioned about using hazardous machines, including motor vehicles, until they are reasonably certain that safinamide does not affect them adversely.

4.8. Undesirable effects

Summary of the safety profile

Dyskinesia was the most common adverse reaction reported in safinamide patients when used in combination with L-dopa alone or in combination with other PD treatments. Serious adverse reactions are known to occur with the concomitant use of SSRIs, 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. With MAO-inhibitors there have been reports of drug interactions with concomitant use of sympathomimetic medicinal products.

Impulse control disorders; pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments.

Tabulated list of adverse reactions

The tabulation below includes all adverse reactions in clinical trials where adverse reactions were considered related.

Adverse reactions are ranked under headings of frequency using the following conventions: 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).

System Organ Class

Very common

Common

Uncommon

Rare

Infections and infestations

Urinary tract infection

Bronchopneumonia, furuncle, nasopharyngitis, pyoderma, rhinitis, tooth infection, viral infection

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

Basal cell carcinoma

Acrochordon, melanocytic naevus, seborrhoeic keratosis, skin papilloma

Blood and lymphatic system disorders

Anaemia, leukopenia, red blood cell abnormality

Eosinophilia, lymphopenia

Metabolism and nutrition disorders

Decreased appetite, hypertriglyceridaemia, increased appetite, hypercholesterolaemia, hyperglycaemia

Cachexia, hyperkalaemia

Psychiatric disorders

Insomnia

Hallucination, depression, abnormal dreams, anxiety, confusional state, affect lability, libido increased, psychotic disorder, restlessness, sleep disorder

Compulsions, delirium, disorientation, illusion, impulsive behaviour, loss of libido, obsessive thoughts, paranoia, premature ejaculation, sleep attacks, social phobia, suicidal ideation

Nervous system disorders

Dyskinesia somnolence, dizziness, headache, Parkinson's disease

Paraesthesia, balance disorder, hypoaesthesia, dystonia, head discomfort, dysarthria, syncope, cognitive disorder

Coordination abnormal, disturbance in attention, dysgeusia, hyporeflexia, radicular pain, Restless Legs Syndrome, sedation

Eye disorders

Cataract

Vision blurred, scotoma, diplopia, photophobia, retinal disorder, conjunctivitis, glaucoma

Amblyopia, chromatopsia, diabetic retinopathy, erythropsia, eye haemorrhage, eye pain, eyelid oedema, hypermetropia, keratitis, lacrimation increased, night blindness, papilloedema, presbyopia, strabismus

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations, tachycardia, sinus bradycardia, arrhythmia

Myocardial infarction

Vascular disorders

Orthostatic hypotension

Hypertension, hypotension, varicose vein

Arterial spasm, arteriosclerosis, hypertensive crisis

Respiratory, thoracic and mediastinal disorders

Cough, dyspnoea, rhinorrhoea

Bronchospasm, dysphonia, oropharyngeal pain, oropharyngeal spasm

Gastrointestinal disorders

Nausea

Constipation, dyspepsia, vomiting, dry mouth, diarrhoea, abdominal pain, gastritis, flatulence, abdominal distension, salivary hypersecretion, gastrooesophageal reflux disease, aphthous stomatitis

Peptic ulcer, retching, upper gastrointestinal haemorrhage

Hepatobiliary disorders

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Hyperhidrosis, pruritus generalised, photosensitivity reaction, erythema

Alopecia, blister, contact dermatitis dermatosis, ecchymosis, lichenoid keratosis, night sweats, pain of skin, pigmentation disorder, psoriasis, seborrhoeic dermatitis

Musculoskeletal and connective tissue disorders

Back pain, arthralgia, muscle spasms, muscle rigidity, pain in extremity, muscular weakness, sensation of heaviness

Ankylosing spondylitis, flank pain, joint swelling, musculoskeletal pain, myalgia, neck pain, osteoarthritis, synovial cyst

Renal and urinary disorders

Nocturia, dysuria

Micturition urgency, polyuria, pyuria, urinary hesitation

Reproductive system and breast disorders

Erectile dysfunction

Benign prostatic hyperplasia, breast disorder, breast pain

General disorders and administration site conditions

Fatigue, asthenia, gait disturbance, oedema peripheral, pain, feeling hot

Drug effect decreased, drug intolerance, feeling cold, malaise, pyrexia, xerosis

Investigations

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

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

Fall

Foot fracture

Contusion, fat embolism, head injury, mouth injury, skeletal injury

Social circumstances

Gambling

Description of selected adverse reactions

Dyskinesia occurred early in treatment, was rated “severe”, led to discontinuation in very few patients (approx. 1.5%), and did not require reduction of dose in any patient.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In one patient suspected of consuming more than the daily prescribed dose of 100 mg for one month, symptoms of confusion, sleepiness, forgetfulness and dilated pupils were reported. These symptoms resolved on discontinuing the medicinal product, without sequelae.

The expected pattern of events or symptoms following intentional or accidental overdose with Safinamide 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 safinamide overdose. If an important overdose occurs, safinamide treatment should be discontinued and supportive treatment should be administered as clinically indicated.