Xadago (Tablets) Instructions for Use

Marketing Authorization Holder

Zambon, S.p.A. (Italy)

ATC Code

N04BD03 (Safinamide)

Active Substance

Safinamide

Dosage Forms

	Xadago	Film-coated tablets, 50 mg: 14, 28, 30, 90 or 100 pcs.
		Film-coated tablets, 100 mg: 14, 28, 30, 90 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blisters (10 pcs.) – carton packs (100 pcs.) – Prescription only
10 pcs. – blisters (3 pcs.) – carton packs (30 pcs.) – Prescription only
10 pcs. – blisters (9 pcs.) – carton packs (90 pcs.) – Prescription only
7 pcs. – blisters (2 pcs.) – carton packs (14 pcs.) – Prescription only
7 pcs. – blisters (4 pcs.) – carton packs (28 pcs.) – Prescription only

Film-coated tablets

10 pcs. – blisters (10 pcs.) – carton packs (100 pcs.) – Prescription only
10 pcs. – blisters (3 pcs.) – carton packs (30 pcs.) – Prescription only
10 pcs. – blisters (9 pcs.) – carton packs (90 pcs.) – Prescription only
7 pcs. – blisters (2 pcs.) – carton packs (14 pcs.) – Prescription only
7 pcs. – blisters (4 pcs.) – carton packs (28 pcs.) – Prescription only

Clinical-Pharmacological Group

Antiparkinsonian drug – selective MAO type B inhibitor

Pharmacotherapeutic Group

Antiparkinsonian drugs; dopaminergic agents; monoamine oxidase type B inhibitors

Pharmacological Action

Safinamide acts through both dopaminergic and non-dopaminergic mechanisms of action.

Safinamide is a highly selective and reversible inhibitor of MAO type B, increasing the extracellular dopamine content in the striatum.

Safinamide is associated with state-dependent inhibition of voltage-gated sodium channels and modulation of stimulated glutamate release.

The extent to which non-dopaminergic effects contribute to the overall effect has not been established.

Pharmacokinetics

After single and repeated oral administration, safinamide absorption is rapid, with the time to reach C_max being 1.8-2.8 hours after administration on an empty stomach.

The absolute bioavailability is high (95%), indicating that Safinamide is almost completely absorbed after oral administration, and first-pass metabolism is negligible.

The high absorption classifies Safinamide as a high-permeability substance.

The V_d is approximately 165 L, which is 2.5 times the body volume, indicating extensive extravascular distribution of safinamide.

The total clearance is 4.6 L/h, which classifies Safinamide as a low-clearance substance.

The binding of safinamide to plasma proteins is 88-90%.

Safinamide is almost completely metabolized (10% of the administered dose was found unchanged in the urine).

Radioactivity associated with the substance was mainly excreted in the urine (76%) and only to a small extent in the feces (1.5%) after 192 hours.

The terminal T_1/2 of total radioactivity was approximately 80 hours.

The T_1/2 of safinamide is 20-30 hours.

Steady state is reached within 1 week.

Indications

Idiopathic Parkinson’s disease of moderate and late stage with fluctuations in patients receiving a stable dose of levodopa, as additional monotherapy or in combination with other drugs for the treatment of Parkinson’s disease.

Dosage Regimen

Administer Xadago orally once daily, in the morning.

Initiate treatment at a dose of 50 mg once daily.

After at least two weeks, consider increasing the dose to 100 mg once daily based on individual clinical need and tolerability.

Do not exceed the maximum recommended daily dose of 100 mg.

Xadago is indicated as adjunctive therapy to a stable dose of levodopa.

If concomitant levodopa dose is reduced, the need for Xadago should be re-evaluated.

For patients with moderate hepatic impairment, the recommended dose is 50 mg; do not use the 100 mg dose.

Contraindicated in patients with severe hepatic impairment.

No dose adjustment is required for patients with renal impairment or for elderly patients.

Swallow the tablet whole; it can be taken with or without food.

Monitor patients for the emergence or worsening of dyskinesia; a dose reduction of levodopa may be required.

Discontinue treatment if hepatic impairment progresses from moderate to severe.

Adverse Reactions

Infections and infestations uncommon – urinary tract infection; rare – bronchopneumonia, furuncle, nasopharyngitis, pyoderma, rhinitis, tooth infection, viral infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps) uncommon – basal cell carcinoma; rare – acrochordon, melanocytic nevus, seborrheic keratosis, skin papilloma.

Blood and lymphatic system disorders uncommon – anemia, leukopenia, erythrocyte abnormality; rare – eosinophilia, lymphopenia.

Metabolism and nutrition disorders uncommon – decreased appetite, hypertriglyceridemia, increased appetite, hypercholesterolemia, hyperglycemia; rare – cachexia, hyperkalemia.

Psychiatric disorders common – insomnia; uncommon – hallucinations, depression, abnormal dreams, anxiety, confusion, affective lability, increased libido, psychotic disorder, restlessness, sleep disorder; rare – obsessive-compulsive disorder, delirium, disorientation, illusions, impulsive behavior, loss of libido, obsessive thoughts, paranoia, premature ejaculation, sleep attacks, social phobia, suicidal thoughts.

Nervous system disorders common – dyskinesia, somnolence, dizziness, headache, Parkinson’s disease; uncommon – paresthesia, balance disorder, hypesthesia, dystonia, dysarthria, syncope, cognitive disorder; rare – coordination abnormal, attention disorder, dysgeusia, hyporeflexia, radicular pain, restless legs syndrome, sedative effect.

Eye disorders common – cataract; uncommon – blurred vision, scotoma, diplopia, photophobia, retinal disorder, conjunctivitis, glaucoma; rare – amblyopia, chromatopsia, diabetic retinopathy, erythropsia, eye hemorrhage, eye pain, eyelid edema, hypermetropia, keratitis, lacrimation increased, night blindness, papilledema, presbyopia, strabismus.

Ear and labyrinth disorders uncommon – vertigo.

Cardiac disorders common – orthostatic hypotension; uncommon – palpitations, tachycardia, sinus bradycardia, arrhythmia, hypertension, hypotension, varicose veins; rare – arterial spasm, atherosclerosis, hypertensive crisis, myocardial infarction.

Respiratory, thoracic and mediastinal disorders uncommon – cough, dyspnea, rhinorrhea: rare – bronchospasm, dysphonia, oropharyngeal pain, oropharyngeal spasm.

Gastrointestinal disorders common – nausea; uncommon – constipation, dyspepsia, vomiting, dry mouth, diarrhea, abdominal pain, gastritis, flatulence, abdominal distension, hypersalivation, gastroesophageal reflux disease, aphthous stomatitis; rare – peptic ulcer, retching, upper gastrointestinal hemorrhage.

Hepatobiliary disorders rare – hyperbilirubinemia.

Skin and subcutaneous tissue disorders uncommon – hyperhidrosis, generalized pruritus, photosensitivity reaction, erythema; rare – alopecia, blisters, contact dermatitis; rare – dermatosis, ecchymosis, lichenoid keratosis, night sweats, skin pain, pigmentation disorder, psoriasis, seborrheic dermatitis.

Musculoskeletal and connective tissue disorders uncommon – back pain, arthralgia, muscle spasms, muscle rigidity, pain in extremity, muscle weakness, heaviness sensation; rare – ankylosing spondylitis, flank pain, joint swelling, musculoskeletal pain, myalgia, neck pain, osteoarthritis, synovial cyst.

Renal and urinary disorders uncommon – nocturia, dysuria; rare – urinary urgency, polyuria, pyuria, urinary retention.

Reproductive system and breast disorders uncommon – erectile dysfunction; rare – benign prostatic hyperplasia, breast disease, breast pain.

General disorders and administration site conditions uncommon – fatigue, asthenia, gait disturbance, peripheral edema, pain, feeling hot, decreased effect of safinamide, intolerance to safinamide, 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, urinalysis abnormal; rare – blood calcium decreased, blood potassium decreased, body temperature increased, cardiac murmur, cardiac stress test abnormal, hematocrit decreased, hemoglobin decreased, international normalized ratio decreased, lymphocyte count decreased, platelet count decreased, very low-density lipoproteins decreased.

Injury, poisoning and procedural complications common – fall; uncommon – foot fracture, contusion, fat embolism, head injury, mouth injury, skeletal injury.

Social circumstances rare – pathological gambling.

Contraindications

Hypersensitivity to safinamide; use in patients with severe hepatic impairment; use in patients with albinism, retinal degeneration, uveitis, hereditary retinopathy, or severe progressive diabetic retinopathy; concomitant treatment with other MAO inhibitors; concomitant treatment with pethidine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Safinamide should not be prescribed to women of childbearing potential unless adequate contraception is used.

Use in Hepatic Impairment

Use of safinamide in patients with severe hepatic impairment is contraindicated.

No dose adjustment is required for patients with mild hepatic impairment.

A lower dose of 50 mg/day is recommended for patients with moderate hepatic impairment.

If hepatic impairment in patients progresses from moderate to severe, safinamide should be discontinued.

Use in Renal Impairment

No dose adjustment is required for patients with renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required for elderly patients.

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

Special Precautions

Caution should be exercised when initiating treatment with safinamide in patients with moderate hepatic impairment.

If hepatic impairment progresses from moderate to severe, treatment with safinamide should be discontinued.

Potential retinal degeneration in patients with a history of prior retinal disease.

Safinamide should not be prescribed to patients with an ophthalmological history that puts them at increased risk of potential retinal effects (e.g., family history of hereditary retinal disease or history of uveitis).

Impulse control disorders may occur in patients receiving dopamine agonists and/or dopaminergic drugs.

Individual reports of impulse control disorders have also been observed with the use of other MAO inhibitors.

Treatment with safinamide has not been associated with any increase in the frequency of impulse control disorders.

Patients and caregivers should be informed about the behavioral symptoms of impulse control disorders that have been observed in patients treated with MAO inhibitors, including cases of compulsive behavior, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behavior, and compulsive spending or buying.

Effect on ability to drive and use machines

Somnolence and dizziness may occur during treatment with safinamide, so patients should be cautioned against using hazardous machinery, including automobiles, until they are reasonably sure that Safinamide does not adversely affect them.

Drug Interactions

Safinamide should not be used concomitantly with other MAO inhibitors (including moclobemide), as there may be a risk of non-selective MAO inhibition, which can lead to hypertensive crisis.

Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors.

Since this may be a side effect, concomitant use of safinamide and pethidine is contraindicated.

Due to the MAO inhibitory activity of safinamide, concomitant use of safinamide and sympathomimetics, such as those contained in nasal and oral decongestants or cold medicines containing ephedrine or pseudoephedrine, requires caution.

Interaction is possible with the concomitant use of dextromethorphan and non-selective MAO inhibitors.

Due to the MAO inhibitory activity of safinamide, concomitant use of safinamide and dextromethorphan is not recommended, or if such concomitant treatment is necessary, it should be used with caution.

Concomitant use of safinamide and fluoxetine or fluvoxamine should be avoided, due to the risk of occurrence, albeit rare, of serious adverse reactions (e.g., serotonin syndrome) that have been observed with the use of SSRIs and dextromethorphan concomitantly with MAO inhibitors.

If necessary, concomitant use of these drugs should be at the lowest effective dose.

Before starting treatment with safinamide, a washout period for previously used SSRIs, corresponding to 5 half-lives, should be considered.

Serious adverse reactions have been reported with the concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors.

Due to the selective and reversible MAO-B inhibitory activity of safinamide, antidepressants can be used concomitantly, but at the lowest necessary doses.

Safinamide may temporarily inhibit BCRP in vitro.

In human drug interaction studies, a weak interaction with rosuvastatin was observed (AUC 1.25-2.00 times), but no significant interaction with diclofenac was found.

It is recommended to monitor patients when safinamide is used concomitantly with drugs that are substrates of BCRP (e.g., rosuvastatin, pitavastatin, pravastatin, ciprofloxacin, methotrexate, topotecan, diclofenac or glyburide), and adjust their dose if necessary.

Elimination of safinamide occurs almost exclusively by metabolism, mainly via high-capacity amidases that have not yet been characterized.

Safinamide, used as an adjunct to levodopa, may enhance the side effects of levodopa, and pre-existing dyskinesia may worsen, requiring a reduction in the dose of levodopa.

This effect was not observed when safinamide was used as an adjunct to dopamine agonists in patients with early-stage Parkinson’s disease.

Safinamide is excreted mainly in the urine.

In human liver microsomes, the N-dealkylation step appears to be catalyzed by the CYP3A4 isoenzyme, since the clearance of safinamide in human liver microsomes was inhibited by ketoconazole by 90%.

Safinamide inhibited the organic cation transporter (OCT) 1 in vitro at clinically relevant concentrations in the portal vein.

Therefore, caution is required when safinamide is taken concomitantly with drugs that are substrates of OCT1 and have a T_1/2 similar to safinamide (2 hours) (e.g., metformin, acyclovir, ganciclovir), as the exposure of these substrates may consequently be increased.

The metabolite NW-1153 is a substrate for OAT3 at clinically relevant concentrations.

Drugs that are inhibitors of OAT3, used concomitantly with safinamide, may reduce the clearance of NW-1153 and thus may increase its systemic exposure.

The systemic exposure of NW-1153 is low (1/10 of the parent safinamide).

This potential increase is most likely not clinically significant, since NW-1153 is the first product of the metabolic pathway that is further converted into secondary and tertiary metabolites.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.