Xadago

Skip the missed dose and take your next dose at the usual time the next day. Do not take a double dose to make up for a missed one.

Contraindications

History of hypersensitivity to safinamide; reactions include swelling of the tongue and oral mucosa, and dyspnea

Severe hepatic impairment (Child-Pugh C: 10-15)

Coadministration with other monoamine oxidase inhibitors (MAOIs) or drugs that are potent inhibitors of MAO (eg, linezolid); combination may result in increased blood pressure, including hypertensive crisis

Coadministration with opioids (eg, meperidine and its derivatives, methadone, tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs); tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John’s wort; combination could result in life-threatening serotonin syndrome

Coadministration with dextromethorphan; combination of MAOIs and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior

Cautions

May cause or exacerbate hypertension; monitor patients for new onset hypertension or hypertension not adequately controlled after initiating therapy; medication adjustment may be necessary if blood pressure elevation is sustained

May cause serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs (see Contraindications)

May cause falling asleep during activities of daily living

May cause or exacerbate dyskinesia; consider levodopa dose reduction to mitigate dyskinesia

May cause hallucinations and psychotic behavior; consider dosage reduction or stopping medication if patient develops hallucinations or psychotic-like behaviors while on therapy

May cause problems with impulse control/compulsive behaviors; consider dose reduction or stopping medication if a patient develops compulsive behavior while on therapy

May cause withdrawal-emergent hyperpyrexia and confusion

Retinal degeneration and loss of photoreceptor cells observed in animal studies (albino and pigmented rats); periodically monitor patients for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy

Drug interaction overview

• Safinamide is contraindicated with other drugs in the MAOI class or other drugs that are potent inhibitors of MAO (see Contraindications)
• Opioids combined with safinamide has caused serious and sometimes fatal reactions and is contraindicated; at least 14 days should elapse between use of safinamide and these drugs to avoid serotonin syndrome (see Contraindications)
• Dextromethorphan and MAOIs is contraindicated, owing to reports of psychosis or bizarre behavior (see Contraindications)
• Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), and therefore could increase plasma concentrations of BCRP substrates (eg, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan)
• Dopamine antagonists (eg, antipsychotics, metoclopramide) may decrease safinamide efficacy
• Serotonergic drugs
  • SNRIs; triazolopyridine, tricyclic, or tetracyclic antidepressants; cyclobenzaprine; or St John’s wort are contraindicated with safinamide; at least 14 days should elapse between use of safinamide and these drugs to avoid serotonin syndrome (see Contraindications)
  • Coadministration with SSRIs: Monitor for symptoms of serotonin syndrome
• Tyramine
  • MAO in the GI tract and liver (primarily type A) provides protection from exogenous amines (eg, tyramine)
  • If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis
  • Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (eg, aged cheese, pickled herring) may cause release of norepinephrine, resulting in a rise in blood pressure (tyramine reaction)
  • Advise patients to avoid foods containing large amounts of tyramine
  • Selectivity for inhibiting MAO-B decreases in a dose-related manner above the highest recommended daily dosage, which may increase the risk for hypertension
  • In addition, isoniazid has some MAO inhibiting activity; monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and safinamide

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take: 

• Other drugs that inhibit monoamine oxidase including:
  • Monoamine oxidase inhibitors (MAOIs) such as tranylcypromine (Parnate), phenelzine (Nardil), selegiline (Eldepryl, Zelapar), isocarboxazid (Marplan), and rasagiline (Azilect)
  • Linezolid (Zyvox)
• Opioid drugs such as meperidine (Demerol), hydrocodone, oxycodone, methadone, propoxyphene, and tramadol
• Dextromethorphan (Delsym)
• Medications that could lead to serotonin syndrome, including antidepressants such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), desvenlafaxine (Pristiq), nefazodone (Serzone), paroxetine (Paxil, Pexeva), sertraline (Zoloft), venlafaxine (Effexor), trimipramine (Surmontil), isocarboxazid (Marplan), amitriptyline (Elavil), nortriptyline (Pamelor, Aventyl), protriptyline (Vivactil), and clomipramine (Anafranil)
• Cyclobenzaprine (Flexeril)
• Medications used for ADHD such as methylphenidate or amphetamines
• St. John's Wort

This is not a complete list of Xadago drug interactions. Ask your doctor or pharmacist for more information. 

It is not known whether this drug is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xadago, a decision should be made by the doctor whether the mother should discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 

Take Xadago exactly as prescribed.

Xadago comes in tablet form and is taken once daily at the same time every day, with or without food. 

If you miss a dose, take the next dose at the usual time the next day. 

• Store Xadago at room temperature: 68°F to 77°F (20°C to 25°C).
•  Keep this and all medicines out of the reach of children. 

You should not use safinamide if you are allergic to it, or if you have:

• severe liver disease.

Some medicines can cause unwanted or dangerous effects (including death) when used with safinamide. You should not use any of the following medicines within 14 days before or 14 days after you take safinamide:

• amphetamines (Adderall, Dexedrine, and others);

• cough medicine that contains dextromethorphan;

• cyclobenzaprine;

• methylphenidate (Concerta, Ritalin, Daytrana, and others);

• St. John's wort;

• another MAO inhibitor--isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others;

• certain antidepressants such as amitriptyline (Elavil), desipramine (Norpramin), desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), maprotiline (Ludiomil) , milnacipran (Savella), trimipramine (Surmontil), venlafaxine (Effexor), vilazodone (Viibryd), and many others; or

• opioid (narcotic) medicine such as meperidine (Demerol), methadone, propoxyphene (Darvon), tramadol (Ultram, Ultracet), and others.

To make sure safinamide is safe for you, tell your doctor if you have ever had:

• liver disease;

• high or low blood pressure;

• bipolar disorder, schizophrenia, or psychosis;

• unusual urges or impulses;

• abnormal muscle movements;

• problems with retina of your eye; or

• narcolepsy or other sleep disorder (or if you take medicine to help you sleep).

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether safinamide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Safinamide is used in combination with levodopa and carbidopa to treat adults with Parkinson's disease who are having "off" episodes. This medicine is a MAO-B inhibitor that works to increase and extend the effects of levodopa and may help to slow the progress of Parkinson's disease.

This medicine is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of safinamide in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of safinamide in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfentanil
• Amineptine
• Amitriptyline
• Amitriptylinoxide
• Amoxapine
• Amphetamine
• Anileridine
• Benzphetamine
• Buprenorphine
• Butorphanol
• Clomipramine
• Codeine
• Cyclobenzaprine
• Desipramine
• Desvenlafaxine
• Deutetrabenazine
• Dextroamphetamine
• Dextromethorphan
• Diacetylmorphine
• Dibenzepin
• Difenoxin
• Dihydrocodeine
• Diphenoxylate
• Doxepin
• Doxylamine
• Duloxetine
• Ethylmorphine
• Fentanyl
• Furazolidone
• Hydrocodone
• Hydromorphone
• Imipramine
• Iproniazid
• Isocarboxazid
• Ketobemidone
• Levomilnacipran
• Levorphanol
• Linezolid
• Lisdexamfetamine
• Lofepramine
• Maprotiline
• Melitracen
• Meperidine
• Methadone
• Methamphetamine
• Methylene Blue
• Methylphenidate
• Milnacipran
• Mirtazapine
• Moclobemide
• Morphine
• Morphine Sulfate Liposome
• Nalbuphine
• Nefazodone
• Nialamide
• Nicomorphine
• Nortriptyline
• Opipramol
• Opium
• Opium Alkaloids
• Oxycodone
• Oxymorphone
• Papaveretum
• Paregoric
• Phenelzine
• Phentermine
• Piritramide
• Procarbazine
• Propoxyphene
• Protriptyline
• Pseudoephedrine
• Rasagiline
• Remifentanil
• Selegiline
• Sibutramine
• St John's Wort
• Sufentanil
• Tapentadol
• Tianeptine
• Tilidine
• Tramadol
• Tranylcypromine
• Trazodone
• Trimipramine
• Venlafaxine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atropine
• Citalopram
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Midodrine
• Oxymetazoline
• Paroxetine
• Sertraline
• Valbenazine
• Vilazodone
• Vortioxetine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acarbose
• Chlorpropamide
• Glimepiride
• Glipizide
• Glyburide
• Insulin
• Insulin Aspart, Recombinant
• Insulin Bovine
• Insulin Degludec
• Insulin Detemir
• Insulin Glargine, Recombinant
• Insulin Glulisine
• Insulin Lispro, Recombinant
• Metformin
• Nateglinide
• Repaglinide
• Tolazamide
• Tolbutamide

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Tyramine Containing Food

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Dyskinesia (abnormal muscle movements) or
• Eye problems (eg, diabetic retinopathy, retinal or macular degeneration, uveitis), or family history of or
• Hypertension (high blood pressure) or
• Mental illness (eg, psychosis)—Use with caution. May make these conditions worse.

• Liver disease, moderate—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Liver disease, severe—Should not be used in patients with this condition.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Blurred vision
• dizziness
• headache
• nervousness
• pounding in the ears
• slow or fast heartbeat
• twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs

• Chills
• cold sweats
• confusion
• dizziness, faintness, or lightheadedness when getting up from lying or sitting position

• Agitation
• confusion
• diarrhea
• feeling that others are watching you or controlling your behavior
• feeling that others can hear your thoughts
• feeling, seeing, or hearing things that are not there
• fever
• overactive reflexes
• poor coordination
• restlessness
• severe mood or mental changes
• shivering
• sweating
• talking or acting with excitement you cannot control
• trembling or shaking
• trouble breathing
• unusual behavior

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Nausea

• Acid or sour stomach
• belching
• cough
• heartburn
• indigestion
• stomach discomfort, upset, or pain
• trouble sleeping

• Skin rash
• swelling of the gums and tongue

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use Xadago as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine at the same time of day.
• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking Xadago as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Xadago is contraindicated in patients with:

• Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid. The combination may result in increased blood pressure, including hypertensive crisis [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
• Concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John's wort. Concomitant use could result in life-threatening serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7.2, 7.3, 7.5)].
• Concomitant use of dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior [see Drug Interactions (7.4)].
• A history of a hypersensitivity to safinamide. Reactions have included swelling of the tongue and oral mucosa, and dyspnea.
• Severe hepatic impairment (Child-Pugh C: 10-15) [see Use in Specific Populations (8.6)].

Hypertension

Xadago may cause hypertension or exacerbate existing hypertension. In clinical trials, the incidence of hypertension was 7% for Xadago 50 mg, 5% for Xadago 100 mg, and 4% for placebo. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting Xadago. Medication adjustment may be necessary if elevation of blood pressure is sustained.

Monitor for hypertension if Xadago is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies [see Drug Interactions (7.5)].

Xadago is a selective inhibitor of MAO-B at the recommended dosages of 50 mg or 100 mg daily. Selectivity for inhibiting MAO-B decreases above the recommended daily dosages [see Clinical Pharmacology (12.2)]. Therefore, Xadago should not be used at daily dosages exceeding those recommended because of the risks of hypertension, exacerbation of existing hypertension, or hypertensive crisis.

Dietary tyramine restriction is not required during treatment with recommended doses of Xadago. However, use with certain foods that contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension, resulting from an increased sensitivity to tyramine in patients taking recommended dosages of Xadago, and patients should be advised to avoid such foods.

Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and Xadago [see Drug Interactions (7.1, 7.6)].

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAO inhibitors (including selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate, amphetamine, and their derivatives. Concomitant use of Xadago with these drugs is contraindicated.

In clinical trials, serotonin syndrome was reported in a patient treated with Xadago and an SSRI. Use the lowest effective dose of SSRIs in patients treated with concomitant Xadago.

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, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Falling Asleep During Activities of Daily Living

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.

In clinical studies, sleep attacks/sudden onset of sleep were reported in patients treated with Xadago 100 mg/day.

If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), Xadago should ordinarily be discontinued. If a decision is made to continue these patients on Xadago, advise them to avoid driving and other potentially dangerous activities.

Dyskinesia

Xadago may cause dyskinesia or exacerbate pre-existing dyskinesia.

In clinical trials, the incidence of dyskinesia was 21% for Xadago 50 mg, 18% for Xadago 100 mg, and 9% for placebo. There was a greater incidence of dyskinesia causing study discontinuation in Parkinson's disease patients treated with Xadago 50 mg or 100 mg (1%), compared to placebo (0%) [see Adverse Reactions (6.1)].

Reducing the patient's daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.

Hallucinations / Psychotic Behavior

Patients with a major psychotic disorder should ordinarily not be treated with Xadago because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of Parkinson's disease [see Drug Interactions (7.8)].

Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking Xadago.

Impulse Control / Compulsive Behaviors

Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Xadago, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Xadago. Consider dose reduction or stopping the medication if a patient develops such urges while taking Xadago.

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.

Retinal Pathology

Retinal degeneration and loss of photoreceptor cells were observed in albino and pigmented rats administered safinamide orally in toxicity studies of up to 6 months duration. In albino rats administered safinamide orally for two years, retinal scarring and cataracts were observed at all doses tested [see Nonclinical Toxicology (13.2)].

Periodically monitor patients for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy (e.g., diabetic retinopathy).

Xadago tablets contain safinamide, which is a MAO-B inhibitor, as the mesylate salt. Safinamide mesylate is (S)-2- [[4-[(3-fluorophenyl) methoxy]phenyl]methyl]aminopropanamide methanesulfonate (1:1) and its structural formula is below.

The molecular formula of safinamide mesylate is C17H19FN2O2∙CH4O3S and its molecular weight is 398.45.

Safinamide mesylate is a white to off-white crystalline powder. Safinamide mesylate is freely soluble in water, methanol and dimethyl sulfoxide. Safinamide mesylate 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 mesylate 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.

Xadago is available as 50 mg and 100 mg film-coated tablets for oral administration. Each Xadago tablet contains 65.88 mg or 131.76 mg of safinamide mesylate, equivalent to 50 mg or 100 mg, respectively, of safinamide free base. The tablets also contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide (red), magnesium stearate, microcrystalline cellulose, polyethylene glycol 6000, potassium aluminum silicate, and titanium dioxide.

Xadago (safinamide) is monoamine oxidase inhibitor type B (MAO-B). This medicine works by allowing a chemical called dopamine (DOE pa meen) to work for longer periods of time in the brain. Low levels of dopamine in the brain are associated with Parkinson's disease.

Xadago is given with levodopa and carbidopa to treat "wearing-off" episodes (muscle stiffness, loss of muscle control) in people with Parkinson's disease.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• imatinib;

• irinotecan;

• lapatinib;

• methotrexate

• metoclopramide;

• mitoxantrone;

• rosuvastatin;

• sulfasalazine; or

• topotecan.

This list is not complete. Other drugs may interact with safinamide, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.