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P T. 2017;42(10): 622-624,637
Drug Forecast

Xadago (Safinamide)

A Monoamine Oxidase B Inhibitor for the Adjunct Treatment of Motor Symptoms in Parkinson’s Disease
Martin Paspe Cruz PharmD, BCGP, BCPP, FASCP

INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative brain disorder with a constellation of motor abnormalities, such as bradykinesia, resting tremor, cogwheel rigidity, and postural instability, as well as neuropsychiatric symptoms including depression, dementia, apathy, hallucinations, and delusions.17 In 2013, approximately 53 million people worldwide were affected by PD, and there were approximately 103,000 PD-related deaths.8 In patients with PD, neurons die, leading to a lack of the available dopamine in the brain responsible for transmitting signals between areas of the brain used for coordination of smooth and balanced muscle movement. Regardless of its severity, PD symptoms are associated with significantly increased disability, caregiver burden, nursing home placement, morbidity, and mortality, and can negatively affect quality of life as well.911

Although there is no cure for PD at present, medications, surgery, deep-brain stimulation, and multidisciplinary management can provide symptom relief. Pharmacotherapy for treating the motor symptoms of PD includes levodopa/carbidopa; catechol-O-methyl transferase (COMT) inhibitors, such as entacapone and tolcapone; anticholinergics, such as benztropine; dopamine agonists, such as bromocriptine, pergolide, pramipexole, ropinirole, and cabergoline; amantadine; and monoamine oxidase B (MAO-B) inhibitors, such as selegiline, rasagiline, and the newest in the class, safinamide (Xadago, U.S. WorldMeds, LLC).13

Randomized, double-blind, placebo-controlled trials demonstrated the safety and efficacy of safinamide for the treatment of motor symptoms in patients with PD who are stable on dopamine agonists and are fluctuating on levodopa. Improvement in daily “on-time” with safinamide was significant and was maintained for at least two years in the trials, without significant worsening of dyskinesia. No specific or additional adverse effects were observed with the drug other than the known safety issues already associated with the use of MAO-B inhibitors.13

DOSAGE AND ADMINISTRATION

The recommended initial dose of safinamide for adjunctive treatment with levodopa/carbidopa in patients with PD is 50 mg once daily taken at the same time each day, with or without meals. Based on clinical need and tolerability after two weeks, the dose may be titrated up to the recommended maximum dose of 100 mg once daily.13

To avoid the risk of withdrawal-emergent hyperpyrexia and confusion, the dose of safinamide should be reduced from 100 mg once daily to 50 mg once daily for one week before discontinuation of treatment. Consumption of foods containing high amounts of tyramine should be avoided while taking safinamide.13

MECHANISM OF ACTION

The antiparkinson mechanism of safinamide is through reversible inhibition of selective MAO-B, as a mesylate salt, thus reducing the degradation of dopamine. It inhibits glutamate release and dopamine reuptake in the brain.6,9,10,13 Safinamide also blocks sodium and calcium channels, although the clinical significance of this to PD is unknown. The chemical name of the drug is (S)-2-[[4-[(3-fluorophenyl) methoxy]phenyl] methyl]aminopropanamide methanesulfonate (1:1) with a molecular formula of C17H19FN2O2·CH4O3S and a molecular weight of 398.45 (Figure 1).1317

PHARMACOKINETICS

Safinamide is absorbed quickly, with a bioavailability of 95%, and a demonstrated time to maximum plasma concentration of 1.8–2.8 hours. It exhibits extensive extravascular distribution with a volume of distribution of approximately 165 L. Safinamide does not undergo significant first-pass metabolism and is mediated by amidase enzymes producing safinamide acid and other metabolites. Safinamide is mediated by cytochrome P450 (CYP) 3A4 isoenzymes. Though not clinically significant, safinamide acid also binds to the organic anion transporter 3 (OAT3). It is 88% to 90% plasma protein-bound and is primarily eliminated through the kidneys (approximately 76%) in the form of its metabolites, with an elimination half-life of 20 to 30 hours. About 1.5% of safinamide is found excreted in the feces. Safinamide exhibits linear pharmacokinetics after oral administration of 50 mg to 300 mg (three times the maximum recommended daily dose) with a steady state reached within five to six days.13,1820

PHARMACODYNAMICS

In clinical studies at dosages greater than 20 mg per day, safinamide completely (greater than 90%) inhibited MAO-B and had greater than 1,000-fold selectivity over MAO-A.13

CLINICAL TRIALS

Two 24-week, randomized, double-blind, placebo-controlled, multinational trials were conducted to establish the efficacy of safinamide in patients with PD exhibiting motor fluctuations or “off-times” while on a stable dose of levodopa/carbidopa or other medications used in PD, such as dopamine agonists, COMT inhibitors, anticholinergics, and/or amantadine. The primary endpoint in both studies was the change from baseline in total daily on-time without troublesome dyskinesia, based on 18-hour diaries completed by the patients for at least three days before each scheduled visit. The off-time during the diary period and the reduction in Unified Parkinson’s Disease Rating Scale Part III (UPDRS–III) motor examination scores during on-time were the secondary endpoints.13

In study 1 (N = 669), patients were administered safinamide 50 mg or 100 mg, or placebo once daily. Patients in both safinamide groups showed a significant increase in daily on-time without symptoms of dyskinesia compared with placebo. The patients in both safinamide groups also had significant reductions in off-time and reductions in UPDRS–III scores during on-time (Table 1).13

In study 2 (N = 549), patients were administered safinamide 100 mg or placebo once daily. Compared with those who received placebo, the safinamide-treated patients experienced significant improvements in the primary and secondary endpoints (Table 2).13

SAFETY PROFILE

Adverse Effects

The most common adverse effects of safinamide 100 mg reported in clinical trials at a rate of 2% or greater versus placebo include dyskinesia, falls, and nausea. Other adverse effects include hypertension, indigestion, hypersensitivity reactions, drowsiness, insomnia, anxiety, and hallucinations.13,19

Contraindications

Safinamide is contraindicated for use in patients with a history of hypersensitivity to safinamide and its derivatives. Its use in patients with severe hepatic impairment (Child–Pugh C score 10–15) or with albinism, retinitis pigmentosa, severe diabetic neuropathy, uveitis, and other disorders of the retina is contraindicated. Concomitant use of safinamide with other MAO inhibitors (MAOIs) or other drugs that are potent inhibitors of MAO, including linezolid, are contraindicated due to a potential increased risk of hypertensive crisis. It is also contraindicated with concomitant use of opioids, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, methylphenidate, amphetamine and its derivatives, and St. John’s wort, due to potential increased risk of life-threatening serotonin syndrome. Due to potential increased risk of psychosis or abnormal behavior, concomitant use of dextromethorphan and safinamide is contraindicated.13,19

Warnings and Precautions

Dosage above the recommended daily dose is not recommended due to an increased risk of hypertension, exacerbation of existing hypertension, or hypertensive crisis. Patients taking safinamide should be monitored for new-onset or exacerbation of pre-existing hypertension. Antihypertensive drugs may require dosage adjustment while taking safinamide. Driving and operating heavy machinery should be avoided with safinamide due to reported daytime sleepiness or episodes of falling asleep during daily activities. Other neurological adverse effects reported include new-onset or worsening dyskinesia and neuroleptic malignant syndrome as a result of rapid dosage reduction, withdrawal, or change in therapy of other dopaminergic drugs. Patients with a history of ophthalmic disorders, such as retinal/macular degeneration, uveitis, retinal disorders, albinism, retinitis pigmentosa, and active retinopathy, should be monitored for visual changes while taking safinamide. The safinamide dose should be reduced or discontinued if patients develop exacerbation of psychotic disorders, compulsive behaviors, or impaired impulse control. Concomitant use of safinamide and foods containing very high tyramine amounts (i.e., greater than 150 mg) should be avoided.13

Use in Specific Populations

Pediatric Use

The safety and efficacy of safinamide have not been established in pediatric populations.13

Pregnancy and Lactation

Due to lack of human data evaluating fetal risk when safinamide is used in pregnant women or women of childbearing age, the benefits and risks of the drug in this population must be weighed prior to starting treatment. Similarly, the presence of safinamide in breast milk and its effect on breastfed infants is unknown.13

Geriatric Use

Although limited clinical trials were conducted in the elderly population, data suggest that the pharmacokinetics of safinamide are not affected by age.13

Renal and Hepatic Impairment

Safinamide was not affected by impaired renal function based on an open-label, parallel-group, single oral dose study comparing patients with normal renal function to those with moderate-to-severe renal impairment.

The recommended maximum dose of safinamide in patients with moderate hepatic impairment (Child–Pugh score 7–9) is 50 mg once daily. Discontinue use if hepatic impairment progresses to severe during use. Safinamide is contraindicated in patients with severe hepatic impairment (Child–Pugh score 10–15).13

Drug–Drug Interactions

Safinamide and its major metabolites did not show significant inhibition or induction of CYP enzymes and did not inhibit MAO-A, levodopa decarboxylase, or aldehyde dehydrogenase enzymes during in vitro metabolism studies at clinically significant dosing concentrations. In addition, it is not a P-glycoprotein (P-gp) substrate and, along with its metabolites, did not inhibit P-gp or other transporters (OCT2, OATP1B1, OATP1B3, BSEP, and OAT1/3/4). At the 100-mg dose, safinamide may inhibit breast cancer resistance protein (BCRP). In vivo studies showed no clinically significant effects on the pharmacokinetics profile of combination therapy with safinamide, ketoconazole, levodopa, and CYP1A2 (e.g., caffeine) and CYP3A4 (e.g., midazolam) substrates.13,20

Due to the potential increased risk of hypertensive crisis, safinamide is contraindicated for use with other MAOIs, including linezolid. Patients taking safinamide and isoniazid concomitantly should be monitored for hypertension and reaction to tyramine-containing foods. Concomitant use of opioids and MAOIs is contraindicated. Serotonergic agents (e.g., SSRI/SNRIs, tri- or tetracyclic antidepressants, cyclobenzaprine, St. John’s wort) are contraindicated with safinamide due to potential drug-induced serotonin syndrome. Dextromethorphan is contra indicated for use with MAOIs due to reported cases of psychosis and bizarre behavior. Sympathomimetic drugs, such as methylphenidate and amphetamine and its derivatives, are contraindicated for use with MAOIs as a result of reported cases of severe hypertensive reactions, including hypertensive crises. At minimum, a 14-day wash-out period is recommended between the discontinuation of safinamide and initiation of therapy with any of these contraindicated drugs.13

Patients treated with safinamide should be monitored for elevated blood pressure when using prescription or over-the-counter sympathomimetic medications such as cold remedies and nasal or oral decongestants.13

Intestinal BCRP substrates, such as methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, and topotecan, may be inhibited by safinamide and its metabolites, which could increase plasma concentrations of the BCRP substrates, leading to increased adverse effects. Monitor patients for decreased efficacy of safinamide and exacerbation of PD symptoms when dopamine antagonists (e.g., anti psychotics, metoclopramide) and safinamide are taken in combination.13

P&T CONSIDERATIONS

The safety and efficacy of safinamide as an adjunct for the treatment of the motor symptoms of PD were established through randomized, double-blind, placebo-controlled trials. Symptom improvement was significant and maintained for at least two years without the worsening of dyskinesia. 13 Safinamide is worthy of formulary consideration for patients unresponsive to other pharmacotherapy options for PD. Unlike the MAO-B inhibitors selegiline and rasagiline, which show dyskinesia as a secondary effect in patients with advanced PD, safinamide does not have methamphetamine metabolites and acts on the glutamatergic pathway.

Safinamide is available in 50-mg and 100-mg tablets. The average wholesale price for a 30-day supply of either strength is $804.21

CONCLUSION

Safinamide, a potent, highly selective, reversible MAO-B inhibitor, can improve motor function in patients with PD without aggravating dyskinesia. This positive effect may be related to its dual mechanism, which acts on both the dopaminergic and glutamatergic pathways.

Figure and Tables

Structural Formula of Safinamide13

Results of Endpoint Measures in Study 113

Treatment Group Patients, n Baseline in Hours, Mean ± SD Change From Baseline to Endpoint, LSD vs. Placebo (95% CI, P value)
Change in Mean Total Daily On-Time
Placebo 212 9.3 ± 2.2
Safinamide 50 mg/day 217 9.4 ± 2.2 0.50 (0.03–0.96; P = 0.0356)
Safinamide 100 mg/day 216 9.6 ± 2.5 0.53 (0.07–1.00; P = 0.0238)
Change in Mean Daily Off-Time
Placebo 212 5.3 ± 2.1
Safinamide 50 mg/day 217 5.2 ± 2.0 −0.55 (−0.93 to −0.17; P = 0.0049)
Safinamide 100 mg/day 216 5.2 ± 2.2 −0.57 (−0.95 to −0.19; P = 0.0037)
Change in UPDRS–III
Placebo 212 28.6 ± 12.0
Safinamide 50 mg/day 217 27.3 ± 12.8 −1.75 (−3.24 to −0.36; P = 0.0212)
Safinamide 100 mg/day 216 28.4 ± 13.5 −2.48 (−3.97 to −1.00; P = 0.0011)

CI = confidence interval; LSD = least squares difference; SD = standard deviation; UPDRS–III = Unified Parkinson’s Disease Rating Scale Part III (UPDRS–III) motor examination scores.

Results of Endpoint Measures in Study 213

Treatment Group Patients, n Baseline in Hours, Mean ± SD Change From Baseline to Endpoint, LSD vs. Placebo (95% CI, P value)
Change in Mean Total Daily On-Time
Placebo 273 9.1 ± 2.5
Safinamide 100 mg/day 270 9.3 ± 2.4 0.99 (0.58–1.39; P < 0.001)
Change in Mean Daily Off-Time
Placebo 273 5.36 ± 2.00
Safinamide 100 mg/day 270 5.35 ± 1.98 −1.06 (−1.43 to −0.69; P < 0.001)
Change in UPDRS–III
Placebo 273 23.03 ± 12.75
Safinamide 100 mg/day 270 22.33 ± 11.79 −1.70 (−2.89 to −0.50; P < 0.005)

CI = confidence interval; LSD = least squares difference; SD = standard deviation; UPDRS–III = Unified Parkinson’s Disease Rating Scale Part III (UPDRS–III) motor examination scores.

Author bio: 
Dr. Cruz is a Clinical Assistant Professor at Virginia Commonwealth University School of Pharmacy in Richmond, Virginia, and Hampton University School of Pharmacy in Hampton, Virginia; Assistant Professor of Clinical Psychiatry at Eastern Virginia Medical School in Norfolk, Virginia; and a Clinical Pharmacy Specialist at the Hampton Veterans Affairs Medical Center in Hampton, Virginia. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi and Associates in New York, New York.

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