Xadago: What Pharmacists Should Know

Parkinson’s disease (PD) is a chronic and progressive movement disorder that affects approximately 1 million Americans. Individuals with PD often experience symptoms of tremor that may progress to stiffness, slowed movement, slurred speech, and difficulty walking. The combined direct and indirect cost of PD is estimated to be nearly $25 billion per year in the United States alone. Although PD can’t be cured, medications have been shown to improve symptoms and quality of life.¹

In March 2017, the Food and Drug Administration (FDA) approved Newron Pharmaceutical's Xadago (safinamide) as add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes.

This article will highlight several key therapeutics areas with Xadago that every pharmacist should know.

History

The manufacturer of Xadago experienced a long road to receive FDA approval. The safinamide compound was first developed in the early 1990s with phase 3 clinical trials starting in 2004.² In 2010, it was announced that in a study of 544 patients with mid- to late-stage PD, safinamide had failed to meet the primary endpoint of improvement in dyskinesia after 24 months of treatment, compared to placebo.³

Four years later and after completing new clinical studies, the manufacturer submitted an NDA (New Drug Application) for safinamide; the FDA subsequently sent back a “Refusal to File Letter” citing organization and navigation issues. The company refiled, but faced another temporary setback in March 2016 when the FDA delayed the drug’s approval in order to request additional information to address possible abuse concerns and dependence/withdrawal effects of the medication. After supplying the requested information, the FDA concluded that the abuse potential of safinamide is low compared to scheduled controls.⁴

The medication was approved in Europe in February 2015 and launched into the market during the next 2 years. It received approval in the United States in March 2017, marking Xadago as the first new treatment in over a decade for PD.² It is expected to launch to the market in the second half of 2017.

Indication

Xadago is a monoamine oxidase type B (MAO-B) inhibitor indicated as adjunctive treatment to levodopa/carbidopa in patients with PD experiencing “off” episodes.

Limitations of Use

Xadago has not been shown to be effective as monotherapy for the treatment of PD. Additionally, it is not known if the medication is safe and effective in children.

Mechanism of Action

The exact mechanism by which safinamide has an effect in PD is not known. The medication has been shown to act as an inhibitor of MAO-B, which blocks the breakdown of dopamine. This is thought to result in higher dopamine levels and increased dopaminergic activity in the brain.⁵ Additional activity of safinamide includes sodium channel blockade and calcium channel modulation, thus inhibiting excessive glutamate release.

Safinamide has been shown to be more selective for MAO-B versus MAO-A than selegiline and rasagiline (1,000 times higher in humans, compared with 127 for selegiline and 103 for rasagiline). This higher selectivity is thought to reduce concerns over diet restrictions with safinamide. Moreover, the MAO-B inhibition is totally reversible, which may limit possible drug—drug interactions. To note, safinamide does not affect L-type calcium channels; therefore, the drug would not be expected to exert significant effects on blood pressure and heart rate.⁶

Formulation, Storage

Xadago is available as 50 mg and 100 mg tablets in bottles of 30 and 90 tablets. It should be stored at room temperature.

Dosing

The recommended starting dose of Xadago is 50 mg administered orally once daily at the same time of day. After two weeks, the dosage may be increased to 100 mg once daily, based on individual need and tolerability. Daily dosages of Xadago above 100 mg have not been shown to provide additional benefit, but may increase the risk for adverse reactions.

Efficacy

The efficacy of Xadago was assessed in 2 double-blind, placebo-controlled studies in patients with PD who were also taking levodopa and were experiencing “off” episodes (i.e. a time when a patient’s medications are not working well causing increased PD symptoms). In both studies, the primary measure of effectiveness was the change from baseline in total daily “on” time (i.e. a time when symptoms are reduced), without troublesome dyskinesia, based on 18-hour diaries completed by patients.

The first study enrolled 645 patients who were randomized to receive Xadago 50 mg, Xadago 100 mg, or placebo. Patients receiving both doses of Xadago experienced significantly increased “on” time without troublesome dyskinesia compared to the placebo group. The increase in “on” time was accompanied by a significant reduction in “off” time and better scores on a measure of motor function assessed during “on” time than before treatment.

In a separate study, 549 participants were randomized to receive Xadago 100 mg or placebo for up to 24 weeks. The mean duration of Parkinson’s disease was approximately 9 years. Study results showed that patients taking Xadago in combination with levodopa treatment had more “on” time without troublesome dyskinesia. They also had better scores on a measure of motor function assessed during “on” time than before treatment.

Safety

The most common adverse reactions seen in patients receiving Xadago during clinical trials included dyskinesia, falls, nausea, and insomnia. Warnings and precautions included within Xadago’s prescribing information include potentially increased risks for hypertension, serotonin syndrome when used together with pro-serotonergic drugs, falling asleep during normal activities, hallucinations and psychotic behavior, impulse control behaviors, and exacerbations of dyskinesia.

Xadago is contraindicated in patients with taking other monoamine oxidase inhibitors, opioid drugs, selective norepehrine reuptake inhibitors, tricyclic antidepressants, cyclobenzaprine, methylphenidate, amphetamines, St. John’s wort, and dextromethorphan. Additionally it should be avoided in patients with severe hepatic impairment (Child-Pugh C)

Counseling Points

Xadago is administered orally once daily, at the same time of day. It can be given without regard to meals. Patients should be advised to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking Xadago due to the potential for large increases in blood pressure. If a dose is missed, patients should be instructed to take the next dose at the usual time on the following day.⁵

Product Comparison

The tablet below shows a comparison of Xadago with other MAO-B inhibitors

Drug

Formulation

Dosing Frequency

Generic

Cost*

Xadago

Oral tablet

QD

N

Not available

Eldepryl (selegiline)

Oral capsule

BID

Y

$138

Zelapar (selegiline)

Oral disintegrating tablet (ODT)

QD

N

$2442

Azilect (rasagiline)

Oral tablet

QD

Y

$749

*Cost based on average wholesale price (AWP) for a 30-day supply of the generic formulation (if available), per Lexi-Drugs.⁷ Cost to the patient will vary based on insurance coverage.

Conclusion

Xadago presents patients with another medication option for add-on therapy in those who are not adequately controlled on levodopa/carbidopa. Due to its mechanism of action, researchers have theorized that Xadago may have more advantageous effects compared to selegiline or rasagiline; however, head-to-head clinical studies are currently lacking.

References:

• What is Parkinson's Disease. Parkinson's Disease Foundation. Available at: www.pdf.org/about_pd. Accessed May 6, 2017
• Newron History. Newron Pharmaceuticals. Available at: https://www.newron.com/ENG/Default.aspx?PAG=133. Accessed May 7, 2017.
• Dennis M. Merck KGaA, Newron's drug safinamide misses goal of Parkinson’s disease study. FirstWorld Pharma. Nov 4, 2010. Available at: http://www.firstwordpharma.com/node/800259
• Center for Drug Evaluation and Research: Application Number 207145Orig1s000. Food and Drug Administration. Version 2/12/16. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/207145Orig1s000AdminCorres.pdf
• Xadago [Prescribing Information]. US WorldMeds, LLC. Louisville, KY. March 2017.
• Kulisevsky J. Emerging Role of Safinamide in Parkinson’s Disease Therapy. European Neurological Review, 2014;9(2):108-112. doi; http://doi.org/10.17925/ENR.2014.09.02.108
• Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; May 10, 2017.