NORTHERA™ (Droxidopa): A New Hope?RUTGERS FORMULARY EVALUATION

GROUP 205SANDEEPKUMAR BALABBIGARI SOOYEON KIM NICOLLE ROCHINO MONICA SORIO

Objectives

Evaluate the benefits and efficacy of using Northera™ (Droxidopa) in treating neurogenic orthostatic hypotension

● Description● Pharmacology● Dosing and Administration● Pharmacokinetics● Efficacy● Safety and Tolerability ● Budget Impact● Conclusion & Recommendation

“Northera™ (Droxidopa) is the first pharmacotherapy for the treatment of [neurogenic orthostatic hypotension] in almost 20 years, and the first to be approved based on improvement of symptoms related to [orthostatic hypotension] rather than just an improvement in upright blood pressure.”8

NORTHERA™ (Droxidopa) BackgroundRUTGERS FORMULARY EVALUATION

Description2,4

Initial U.S. Approval: 2014

FDA-approved under Chelsea Therapeutics Inc.

Rights gained by Lundbeck LLC after acquiring Chelsea Therapeutics Inc. 2

Therapeutic Category: Vasopressor

AHFS Classification: α- and β-adrenergic agonists 4

Approved under FDA’s accelerated approval program

Oral Capsules

● Hard gelatin capsules● Each capsule is branded with “Northera”● Each bottle contains 90 capsules● 100 mg: light blue cap (67386-820-19)● 200 mg: light yellow cap (67386-821-19)● 300 mg: light green cap (67389-822-19)

Storage: 20°C to 25°C (68°F to 77°F)

Symptomatic Neurogenic Orthostatic Hypotension (nOH)

nOH

● Characterized by orthostatic dizziness and lightheadedness● Caused by primary autonomic failure, dopamine β-hydroxylase deficiency,

and non-diabetic autonomic neuropathy

Only indicated for use in the adult population

Long-term efficacy has not yet been determined

FDA-Approved Indication5,10

Northera™ (Droxidopa) Norepinephrine (NE)

L-aromatic-amino-acid decarboxylase

Effects of Droxidopa-Induced NE

● Increases blood pressure● Peripheral arterial and venous vasoconstriction● Vasoconstriction increases blood pressure and relieves

orthostatic hypotension

Mechanism of Action6,12

L-threo-3,4-dihydroxyphenylserineL-DOPS

Non-Pharmacologic

● Increase water intake ● Increase salt intake● Compression or abdomen

stockings● Physical activity● Head tilt, leg crossing

Other nOH Treatments10

Pharmacologic

● Midodrine● Fludrocortisone● Recombinant EPO● Pseudoephedrine● Pyridostigmine● Yohimbine

NORTHERA™ (Droxidopa) EfficacyRUTGERS FORMULARY EVALUATION

Droxidopa for Short-Term Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Parkinson’s Disease (nOH306B)7

Objective● Clinical efficacy of droxidopa compared to placebo

Study Design● Double-blind, phase III, multicenter, randomized, placebo-controlled study● 8 weeks● Inclusion Criteria: Diagnosis of PD, > 18 years old; signs and symptoms of nOH (ex: BP decrease > 20

mmHg systolic or > 10 mmHg diastolic upon standing for 3 minutes); > 3 score on cCGI-S scale● Exclusion Criteria: Use of vasoconstricting agents or long-acting anti-HTN meds; sustained, severe HTN

(> 180/110 mmHg while seated or supine); a MMSE score < 23; history of heart disease

Treatment Regimens● Two treatment groups (droxidopa group and placebo group)● For the droxidopa group, the dosages were titrated upwards until efficacy or intolerability to a maximum

dose (if tolerated) of 600 mg TID

Clinical Trials

Study Endpoint

● OHQ composite score at 8 weeks

Results

● Changes in cCGI-S scores favored droxidopa over placebo at weeks 1, 2, and 8, but pCGI-scores showed no notable differences

● Placebo-group had a higher incidence of fall-related injury (23.6%) versus those in the droxidopa group (16.9%). No statistical analysis.

Adverse Events

● No clinically significant differences overall in vital signs, lab values, and ECG findings between the two treatment groups

● No subjects died

Conclusion

● No significant difference in OHSA scores between droxidopa and placebo. More power or dose titration needed7

Clinical Trials

Randomized Withdrawal Study of Patients with Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa8

Objective

● Evaluate effects of continuing on droxidopa therapy versus withdrawal to placebo in patients with symptomatic nOH

Study Design

● Phase III, randomized, multinational, multicenter, placebo-controlled, double-blind, parallel group, enriched enrollment withdrawal study

● Droxidopa dose optimization/titration lasting up to 14 days followed by a study of 14 days with the patient either continuing on droxidopa or discontinuing to placebo

● Inclusion Criteria: Subject responsive to droxidopa; > 18 years old; diagnosis of symptomatic OH associated with PD, multiple system atrophy, pure ANS failure, dopamine-beta-hydroxylase deficiency, or non diabetic autonomic neuropathy; documented decrease of > 20 mmHg SBP or > 10 mm Hg diastolic BP within 3 minutes after standing

● Exclusion Criteria: Pre-existing sustained, severe HTN (> 180/110 mmHg while sitting); Afib or other significant cardiac arrythmia; current use of TCA’s or other NE reuptake inhibitors; current use of anti-HTN medication (except short acting agents at bedtime); or use of vasoconstrictive agents within 2 days before baseline

Treatment Regimens

● Droxidopa Optimization (< 2 weeks) → Responders continue optimized dose of droxidopa (1 week) → randomization to two groups, either double-blinded droxidopa or placebo (2 weeks)

Clinical Trials

Study Endpoint

● Each patient’s change on OHSA item 1 (dizziness/lightheadedness) from randomization to the end of treatment

Results

● OHSA item 1 (dizziness/lightheadedness, the primary end-point) worsened in the droxidopa group versus placebo

● The only statistically significant therapeutic differences favoring droxidopa were for activities standing a long time and activities involving standing a short time

● No significant difference between treatment groups for CGI improvement

Adverse Events

● ADR’s reported during open-label treatment was considered to only be mild/moderate and resolved without intervention

Conclusion

● The placebo group did not return to baseline as expected, but rather experienced continuing relief of the dizziness/lightheaded score and standing SBP at the end of the study compared to baseline

● Cannot conclude droxidopa is effective in this trial for nOH because did not show a significant difference for the primary endpoint8

Clinical Trials

Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension13

Objective

● Examined the effect of carbidopa administered together with L-DOPS [L-threo-3,4-dihydroxyphenylserine, or droxidopa] on blood pressure and NE generation

Study Design

● Double-blind, placebo-controlled with individualized dosing● 3-day trial, n =6; 3 men and 3 women; age 63 +/- 4 years● 4 different treatment groups: L-DOPS, carbidopa, L-DOPS + carbidopa, and placebo● Inclusion Criteria: Severe symptomatic orthostatic hypotension. 11 of the patients had multiple system

atrophy (9 had parkinsonism, 2 had cerebellar dysfunction), 8 had pure autonomic failure but without motor or sensory deficits

● Exclusion Criteria: Sustained, severe hypertension (>180/110 mmHg sitting); clinically significant coronary, peripheral, or cerebrovascular disease; cardiac arrhythmias

Treatment Regimens

● Optimal dose of L-DOPS for each patient was determined in a single-blind, dose-ranging study● For the treatment group on both L-DOPS and carbidopa, subjects received L-DOPS alone on day 1,

followed by 200 mg of carbidopa alone on day 2 and 200 mg of carbidopa combined with L-DOPS on day 3

Clinical Trials

Study Endpoint

● Differences in blood pressure, heart rate, and NE levels between the 4 treatment groups

Results

● Ingestion of carbidopa abolished the pressor responses to L-DOPS● BP and HR were similar when patients were treated with placebo, carbidopa alone, and carbidopa with

L-DOPS

Adverse Events

● L-DOPS was well tolerated by all patients, and there were no permanent side effects● One patient had hyponatremia, which reversed after saline infusion● Another patient had transient anginal pain with ST-depression

Conclusion

● Carbidopa antagonized both the pressor effect and plasma NE conversion by L-DOPS● L-DOPS may be ineffective in patients with Parkinson disease where levodopa/carbidopa is a gold-

standard of therapy13

Clinical Trials

NORTHERA™ (Droxidopa) PharmacokineticsRUTGERS FORMULARY EVALUATION

Dosing

● Initial dose: 100 mg TID○ Dose titration: in increments of 100 mg TID every 24-48 hours

● Max dose: 1800 mg/day (i.e. 600 mg TID)● No dose adjustments necessary for mild-moderate renally impaired and elderly patients● No dose adjustments provided for hepatically impaired in the PI● If miss dose: take next scheduled dose; do not double up

Administration

● Take the capsule whole● Take consistently with or without food● Schedule doses upon arising in the morning, at midday, and in the late afternoon (at least 3 hours

before bedtime to reduce the potential for supine hypertension during sleep)● Do not take with fatty meals (decreases absorption)● Avoid taking Northera™ with other medications that increase blood pressure

Dosing and Administration1,13

Absorption

● Cmax: 1-4 hours after dosing● High-fat meals decrease the Cmax (35%)

and AUC (20%)● Cmax delayed by approx. 2 hours with a

fatty meal

Distribution

● Crosses blood brain barrier● Protein binding 25-75%● Vd ~ 200 L

Pharmacokinetics1

Metabolism

● Catecholamine pathway● Active metabolite: norepinephrine

Elimination

● Elimination half life ~ 2.5 hours● Renally excreted ● Urine ~75%

Mild to Moderate Renal Impairment (GFR > 30 ml/min)

● No dose adjustments required● Dose adjustments for severe renal

impairment have not been studied

Pregnancy

● Category C

Nursing mothers

● Lack of data ● In rats, excreted in breast milk →

reduced weight gain and survival in offspring

Special Populations1,13

Pediatrics

● Safety and effectiveness not established

Geriatric

● No overall differences in safety or effectiveness when compared to younger subjects

Cardiac Electrophysiology

● No effect on the QTc interval

No clinically relevant effects of age, BMI, or sex on the pharmacokinetics of Northera™

NORTHERA™ (Droxidopa) Safety & TolerabilityRUTGERS FORMULARY EVALUATION

Safety & Tolerability1,3

Contraindications

● None identified

Warnings and Precautions

● Supine hypertension (Black Box Warning)○ Raise upper body when resting and sleeping○ Monitor blood pressure in supine and elevated position ○ Reduce dose or discontinue if hypertension persists○ Late afternoon doses should be taken at least 3 hours before bedtime

● Hyperpyrexia and Confusion○ Monitor patients when reducing and/or discontinuing doses if they are

taking neuroleptics

Safety & Tolerability1

● Exacerbation of ischemic heart disease, arrhythmias, and congestive heart failure

● Allergic Reactions○ Yellow No. 5 (tartrazine)

● Adverse Reactions○ Headache○ Dizziness○ Nausea ○ Hypertension (as mentioned previously)

Safety & Tolerability1, 12, 14

Drug Interactions

● Administration with other drugs that increase BP → supine hypertension○ eg. Norepinephrine, ephedrine, midodrine, and “triptans”

● Co-administration with dopa-decarboxylase inhibitors decrease efficacy of droxidopa○ eg. Carbidopa

Overdose

● Hypertensive crisis○ No known antidote

Medication Errors (LASA)3, 13

DroxiDOPA vs. MethylDOPA

NORTHEra vs. NORETHindrone

DROXIdopa vs. DROXIa

NORTHERA™ (Droxidopa) Administrative Information RUTGERS FORMULARY EVALUATION

● No generic available● Only available in package size of 90 oral capsules● Dosing

○ Starting Dose: 100 mg TID○ Titrated by 100 mg up to a maximum of 600 mg TID

100 mg (90): $1,690.80200 mg (90): $3,381.60300 mg (90): $5,072.40

Budget Impact1,9

Midodrine HCl

● Generic● Oral tablet● Dosing

○ Starting Dose: 2.5 mg TID○ Titrated to a maximum of 10 mg TID

2.5 mg (100): $120.225 mg (100): $242.0610 mg (100): $483.64

Budget Impact9,15

30 Day Supply Cost

● Initial Dosing○ Northera™: $1,690.80○ Midodrine HCl: $108.20

● Maximum Dosing○ Northera™: $10,144.80○ Midodrine HCl: $435.28

Conclusion & Recommendation

Conclusion

● Further studies need to be conducted to confirm the efficacy of both midodrine and Northera™

○ Current evidence is inconsistent● Northera™ lacks long-term studies

concerning safety and efficacy● Short-term use of droxidopa was not

more effective than placebo● Head-to-head trials need to be conducted● The classic first-line agent, midodrine,

has been available on the market longer and is more cost-effective

We do not currently recommend Northera™ to be added to the formulary.

References

1) Northera [package insert]. Deerfield, IL; Lundbeck NA Ltd; August 2014.

2) "Lundbeck Successfully Completes Tender Offer for Chelsea Therapeutics."Lundbeck. Lundbeck, 23 June 2014. Web. 4 Feb. 2015.

3) Droxidopa. DrugDex. Micromedex 2.0 [online]. February 2015. Available from Truven Health Analytics, Inc. Accessed February 11, 2015.

4) AHFS® Drug Information [database online]. Bethesda, MD: American Society of Health-System Pharmacists. Updated periodically. Accessed February 4, 2013.

5) Freeman R. Chapter 20. Syncope. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012. http://accesspharmacy.mhmedical.com/content.aspx?bookid=331&Sectionid=40726731. Accessed February 11, 2015.

6) Keating GM et al. Droxidopa: a review of its use in symptomatic neurogenic orthostatic hypotension [Internet]. Auckland (NZ): ADIS Drug Evaluation (NZ); c2015 [updated 2015 Jan 6; cited 2015 Feb 7]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25559422

7) Hauser RA, Isaacson S, Lisk JP, et al. Droxidopa for the Short-Term Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Parkinson’s Disease (nOH306B) [Internet]. Tampa (FL): Movement Disorders (US); c2014 [updated 2015 Oct 7; cited 2015 Feb 7]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/mds.26086/abstract;jsessionid=40729AF8AAAF3CD85022073A0C1A2C40.f03t02

8) Biaggioni I, Freeman R, Mathias CJ, et al. Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa [Internet]. Nashville (TN): Hypertension (US); c2014 [updated 2014 Aug 28; cited 2015 Feb 7]. Available from: http://hyper.ahajournals.org/cgi/pmidlookup?view=long&pmid=25350981

9) Red Book Online [database online]. Greenwood Village, CO: Truven Health Analytics, Inc. Updated periodically. Accessed February 6, 2015.

10) Metzler M, Duerr S, Granata R, Krismer F, Robertson D, Wenning GK. Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. Journal of Neurology 2013;260(9):2212-2219. doi:10.1007/s00415-012-6736-7.

11) "FDA Approves Northera to Treat Neurogenic Orthostatic Hypotension."Aurous HealthCare CRO. N.p., 05 Mar. 2014. Web. 19 Feb. 2015.

12) Kaufmann H, Saadia D, voustianiouk A, et al. Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension [Internet]. New York (NY): Circulation (US); c2003 [updated 2003, May 21; cited 2015 Feb 10]. Available from: http://ovidsp.tx.ovid.com/sp-3.14.0b/ovidweb.cgi?&S=ALJPFPGELHDDFCCMNCLKPHIBBAJEAA00&Link+Set=S.sh.21%7c1%7csl_10

13) Droxidopa. Lexi-Drugs Online. Lexi-Comp Online [database online]. Hudson, Ohio: Lexi-Comp, Inc.; Updated January 7, 2015. Accessed February 9, 2015.

14) Schroeder C, Jordan J, Kaufmann H, et al. Management of Neurogenic Orthostatic Hypotension with Autonomic Failure.[Internet]. New York (NY): Drugs (US); c2013 [updated 2013 Jul 16; cited 2015 Feb 11]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23857549

15) ProAmatine[package insert]. Newport, KY; Shire; October 2003.

Thank you!Any Questions?