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Droxidopa

Class: alpha- and beta-Adrenergic Agonists
Chemical Name: (βR)-β,3-Dihydroxy-l-tyrosine
Molecular Formula: C9H11NO5
CAS Number: 23651-95-8
Brands: Northera

Warning(s)

  • Supine Hypertension
  • May cause or exacerbate supine hypertension in patients with neurogenic orthostatic hypotension (NOH).1 Risk of cardiovascular events may be increased in patients with uncontrolled supine hypertension.1

  • Monitor supine BP prior to and during treatment and more frequently when increasing doses.1 To reduce the risk of supine hypertension, advise patients to elevate the head of the bed when sleeping or resting.1 Reduce dosage of droxidopa or discontinue drug if supine hypertension persists.1

Introduction

Synthetic amino acid analog and prodrug of norepinephrine.1 4 7 8 9

Uses for Droxidopa

Symptomatic Neurogenic Orthostatic Hypotension (NOH)

Management of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in patients with symptomatic NOH caused by primary autonomic failure (Parkinson's disease, multiple system atrophy, or pure autonomic failure), dopamine β-hydroxylase deficiency, or non-diabetic autonomic neuropathy.1 2 3 4 5 8 9 16 17

Has been designated an orphan drug by FDA for treatment of symptomatic NOH in patients with primary autonomic failure, dopamine β-hydroxylase deficiency, or nondiabetic autonomic neuropathy.2

Efficacy in symptomatic NOH beyond 2 weeks not established; reassess continued benefit periodically during therapy.1 3

Droxidopa Dosage and Administration

General

Restricted Distribution

  • Available only through a specialty pharmacy.10 For more information, contact manufacturer at 844-601-0101 or .10

Administration

Oral Administration

Administer orally 3 times daily: upon arising in the morning, at midday, and in the late afternoon at least 3 hours before bedtime.1 Take consistently, either with food or without food.1 Swallow capsules whole.1

Monitor supine BP prior to initiating droxidopa, periodically during treatment, and after dosage increases.1 (See Supine Hypertension under Cautions.)

If a dose is missed, skip the dose and take the next dose at the regularly scheduled time.1

Dosage

Adults

Symptomatic NOH
Oral

Initially, 100 mg 3 times daily.1 May increase dosage based on symptomatic response and tolerance in increments of 100 mg 3 times daily at intervals of 24–48 hours.1

Efficacy beyond 2 weeks not established; periodically reassess continued benefit.1

Prescribing Limits

Adults

Symptomatic NOH
Oral

600 mg 3 times daily (1.8 g daily).1

Special Populations

Renal Impairment

Mild or moderate renal impairment when GFR >30 mL/minute: Dosage adjustment not necessary.1

Limited experience in patients with severe renal impairment (GFR <30 mL/minute); no dosage recommendations provided by manufacturer.1

Geriatric Patients

Manufacturer makes no special dosage recommendations.1

Cautions for Droxidopa

Contraindications

  • None.1

Warnings/Precautions

Warnings

Supine Hypertension

May cause or exacerbate supine hypertension.1 Risk of cardiovascular events may be increased in patients with uncontrolled supine hypertension.1

Instruct patients to elevate the head of the bed when sleeping or resting to reduce risk of supine hypertension.1

Monitor BP prior to initiating droxidopa, periodically during treatment, and more frequently when increasing dosage; measure BP both in the supine position and the recommended head-elevated sleeping position.1

If supine hypertension persists, reduce dosage or discontinue droxidopa.1

Sensitivity Reactions

Tartrazine Sensitivity

Preparations contain tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals.1 Although the incidence of tartrazine sensitivity is low, it frequently occurs in aspirin-sensitive individuals.1

General Precautions

Neuroleptic Malignant Syndrome (NMS)-like Reactions

Potentially life-threatening NMS-like reactions reported with droxidopa.1

Symptoms may include hyperpyrexia, muscle rigidity, altered mental status (e.g., confusion), and autonomic instability.1 Monitor patients receiving droxidopa for the development of NMS-like symptoms; early diagnosis important for appropriate management.1

Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure

May exacerbate ischemic heart disease, arrhythmias, and CHF.1 Consider risk in patients with these conditions when contemplating droxidopa therapy.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety or efficacy in geriatric patients compared with younger adults, but increased sensitivity cannot be ruled out.1

Renal Impairment

Frequency of adverse events not affected by mild or moderate renal impairment when GFR >30 mL/minute.1 Insufficient experience in patients with severe renal impairment (GFR <30 mL/minute).1

Common Adverse Effects

Headache,1 6 dizziness,1 6 nausea,1 6 hypertension.1 6 9 Longer-term open label studies: falls,1 urinary tract infections,1 headache,1 syncope,1 dizziness.1

Interactions for Droxidopa

Metabolized via catecholamine pathway by catechol-O-methyltransferase (COMT), aromatic L-amino acid decarboxylase, and dihydroxyphenylserine (DOPS) aldolase.1

Not metabolized by CYP isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

No formal drug interaction studies to date.1 No interactions expected.1

Drugs that Increase Blood Pressure

Possible increased risk for supine hypertension; use concomitantly with caution.1

Specific Drugs

Drug

Interaction

Comments

Amantadine derivatives

No effect on droxidopa clearance1

No dosage adjustment required1

Aromatic L-amino acid decarboxylase inhibitors (e.g., carbidopa)

May prevent conversion of droxidopa to norepinephrine outside the CNS1 7 8 9

Carbidopa: Decreased clearance of droxidopa and attenuated rises in plasma norepinephrine and BP reported1 7 8 9

Dosage adjustment of droxidopa may be required1

Dopamine agonists

No effect on droxidopa clearance1

No dosage adjustment required1

MAO-B inhibitors

No effect on droxidopa clearance1

No dosage adjustment required1

Serotonin type 1 (5-HT1) receptor agonists (triptans)

Possible increased risk for supine hypertension1

Use concomitantly with caution1

Droxidopa Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained in approximately 1–4 hours (mean: about 2 hours) following oral administration.1 Plasma norepinephrine concentrations peak within 3–4 hours of oral administration but have no consistent relationship to droxidopa dosage.1

Food

Administration with a high-fat meal delays absorption approximately 2 hours; peak plasma concentration and overall AUC decreased by 35 and 20%, respectively.1

Distribution

Extent

Thought to cross the blood-brain barrier.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

75% plasma protein bound at 100 ng/mL and 26% at 10,000 ng/mL.1

Elimination

Metabolism

Metabolized via catecholamine pathway by catechol-O-methyltransferase (COMT), dopa-decarboxylase, and DOPS aldolase.1

Elimination Route

Following oral administration of radiolabeled dose in animals, approximately 75% of total radioactivity recovered in urine within 24 hours.1 1

Half-life

Approximately 2.5 hours.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Actions

  • Converted to norepinephrine by aromatic L-amino acid decarboxylase.1 4 7 8 9

  • Precise mechanism of action not known, thought to be through action of norepinephrine, which causes peripheral vasoconstriction and increases BP.1

Advice to Patients

  • Risk of increased BP and supine hypertension, which may lead to strokes, heart attacks, and death.1 Importance of advising patients to sleep in a position with upper body elevated and to monitor BP prior to initiating droxidopa, periodically during therapy, and during dosage increases.1 Importance of taking the late-afternoon dose of droxidopa at least 3 hours before bedtime.1

  • Importance of instructing patients to take droxidopa in a consistent manner, either with or without food.1

  • If a dose is missed, the dose should be skipped and the next dose taken at the regularly scheduled time.1 Importance of advising patients not to take 2 doses of the drug at the same time.1

  • Importance of advising patients to notify their clinician if they are allergic to tartrazine (FD&C yellow No. 5) or aspirin.1

  • Importance of advising patients to notify their clinician if any signs or symptoms of an allergic reaction (e.g., rash, hives, swelling, difficulty breathing) develop during droxidopa therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements that may have an additive effect with droxidopa, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of droxidopa is restricted.10 (See Restricted Distribution under Dosage and Administration.)

Droxidopa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg

Northera

Lundbeck

200 mg

Northera

Lundbeck

300 mg

Northera

Lundbeck

AHFS DI Essentials. © Copyright 2016, Selected Revisions July 15, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Lundbeck. Northera (droxidopa) capsules prescribing information. Deerfield, IL; 2014 Aug.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2014 May 7.

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203202: Summary Review. From FDA website. Accessed 2014 May 12.

4. Isaacson SH, Skettini J. Neurogenic orthostatic hypotension in Parkinson's disease: evaluation, management, and emerging role of droxidopa. Vasc Health Risk Manag. 2014; 10:169-176. [PubMed 24729712]

5. Metzler M, Duerr S, Granata R et al. Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. J Neurol. 2013; 260:2212-9. [PubMed 23180176]

6. Kaufmann H, Freeman R, Biaggioni I et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014; 83: Published online June 18, 2014.

7. Goldstein DS, Holmes C, Sewell L et al. Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine prodrug L-DOPS. J Clin Pharmacol. 2011; 51:66-74. [PubMed 20220040]

8. Mathias CJ. L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience. Clin Auton Res. 2008; 18 Suppl 1:25-9. [PubMed 18368304]

9. Kaufmann H, Saadia D, Voustianiouk A et al. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 2003; 108:724-8. [PubMed 12885750]

10. Lundbeck. Lundbeck announces the availability of NortheraTM (droxidopa) capsules in the U.S. for symptomatic neurogenic orthostatic hypotension. Deerfield, IL; 2014 Sep 2. Press release.

11. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med. 2008; 358:615-24. [PubMed 18256396]

12. Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: as easy as A, B, C. Cleve Clin J Med. 2010; 77 (5):298-306.

13. Shibao C, Lipsitz LA, Biaggioni I. ASH position paper: evaluation and treatment of orthostatic hypotension. J Clin Hypertens (Greenwich). 2013; 15(3):147-53.

14. Lundbeck. Product information on Northera (droxidopa) dosing and titration. Deerfield, IL; 2014 Aug.

15. Lundbeck, Deerfield, IL: Personal communication.

16. Hauser RA, Isaacson S, Lisk JP et al. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B). Mov Disord. 2015; 30:646-54. [PubMed 25487613]

17. Biaggioni I, Freeman R, Mathias CJ et al. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015; 65:101-7. [PubMed 25350981]

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