Pharmacology Update: Droxidopa Capsules (Northera)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern
California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A new drug for the treatment of neurogenic orthostatic hypotension (NOH) has been approved by the FDA under its accelerated approval program. Droxidopa is a prodrug to norepinephrine. It is the second drug to be approved for this indication after midodrine. Droxidopa is marketed by Chelsea Therapeutics, Inc., as Northera. The drug has been approved and used in Japan since 1989.
Droxidopa is indicated for the treatment of orthostatic dizziness, lightheadness, or the "feeling that you are to black out" in adults with symptomatic NOH caused by primary autonomic failure and pure autonomic failure.1 Primary autonomic failure includes Parkinson’s disease and multiple system atrophy, and pure failure includes dopamine beta-hydroxylase deficiency and non-diabetic autonomic neuropathy.1
The recommended starting dose is 100 mg three times daily and may be titrated by 100 mg three times daily (every 24-48 hours) up to a maximum dose of 600 mg three times daily.1 The capsules should be taken consistently with or without food. The last daily dose should be taken at least 3 hours before bedtime and the head of the bed should be elevated to reduce supine hypertension.1 Droxidopa is available as 100 mg, 200 mg, and 300 mg capsules.
Droxidopa is only the second drug approved for NOH and is an alternative to midodrine. The latter appears to have a stronger warning for elevation of supine blood pressure.
The product was approved with limited evidence of efficacy.2 Droxidopa’s effectiveness beyond 2 weeks is uncertain.1 The drug may cause or exacerbate supine hypertension and may exacerbate ischemic heart disease, arrhythmias, and congestive heart failure.1 Neuroleptic malignant syndrome-like symptoms have been reported during postmarketing surveillance in Japan.1 Patients on dopa-decarboxylase inhibitors (e.g., carbidopa) may need dose adjustment for droxidopa. The capsules contain FD&C yellow #5 (tartrazine). This dye may cause allergic-type reaction in susceptible individuals (e.g., those with aspirin hypersensitivity).
Droxidopa is converted by two enzymes (catechol-O-methyltransferase and DOPA decarboxylase) to norepinephrine. The approval of the drug was based mainly on two enriched studies, one with a short-term treatment period of 1 week and the other with an 8-week treatment period.1,2 In the first study, subjects with symptomatic NOH (n = 263) were titrated up to 600 mg droxidopa three times a day and only responders were then randomized to droxidopa (n = 82) or placebo (n = 80). The primary endpoint was based on the composite Orthostatic Hypotension Questionnaire (OHQ) 7 days after randomization. OHQ is comprised of two questionnaires, the Orthostatic Hypotension Symptom Assessment (OHSA), a six-item questionnaire pertaining to symptoms, and the Orthostatic Hypotension Daily Activity Scale, which is four items pertaining to ability to stand and walk. Statistically significant treatment effect was not demonstrated with OHQ. Item 1 of OHSA (symptoms of dizziness, lightheadedness, feeling faint, and feeling like you might black out) barely missed statistical significance (P = 0.06). In the 8-week study, subjects with symptomatic NOH and Parkinson’s disease and a decrease of at least 20 mmHg (systolic blood pressure [SBP]) or 10 mmHg (diastolic blood pressure [DBP]) were titrated up to 600 mg three times a day with droxidopa (n = 87) or placebo (n = 84). Those intolerant of droxidopa at the lowest dose were discontinued from the study. Others were continued for an 8-week treatment period. The primary endpoint was item #1 on OHSA assessed at weeks 1, 2, 4, and 8 of the treatment period. Statistical significance was achieved at week 1 (P = 0.028) but not beyond. There was high intra-individual variability. Two other studies, one lasting 2 weeks and another lasting 3 months, were followed with a withdrawal phase. Neither study showed statistical difference between droxidopa and placebo.1,2 There are no data on mortality or morbidity.
NOH can be a severely disabling condition due to reduction of SBP of at least 20 mmHg or DBP of 10 mmHg within 3 minutes of standing. This is believed to be due to the failure of the autonomic nervous system to respond to the change in position.2 Current approved pharmacological treatment includes midodrine, with droxidopa being the latest approval for NOH. The approval, however, was based on limited efficacy data as well as limited duration of action. In addition, the enrichment design of the trials makes it difficult to have a true placebo group to compare relative adverse reaction profiles. Twenty-nine cases of neuroleptic malignant syndrome were reported from Japan’s postmarketing surveillance data.2 The cost of droxidopa was not available at the time of this review.
- Northera Prescribing Information. Charlotte, NC:
Chelsea Therapeutics, Inc.; February 2014.
- http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm381154.pdf. Accessed March 12, 2014.