NORTHERA

Vasopressors

Administer capsules three times daily at the following times: upon arising in the morning, at midday, and in the late afternoon at least 3 hours prior to bedtime (to reduce the potential for supine hypertension during sleep).
May be administered with or without food, but should be taken consistently in regard to food to ensure consistent absorption of droxidopa.
Swallow capsules whole.
Instruct patients to rest and sleep in an upper body elevated position and to monitor blood pressure (to reduce the potential for supine hypertension).

stroke / Early / Incidence not known
neuroleptic malignant syndrome-like symptoms / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
angioedema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
pancreatitis / Delayed / Incidence not known

hypertension / Early / 1.5-7.0
chest pain (unspecified) / Early / Incidence not known
delirium / Early / Incidence not known
hallucinations / Early / Incidence not known
psychosis / Early / Incidence not known
memory impairment / Delayed / Incidence not known
blurred vision / Early / Incidence not known

infection / Delayed / 0-15.0
headache / Early / 6.1-13.2
syncope / Early / 0-13.0
dizziness / Early / 3.8-10.0
nausea / Early / 1.5-8.8
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
agitation / Early / Incidence not known
fatigue / Early / Incidence not known
diarrhea / Early / Incidence not known
abdominal pain / Early / Incidence not known
vomiting / Early / Incidence not known

Droxidopa may cause or exacerbate supine hypertension in patients with neurogenic orthostatic hypotension (NOH). If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events, particularly stroke. Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses. Advise patients to elevate the head of the bed when resting or sleeping in order to lessen the risk of supine hypertension. Blood pressure should be monitored, both in the supine position and in the recommended head-elevated sleeping position. Reduce or discontinue droxidopa if supine hypertension persists despite management by elevation of the head of the bed.

NORTHERA

Rx

Oral synthetic amino acid precursor of norepinephrine
Used to increase blood pressure in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy
May cause supine hypertension

100 mg PO 3 times daily, initially. Titrate dose by 100 mg 3 times daily every 24 to 48 hours to symptomatic response up to 600 mg PO 3 times daily (Max: 1,800 mg/day). Effectiveness beyond 2 weeks of treatment has not been established.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

eGFR >= 30 mL/min/1.73 m2: No dosage adjustment needed.
eGFR < 30 mL/min/1.73 m2: Clinical experience is limited. Droxidopa and its metabolites are primarily excreted renally. Therefore, the benefit-risk for the use of droxidopa in these patients should be individually assessed.

Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Acetaminophen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Acrivastine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Almotriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Atomoxetine: (Major) Due to the potential for increases in blood pressure and heart rate, atomoxetine should be used cautiously with vasopressors such as droxidopa. Consider monitoring the patient's blood pressure and heart rate at baseline and regularly if vasopressors are coadministered with atomoxetine.
Brompheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Carbidopa: (Major) Droxidopa is directly metabolized to norepinephrine by dopa-decarboxylase; therefore, coadministration with dopa-decarboxylase inhibitors (e.g., carbidopa) may prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS). Patients in the clinical trials with droxidopa received concomitant medications used to treat Parkinson's disease. Patients taking droxidopa with levodopa/dopa-decarboxylase inhibitor combinations (e.g., carbidopa; levodopa or carbidopa; levodopa; entacapone) had decreased clearance of droxidopa, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. No dose adjustments are expected to be required. However, the manufacturer states that in some patients, it is possible that dose adjustments for droxidopa will be required.
Carbidopa; Levodopa: (Major) Droxidopa is directly metabolized to norepinephrine by dopa-decarboxylase; therefore, coadministration with dopa-decarboxylase inhibitors (e.g., carbidopa) may prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS). Patients in the clinical trials with droxidopa received concomitant medications used to treat Parkinson's disease. Patients taking droxidopa with levodopa/dopa-decarboxylase inhibitor combinations (e.g., carbidopa; levodopa or carbidopa; levodopa; entacapone) had decreased clearance of droxidopa, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. No dose adjustments are expected to be required. However, the manufacturer states that in some patients, it is possible that dose adjustments for droxidopa will be required.
Carbidopa; Levodopa; Entacapone: (Major) Droxidopa is directly metabolized to norepinephrine by dopa-decarboxylase; therefore, coadministration with dopa-decarboxylase inhibitors (e.g., carbidopa) may prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS). Patients in the clinical trials with droxidopa received concomitant medications used to treat Parkinson's disease. Patients taking droxidopa with levodopa/dopa-decarboxylase inhibitor combinations (e.g., carbidopa; levodopa or carbidopa; levodopa; entacapone) had decreased clearance of droxidopa, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. No dose adjustments are expected to be required. However, the manufacturer states that in some patients, it is possible that dose adjustments for droxidopa will be required.
Cardiac glycosides: (Moderate) Carefully monitor patients receiving cardiac glycosides and vasopressors concurrently due to the increased risk of arrhythmia.
Cetirizine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Chlorpheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Desloratadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Dexbrompheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Diethylpropion: (Major) Diethylpropion has vasopressor effects. Coadministration with other vasopressors may have the potential for serious cardiac adverse effects such as hypertensive crisis and cardiac arrhythmias.
Digoxin: (Moderate) Carefully monitor patients receiving cardiac glycosides and vasopressors concurrently due to the increased risk of arrhythmia.
Dihydroergotamine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
Dopamine: (Moderate) Monitor blood pressure during concomitant use of dopamine and other vasopressors, such as droxidopa, due to the risk for severe hypertension.
Eletriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Ergoloid Mesylates: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
Ergot alkaloids: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
Ergotamine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
Ergotamine; Caffeine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
Fexofenadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Frovatriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Ibuprofen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Ionic Contrast Media: (Major) The intravascular injection of a contrast medium should never be made after the administration of vasopressors since they strongly potentiate neurologic effects. Serious neurologic sequelae, including permanent paralysis, have been reported after cerebral arteriography, selective spinal arteriography, and arteriography of vessels supplying the spinal cord.
Isocarboxazid: (Major) Avoid concurrent use of droxidopa and isocarboxazid, a non-selective MAOI, as there is a potential for increased blood pressure when taken together.
Linezolid: (Major) Avoid concurrent use of droxidopa and linezolid, a non-selective MAOI, as there is a potential for increased blood pressure when taken together.
Loratadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Methylergonovine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
Methylphenidate Derivatives: (Moderate) Methylphenidate derivatives can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
Naproxen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Naratriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Non-Ionic Contrast Media: (Major) Do not administer non-ionic contrast media intra-arterially after the administration of vasopressors since they strongly potentiate neurologic effects.
Phendimetrazine: (Major) Phendimetrazine is a phenylalkaline sympathomimetic agent. All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving phendimetrazine. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmia.
Phenelzine: (Major) Avoid concurrent use of droxidopa and phenelzine, a non-selective MAOI, as there is a potential for increased blood pressure when taken together.
Phentermine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
Phentermine; Topiramate: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Pseudoephedrine; Triprolidine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
Racepinephrine: (Major) Racepinephrine is a sympathomimetic drug with agonist actions at both the alpha and beta receptors. Patients using racepinephrine inhalation are advised to avoid other non-prescription products containing sympathomimetics since additive adverse effects on the cardiovascular and nervous system are possible, some which may be undesirable. Side effects such as nausea, tremor, nervousness, difficulty with sleep, and increased heart rate or blood pressure may be additive. Patients should avoid use of non-prescription decongestants, such as phenylephrine and pseudoephedrine, while using racepinephrine inhalations. Patients should avoid dietary supplements containing ingredients that are reported or claimed to have a stimulant or weight-loss effect, such as ephedrine and ephedra, Ma huang, and phenylpropanolamine.
Rizatriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Serotonin-Receptor Agonists: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and vasopressors. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
Sumatriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Sumatriptan; Naproxen: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.
Tranylcypromine: (Major) Avoid concurrent use of droxidopa and tranylcypromine, a non-selective MAOI, as there is a potential for increased blood pressure when taken together.
Zolmitriptan: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events.

Droxidopa/NORTHERA Oral Cap: 100mg, 200mg, 300mg

1,800 mg/day PO.

1,800 mg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

The exact mechanism of action of droxidopa in the treatment of neurogenic orthostatic hypotension is unknown. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which is extensively distributed throughout the body. It is believed that the pharmacological effects of droxidopa are through norepinephrine and not through the parent molecule or other metabolites. Droxidopa in humans induces small and transient rises in plasma norepinephrine. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure.

Droxidopa is administered orally. Pre-clinical studies suggest that droxidopa can cross the blood-brain barrier. Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL. The estimated apparent volume of distribution of droxidopa is about 200 L. Total clearance is approximately 400 mL/hour. The metabolism of droxidopa is via the catecholamine pathway. Droxidopa is initially converted to methoxylated dihydroxyphenylserine (3-OM-DOPS), a major metabolite, by catechol-O-methyltransferase (COMT), to norepinephrine by DOPA decarboxylase (DDC), or to protocatechualdehyde by DOPS aldolase. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood. The mean elimination half-life of droxidopa is approximately 2.5 hours. The major route of elimination of droxidopa and its metabolites is via the kidneys. Studies in animals showed that approximately 75% of the radiolabeled dose was excreted in urine within 24 hours of oral dosing.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

After oral dosing in humans, plasma norepinephrine levels peak within 3 to 4 hours but are generally very low (less than 1 ng/mL) and variable with no consistent relationship with dose. Peak plasma concentrations (Cmax) of droxidopa were reached by 1 to 4 hours post-dose (mean of approximately 2 hours) in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and area under the plasma concentration-time curve (AUC) decreasing by 35% and 20%, respectively. The Cmax was delayed by approximately 2 hours with a high-fat meal.

There are no available data on the use of droxidopa during human pregnancy or the risk of major birth defects and miscarriage. Droxidopa did not produce significant reproductive toxicity in pregnant female rats or rabbits or their fetuses. However, when pregnant female rats were given doses corresponding to 0.3, 1, and 3 times the maximum recommended human dose during organogenesis and when their male and female offspring were subsequently bred, the female offspring exhibited a dose-dependent reduction in the number of live fetuses at all 3 doses and an increased number of embryonic/fetal deaths at the 2 higher doses.

There is no information available on the presence of droxidopa or its active metabolite in human milk or the effects of droxidopa on the breast-fed child or milk production/excretion. Women should avoid breast-feeding during droxidopa treatment because of the potential for serious adverse reactions, including reduced weight gain in breast-fed infants.