Droxidopa (droxidopa)

For the management of symptomatic neurogenic orthostatic hypotension (NOH), the recommended initial dosage of droxidopa in adults is 100 mg 3 times daily, given upon arising in the morning, at midday, and in the late afternoon at least 3 hours before bedtime. Dosage may be increased in increments of 100 mg 3 times daily at intervals of 24-48 hours based on symptomatic response and tolerance. The maximum recommended dosage of droxidopa is 600 mg 3 times daily (1.8 g daily). After dosage titration over 7-14 days in a study in patients with symptomatic NOH and Parkinson's disease (study 306B), less than 10% of patients remained at the initial droxidopa dosage of 100 mg 3 times daily, and approximately 40% of patients received the maximum dosage of 600 mg 3 times daily.

Efficacy of droxidopa beyond 2 weeks has not been established; continued benefit of droxidopa should be reassessed periodically during treatment.

Droxidopa is administered orally upon arising in the morning, at midday, and in the late afternoon at least 3 hours before bedtime. The drug may be taken either with or without food but should be taken consistently either way. Droxidopa capsules should be swallowed whole.

Supine blood pressure should be monitored prior to initiating droxidopa, periodically during treatment, and after dosage increases. To minimize the risk of supine hypertension, the manufacturer recommends that the head of the bed be elevated when resting or sleeping and that the last dose of the day be given at least 3 hours prior to bedtime. (See Supine Hypertension, under Warnings/Precautions: Warnings, in Cautions.)

If a dose of droxidopa is missed, the dose should be skipped and the next dose taken at the regularly scheduled time. (See Advice to Patients.)

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Sympathomimetics/Dihydroergotamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1)

CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1)

DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Droxidopa/Maois

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: MAOIs inhibit the enzyme responsible for degradation of norepinephrine which is formed by droxidopa.

CLINICAL EFFECTS: Concurrent use of MAOIs and droxidopa may result in increased effects of droxidopa, including headache, dizziness, nausea, and hypertensive crisis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of droxidopa recommends concurrent use with non-selective MAOIs should be avoided. Selective MAO-B inhibitors, including rasagiline and selegiline, were used concurrently in clinical trials without an increase in risk of hypertensive crisis. If concurrent therapy is warranted, monitor patient closely for increases in blood pressure.

DISCUSSION: Hypertensive reactions are possible as a result of this interaction. This interaction may be possible for several weeks after the discontinuation of a MAO inhibitor. Furazolidone and linezolid have been shown to inhibit MAO. Metaxalone is a weak inhibitor of MAO.

Select Indirect-Acting Sympathomimetics/Tricyclic Compounds

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use of tricyclic compounds and indirect-acting sympathomimetics should be approached with caution. Monitor patients receiving concurrent therapy for decreased sympathomimetic efficacy.

DISCUSSION: The pressor effects of the indirect-acting sympathomimetic amines (e.g., amphetamines, ephedrine, and methylphenidate) are antagonized by tricyclic antidepressants.

Sympathomimetics/Ergot Alkaloids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.

CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary.

DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine.

Sympathomimetics/Selected Inhalation Anesthetic Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1)

CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1)

DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Comt-Metabolized Agents/Entacapone; Opicapone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Entacapone and opicapone are selective and reversible inhibitors of catechol-O-methyltransferase (COMT) and drugs that are metabolized by COMT can not be fully metabolized when given with entacapone or opicapone.(1)

CLINICAL EFFECTS: COMT-metabolized agents can interact with entacapone or opicapone and may result in an increased heart rates, arrhythmias, or an excessive change in blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of entacapone and opicapone recommend using caution when administering entacapone or opicapone and a COMT-metabolized agent regardless of the route of administration (including inhalation).(1-3)

DISCUSSION: In an interaction study, ventricular tachycardia was observed after epinephrine and entacapone administration.(1) Another study on the effect of entacapone given with isoproterenol and epinephrine concluded that entacapone may potentiate the chronotropic and arrhythmogenic effects of isoproterenol and epinephrine.(4)

Sympathomimetics (Direct, Mixed-Acting)/Guanethidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Direct or mixed-acting sympathomimetics may inhibit uptake of guanethidine at the adrenergic neuron.

CLINICAL EFFECTS: Decreased antihypertensive effectiveness. Effects may be seen for several days after discontinuation of the direct or mixed-acting sympathomimetic.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If both drugs are administered, adjust the guanethidine dose as needed based on blood pressure.

DISCUSSION: Documentation supports routine monitoring of this interaction. It should be noted that this interaction can occur quickly.

Sympathomimetics (Direct, Mixed-Acting)/Methyldopa

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: The pressor response to sympathomimetics may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Start with low doses of sympathomimetics and monitor blood pressure of patients during concurrent administration of sympathomimetics and methyldopa.

DISCUSSION: The pressor response to sympathomimetics has been reported to be increased during methyldopa administration. In addition to increased duration of pressor response, severe hypertension has been reported.

The manufacturer states that there are no contraindications to the use of droxidopa.

There are no contraindication contraindications for this drug.

• Neuroleptic malignant syndrome
• Supine hypertension

• Cardiac arrhythmia
• Chronic heart failure
• Coronary artery disease

Adverse effects reported in more than 5% of patients receiving droxidopa and at an incidence at least 3% greater than that with placebo in controlled trials include headache, dizziness, nausea, and hypertension. In longer-term open-label trials, commonly reported adverse effects included falls, urinary tract infections, headache, syncope, and dizziness.

Rare or Very Rare

• Acute cognitive impairment
• Anaphylaxis
• Angioedema
• Bronchospastic pulmonary disease
• Drug-induced psychosis
• Fever
• Myocardial ischemia
• Neuroleptic malignant syndrome
• Pancreatitis
• Supine hypertension
• Worsening of chronic heart failure

More Frequent

• Dizziness
• Fatigue
• Hypertension
• Nausea

Rare or Very Rare

• Acute abdominal pain
• Agitation
• Blurred vision
• Chest pain
• Delirium
• Diarrhea
• Hallucinations
• Headache disorder
• Memory impairment
• Skin rash
• Urticaria
• Vomiting

No enhanced messaging available.

Safety and efficacy of droxidopa in pediatric patients have not been established.

Category C. (See Users Guide.)

There are no adequate and well-controlled studies to date in pregnant women. In animal studies, droxidopa has been associated with reduced body weight and occurrence of undulant rib (which were slight and reversed after birth), reduced gestation period, and low incidences of renal lesions on the kidney surface; no other potentially teratogenic effects were observed. Droxidopa should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

It is not known whether droxidopa is distributed into human milk. However, droxidopa is distributed into milk in rats and has been associated with reduced weight gain and reduced survival of offspring when administered to nursing dams during lactation. Because of the potential for serious adverse reactions to droxidopa in nursing infants, a decision should be made whether to discontinue nursing or the drug.

Clinical trials with droxidopa included 197 patients 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric and younger patients in these trials, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.