Droxidopa

1 INDICATIONS AND USAGE Droxidopa capsules indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (nOH) caused by primary autonomic failure (Parkinson's disease [PD], multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Effectiveness beyond 2 weeks of treatment has not been established. The continued effectiveness of droxidopa capsules should be assessed periodically. Droxidopa capsules are indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (nOH) caused by primary autonomic failure (Parkinson's disease [PD], multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Effectiveness beyond 2 weeks of treatment has not been established. The continued effectiveness of droxidopa capsules should be assessed periodically.

12.1 Mechanism of Action 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. Droxidopa is believed to exert its pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction. Droxidopa in humans induces small and transient rises in plasma norepinephrine.

2 DOSAGE AND ADMINISTRATION • Starting dose is 100 mg three times during the day (2.1) • Titrate by 100 mg three times daily, up to a maximum dose of 600 mg three times daily (2.1) • Take consistently with or without food (2.1) • To reduce the potential for supine hypertension, elevate the head of the bed and give the last dose at least 3 hours prior to bedtime (2.1) • Take droxidopa capsule whole (2.1) 2.1 Dosing Information The recommended starting dose of droxidopa capsules is 100 mg, taken orally three times daily: 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). Administer droxidopa capsules consistently, either with food or without food. Take droxidopa capsule whole. Titrate to symptomatic response, in increments of 100 mg three times daily every 24 to 48 hours up to a maximum dose of 600 mg three times daily (i.e., a maximum total daily dose of 1,800 mg). Monitor supine blood pressure prior to initiating droxidopa capsules and after increasing the dose. Patients who miss a dose of droxidopa capsules should take their next scheduled dose.

6 ADVERSE REACTIONS The following adverse reactions with droxidopa are included in more detail in the Warnings and Precautions section of the label: • Supine Hypertension [see Warnings and Precautions (5.1) ] • Hyperpyrexia and Confusion [see Warnings and Precautions (5.2) ] • May exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure [see Warnings and Precautions (5.3) ] The most common adverse reactions (>5% and ≥3% compared to placebo) are headache, dizziness, nausea, and hypertension (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LCC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety evaluation of droxidopa is based on two placebo-controlled studies 1 to 2 weeks in duration (Studies 301 and 302), one 8-week placebo-controlled study (Study 306), and two long-term, open-label extension studies (Studies 303 and 304). In the placebo-controlled studies, a total of 485 patients with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy were randomized and treated, 245 with droxidopa and 240 with placebo [see Clinical Studies (14) ] . Placebo-Controlled Experience The most commonly observed adverse reactions (those occurring at an incidence of greater than 5% in the droxidopa group and with at least a 3% greater incidence in the droxidopa group than in the placebo group) in droxidopa-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, and hypertension. The most common adverse reactions leading to discontinuation from droxidopa were hypertension or increased blood pressure and nausea. Table 1. Most Common Adverse Reactions Occurring More Frequently in the Droxidopa Group Study 301 and Study 302 (1 to 2 Weeks Randomized Treatment) Study 306 (8 to 10 Weeks Randomized Treatment) Placebo (N=132) n (%) Droxidopa (N=131) n (%) Placebo (N=108) n (%) Droxidopa (N=114) n (%) Headache 4 (3.0) 8 (6.1) 8 (7.4) 15 (13.2) Dizziness 2 (1.5) 5 (3.8) 5 (4.6) 11 (9.6) Nausea 2 (1.5) 2 (1.5) 5 (4.6) 10 (8.8) Hypertension 0 2 (1.5) 1 (0.9) 8 (7.0) Note: n=number of patients. Adverse reactions that were reported in greater than 5% of patients in the droxidopa group and with at least a 3% greater incidence in the droxidopa group than in the placebo group were from Study 306. Long-Term, Open-Label Trials with Droxidopa In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with droxidopa for a mean total exposure of approximately one year. The commonly reported adverse events were falls (24%), urinary tract infections (15%), headache (13%), syncope (13%), and dizziness (10%). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of droxidopa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders : Chest pain Eye Disorders : Blurred vision Gastrointestinal Disorders : Pancreatitis, abdominal pain, vomiting, diarrhea General Disorders and Administration Site Conditions : Fatigue Nervous System Disorders : Cerebrovascular accident Psychiatric Disorders : Psychosis, hallucination, delirium, agitation, memory disorder

5 WARNINGS AND PRECAUTIONS • Droxidopa may cause supine hypertension and may increase cardiovascular risk if supine hypertension is not well-managed (5.1) • Hyperpyrexia and confusion (5.2) • May exacerbate symptoms in patients with existing ischemic heart disease, arrhythmias, and congestive heart failure (5.3) • Allergic reactions (5.4) 5.1 Supine Hypertension Droxidopa therapy may cause or exacerbate supine hypertension in patients with nOH. Patients should be advised to elevate the head of the bed when resting or sleeping. Monitor blood pressure, both in the supine position and in the recommended head-elevated sleeping position. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events, particularly stroke. 5.2 Hyperpyrexia and Confusion Postmarketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with droxidopa use during postmarketing surveillance. Observe patients carefully when the dosage of droxidopa is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients. 5.3 Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure Droxidopa may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. Careful consideration should be given to this potential risk prior to initiating therapy in patients with these conditions. 5.4 Allergic Reactions Hypersensitivity reactions including anaphylaxis, angioedema, bronchospasm, urticaria and rash have been reported in postmarketing experience. Some of these reactions resulted in emergency treatment. If a hypersensitivity reaction occurs, discontinue the drug and initiate appropriate therapy.

4 CONTRAINDICATIONS Droxidopa is contraindicated in patients who have a history of hypersensitivity to the drug or its ingredients [see Warnings and Precautions (5.4) ]. History of hypersensitivity to the drug or its ingredients

10 OVERDOSAGE 10.1 Symptoms There have been cases of overdose reported during postmarketing surveillance. A patient ingested 7,700 mg of droxidopa and experienced a hypertensive crisis that resolved promptly with treatment. Another patient treated with a total daily dose of 2,700 mg of droxidopa experienced hypertension and an intracranial hemorrhage. 10.2 Treatment There is no known antidote for droxidopa overdosage. In case of an overdose that may result in an excessively high blood pressure, discontinue droxidopa and treat with appropriate symptomatic and supportive therapy. Counsel patients to remain in a standing or seated position until their blood pressure drops below an acceptable limit.