Droxidopa

Contraindications ( 4 ) 10/2016 Warnings and Precautions, Supine Hypertension ( 5.1 ) 02/2017 Warnings and Precautions, Hyperpyrexia and Confusion ( 5.2 ) 10/2016 Warnings and Precautions, Allergic Reactions ( 5.4 ) 10/2016

1 INDICATIONS AND USAGE 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. 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 ( 1 ).

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 capsule 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 capsule 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 and after increasing the dose. Patients who miss a dose of Droxidopa should take their next scheduled dose.

2.1 Dosing Information The recommended starting dose of Droxidopa capsule 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 capsule 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 and after increasing the dose. Patients who miss a dose of Droxidopa should take their next scheduled dose.

3 DOSAGE FORMS AND STRENGTHS Droxidopa capsules are available in 100 mg, 200 mg, and 300 mg strengths as specified below. 100 mg: Hard gelatin, size '4' capsules with opaque white body and opaque light blue cap, imprinted with "733" in black ink on cap and "100 mg" in black ink on body, containing off white to light brown powder. 200 mg: Hard gelatin, size ‘2’ capsule, with an opaque white body and opaque light yellow cap, imprinted with “734” in black ink on cap and “200 mg” in black ink on body, containing off white to light brown powder. 300 mg: Hard gelatin, size ‘1’ capsule, with an opaque white body and opaque light green cap, imprinted with “735” in black ink on cap and “300 mg” in black ink on body, containing off white to light brown powder. 100 mg, 200 mg, and 300 mg capsules ( 3 )

4 CONTRAINDICATIONS Droxidopa capsules are 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 ( 4 )

6 ADVERSE REACTIONS The following adverse reactions with Droxidopa capsule 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 Bionpharma Inc. at 1-888-235-2466 or FDA at 1-800-FDA-1088 or w ww.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 capsule 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 capsule 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 capsule group and with at least a 3% greater incidence in the Droxidopa capsule group than in the placebo group) in Droxidopa capsule-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, and hypertension. The most common adverse reactions leading to discontinuation from Droxidopa capsule were hypertension or increased blood pressure and nausea. Table 1 Most Common Adverse Reactions Occurring More Frequently in the Droxidopa capsule 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 capsule (N=131) n (%) Placebo (N=108) n (%) Droxidopa capsule (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 capsule group and with at least a 3% greater incidence in the Droxidopa capsule group than in the placebo group were from Study 306. Long-Term, Open-Label Trials with Droxidopa capsule In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with Droxidopa capsule 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 Post marketing Experience The following adverse reactions have been identified during post-approval use of Droxidopa capsule. 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

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a …

7 DRUG INTERACTIONS Use of DOPA decarboxylase inhibitors may require dose adjustments for Droxidopa capsule ( 7.2 ) 7.1 Drugs that Increase Blood Pressure Administering Droxidopa capsule in combination with other agents that increase blood pressure (e.g., norepinephrine, ephedrine, midodrine, and triptans) would be expected to increase the risk for supine hypertension. 7.2 Parkinson's Medications Dopa-decarboxylase inhibitors may require dose adjustments for Droxidopa capsule. 7.3 Non-selective MAO inhibitors The concomitant use of selective MAO-B inhibitors, such as rasagiline or selegiline, was permitted in the Droxidopa capsule clinical trials. However, based on mechanism of action, the use of non-selective MAO inhibitors and linezolid should be avoided as there is a potential for increased blood pressure when taken with Droxidopa capsule.

7.1 Drugs that Increase Blood Pressure Administering Droxidopa capsule in combination with other agents that increase blood pressure (e.g., norepinephrine, ephedrine, midodrine, and triptans) would be expected to increase the risk for supine hypertension.

7.2 Parkinson's Medications Dopa-decarboxylase inhibitors may require dose adjustments for Droxidopa capsule.

7.3 Non-selective MAO inhibitors The concomitant use of selective MAO-B inhibitors, such as rasagiline or selegiline, was permitted in the Droxidopa capsule clinical trials. However, based on mechanism of action, the use of non-selective MAO inhibitors and linezolid should be avoided as there is a potential for increased blood pressure when taken with Droxidopa capsule.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended ( 8.2 ) Patients with Renal Impairment: Dosing recommendations cannot be provided for patients with GFR less than 30 mL/min ( 8.6 ) 8.1 Pregnancy Risk Summary There are no available data on use of Droxidopa capsule in pregnant women and risk of major birth defects or miscarriage. Droxidopa capsule did not produce significant reproductive toxicity in pregnant female rats or rabbits or in their fetuses. However, when pregnant female rats were dosed during days 7-17 of gestation (the period of fetal organogenesis) with doses of Droxidopa capsule corresponding to 0.3, 1 and 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patient, based on body surface area, and when their male and female offspring (who were exposed only during fetal life) were subsequently bred, the female offspring exhibited a dose-dependent reduction in the number of live fetuses across all three doses and an increased number of embryonic/fetal deaths at the two higher doses (see Data). The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data During a multigenerational reproductive toxicity study in rats, pregnant females were dosed during days 7-17 of gestation (the period of fetal organogenesis) with doses of Droxidopa capsule corresponding to 0.3, 1 and 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patient. Reduced weight gain, renal lesions, and a small number of deaths were observed in females treated with the two higher doses. When their male and female offspring (who were exposed to Droxidopa capsule only during fetal life) were subsequently bred, the female offspring exhibited a dose-dependent reduction in the number of live fetuses across all three doses and an increased number of embryonic/fetal deaths at the two higher doses. 8.2 Lactation Risk Summary There is no information regarding the presence of Droxidopa or its active metabolite(s) in human milk, the effects of Droxidopa capsule on the breastfed child, nor the effects of Droxidopa capsule on milk production/excretion. Droxidopa is present in rat milk with peak concentrations seen 4 hours after oral drug administration and drug excretion into milk still occurring 48 hours after administration (see Data). However, due to species-specific differences in lactation physiology, animal lactation data typically do not reliably predict levels in humans. Because of the potential for serious adverse reactions, including reduced weight gain in breastfed infants, advise a woman not to breastfeed during treatment with Droxidopa capsule. Data Animal Data In rats, oral administration of droxidopa resulted in excretion into breast milk with peak concentrations seen 4 hours after administration, and excretion still occurring 48 hours after administration. When the drug was administered to nursing dams during the period of lactation at a dose corresponding to 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patient when based on body surface area, reduced weight gain and reduced survival were observed in the offspring. Despite the observed decreased weight gain, physical development was normal (with respect to timing and organ morphology). 8.4 Pediatric Use The safety and effectiveness of Droxidopa capsule in pediatric patients have not been established. 8.5 Geriatric Use A total of 197 patients with symptomatic nOH aged 75 years or above were included in the Droxidopa capsule clinical program. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity …

12.1 Mechanism of Action The exact mechanism of action of droxidopa capsules in the treatment of neurogenic orthostatic hypotension is unknown. Droxidopa capsules is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which is extensively distributed throughout the body. Droxidopa capsules 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 capsules in humans induces small and transient rises in plasma norepinephrine.

11 DESCRIPTION Droxidopa capsules contain droxidopa, which is a synthetic amino acid precursor of norepinephrine, for oral administration. Chemically, droxidopa is (–)-threo-3-(3,4-Dihydroxyphenyl)-L-serine. It has the following structural formula: Droxidopa is an odorless, tasteless, white to off-white crystals or crystalline powder. It is slightly soluble in water, and practically insoluble in methanol, glacial acetic acid, ethanol, acetone, ether, and chloroform. It is soluble in dilute hydrochloric acid. It has a molecular weight of 213.19 and a molecular formula of C 9 H 11 NO 5 . Droxidopa capsules also contain the following inactive ingredients: mannitol, corn starch, and magnesium stearate. The capsule shell is printed with black ink. The black inks contain shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water. The capsule shell contains the following inactive ingredients: 100 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black iron oxide, red iron oxide, water and SLS; 200 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black iron oxide, iron oxide yellow, water and SLS; 300 mg – gelatin, titanium dioxide, FD&C Blue No. 1, FD&C Yellow No.,5 (tartrazine), FD&C Red No. 40, water and SLS. Droxidopa capsules differ in size and color by strength [see Dosage Forms and Strengths (3) ] . chemicalstructure

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 capsule experienced hypertension and an intracranial hemorrhage. 10.2 Treatment There is no known antidote for Droxidopa capsules overdosage. In case of an overdose that may result in an excessively high blood pressure, discontinue Droxidopa capsule 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.

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 capsule experienced hypertension and an intracranial hemorrhage.

10.2 Treatment There is no known antidote for Droxidopa capsules overdosage. In case of an overdose that may result in an excessively high blood pressure, discontinue Droxidopa capsule 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Droxidopa capsules are supplied in the following dosage strengths: 100 mg: Hard gelatin, size '4' capsules with opaque white body and opaque light blue cap, imprinted with "733" in black ink on cap and "100 mg" in black ink on body, containing off white to light brown powder. 200 mg: Hard gelatin, size 2 capsule, with an opaque white body and opaque light yellow cap, imprinted with “734” in black ink on cap and “200 mg” in black ink on body, containing off white to light brown powder. 300 mg: Hard gelatin, size 1 capsule, with an opaque white body and opaque light green cap, imprinted with “735” in black ink on cap and “300 mg” in black ink on body, containing off white to light brown powder 100 mg 90-count bottle (NDC code# 69452-256-19) 200 mg 90-count bottle (NDC code# 69452-257-19) 300 mg 90-count bottle (NDC code# 69452-258-19) Dispense in a tight, Light-resistant container. Do not use if the printed seal under the cap is broken or missing. 16.2 Storage and Handling Droxidopa capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

16.1 How Supplied Droxidopa capsules are supplied in the following dosage strengths: 100 mg: Hard gelatin, size '4' capsules with opaque white body and opaque light blue cap, imprinted with "733" in black ink on cap and "100 mg" in black ink on body, containing off white to light brown powder. 200 mg: Hard gelatin, size 2 capsule, with an opaque white body and opaque light yellow cap, imprinted with “734” in black ink on cap and “200 mg” in black ink on body, containing off white to light brown powder. 300 mg: Hard gelatin, size 1 capsule, with an opaque white body and opaque light green cap, imprinted with “735” in black ink on cap and “300 mg” in black ink on body, containing off white to light brown powder 100 mg 90-count bottle (NDC code# 69452-256-19) 200 mg 90-count bottle (NDC code# 69452-257-19) 300 mg 90-count bottle (NDC code# 69452-258-19) Dispense in a tight, Light-resistant container. Do not use if the printed seal under the cap is broken or missing.

16.2 Storage and Handling Droxidopa capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].