DROXIDOPA: 20,119 Adverse Event Reports & Safety Profile

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

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 ).

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.

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 )

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&apos;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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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 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&apos;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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>. 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

AND PRECAUTIONS Droxidopa capsule 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 capsule 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 capsule if supine hypertension persists. If supine hypertension is not well-managed, Droxidopa capsule 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 capsule use during post marketing surveillance. Observe patients carefully when the dosage of Droxidopa capsule 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 capsule 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 post marketing experience. Some of these reactions resulted in emergency treatment. If a hypersensitivity reaction occurs, discontinue the drug and initiate appropriate therapy. This product contains FD&amp;C Yellow No. 5 (tartrazine) which may also cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&amp;C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.1 Supine Hypertension Droxidopa capsule 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 capsule if supine hypertension persists. If supine hypertension is not well-managed, Droxidopa capsule 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 capsule use during post marketing surveillance. Observe patients carefully when the dosage of Droxidopa capsule 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 capsule 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 post marketing experience. Some of these reactions resulted in emergency treatment. If a hypersensitivity reaction occurs, discontinue the drug and initiate appropriate therapy. This product contains FD&amp;C Yellow No. 5 (tartrazine) which may also cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&amp;C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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&apos;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&apos;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.