Droxidopa

NORTHERA is 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 NORTHERA should be assessed periodically. NORTHERA is 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 NORTHERA should be assessed periodically ( 1 ).

NORTHERA capsules are available in 100 mg, 200 mg, and 300 mg strengths as specified below. 100 mg: Hard gelatin capsules with “Northera” on the white body and “100” on the light blue cap 200 mg: Hard gelatin capsules with “Northera” on the white body and “200” on the light yellow cap 300 mg: Hard gelatin capsules with “Northera” on the white body and “300” on the light green cap 100 mg, 200 mg, and 300 mg capsules ( 3 )

NORTHERA 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 ( 4 )

NORTHERA 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 NORTHERA 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 NORTHERA if supine hypertension persists. If supine hypertension is not well-managed, NORTHERA 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 NORTHERA use during postmarketing surveillance. Observe patients carefully when the dosage of NORTHERA 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 NORTHERA 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. This product contains FD&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&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity [see Contraindications ( 4 )].

The following adverse reactions with NORTHERA 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 Lundbeck at 1-800-455-1141 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 NORTHERA 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 NORTHERA 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 NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group) in NORTHERA-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, and hypertension. The most common adverse reactions leading to discontinuation from NORTHERA were hypertension or increased blood pressure and nausea. Table 1. Most Common Adverse Reactions Occurring More Frequently in the NORTHERA Group Study 301 and Study 302 (1 to 2 Weeks Randomized Treatment) Study 306 (8 to 10 Weeks Randomized Treatment) Placebo (N=132) n (%) NORTHERA (N=131) n (%) Placebo (N=108) n (%) NORTHERA (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 NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group were from Study 306. Long-Term, Open-Label Trials with NORTHERA In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with NORTHERA 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 NORTHERA. 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

Use of DOPA decarboxylase inhibitors may require dose adjustments for NORTHERA ( 7.2 )

7.1 Drugs that Increase Blood Pressure Administering NORTHERA 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 NORTHERA.

7.3 Non-selective MAO Inhibitors The concomitant use of selective MAO-B inhibitors, such as rasagiline or selegiline, was permitted in the NORTHERA 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 NORTHERA.

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 NORTHERA in pregnant women and risk of major birth defects or miscarriage. NORTHERA 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 NORTHERA 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 NORTHERA 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 NORTHERA 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 NORTHERA or its active metabolite(s) in human milk, the effects of NORTHERA on the breastfed child, nor the effects of NORTHERA 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 NORTHERA. 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 NORTHERA 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 NORTHERA 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 of some older individuals cannot be ruled out.

8.6 Renal Impairment NORTHERA and its metabolites are primarily cleared renally. Patients with mild or moderate renal impairment (GFR greater than 30 mL/min) were included in clinical trials and did not have a higher frequency of adverse reactions. Clinical experience with NORTHERA in patients with severe renal function impairment (GFR less than 30 mL/min) is limited.

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