Northera

1 INDICATIONS AND USAGE 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.

Starting dose is 100 mg three times during the day Titrate by 100 mg three times daily, up to a maximum dose of 600 mg three times daily Take consistently with or without food 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 Take NORTHERA capsule whole

2.1Dosing Information The

recommended starting dose of NORTHERA 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 NORTHERA consistently, either with food or without food. Take NORTHERA 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 NORTHERA and after increasing the dose. Patients who miss a dose of NORTHERA should take their next scheduled dose.

5 WARNINGS AND PRECAUTIONS NORTHERA may cause supine hypertension and may increase cardiovascular risk if supine hypertension is not well-managed. Hyperpyrexia and confusion May exacerbate symptoms in patients with existing ischemic heart disease, arrhythmias, and congestive heart failure Allergic reactions

5.1Supine 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.

5.2Hyperpyrexia 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.

5.3Ischemic 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.

5.4Allergic 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 .

4 CONTRAINDICATIONS NORTHERA is contraindicated in patients who have a history of hypersensitivity to the drug or its ingredients . History of hypersensitivity to the drug or its ingredients

8.1Pregnancy 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 . 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.

The following adverse reactions with NORTHERA are included in more detail in the Warnings and Precautions section of the label: Supine Hypertension Hyperpyrexia and Confusion May exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure The most common adverse reactions (>5% and ≥3% compared to placebo) are headache, dizziness, nausea, and hypertension To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 . 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 8 8 15 Dizziness 2 5 5 11 Nausea 2 2 5 10 Hypertension 0 2 1 8 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%).

6.2Postmarketing 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