Northera 300 MG Oral Capsule
Generic Name: DROXIDOPA
Brand Name: Northera
- Substance Name(s):
- DROXIDOPA
DRUG INTERACTIONS
7 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.
OVERDOSAGE
10 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 NORTHERA experienced hypertension and an intracranial hemorrhage.
10.2 Treatment There is no known antidote for NORTHERA overdosage.
In case of an overdose that may result in an excessively high blood pressure, discontinue NORTHERA 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.
DESCRIPTION
11 NORTHERA 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 C9H11NO5.
NORTHERA 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 glaze, ethanol, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide.
The capsule shell contains the following inactive ingredients: 100 mg – gelatin, titanium dioxide, FD&C Blue No.
2, black and red iron oxide; 200 mg – gelatin, titanium dioxide, FD&C Blue No.
2, black and yellow iron oxide; 300 mg – gelatin, titanium dioxide, FD&C Blue No.
1, FD&C Yellow No.
5 (tartrazine), and FD&C Red No.
40.
NORTHERA capsules differ in size and color by strength [see Dosage Forms and Strengths (3)].
northera-01
CLINICAL STUDIES
14 14.1 Studies in Neurogenic Orthostatic Hypotension Clinical studies (described below) examined the efficacy of NORTHERA in the short-term (1 to 2 weeks) and over longer-term periods (8 weeks; 3 months).
Studies 301 and 306B showed a treatment effect of NORTHERA at Week 1, but none of the studies demonstrated continued efficacy beyond 2 weeks of treatment.
Study 306B was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic nOH and Parkinson’s disease.
Patients entering the study were required to have a decrease of at least 20 mm Hg or 10 mm Hg, respectively, in systolic or diastolic blood pressure, within 3 minutes after standing, as well as symptoms associated with neurogenic orthostatic hypotension.
The study had an initial dose titration period that lasted up to 2 weeks in which patients received placebo or 100 to 600 mg of NORTHERA three times daily, followed by an 8-week treatment period.
Efficacy was measured using the OHSA Item #1 score (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) at Week 1, in patients who had completed titration and 1 week of maintenance therapy.
A total of 171 patients were enrolled, and 147 patients were included in the efficacy analysis.
The mean age was 72 years, and patients were mostly Caucasian.
During the study, 94% of placebo-treated patients and 88% on NORTHERA were taking dopa-decarboxylase inhibitors; 17% of placebo-treated patients and 26% on NORTHERA were taking fludrocortisone.
There were more premature discontinuations in the NORTHERA group (28%) than in the placebo group (20%).
In both groups, the mean baseline dizziness score was 5.1 on an 11-point scale.
At Week 1, patients showed a statistically significant mean 0.9 unit decrease in dizziness with NORTHERA versus placebo (P=0.028), but the effect did not persist beyond Week 1.
The data at all time points are shown in Figure 1.
Patients receiving NORTHERA also had a greater increase, compared to placebo, in the Week 1 lowest standing systolic blood pressure within 3 minutes after standing (5.6 mm Hg; P=0.032).
Figure 1.
Mean Change in OHSA Item 1 Score by Week in Study 306B Note: The graph is based on observed data only.
The error bars are the 95% confidence interval of the mean change from baseline in OHSA Item 1 scores.
Figure 2.
Distribution of Patients by Change in OHSA Item 1, Baseline to Week 1, in Study 306B Figure 2 shows the distribution of changes from Baseline to Week 1 in the OHSA Item #1 score.
Overall the figure shows that patients treated with NORTHERA improved more than those treated with placebo.
Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic neurogenic orthostatic hypotension.
The study included an initial open-label dose titration period, a 7-day washout period, and a randomized double-blind 7-day treatment period.
To be eligible for enrollment, patients were required to have a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within 3 minutes after standing.
The study was enriched, such that only patients who had been identified as “responders” during the titration period were randomized to NORTHERA or placebo.
To be considered a responder, a patient had to demonstrate improvement on the OHSA Item #1 score by at least 1 point, as well as an increase in systolic blood pressure of at least 10 mm Hg post-standing, during the open-label dose titration period.
Patients who dropped out during the titration period because of side effects or other reasons were also not included in the double-blind portion of the study.
Patients had a primary diagnosis of Parkinson’s disease (n=60), pure autonomic failure (n=36), or multiple system atrophy (n=26).
The mean age was 60 years, and most were Caucasian.
45% of patients were taking dopa-decarboxylase inhibitors, and 29% were taking fludrocortisone.
Efficacy was measured using the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported outcome that measures symptoms of nOH and their impact on the patient’s ability to perform daily activities that require standing and walking.
The OHQ includes OHSA Item #1 as one of several components.
A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, P=0.19).
The mean baseline dizziness score on OHSA Item #1 (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) was 5.2 units on an 11-point scale.
At Week 1 of treatment, patients showed a mean 0.7 unit decrease in dizziness with NORTHERA versus placebo (P=0.06).
Study 302 (n=101) was a placebo-controlled, 2-week randomized withdrawal study of NORTHERA in patients with symptomatic nOH.
Study 303 (n=75) was an extension of Studies 301 and 302, where patients received their titrated dose of NORTHERA for 3 months and then entered a 2-week randomized withdrawal phase.
Neither study showed a statistically significant difference between treatment arms on its primary endpoint.
Considering these data, the effectiveness of NORTHERA beyond 2 weeks is uncertain, and patients should be evaluated periodically to determine whether NORTHERA is continuing to provide a benefit.
Mean Change in OHSA Distribution of Patients by Change in OHSA
HOW SUPPLIED
16.1 How Supplied NORTHERA capsules are supplied in the following dosage strengths: 100 mg: Hard gelatin, size 3 capsule, with an opaque light blue cap and an opaque white body, printed with “Northera” on body and “100” on cap, filled with a white to light brown powder.
200 mg: Hard gelatin, size 2 capsule, with an opaque light yellow cap and an opaque white body, printed with “Northera” on body and “200” on cap, filled with a white to light brown powder.
300 mg: Hard gelatin, size 1 capsule, with an opaque light green cap and an opaque white body, printed with “Northera” on body and “300” on cap, filled with a white to light brown powder.
100 mg 90-count bottle (NDC code# 67386-820-19) 200 mg 90-count bottle (NDC code# 67386-821-19) 300 mg 90-count bottle (NDC code# 67386-822-19)
RECENT MAJOR CHANGES
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
GERIATRIC USE
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.
DOSAGE FORMS AND STRENGTHS
3 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)
MECHANISM OF ACTION
12.1 Mechanism of Action 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.
INDICATIONS AND USAGE
1 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).
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of NORTHERA in pediatric patients have not been established.
PREGNANCY
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.
BOXED WARNING
WARNING: SUPINE HYPERTENSION Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses.
Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position.
If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue NORTHERA [see Warnings and Precautions (5.1)].
WARNING: SUPINE HYPERTENSION See full prescribing information for complete boxed warning.
Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses.
Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position.
If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue NORTHERA [see Warnings and Precautions (5.1)].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS 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)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Elevations in Blood Pressure Counsel patients that NORTHERA causes elevations in blood pressure and increases the risk of supine hypertension, which could lead to strokes, heart attacks, and death.
Instruct patients to rest and sleep in an upper-body elevated position and monitor blood pressure.
Instruct patients how to manage observed blood pressure elevations.
To reduce the risk of supine hypertension, in addition to raising the upper body, the late afternoon dose of NORTHERA should be taken at least three hours before bedtime [see Warnings and Precautions (5.1)].
Concomitant Treatments Counsel patients about the concomitant use of drugs to treat other conditions that may have an additive effect with NORTHERA [see Drug Interactions (7)].
Allergic Reactions Counsel patients to discontinue NORTHERA and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction such as anaphylaxis, angioedema, bronchospasm, urticaria or rash occur [see Warnings and Precautions (5.4)].
Lactation Advise women not to breastfeed during treatment with NORTHERA [see Use in Specific Populations (8.2)].
Food Patients should take NORTHERA the same way each time, either with food or without food [see Dosage and Administration (2.1)].
Missed Dose If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.
Manufactured by: Patheon, Whitby, ON L1N 5Z5, Canada For: Lundbeck, Deerfield, IL 60015, U.S.A.
NORTHERA is a registered trademark of Lundbeck NA Ltd.
DOSAGE AND ADMINISTRATION
2 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 NORTHERA capsule whole (2.1) 2.1 Dosing 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.