Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

NORTHERA (NDA-203202)

(DROXIDOPA)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/10/2017 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Supine Hypertension

(additions underlined)

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.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

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

10/03/2016 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

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

5 Warnings and Precautions

5.4 Allergic Reactions

Hypersensitivity reactions including anaphylaxis, angioedema, bronchospasm, urticarial 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.

6 Adverse Reactions

6.2 Post Marketing Experience

Cardiac Disorders: Chest pain

Eye Disorders: Blurred vision

Gastrointestinal Disorders: Pancreatitis, abdominal pain, vomiting, diarrhea

General Disorders and Administration Site Conditions: Fatigue

Psychiatric Disorders: Psychosis, hallucination, delirium, agitation, memory disorder

7 Drug Interactions

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.

8 Use in Specific Populations

8.1 Pregnancy (PLLR Conversion)

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.

8.2 Lactation (PLLR Conversion)

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. 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).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

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.

Lactation

Advise women not to breastfeed during treatment with NORTHERA.