Northera

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.

Pregnancy

Risk Summary

Thereare no available data on use of NORTHERA in pregnant women and risk of majorbirth defects or miscarriage. NORTHERAdid not produce significant reproductive toxicity in pregnant female rats or rabbitsor in their fetuses. However, when pregnant female rats were dosed during days7-17 of gestation (the period of fetal organogenesis) with doses of NORTHERAcorresponding to 0.3, 1 and 3 times the maximum recommended daily dose of 1,800mg in a 60 kg patient, based on body surface area, and when their male andfemale offspring (who were exposed only during fetal life) were subsequentlybred, the female offspring exhibited a dose-dependent reduction in the numberof live fetuses across all three doses and an increased number ofembryonic/fetal deaths at the two higher doses (see Data).

The estimatedbackground risk of major birth defects and miscarriage in the indicatedpopulation is unknown. Inthe U.S. general population, the estimated background risk of major birthdefects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15to 20%, respectively.

Data

Animal Data

During a multigenerational reproductivetoxicity study in rats, pregnant females were dosedduring days 7-17 of gestation (the period of fetal organogenesis) with doses ofNORTHERA corresponding to 0.3, 1 and 3 times the maximum recommended daily doseof 1,800 mg in a 60 kg patient. Reduced weight gain, renal lesions, and a smallnumber of deaths were observed in females treated with the two higher doses.When their male and female offspring (who were exposed to NORTHERA only duringfetal life) were subsequently bred, the female offspring exhibited adose-dependent reduction in the number of live fetuses across all three dosesand an increased number of embryonic/fetal deaths at the two higher doses.

Lactation

Risk Summary

Thereis no information regarding the presence of NORTHERA or its activemetabolite(s) in human milk, the effects of NORTHERA on the breastfed child, northe 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-specificdifferences in lactation physiology, animal lactation data typically do notreliably predict levels in humans. Because of the potential for seriousadverse reactions, including reduced weight gain in breastfed infants, advise awoman not to breastfeed during treatment with NORTHERA.

Data

Animal Data

Inrats, oral administration of droxidopa resulted in excretion into breast milkwith peak concentrations seen 4 hours after administration, and excretion stilloccurring 48 hours after administration. When the drug was administered tonursing dams during the period of lactation at a dose correspondingto 3 times the maximum recommended daily dose of 1,800 mg in a 60 kg patientwhen based on body surface area, reduced weight gain and reduced survival wereobserved in the offspring. Despite the observed decreased weight gain, physicaldevelopment was normal (with respect to timing and organ morphology).

Pediatric Use

The safety and effectiveness of NORTHERA in pediatric patients have not been established.

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.

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.