DROXIDOPA (Page 2 of 4)

6.2 Post marketing Experience

The following adverse reactions have been identified during post-approval use of Droxidopa capsule. 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

7 DRUG INTERACTIONS

7.1 Drugs that Increase Blood Pressure

Administering Droxidopa capsule 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 Droxidopa capsule.

7.3 Non-selective MAO inhibitors

The concomitant use of selective MAO-B inhibitors, such as rasagiline or selegiline, was permitted in the Droxidopa capsule 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 Droxidopa capsule.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on use of Droxidopa capsule in pregnant women and risk of major birth defects or miscarriage. Droxidopa capsule 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 Droxidopa capsule 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 Droxidopa capsule 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 Droxidopa capsule 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 Droxidopa or its active metabolite(s) in human milk, the effects of Droxidopa capsule on the breastfed child, nor the effects of Droxidopa capsule 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 Droxidopa capsule.

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 Droxidopa capsule 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 Droxidopa capsule 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

Droxidopa capsule 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 Droxidopa capsule in patients with severe renal function impairment (GFR less than 30 mL/min) is limited.

10 OVERDOSAGE

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 Droxidopa capsule experienced hypertension and an intracranial hemorrhage.

10.2 Treatment

There is no known antidote for Droxidopa capsules overdosage. In case of an overdose that may result in an excessively high blood pressure, discontinue Droxidopa capsule 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.

11 DESCRIPTION

Droxidopa 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:

chemicalstructure

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 C 9 H 11 NO 5 .

Droxidopa 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, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water. The capsule shell contains the following inactive ingredients: 100 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black iron oxide, red iron oxide, water and SLS; 200 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black iron oxide, iron oxide yellow, water and SLS; 300 mg – gelatin, titanium dioxide, FD&C Blue No. 1, FD&C Yellow No.,5 (tartrazine), FD&C Red No. 40, water and SLS. Droxidopa capsules differ in size and color by strength [see Dosage Forms and Strengths (3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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