Orenitram Drug Information

Pulmonary Arterial Hypertension Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).

Recommended Dosing Take Orenitram with food. Swallow Orenitram tablets whole; do not crush, split, or chew. Increase the dose to the highest tolerated dose.

The recommended maximum daily dose is 120 mg. If dose increments are not tolerated, consider titrating slower. If intolerable pharmacologic effects occur, decrease the dose in increments of 0.125 mg TID or 0.25 mg BID.

Avoid abrupt discontinuation.

Transitioning from Subcutaneous or Intravenous Routes of Administration of Treprostinil Decrease the dose of Remodulin while simultaneously increasing the dose of Orenitram. The dose of Remodulin can be reduced up to 30 ng/kg/min per day and the dose of Orenitram simultaneously increased up to 6 mg per day (2 mg TID) if tolerated. The following equation can be used to estimate a target total daily dose of Orenitram in mg using a patient's dose of intravenous (IV)/subcutaneous (SC) treprostinil (in ng/kg/min) and weight (in kg).

Orenitram total daily dose (mg) = 0.0072 × Remodulin dose (ng/kg/min) × weight (kg)

Dose Adjustment in Patients with Hepatic Impairment

In patients with mild hepatic impairment (Child Pugh Class A) start at 0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days. Avoid use of Orenitram in patients with moderate hepatic impairment (Child Pugh Class B). Orenitram is contraindicated in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.

Dose Adjustment for Use with CYP2C8 Inhibitors

When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil) the initial dose is 0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days.

Interruptions and Discontinuation If a dose of medication is missed, the patient should take the missed dose as soon as possible, with food. If a patient misses two or more doses, restart at a lower dose and re-titrate. In the event of a planned short-term treatment interruption for patients unable to take oral medications, consider a temporary infusion of subcutaneous or intravenous treprostinil.

Clinical 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. In a 12-week, placebo-controlled, monotherapy study (Study 1; WHO Group 1; functional class II-III), and an event-driven, placebo-controlled, combination therapy study (Study 4; WHO Group 1; functional class I-III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, diarrhea, nausea, and flushing. Orenitram patients in Study 1 (N=151) had access to 0.25 mg tablets at randomization.

Overall, 19% of patients treated with Orenitram discontinued treatment in Study 4 due to an adverse event (compared to 4% of patients receiving placebo). The exposure to Orenitram in Study 4 was up to 5.1 years with a median duration of exposure of 1.2 years. About 70% of patients continued treatment with Orenitram for at least a year.

The mean dose was 4.2 mg BID at one year. The adverse reactions were similar to those observed in the placebo-controlled trials. The safety of Orenitram was also evaluated in an open-label study transitioning patients from Remodulin.

The safety profile during this study was similar to that observed in the three pivotal studies.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of Orenitram: dizziness, dyspepsia, vomiting, myalgia, and arthralgia. 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.

Effect of CYP2C8 Inhibitors on Treprostinil Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult volunteers increases exposure to treprostinil.

Pregnancy Risk Summary Limited published data from case reports with Orenitram use in pregnant women are not sufficient to assess for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with pulmonary arterial hypertension (see Clinical Considerations ). Animal reproductive studies with treprostinil diolamine administered orally have shown an adverse effect on the fetus.

In rats, administration of treprostinil to pregnant rats during the period of organogenesis at doses ≥10 mg/kg/day (approximately 15 times the human exposure at the dose of 3.5 mg BID on an AUC basis) resulted in decreased pregnancy rate, increased post-implantation loss, and decreased fetal viability and growth. In rabbits, teratogenicity and decreased fetal viability and growth were observed at doses ≥1.5 mg/kg/day (approximately 7 times the human exposure at the dose of 3.5 mg BID on an AUC basis) (see Animal Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations Disease-associated maternal and embryo-fetal risk Pulmonary arterial hypertension in pregnancy increases the risk of maternal heart failure, stroke and death, preterm delivery, low birth weight, and stillbirth.

Data Animal Data In pregnant rats, reversible, dose-dependent decreases in body weight gain and food consumption were observed during the first four days of dosing in animals administered 10, 20, and 30 mg/kg/day treprostinil diolamine. In a dose range-finding study, there was a 17% decrease in the pregnancy rate in the animals administered 20 and 30 mg/kg/day. One dam in each of the 20 and 30 mg/kg/day had litters with no viable fetuses.

In the definitive study mg/kg/day, there were four treatment-related deaths, and a 32% decrease in the pregnancy rate for rats administered 20 mg/kg/day. There was an 8% decrease in the pregnancy rate in the animals administered 10 mg/kg/day. Across both studies, an increase in post-implantation loss was observed in animals administered 10 to 30 mg/kg/day, and a significant decrease in the mean number of live births was seen at dose levels ≥10 mg/kg/day.

The no observed adverse effect level was 5 mg/kg/day (maternal, fetal viability and growth), and 20 mg/kg/day (teratogenicity), the highest dose tested in the definitive study. For F 1 progeny, a decreased copulation index was observed at the 5 and 10 mg/kg/day treprostinil diolamine dose levels in rats. The no observed effect levels for physical development, reflex development, exploratory behavior, learning and memory, and sexual maturation was 10 mg/kg/day.

In pregnant rabbits, the primary maternal adverse effect was gastrointestinal disturbance; dose-dependent decreases in mean body weight, body weight gain, and food consumption were observed. During the post-dose phase, the effect was reversed. Two dams administered 4 mg/kg/day had litters with no viable fetuses; the mean fetal weight was slightly decreased in animals administered 4 mg/kg/day.

In the definitive study, mean fetal weights were significantly decreased in animals administered 0.5 to 3 mg/kg/day of treprostinil diolamine. At doses of 1.5 and 3 mg/kg/day, external fetal and soft tissue malformations were observed in a few fetuses, and the total fetal skeletal malformations were significantly increased. The no observed adverse effect level was less than 0.5 mg/kg/day (maternal), 1.5 mg/kg/day (fetal viability and growth), and 0.5 mg/kg/day (teratogenicity).

The 0.5 mg/kg/day dose represents about 3 times the human exposure at the dose of 3.5 mg BID on an AUC basis.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Severe hepatic impairment (Child Pugh Class C).

Signs and symptoms of overdose with Orenitram during clinical trials reflect its dose-limiting pharmacologic effects and include severe headache, nausea, vomiting, diarrhea, and hypotension. Treat supportively.