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Worsening PAH Symptoms Upon Abrupt Withdrawal
Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
Risk Of Bleeding
Orenitram inhibits platelet aggregation and increases the risk of bleeding.
Use In Patients With Blind-end Pouches
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
- Abrupt discontinuation of therapy could result in worsening of PAH symptoms.
- Take Orenitram with food.
- Swallow Orenitram tablets whole. Do not split, chew, crush, or break. Do not take a tablet that is damaged or broken.
- The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Treprostinil diolamine did not demonstrate any carcinogenic effects in mouse or rat carcinogenicity studies. Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10 and 20 mg/kg/day in males and 0, 3, 7.5 and 15 mg/kg/day in females daily for 26 weeks did not significantly increase the incidence of tumors. The exposures obtained at the highest dose levels used in males and females are about 8- and 17-fold, respectively, the human exposure at the mean dose of 3.4 mg BID. Oral administration of treprostinil diolamine to Sprague Dawley rats at 0, 1, 3 and 10 mg/kg/day daily for 104 weeks did not significantly increase the incidence of tumors. The exposures obtained at the highest dose levels used in males and females are about 21- and 29-fold, respectively, the human exposure.
In vitro genotoxicity studies with high doses of treprostinil did not demonstrate any mutagenic or clastogenic effects. Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an increased incidence of micronucleated polychromatic erythrocytes.
No adverse effect doses for fertility, fetal viability / growth, fetal development (teratogenicity), and postnatal development were determined in rats. In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred with the no observed adverse effect level for these adverse effects of 0.5 mg/kg/day (5 times the human exposure) [see Use in Specific Populations].
Use In Specific Populations
Pregnancy Category C
Animal reproductive studies with treprostinil diolamine have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in humans.
In rats, treatment with treprostinil diolamine had no effect on reproductive performance or sperm motility at doses up to 10 mg/kg/day. The exposures at this dose level are about 10- (male) to 18- (female) fold the usual human exposure at the mean dose of 3.4 mg BID.
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 (0, 5, 10 and 20 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 postimplantation 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. The exposures at 5 and 20 mg/kg/day doses represent 13 and 55 times, respectively, the human exposure.
For F1 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. The no observed effect level for F1 progeny general development (based on body weight) was 10 mg/kg/day for females and ≤ 2.5 mg/kg/day for males; the no observed effect level for F1 reproductive performance was 2.5 mg/kg/day or 6 times the human exposure.
In pregnant rabbits, the primary maternal adverse effects were gastrointestinal disturbance; dosedependent decreases in mean body weight, body weight gain, and food consumption were observed. During the post-dose phase, the effect was reversed. In a dose range-finding study, there was a 17% decrease in the pregnancy rate for animals administered 4 mg/kg/day. A dosedependent increase in post-implantation loss was observed. 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 5 times the human exposure.
Labor And Delivery
The effect of Orenitram on labor and delivery in humans is unknown. No treprostinil treatmentrelated effects on labor and delivery were seen in animal studies.
It is not known whether treprostinil is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, choose Orenitram or breastfeeding.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Orenitram did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic or cardiac function, and of concomitant disease or other drug therapy.
Patients With Hepatic Impairment
Patients With Renal Impairment
Last reviewed on RxList: 4/7/2016
Additional Orenitram Information
Report Problems to the Food and Drug Administration
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