Orenitram Drug Information
Generic name: TREPROSTINIL
Prostacycline Vasodilator [EPC]
Uses of Orenitram
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%).
Dosage & Administration of Orenitram
Side Effects of Orenitram
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.
Approximately 91% of such patients in Study 1 experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). Study 4 enrolled a total of 690 patients, 346 received Orenitram and 344 received placebo. 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. Table 1 summarizes adverse events with rates at least 5% higher on Orenitram therapy than on placebo that were reported in either Study 1 or 4. Table 1: Adverse Events with Rates at Least 5% Higher on Orenitram Therapy than on Placebo in Either Study 1 or Study 4 Reaction Study 1 N=228 Includes all subjects in the Primary Analysis Population Study 4 N=690 Orenitram n=151 Placebo n=77 Orenitram n=346 Placebo n=344 Headache 63% 19% 75% 35% Diarrhea 30% 16% 69% 29% Nausea 30% 18% 40% 23% Vomiting 17% 16% 36% 10% Flushing 15% 6% 45% 8% Pain in jaw 11% 4% 18% 3% Pain in extremity 14% 8% 18% 9% Hypokalemia 9% 3% 4% 3% Abdominal discomfort 6% 0% 8% 4% Upper abdominal pain 5% 3% 12% 5% Orenitram was studied in a long-term, open-label, extension study in which 824 patients were dosed for a mean duration of approximately 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.
Warnings & Cautions for Orenitram
Worsening
PAH Symptoms upon Abrupt Withdrawal Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
Use in Patients with Blind-end Pouches
The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.
Drug Interactions with Orenitram
Effect of
CYP2C8 Inhibitors on Treprostinil Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult volunteers increases exposure to treprostinil. Reduce the starting dose of Orenitram to 0.125 mg BID and use 0.125 mg BID increments not more frequently than every 3 to 4 days .
Pregnancy Safety for Orenitram
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 2 to 4% and 15 to 20%, 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 (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 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. The exposures at 5 and 20 mg/kg/day doses represent 8 and 33 times, respectively, the human exposure at the dose of 3.5 mg BID on an AUC basis.
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. The no observed effect level for F 1 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 F 1 reproductive performance was 2.5 mg/kg/day (approximately 4 times the human exposure at the dose of 3.5 mg BID on an AUC basis). 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. In a dose range-finding study, there was a 17% decrease in the pregnancy rate for animals administered 4 mg/kg/day. A dose-dependent 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 3 times the human exposure at the dose of 3.5 mg BID on an AUC basis.
Pediatric Use of Orenitram
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Contraindications for Orenitram
Severe hepatic impairment (Child Pugh Class C) . Severe hepatic impairment (Child Pugh Class C).
Overdosage Information for Orenitram
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.
Clinical Studies of Orenitram
Clinical Trials in Pulmonary Arterial Hypertension Four multicenter, randomized, double-blind studies were
conducted and compared Orenitram to placebo in a total of 349 (Study 1), 350 (Study 2), 310 (Study 3), and 690 (Study 4) patients with PAH. Study 1 (effect seen with no background vasodilator) Study 1 was a 12-week, randomized (2:1 Orenitram to placebo), double-blind, placebo-controlled, international efficacy and safety study of Orenitram in patients with WHO Group 1 PAH not currently receiving PAH therapy. The primary efficacy endpoint was placebo-corrected change in six-minute walk distance (6MWD) from Baseline to Week 12. Study drug dose was titrated to a maximum of 12 mg BID based on clinical response and study drug tolerability. Study 1 enrolled 349 patients (overall analysis population) who were not receiving any PAH medication.
At the beginning of the study, subjects were dosed with only the 1 mg tablets with 0.5 and 0.25 mg tablets introduced at sequentially later dates during the study. The primary analysis population consisted of the 228 patients who had access to the 0.25 mg tablet at the time of randomization. Patients were administered Orenitram or placebo twice daily, with the doses titrated to effect over the course of the 12-week trial.
Patients were in WHO functional class II (~33%) and class III (~66%) with either idiopathic or heritable PAH (~75%), collagen vascular disease associated PAH (~19%), or PAH associated with HIV (1%) or congenital heart defect (5%) or other conditions (~6%). The patients' mean baseline 6MWD was approximately 330 meters. In the primary analysis population, 17% of patients discontinued Orenitram compared to 14% of patients on placebo. The primary efficacy endpoint of the trial was the change in 6MWD at 12 weeks for the primary analysis population.
Analysis of Study 1 results demonstrated that those patients receiving Orenitram compared to patients receiving placebo improved their median change in 6MWD by approximately 23 meters (p=0.013) as compared to patients receiving placebo as demonstrated in (Figure 2). The within group median change from baseline was +25 meters for Orenitram and -5 meters for placebo at Week 12 (N=228). Mean dose (±SD) in the Orenitram group was 2.3 ± 1.3, 3.2 ± 1.9, and 3.4 ± 1.9 mg BID at Weeks 4, 8, and 12, respectively, with a maximum dose of 12 mg BID. The distribution of the 6MWD change from baseline at Week 12 was also plotted across the range of observed values (Figure 3). Figure 2: Estimate of Treatment Effect by Visit for the Primary Analysis Population (Study 1) Figure 3: Plot of the Distribution of Peak 6MWD Changes at Week 12 for the Primary Analysis Population (Study 1) The placebo-corrected median treatment effect on 6MWD was estimated within various subpopulations defined by age, gender, disease etiology, and baseline 6MWD (Figure 4). Figure 4: Placebo Corrected Median Treatment Effect (with 95% CI) on 6MWD Change from Baseline at Week 12 for Various Subgroups in the Primary Analysis Population (Study 1) Figure 2 Figure 3 Figure 4 Studies 2 and 3 (no effect on a background of ERA, PDE-5 inhibitor, or both) Studies 2 (N=350) and 3 (N=310) were 16-week, randomized, double-blind, placebo-controlled, international efficacy and safety studies of Orenitram in patients with WHO Group 1 PAH. The primary efficacy endpoint was placebo-corrected change in 6MWD from Baseline to Week 16. Patients were in WHO functional class II (~23%) and class III (~77%) with either idiopathic or heritable PAH (~66%), collagen vascular disease associated PAH (~29%), or PAH associated with HIV (1%) or congenital heart defect (4%). The patients' mean baseline 6MWD was approximately 340 meters. Approximately 40% were receiving both an ERA and a PDE-5 inhibitor. The results did not demonstrate a benefit in exercise testing with median 6MWD at Week 16. Study 4 (effect seen with a single background PAH therapy) The effect of Orenitram on the progression of PAH was demonstrated in an international, multicenter, double-blind, event-driven study in patients with WHO Group 1 PAH randomized 1:1 to Orenitram or placebo (Study 4). The primary efficacy endpoint was the time to first clinical worsening (morbidity or mortality) event.
Study drug dose was titrated starting at 0.125 mg TID to a maximum of 12 mg TID based on clinical response and study drug tolerability. Study 4 enrolled a total of 690 patients (primary efficacy analysis population) who were currently receiving a single approved PAH therapy (PDE-5 inhibitor or soluble guanylate cyclase (sGC) ; ERA ). The median age was 43 years and most patients were white (52%) and female (79%). The majority of patients were lower risk in WHO functional class II (63%) with a mean (±SD) baseline 6MWD of 396 (±96) meters. Most patients had either idiopathic or heritable PAH (63%) or collagen vascular disease associated PAH (26%). Patients treated with Orenitram achieved a median dose of 3.6 mg TID at Week 24, which continued to increase until approximately Week 60 where the median dose of Orenitram was approximately 5 mg TID. Treatment with Orenitram resulted in a significant increase in the time to first clinical worsening event compared with patients who received placebo, which was associated with a reduction in the risk of an event (HR=0.75 ; p=0.039; Figure 5). The beneficial effect of Orenitram was primarily attributable to a delay in disease progression—defined as a 15% decline in 6MWD plus an increase in either WHO Functional Class or worsening of signs or symptoms of right heart failure—(HR=0.39 ; Figure 6), but there was no effect on the other components of clinical worsening (Table 2). Figure 5: Kaplan-Meier Plot of Time to Clinical Worsening Events for the Primary Analysis Population (Study 4) Table 2: Primary Endpoint Events (Study 4) Orenitram % N=346 Placebo % N=344 HR (95% CI) 6MWD, 6-minute walk distance; CI, confidence interval; HR, hazard ratio; IV PGI 2, intravenously administered prostacyclin; PAH, pulmonary arterial hypertension; RHF, right heart failure; WHO, World Health Organization Clinical worsening 26 36 0.75 Any of these All-cause mortality 4.3
Hospitalization for
PAH 10 10 Inhaled/IV PGI 2 0.6
Unsatisfactory long-term clinical response 5.5 5.8 Disease progression 5.5 14.5 0.39
This → 15% decrease in 6MWD 5.5
Plus one of these Increase in
WHO functional class 2.6
Increased
RHF symptoms 2.9
Figure 6: Kaplan-Meier Plot of Time to Disease Progression for the Primary
Analysis Population (Study 4) The treatment effect on time to first clinical worsening event due to disease progression was consistent for various subgroups defined by age, sex, baseline 6MWD, WHO functional class, disease etiology, geographical regions, and background therapy (Figure 7). Figure 7: Forest Plot of Subgroup Analyses of Time to Disease Progression for Various Subgroups in the Primary Analysis Population (Study 4) Figure 5 Figure 6 Figure 7 Long-Term Treatment of Pulmonary Arterial Hypertension Patients (N=824) from the placebo-controlled studies entered a long-term, uncontrolled, open-label extension study. The average exposure to Orenitram was approximately 2 years with a maximum exposure of approximately 6 years. The dose of Orenitram continued to increase over time with doses (mean ± SD) of 3.6 ± 2.7, 4.2 ± 3.1, and 5 ± 3.7 mg BID at 6 (n=649), 12 (n=433), and 24 months (n=238), respectively, with a maximum dose of 21 mg BID. Reasons for discontinuation from the study included adverse event (16%), progression of disease (15%), death (13%), and withdrawn consent (7%). In the 522 subjects that completed the 12-month efficacy assessment, their mean 6MWD improved by 24 meters compared to baseline (30 meters in monotherapy patients and 20 meters when Orenitram was used in combination with an ERA and/or a PDE-5 inhibitor). Of the patients that remained in the study, overall survival was 92%, 87%, and 82% at the end of 1, 2, and 3 years, respectively, with progression-free survival (progression defined as death, discontinuation, or addition of a PAH therapy) of 74%, 61%, and 47%. Without a control group, these data must be interpreted cautiously.
Remodulin to Orenitram Transition Study A 24-week, multicenter, open-label study enrolled 33 WHO Group 1 patients on stable doses of Remodulin. All patients received background therapy with a PDE-5 inhibitor and/or ERA. Patients were WHO functional class I or II and hemodynamically stable at baseline with a cardiac index >
L/m 2
RAP <11 mmHg, and PVR <10 Wood units. The primary endpoint of the study was the safety and tolerability of the transition. Successful transition was defined as transition from Remodulin to Orenitram at Week 4 (no longer receiving Remodulin) and clinically maintained on Orenitram through Week 24 (as measured by 6MWD and hemodynamics). All patients transitioned from Remodulin to Orenitram (median time to transition of 3 days) with thirty-one patients (94%) completing transition in 5 days (range 2 to 29 days). Two subjects discontinued Orenitram.
After 24 weeks of treatment with Orenitram, 6MWD and hemodynamics remained stable. Without a control group, these data must be interpreted cautiously.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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