Orenitram

Pulmonary Arterial Hypertension

Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).

Pulmonary Arterial Hypertension In Patients Requiring Transition From Epoprostenol

In patients with PAH requiring transition from epoprostenol, Orenitram is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

General

Orenitram can be administered with or without further dilution with Sterile Diluent for Orenitram or similar approved high-pH glycine diluent (e.g., Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1 below for storage and administration time limits for the different diluents.

Diluted Orenitram has been shown to be stable at ambient temperature when stored for up to 14 days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL).

Table 1: Selection of Diluent

Initial Dose For Patients New To Prostacyclin Infusion Therapy

Orenitram is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous infusion. Orenitram is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated because of severe site pain or reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.

Initial Dose For Patients Transitioning To An Implantable Intravenous Infusion Pump

The initial dose of Orenitram should be the same as the current dose the patient is receiving using the external infusion pump at the time of transition.

Dosage Adjustments

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of Orenitram (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction).

The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. Dosage adjustments may be undertaken more often if tolerated. Avoid abrupt cessation of infusion. Restarting a Orenitram infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Orenitram to be re-titrated.

Patients With Hepatic Insufficiency

In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Orenitram to 0.625 ng/kg/min ideal body weight. Orenitram has not been studied in patients with severe hepatic insufficiency.

Administration

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Preparation

Orenitram is administered by subcutaneous or intravenous infusion at a calculated rate based on a patient's dose (ng/kg/min), weight (kg) and the Orenitram concentration (mg/mL).

For administration of Undiluted Orenitram the rate is calculated using the following formula:

For administration of Diluted Orenitram the rate and concentration is calculated using the following formulas:

Step 1

The volume of Orenitram Injection needed to make the required diluted Orenitram concentration for the given reservoir size can then be calculated using the following formula:

Step 2

The calculated volume of Orenitram Injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir.

Subcutaneous Infusion

Orenitram is administered subcutaneously by continuous infusion, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. The infusion pump should: (1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better, (4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Orenitram. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.

Intravenous Infusion

External Intravenous Infusion Pump

Orenitram is administered intravenously by continuous infusion via a surgically placed indwelling central venous catheter using an external infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of Orenitram. Use of a peripheral intravenous infusion for more than a few hours increases the risk of thrombophlebitis. The infusion pump used to administer Orenitram should: (1) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better of the hourly dose, (3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Orenitram. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets.

Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.

Implantable Intravenous Infusion Pump

Use an implantable intravenous infusion pump approved for use with Orenitram, such as the Implantable System for Orenitram® (ISR). Refer to the pump manufacturer's manual for specific instructions regarding preparation, programing, implantation, and refilling.

Patients Requiring Transition From Epoprostenol

Transition from epoprostenol to Orenitram is accomplished by initiating the infusion of Orenitram and increasing it, while simultaneously reducing the dose of intravenous epoprostenol. The transition to Orenitram should take place in a hospital with constant observation of response (e.g., walk distance and signs and symptoms of disease progression).

Initiate Orenitram at a recommended dose of 10% of the current epoprostenol dose, and then escalate as the epoprostenol dose is decreased (see Table 2 for recommended dose titrations).

Patients are individually titrated to a dose that allows transition from epoprostenol therapy to Orenitram while balancing prostacyclin-limiting adverse events. Treat increases in the patient's symptoms of PAH first with increases in the dose of Orenitram. Treat side effects normally associated with prostacyclin and prostacyclin analogs first by decreasing the dose of epoprostenol.

Table 2: Recommended Transition Dose Changes

None

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Catheter-Related Bloodstream Infection

Chronic intravenous infusions of Orenitram delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous infusion is the preferred mode of administration.

In an open-label study of IV treprostinil (n=47) using an external infusion pump, there were seven catheter-related line infections during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined as any positive blood culture) event per 3 years of use.

Administration of IV Orenitram with a high pH glycine diluent has been associated with a lower incidence of BSIs when compared to neutral diluents (sterile water, 0.9% sodium chloride) when used along with catheter care guidelines.

In an open-label study of an implantable pump (n=60), there were two blood stream infections (BSIs) related to the implant procedure during approximately 265 patient years.

Worsening PAH Upon Abrupt Withdrawal Or Sudden Large Dose Reduction

Avoid abrupt withdrawal or sudden large reductions in dosage of Orenitram, which may result in worsening of PAH symptoms.

Patients With Hepatic Or Renal Insufficiency

Titrate Orenitram slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function.

Risk Of Symptomatic Hypotension

Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Orenitram may produce symptomatic hypotension.

Risk Of Bleeding

Orenitram inhibits platelet aggregation and increases the risk of bleeding.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

A two-year rat carcinogenicity study was performed with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential associated with treprostinil inhalation in rats at systemic exposure levels up to about 34 and 1 times the human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not affect fertility or mating performance of male or female rats given continuous subcutaneous (sc) infusions at rates of up to 450 ng treprostinil/kg/min [about 59 times the recommended starting human sc infusion rate (1.25 ng/kg/min) and 8 times the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m² basis]. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6.

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, when based on AUC, obtained at the highest dose levels used in males and females are about 7-and 15-fold, respectively, the human exposure of the average subcutaneous infusion rate achieved in clinical trials. 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 18-and 26-fold, respectively, the human exposure of the average subcutaneous infusion rate achieved in clinical trials.

Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an increased incidence of micronucleated polychromatic erythrocytes.

Use In Specific Populations

Pregnancy

Risk Summary

Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated with pulmonary arterial hypertension (see Clinical Considerations). In animal studies, no adverse reproductive and developmental effects were seen in rats at about 123 and 48 times the human exposure based on Cmax and AUC, respectively. In rabbits, external fetal and soft tissue malformations and skeletal malformations were observed at about 7 and 5 times the human exposure based on Cmax and AUC, respectively (see 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 is associated with an increased risk of maternal and fetal mortality.

Data

Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous administration and with treprostinil diolamine administered orally. In pregnant rats, continuous subcutaneous infusions of treprostinil during organogenesis and late gestational development, at doses as high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous infusion rate, on a ng/m² basis and about 16 times the average rate achieved in clinical trials), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infusions of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous infusion rate, on a ng/m² basis, and 5 times the average rate used in clinical trials). In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at doses of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. In studies with orally administered treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development (teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose tested (20 mg/kg/day), which represents about 123 and 48 times the human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no adverse effects were seen (0.5 mg/kg/day) represents about 7 and 5 times the human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. No treprostinil treatment-related effects on labor and delivery were seen in animal studies. Animal reproduction studies are not always predictive of human response.

Lactation

Risk Summary

There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Clinical studies of Orenitram did not include sufficient numbers of patients aged ≤16 years to determine whether they respond differently from older patients.

Geriatric Use

Clinical studies of Orenitram did not include sufficient numbers of patients aged 65 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, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients With Hepatic Insufficiency

Orenitram clearance is reduced in patients with hepatic insufficiency. In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Orenitram to 0.625 ng/kg/min ideal body weight, and monitor closely. Orenitram has not been studied in patients with severe hepatic insufficiency.

Patients With Renal Impairment

No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by dialysis.

The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration.

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 practice.

Adverse Events With Subcutaneously Administered Orenitram

Patients receiving Orenitram as a subcutaneous infusion reported a wide range of adverse events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of Orenitram, infusion site pain and reaction were the most common adverse events among those treated with Orenitram. Infusion site reaction was defined as any local adverse event other than pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of treatment.

Table 3: Percentages of Subjects Reporting Subcutaneous Infusion Site Adverse Events

Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these are generally considered to be related to the pharmacologic effects of Orenitram, whether administered subcutaneously or intravenously.

Adverse Reactions During Chronic Dosing

Table 4 lists adverse reactions that occurred at a rate of at least 3% more frequent in patients treated with subcutaneous Orenitram than with placebo in controlled trials in PAH.

Table 4: Adverse Reactions in Controlled 12-Week Studies of Subcutaneous Orenitram and at least 3% more frequent than on Placebo

Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included with the exception of those too general to be informative, and those not plausibly attributable to the use of the drug, because they were associated with the condition being treated or are very common in the treated population.

While hypotension occurred in both groups, the event was experienced twice as frequently in the Orenitram group as compared to the placebo group (4% in Orenitram treatment group versus 2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the administration of Orenitram.

The safety of Orenitram was also studied in a long-term, open-label extension study in which 860 patients were dosed for a mean duration of 1.6 years, with a maximum exposure of 4.6 years. Twenty-nine (29%) percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min). The safety profile during this chronic dosing study was similar to that observed in the 12-week placebo controlled study except for the following suspected adverse drug reactions (occurring in at least 3% of patients): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.

Adverse Events Attributable To The Drug Delivery System

In controlled studies of Orenitram administered subcutaneously, there were no reports of infection related to the drug delivery system. There were 187 infusion system complications reported in 28% of patients (23% Orenitram, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 Orenitram, 4 Placebo) reported non-serious adverse events resulting from infusion system complications. Adverse events resulting from problems with the delivery systems were typically related to either symptoms of excess Orenitram (e.g., nausea) or return of PAH symptoms (e.g., dyspnea). These events were generally resolved by correcting the delivery system pump or infusion set problem such as replacing the syringe or battery, reprogramming the pump, or straightening a crimped infusion line. Adverse events resulting from problems with the delivery system did not lead to clinical instability or rapid deterioration. In addition to these adverse events due to the drug delivery system during subcutaneous administration, the following adverse events may be attributable to the IV mode of infusion including arm swelling, paresthesias, hematoma and pain.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of Orenitram. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The following events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting, and potential connection to Orenitram. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia, bone pain, pruritus, dizziness, arthralgia, myalgia/muscle spasm, and pain in extremity. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.

Signs and symptoms of overdose with Orenitram during clinical trials are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of Orenitram.

In controlled clinical trials using an external infusion pump, seven patients received some level of overdose and in open-label follow-on treatment seven additional patients received an overdose; these occurrences resulted from accidental bolus administration of Orenitram, errors in pump programmed rate of administration, and prescription of an incorrect dose. In only two cases did excess delivery of Orenitram produce an event of substantial hemodynamic concern (hypotension, near-syncope).

One pediatric patient was accidentally administered 7.5 mg of Orenitram via a central venous catheter. Symptoms included flushing, headache, nausea, vomiting, hypotension and seizure-like activity with loss of consciousness lasting several minutes. The patient subsequently recovered.

In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed.

Treprostinil produces vasodilation and tachycardia. Single doses of treprostinil up to 84 mcg by inhalation produce modest and short-lasting effects on QTc, but this is apt to be an artifact of the rapidly changing heart rate. Treprostinil administered by the subcutaneous or intravenous routes has the potential to generate concentrations many-fold greater than those generated via the inhaled route; the effect on the QTc interval when treprostinil is administered parenterally has not been established.

The pharmacokinetics of continuous subcutaneous Orenitram are linear over the dose range of 2.5 to 125 ng/kg/min (corresponding to plasma concentrations of about 260 pg/mL to 18,250 pg/mL) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 ng/kg/min has not been studied.

Subcutaneous and intravenous administration of Orenitram demonstrated bioequivalence at steady state at a dose of 10 ng/kg/min.

Absorption

Orenitram is relatively rapidly and completely absorbed after subcutaneous infusion, with an absolute bioavailability approximating 100%. Steady-state concentrations occurred in approximately 10 hours. Concentrations in patients treated with an average dose of 9.3 ng/kg/min were approximately 2,000 ng/L.

Distribution

The volume of distribution of the drug in the central compartment is approximately 14 L/70 kg ideal body weight. Orenitram at in vitro concentrations well above what is clinically relevant was 91% bound to human plasma protein.

Metabolism And Excretion

Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. In a study conducted in healthy volunteers using [¹⁴C] treprostinil, 79% and 13% of the subcutaneous dose was recovered in the urine and feces, respectively, over 10 days. Only 4% was excreted as unchanged treprostinil in the urine. Five metabolites were detected in the urine, ranging from 10% to 16% and representing 64% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative (treprostinil glucuronide). The identified metabolites do not appear to have activity.

The elimination of treprostinil (following subcutaneous administration) is biphasic, with a terminal elimination half-life of approximately 4 hours using a two-compartment model. Systemic clearance is approximately 30 L/hour for a 70 kg person.

Based on in vitro studies treprostinil does not inhibit or induce major CYP enzymes.