Treprostinil Injection (DR Reddy's Laboratories) Product Monograph

INDICATIONS AND CLINICAL USE

Treprostinil Injection (treprostinil) is indicated for the long-term, subcutaneous or intravenous treatment of pulmonary arterial hypertension (PAH) in NYHA Class III and IV patients who did not respond adequately to conventional therapy.

Treprostinil Injection should be used only by clinicians experienced in the diagnosis and treatment of PAH. Treprostinil Injection is a potent pulmonary and systemic vasodilator. Initiation of Treprostinil Injection must be performed in a setting with adequate personnel and equipment for physiological monitoring and emergency care. Treprostinil Injection is infused continuously through a subcutaneous or surgically placed indwelling central venous catheter. Therapy with Treprostinil Injection may be used for prolonged periods, and the patient’s ability to administer Treprostinil Injection and care for an infusion system should be carefully considered. In order to reduce the risk of infection, aseptic technique must be used in the preparation and administration of Treprostinil Injection.

Geriatrics (> 65 years of age):

Safety and effectiveness in geriatric patients have not been established. (See WARNINGS and PRECAUTIONS, Special Populations, Geriatrics)

Pediatrics (< 16 years of age):

Safety and effectiveness in pediatric patients have not been established. (See WARNINGS and PRECAUTIONS, Special Populations, Pediatrics)

CONTRAINDICATIONS

Treprostinil Injection is contraindicated in patients with known hypersensitivity to the drug, any of

its excipients, or to structurally related compounds. For a complete listing of Treprostinil Injection excipients, see the Dosage Forms, Composition and Packaging section of the product monograph.

WARNINGS AND PRECAUTIONS

General Conditions of Use

Treprostinil Injection is a potent pulmonary and systemic vasodilator. Treprostinil Injection is indicated for subcutaneous or intravenous use only.

Treprostinil Injection should be used only by clinicians experienced in the diagnosis and treatment of PAH. Dosage adjustments in clinical trials were based on the patient’s signs and symptoms of PAH and side effects of treprostinil. Dosage of Treprostinil Injection should be adjusted at the first sign of recurrence or worsening of symptoms attributable to PAH or the occurrence of intolerable adverse events associated with Treprostinil Injection. (See DOSAGE and ADMINISTRATION.)

The decision to initiate therapy with Treprostinil Injection should be based on the understanding that there is a high likelihood that subcutaneous or intravenous therapy with Treprostinil Injection will be needed for prolonged periods, possibly years, and the patient’s ability to administer Treprostinil Injection and care for an infusion system should be carefully considered.

As with any potent vasodilator, abrupt withdrawal or sudden large reductions in dosage of Treprostinil Injection may result in worsening of PAH symptoms. Avoid abrupt withdrawal of Treprostinil Injection if at all possible. Although in clinical trials, no patient death from discontinuation of treprostinil was judged directly attributable to the interruption of the drug, 2 of 11 patients who abruptly discontinued subcutaneous treprostinil therapy died within 24 hours. Although their death may have been related to their deteriorating clinical condition, it seems most appropriate to wean patients from Treprostinil Injection. Only 3 of 55 (5%) patients with abrupt disruption of treprostinil developed increased symptoms of PAH, and no patients developed hemodynamic instability. In addition, among patients who discontinued treprostinil abruptly, no relationship has been established between abrupt discontinuation and rebound pulmonary hypertension.

Risk of Catheter-Related Blood Stream Infections

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

Carcinogenesis and Mutagenesis

Long-term studies in humans have not been performed to evaluate the carcinogenic potential of treprostinil. (See TOXICOLOGY for results from animal studies)

Endocrine and Metabolism

Obese subjects (BMI >30.0 kg/m²) clear treprostinil at a slower rate. Since doses of treprostinil are increased from very low initial doses to doses that improve disease symptoms while minimizing adverse effects, dosing to ideal body weight in obese patients should not be necessary.

Hepatic/Biliary/Pancreatic

An acute study of treprostinil administered subcutaneously at a dose of 10 ng/kg/min for 150 minutes was conducted in nine patients with portopulmonary hypertension and stable, mild or moderate hepatic dysfunction. Treprostinil was well tolerated and improved cardiopulmonary hemodynamics. Hepatic dysfunction reduced plasma clearance of treprostinil by up to 80% compared to healthy adult volunteers primarily by lowering the volume of distribution without affecting plasma half-life.

Treprostinil Injection should be increased more conservatively in patients with hepatic dysfunction, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic function. These patients should be closely monitored for signs and symptoms or emergence of adverse reactions due to excess treprostinil. Treprostinil has not been studied in patients with severe hepatic dysfunction.

Renal

No studies have been performed in patients with renal impairment. Treprostinil is not excreted to any significant degree by the kidney, however, its metabolites are excreted mainly by the kidney. Based on the individual patient dose titration recommended for Treprostinil Injection, doses of Treprostinil Injection should be increased more conservatively in patients with renal insufficiency.

Special Populations

Pregnant Women: The extent of exposure in pregnancy during clinical trials is very limited. There are no adequate and well controlled studies in pregnant women. No developmental toxicity was seen in rats at any dose of treprostinil up to 900 ng/kg/min and in rabbits at 50 ng/kg/min.

In pregnant rabbits, developmental toxicity characterized by minimal increases in fetal skeletal variations per litter was observed at doses of 150 and 300 ng/kg/min and was associated with maternal toxicity.

Nursing Women: It is not known whether treprostinil is excreted in human milk. Because many drugs are excreted in human milk, and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (<16 years of age): Safety and effectiveness in pediatric patients have not been established. Clinical studies of treprostinil did not include sufficient numbers of patients aged <16 years to determine whether they respond differently from older patients. In general, dose selection should be cautious.

Geriatrics (> 65 years of age): Clinical studies of treprostinil 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, renal or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Overview

Interpretation of adverse events (AEs) reported during clinical trials should be undertaken with an awareness of expected events attributable to the progression of the underlying disease, to treprostinil, and/or to the drug delivery system.

Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacological effects of treprostinil (e.g., dizziness, syncope). Adverse events probably related to the underlying disease include dyspnea, fatigue, chest pain, right ventricular heart failure and pallor. During clinical trials with subcutaneous infusion of treprostinil, infusion site pain and reaction were the most common adverse events among those treated with treprostinil. 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.

Adverse reactions included headache, diarrhea, vomiting, jaw pain, swelling/edema, flushing/ vasodilatation, muscle or joint pain, low systemic blood pressure, pain in extremities and nausea, and these are generally considered to be related to the pharmacologic effects of treprostinil, whether administered subcutaneously or intravenously.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse Reactions During Chronic Treatment: In an effort to separate the adverse reactions on treprostinil from those of the underlying disease, Table 1 lists adverse events that occurred at a rate greater than 1% in PAH patients participating in placebo-controlled trials of subcutaneous treprostinil.

Table 1: Frequency of Adverse Events Regardless of Attribution Occurring in >1% of Patients with PAH in Placebo-Controlled Studies of Subcutaneous Treprostinil

Adverse Event Description as COSTART Preferred Term

Table 2 lists all adverse reactions reported in controlled clinical trials of patients with PAH, that were significantly more frequently encountered in the subcutaneous treprostinil group than in the placebo group, regardless of attribution.

Table 2: Adverse Reactions Occurring Significantly (p<0.1) More Frequently in the Subcutaneous Treprostinil Group than in the Placebo Group, Regardless of Attributability

Adverse Events Attributable to the Drug Delivery System: In controlled studies of treprostinil 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% treprostinil, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 treprostinil, 4 placebo) reported non-serious adverse events resulting in infusion system complications. Adverse events resulting from problems with the delivery system did not lead to clinical instability or rapid deterioration, although in some cases PAH symptoms reappeared. 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.

There are a limited number of clinical studies with treprostinil administered via central venous infusion. The overall adverse event profile in these intravenous studies is similar to that of treprostinil administered subcutaneously, as would be expected based on the established bioequivalence of subcutaneous and intravenous routes of administration. However, as with any chronic indwelling central venous catheter, there are risks associated with delivery of therapy by this route. These risks include pain at the catheter insertion site, local infection, sepsis, thrombus formation and subsequent line occlusion, and malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in treprostinil which could produce symptoms related to excess or insufficient treprostinil, respectively.

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

Among patients randomized in a 12-week placebo-controlled study in India to either intravenous treprostinil (n=30) or placebo (n=15), vomiting, headache, diarrhea, jaw pain and extremity pain were more common in patients treated with treprostinil than placebo. Serious AEs were no more common in the treprostinil group than the placebo group, and included sepsis, congestive heart failure, pulmonary embolism, thrombophlebitis, catheter related complications, pseudomonal sepsis and pseudomonas infection.

Post-Market Adverse Drug Reactions

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of treprostinil. 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 treprostinil. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia, bone pain, pruritus, dizziness, arthralgia, myalgia, and muscle spasm. Treprostinil inhibits platelet aggregation and increases the risk of bleeding. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.

DRUG INTERACTIONS

Overview

In clinical studies, no untoward clinical manifestations have been observed in patients in whom treprostinil was used concurrently with the following classes of drugs: Anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatory drugs, opioids and corticosteroids.

Antihypertensive Agents or other Vasodilators

Additional reductions in blood pressure may occur when Treprostinil Injection is administered with diuretics, antihypertensive agents, or other vasodilators.

Anticoagulants and Antiplatelet Agents

When antiplatelet agents or anticoagulants are used concomitantly with Treprostinil Injection there is the potential for increased risk of bleeding due to the antiplatelet effect of treprostinil. However, patients receiving treprostinil in clinical trials were maintained on anticoagulants without evidence of increased bleeding. Treprostinil investigated in healthy volunteers had no effect in vivo on warfarin pharmacodynamics as measured by the effect on INR. Treprostinil also had no effect on pharmacokinetics of either the R- or S-enantiomer of warfarin.

Pharmacokinetics

Effect of Cytochrome P450 Inhibitors and Inducers on Treprostinil

Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diethanolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor gemfibrozil increases exposure (both C_max and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer rifampin decreases exposure to treprostinil. It has not been determined if the safety and efficacy of treprostinil by the parenteral (subcutaneously or intravenously) route are altered by inhibitors or inducers of CYP2C8.

Interaction potential with alcohol has not been established.

Modest interaction was observed between treprostinil and furosemide. Treprostinil Injection dose reduction in patients receiving furosemide is not recommended, although patients should be monitored for excess adverse effects of Treprostinil Injection.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Patients with hepatic impairment (See Dosage in Patients with Hepatic Impairment).

Recommended Dose and Dosage Adjustment

Treprostinil Injection can be administered without further dilution for subcutaneous administration, or diluted for intravenous infusion with 0.9% Sodium Chloride Injection or Sterile Water for Injection at concentrations as low as 0.004 mg/mL prior to administration.

Initial Dose: Treprostinil Injection is administered by continuous subcutaneous or continuous intravenous infusion. Treprostinil Injection 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.

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 treprostinil (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 adjustment may be undertaken more often if tolerated and adjusted based on PAH signs and symptoms and treprostinil side effects. Dose-related symptoms may necessitate a decrease in infusion rate; however, the event may resolve without dosage adjustment. Should an adverse event worsen and/or become intolerable, the infusion rate should be reduced, or infusion should be discontinued. Abrupt cessation of infusion should be avoided (See WARNINGS AND PRECAUTIONS). Restarting a Treprostinil Injection infusion within a few hours after interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Treprostinil Injection to be re-titrated.

Effects of Other Drugs on Treprostinil: Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) increases exposure (both Cmax and AUC) to treprostinil.

Treprostinil Injection dose reduction should be considered. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) decreases exposure to treprostinil. Treprostinil Injection dose increases should be considered.

Dosage in Patients with Hepatic Impairment: In patients with mild to moderate hepatic insufficiency, decrease the initial dose of Treprostinil Injection to 0.625 ng/kg/min ideal body weight. The dose should be increased more conservatively in patients with hepatic dysfunction, and these patients should be closely monitored for signs and symptoms or emergence of adverse events due to excess treprostinil. Treprostinil has not been studied in patients with severe hepatic insufficiency.

Missed Dose

As with any potent vasodilator, abrupt withdrawal or sudden large reductions in dosage of Treprostinil Injection may result in worsening of PAH symptoms. Abrupt withdrawal of Treprostinil Injection should be avoided if at all possible. Although in clinical trials, no patient death from discontinuation of treprostinil was judged directly attributable to the interruption of the drug, 2 of 11 patients who abruptly discontinued treprostinil therapy died within 24 hours. Although their death may have been related to their deteriorating clinical condition, it seems most appropriate to wean patients from Treprostinil Injection. Only 3 of 55 (5%) patients with abrupt disruption of treprostinil developed increased symptoms of PAH, and no patients developed hemodynamic instability. In addition, among patients who discontinued treprostinil abruptly, no relationship has been established between abrupt discontinuation and rebound pulmonary hypertension.

Restarting a Treprostinil Injection 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 Treprostinil Injection to be re- titrated.

Administration

Treprostinil Injection should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, discoloration, or leakage should not be used. Discard unused portion.

Treprostinil Injection is administered using a suitable ambulatory infusion pump that should:

• (1) be small and lightweight,
• (2) be able to adjust infusion rates in approximately 0.002 mL/hr,
• (3) have occlusion/no delivery, low battery, programming error and motor malfunction alarms,
• (4) have delivery accuracy of ±6% or better, and
• (5) be positive pressure driven.

The reservoir should be made of polyvinyl chloride, polypropylene, or glass.

Subcutaneous Infusion: Treprostinil Injection is administered subcutaneously by continuous infusion without further dilution, via a self-inserted subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.

For subcutaneous infusion, Treprostinil Injection is delivered without further dilution at a calculated Subcutaneous Infusion Rate (mL/hr) based on a patients Dose (ng/kg/min), Weight (kg), and the Vial Strength (mg/mL) of Treprostinil Injection being used. During use, a single reservoir (syringe) of undiluted Treprostinil Injection can be administered up to 72 hours at 37 °C.

The Subcutaneous Infusion rate is calculated using the following formula:

*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng Example calculations for Subcutaneous Infusion are as follows:

Example 1:

For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/mL Treprostinil Injection Vial Strength, the infusion rate would be calculated as follows:

Example 2:

For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Treprostinil Injection Vial Strength, the infusion rate would be calculated as follows:

Intravenous Infusion: Treprostinil Injection must be diluted with Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. Diluted Treprostinil Injection is administered intravenously by continuous infusion, via a surgically placed indwelling central venous catheter, using an 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 Treprostinil Injection. Use of a peripheral intravenous infusion for more than a few hours may be associated with an increased risk of thrombophlebitis. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. The infusion set should also contain 0.22 or 0.2 µm pore size in-line filter and an anti-siphon valve.

Diluted Treprostinil Injection has been shown to be stable at ambient temperature for up to 48 hours using 0.9% Sodium Chloride Injection or Sterile Water for Injection as the diluent at concentrations as low as 0.004 mg/mL.

When using an appropriate infusion pump and reservoir, a predetermined intravenous infusion rate should first be selected to allow for a desired infusion period length of up to 48 hours between system changes. Typical intravenous infusion system reservoirs have volumes of 50 or 100 mL. With this selected Intravenous Infusion Rate (mL/hr) and the patient’s Dose (ng/kg/min) and Weight (kg), the Diluted Intravenous Treprostinil Injection Concentration (mg/mL) can be calculated using the following formula:

Step 1

The volume of Treprostinil Injection needed to make the required Diluted Intravenous Treprostinil Injection Concentration for the given reservoir size can then be calculated using the following formula:

Step 2

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

Example calculations for Intravenous Infusion are as follows:

Example 3:

For a 60 kg person at a dose of 5 ng/kg/min, with a predetermined intravenous infusion rate of 1 mL/hr and a reservoir of 50 mL, the Diluted Intravenous Treprostinil Injection Solution Concentration would be calculated as follows:

Step1

The volume of Treprostinil Injection (using 1 mg/mL Vial Strength) needed for a total Diluted Treprostinil Injection Concentration of 0.018 mg/mL and a total volume of 50 mL would be calculated as follows:

Step 2

The diluted intravenous Treprostinil Injection concentration for the person in Example 3 would thus be prepared by adding 0.9 mL of 1 mg/mL Treprostinil Injection to a suitable reservoir along with a sufficient volume of diluent to achieve a total volume of 50 mL in the reservoir. The pump flow rate for this example would be set at 1 mL/hr.

Example 4:

For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion rate of 2 mL/hr, and a reservoir of 100 mL, the diluted intravenous Treprostinil Injection solution concentration would be calculated as follows:

Step 1

The volume of Treprostinil Injection (using 2.5 mg/mL Vial Strength) needed for a total diluted Treprostinil Injection concentration of 0.0675 mg/mL and a total volume of 100 mL would be calculated as follows:

Step 2

The diluted intravenous Treprostinil Injection concentration for the person in Example 4 would thus be prepared by adding 2.7 mL of 2.5 mg/mL Treprostinil Injection to a suitable reservoir along with a sufficient volume of diluent to achieve a total volume of 100 mL in the reservoir. The pump flow rate for this example would be set at 2 mL/hr.

OVERDOSAGE

Signs and symptoms of overdose with treprostinil 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 treprostinil.

In controlled clinical trials, seven patients received some level of overdose and in chronic, open- label follow-on treatment, seven additional patients received an overdose; these occurrences resulted from accidental bolus administration of treprostinil, errors in pump programmed rate of administration, and prescription of incorrect dose. The amount of excess treprostinil actually administered varied in each patient. Three placebo patients in controlled clinical trials were inadvertently administered treprostinil with doses initiated at 8.5, 10 and 15 ng/kg/min, respectively. Six patients received excess treprostinil due to incorrect pump settings (excess doses ranged from two to forty-six times their prescribed dose). The remaining five patients received excess treprostinil as a result of accidental bolus administration while in the process of changing syringes or tubing. Typical symptoms elicited were expected pharmacologic effects and included flushing, headache, hypotension, nausea, vomiting and diarrhea. The symptoms resolved with reduction of treprostinil dose or withholding treprostinil for a short time. In only two cases did excess delivery of treprostinil produce an event of substantial hemodynamic concern (hypotension, near-syncope). No deaths occurred as a result of overdose.

One pediatric patient was accidentally administered 7.5 mg of treprostinil 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

For management of a suspected drug overdose, contact your regional poison control centre immediately.

Treprostinil is a tricyclic benzindene analogue of prostacyclin (PGI2). The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of treprostinil on heart rate in animals varies with dose. No major effects on cardiac conduction have been observed.

Pharmacodynamics

Clinical Trials in Pulmonary Arterial Hypertension (PAH)

Hemodynamic Effects: Acute infusion of treprostinil at 10 ng/kg/min intravenously for 75 minutes followed by a 10 ng/kg/min infusion subcutaneously for 150 minutes, in patients with primary pulmonary hypertension produced increases in cardiac index (CI) and mixed venous oxygen saturation (SvO₂), and decreases in mean pulmonary arterial pressure (PAPm), mean right atrial pressure (RAPm) and pulmonary vascular resistance indexed (PVRI), with little effect on mean systemic arterial pressure (SAPm), or heart rate (HR).

Chronic continuous, subcutaneous infusion of treprostinil in NYHA Class II, III, or IV patients with PAH was studied in two identical, 12-week, double-blind, placebo-controlled, multicenter, parallel-group, randomized trials comparing treprostinil plus conventional therapy to conventional therapy alone. Dosage of treprostinil averaged 9.3 ng/kg/min at Week 12.

The hemodynamic effects from the two placebo-controlled studies are shown in Table 3. The hemodynamic effects after chronic therapy with treprostinil were generally consistent with the pharmacological effects seen acutely. There were statistically significant increases in CI and SvO₂, and statistically significant decreases in PAPm, RAPm, PVRI, and SVRI in patients treated with treprostinil for 12 weeks compared to patients treated with placebo. Heart rate and SAPm were unchanged. In patients with pulmonary hypertension, elevated RAPm and PAPm, and reduced CO and SvO2 are predictive of mortality.

Table 3: Hemodynamics During Chronic Subcutaneous Administration of Subcutaneous Treprostinil in Patients with PAH

*Denotes statistically significant difference between treprostinil and placebo, p<0.0005.

CI = cardiac index; PAPm = mean pulmonary arterial pressure; PVRI = pulmonary vascular pressure indexed; RAPm = mean right atrial pressure, SAPm = mean systemic arterial pressure; SVRI = systemic vascular resistance indexed; SvO2 = mixed venous oxygen saturation, HR = heart rate.

Pharmacokinetics

Table 4 provides data from a randomized, two-period, cross-over study of treprostinil in normal volunteers. In this study, subcutaneous and intravenous administration of treprostinil (10 ng/kg/min) for 72 hours demonstrated bioequivalence at steady-state, between 48 and 72 hours.

Table 4: Summary of Pharmacokinetic Parameters of Treprostinil

Steady-state (ss) comparisons were made based on extensive plasma sampling between 48 and 72 hours.

In a [¹⁴C] treprostinil mass balance and metabolic fate study in healthy volunteers, 78.6% and 13.4% of the subcutaneous radioactive dose were recovered in the urine and feces, respectively, over a period of 224 hours. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% of the dose administered. These five metabolites accounted for a combined total of 64.4%. Three metabolites are products of oxidation of the 3-hydroxyloctyl side chain, one is glucuronide conjugate (treprostinil glucuronide) and one is unidentified. Only 3.7% of the dose was recovered in the urine as unchanged parent drug.

In a chronic pharmacokinetic study in normal volunteers with chronic subcutaneous treprostinil doses ranging from 2.5 to 15 ng/kg/min, steady-state plasma treprostinil concentrations achieved peak levels twice (at 1 a.m. and 10 a.m., respectively) and achieved trough levels twice (at 7 a.m. and 4 p.m., respectively). The peak concentrations were ~20% to 30% higher than trough concentrations. Dose adjustments are not deemed to be necessary due to diurnal variation.

Absorption: Treprostinil is 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 µg/L.

Distribution: The volume of distribution of the drug in the central compartment is approximately 14L/70 kg ideal body weight. Treprostinil at in vitro concentrations ranging from 330-10,000 µg/L was 91% bound to human plasma protein.

Metabolism: Treprostinil is substantially metabolized by the liver, but the precise enzymes responsible are unknown. Five metabolites have been described (HU1 through HU5). The biological activity and metabolic fate of these metabolites are unknown. The chemical structure of HU1 is unknown. HU5 is the glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3) or dehydration (HU4). Based on the results of in vitro human hepatic cytochrome P450 studies, treprostinil does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether treprostinil induces these enzymes has not been studied.

Excretion: The elimination of treprostinil is biphasic, with a terminal half-life of approximately 4 hours. Approximately 79% of an administered dose is excreted in the urine as unchanged drug (4%) and as the identified metabolites (64%). Approximately 13% of a dose is excreted in the feces. Systemic clearance is approximately 30 L/h for a 70 kg ideal body weight person.

Special Populations and Conditions

Hepatic Insufficiency: (See WARNINGS and PRECAUTIONS, Hepatic/Biliary/Pancreatic)

Renal Insufficiency: (See WARNINGS and PRECAUTIONS, Renal)

STORAGE AND STABILITY

Treprostinil Injection should be stored at room temperature at 15° to 30 °C. A single vial of Treprostinil Injection should be used for no more than 30 days after the initial puncture of the rubber stopper.

Treprostinil Injection can be administered without further dilution for subcutaneous administration, or diluted for intravenous infusion with Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration to concentrations as low as 0.004 mg/mL. See Table 5 for storage and administration time limits.

Table 5: Storage

SPECIAL HANDLING INSTRUCTIONS

Avoid contact with skin or eyes. For skin contact, wash affected area immediately with soap and water and contact physician. For eye contact, flush eyes immediately with large amounts of water and contact physician.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Treprostinil Injection is supplied in 20 mL multi-use vials at concentrations of 1 mg / mL, 2.5 mg / mL, 5 mg / mL, and 10 mg / mL of treprostinil for subcutaneous or intravenous use.

Each mL of Treprostinil Injection, 1 mg / mL, contains 1 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 5.3 mg sodium chloride, 3 mg metacresol, 0.24 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

Each mL of Treprostinil Injection, 2.5 mg / mL, contains 2.5 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 5.3 mg sodium chloride, 3 mg metacresol, 0.32 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

Each mL of Treprostinil Injection, 5 mg / mL, contains 5 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 5.3 mg sodium chloride, 3 mg metacresol, 0.62 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

Each mL of Treprostinil Injection, 10 mg / mL, contains 10 mg treprostinil (as treprostinil sodium) and the following non-medicinal ingredients: 6.3 mg sodium citrate, 4 mg sodium chloride, 3 mg metacresol, 1.2 mg sodium hydroxide, and water for injection. Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Treprostinil (treprostinil sodium, the soluble sodium salt of treprostinil, is formed during the finished product manufacturing process)

Chemical name: [[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3- hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid (IUPAC)

Molecular formula and molecular mass: C₂₃H₃₄O₅ 390.52 g / mol

Structural formula:

Physicochemical properties:

Description: White to cream-colored powder, practically insoluble in water and low pH buffers.

pKa: 4.5 (aqueous titration with 20% ethanol as co-solvent).

Partition Coefficient: Distribution coefficient of treprostinil in various buffer solutions at various pHs indicates distribution into octanol layers at all pHs (2-10).

Melting Range: NLT 120.0°C and NMT 126.0°C.

CLINICAL TRIALS

Study demographics and trial design

Table 6: Summary of Patient Demographics for Study P01:04/05 in Patients with PAH

PAH = Pulmonary Arterial Hypertension

Two 12-week, multicenter, randomized, double-blind studies compared continuous subcutaneous infusion of treprostinil to placebo in a total of 470 patients with NYHA Class II (11%), III (81%), or IV (7%) pulmonary arterial hypertension (PAH). PAH was idiopathic/heritable in 58% of patients, associated with connective tissue diseases in 19%, and the result of congenital systemic-to-pulmonary shunts in 23%. The mean age was 45 (range 9 to 75 years). About 81% were female and 84% were Caucasian. Pulmonary arterial hypertension had been diagnosed for a mean of 3.8 years. The primary endpoint of the studies was change in

6-minute walking distance, a standard measure of exercise capacity. There were many assessments of symptoms related to heart failure, but local discomfort and pain associated with subcutaneous treprostinil may have substantially unblinded those assessments. The 6-minute walking distance and an associated subjective measurement of shortness of breath during the walk (Borg dyspnea score) were administered by a person not participating in other aspects of the study. Treprostinil was administered as a subcutaneous infusion, and the dose averaged 9.3 ng/kg/min at Week 12. Few subjects received doses > 40 ng/kg/min. Background therapy, determined by the investigators, could include anticoagulants, oral vasodilators, diuretics, digoxin, and oxygen but not an endothelin receptor antagonist or epoprostenol.

Study results

Table 7: Results of Study P01:04/05 in Patients with PAH

Clinical Effects: As the two 12-week studies were identical in design and conducted simultaneously, results were analyzed both pooled and individually. Exercise capacity, as measured by the Six-Minute Walk Test, improved significantly in Class II, III, and IV patients receiving continuous subcutaneous treprostinil plus conventional therapy (N=232) for 12 weeks, with a median increase of 10 meters in this group compared to those receiving conventional therapy plus placebo (N=236) (p=0.0064). Table 7 specifies the improvements in Six-Minute Walk distance at Week 12 for treprostinil patients with NYHA Class III and IV PAH, for which treprostinil is indicated. Improvements, although not statistically significant, were apparent as early as Week 6 of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Dyspnea-Fatigue Rating and Borg Scale. Signs and symptoms of PAH also improved, as did the Physical Dimension component of a Quality of Life Scale. Treprostinil was shown to be effective for the treatment of PAH, either primary (PPH), or secondary to the scleroderma spectrum of diseases or associated with congenital systemic-to-pulmonary shunts (repaired or unrepaired), in NYHA Class III and IV patients who did not respond adequately to conventional therapy.

Hemodynamic Effects: As shown previously in Table 3, and the ACTION and CLINICAL PHARMACOLOGY, Pharmacodynamics Section, hemodynamic effects after chronic subcutaneous therapy with treprostinil were generally consistent with the pharmacological effects seen acutely. There were statistically significant increases in CI and SvO₂, and statistically significant decreases in PAPm, RAPm, PVRI, and SVRI in patients treated with treprostinil for 12 weeks compared to patients treated with placebo. Heart rate and SAPm were unchanged. In patients with pulmonary hypertension, elevated RAPm and PAPm, and reduced CO and SvO₂ are predictive of mortality.

Comparative Bioavailability Studies

Study REM01:14 was a randomized, open-label, two-period crossover bioequivalence study comparing intravenous versus subcutaneous administration of treprostinil in healthy adult volunteers. The objective of the study was to demonstrate steady-state bioequivalence.

Subjects were to receive 72 hours of treprostinil infusion (10 ng/kg/min) by both the intravenous and subcutaneous routes for pharmacokinetic comparisons. Steady-state comparisons were made based on extensive plasma sampling between 48 and 72 hours, for each respective route of administration. A total of 55 adult volunteers (60% male, mean age 36.2 years mean body weight was 73.9 kg) received study drug and were included in the safety population for the study. Fifty-one volunteers received at least 24 hours of treprostinil infusion by both routes and were included in the primary pharmacokinetic analyses.

The primary analysis results are shown in Table 8 and Table 9.

Table 8: Summary of Primary Steady State Pharmacokinetic Parameters (n=51)

1 Point Estimate (90% Confidence Interval)

The 90% confidence intervals for the ratios of adjusted geometric means (IV/SC) are well within the bioequivalence boundaries (confidence intervals between 80% – 125%) for both AUC_ss and Cmax_ss. Therefore, intravenous and subcutaneous treprostinil are bioequivalent at steady state.

Other pharmacokinetic assessments included AUC_0-96h, AUC_inf, Cmax, observed time to maximal plasma concentration (T_max), apparent plasma clearance (CL), apparent volume of distribution (Vz), elimination rate constant of the terminal disposition phase (λz), and elimination half-life (T_1/2). As shown in Table 9, these parameters were comparable between the two routes of administration. Of note, the apparent mean elimination half-life following cessation of IV infusion of treprostinil was 4.4 hours compared to 4.6 hours for SC.

Table 9: Summary of Pharmacokinetic Parameters Related to the Full Profile

DETAILED PHARMACOLOGY

Pharmacodynamics

Treprostinil is a tricyclic benzindene analogue of prostacyclin (PGI₂, epoprostenol) with potent systemic and pulmonary vasodilatory and platelet antiaggregatory effects when studied in vitro and in vivo, and without limiting cardiac effects.

Treprostinil (1-1000 nM) produces concentration-dependent relaxation of isolated rabbit precontracted mesenteric arteries and is approximately 45 times more potent than PGE₂. In anesthetized rats, treprostinil produces dose-dependent decreases in mean arterial blood pressure when administered by the subcutaneous (29-60 mmHg at 25-100 μg/kg/min), or oral (35 and

55 mmHg at 1 and 5 mg/kg) routes, respectively. In anesthetized rats, intravenous treprostinil is approximately 10 times less potent than PGI₂. In anesthetized rabbits, treprostinil and PGI₂ (140 and 200 ng/kg/min, i.v. respectively) decrease mean arterial blood pressure 10 and

16 mmHg, respectively.

In anesthetized closed-chest cats, treprostinil (3-30 μg/kg/min, i.v., 20 min each dose) produces dose-dependent decreases in diastolic blood pressure (22-74 mmHg). Maximum hypotension occurs within 5 minutes and returns to baseline within 40 minutes upon terminating the infusion.

In anesthetized open-chest cats, treprostinil (0.1-3.0 μg/kg/min, i.v. 20 min each dose) produces dose-dependent decreases in mean systemic arterial and mean pulmonary arterial blood pressure with little effect on heart rate. At 0.3 to 3.0 μg/kg/min, treprostinil produces dose-dependent reductions in hypoxia-induced increments in pulmonary arterial blood pressure and pulmonary vascular resistance. Treprostinil is approximately 3 to 10 times less potent than PGI₂ as a vasodilator under hypoxic and normoxic conditions.

In anesthetized newborn piglets, treprostinil (6 and 12 μg/kg, i.v. bolus) abolished hypoxia- induced increases in pulmonary vascular resistance.

In anesthetized dogs, intravenous boluses (0.32-3.2 μg/kg) or infusions (0.1-1.0 μg/kg/min for 10 min) of treprostinil produce dose-dependent decreases in blood pressure. Four-hour intravenous infusions of treprostinil (0.1-3.0 μg/ kg/min) produce dose-dependent decreases in mean systemic arterial and mean pulmonary arterial blood pressures mediated through decreases in vascular resistance in these circulatory beds. The vascular effects of treprostinil are rapid in onset achieving maximum effect within 5-10 minutes with equally rapid recovery upon termination of the infusions.

Treprostinil produces equivalent effects to those of PGI₂ on the systemic and pulmonary vascular beds yet is approximately 10 times less potent than PGI₂. Treprostinil and PGI₂ treatment-related cardiac effects include modest decreases in inotropy and lusitropy and modest increases in heart rate. ECG changes observed in the dog were inconsistent (occurring predominantly post-infusion) and considered not to be related to treprostinil. The cardiac effects are not major, are not dose dependent, are not sustained throughout treatment, and are interpreted to be generally secondary to the prominent vascular effect and not due to a direct effect on the myocardium. Treprostinil treatment is associated with dose-dependent increases in plasma angiotensin II concentration, which correlate with the decreases in mean arterial blood pressure. Pretreatment of animals with enalapril blocks, digoxin attenuates, and furosemide potentiates the treprostinil treatment-related increases in plasma angiotensin II concentration without significantly affecting the hemodynamic profile of treprostinil.

In conscious dogs, infusions of treprostinil (0.3-3 μg/kg/min, i.v. 10 minutes each) produce dose- related decreases in systolic (18-40 mmHg) and diastolic (13-45 mmHg) arterial blood pressures accompanied by small increases in heart rate (13-30 bpm).

There were no adverse effects of treprostinil in autonomic, respiratory, gastrointestinal, uterine motility, inflammatory, or platelet aggregation secondary pharmacologic evaluations.

Pharmacokinetics

In a series of 13- and 26-week toxicological/toxicokinetic studies in rats and dogs, treprostinil was delivered to the systemic circulation when administered by continuous subcutaneous or intravenous infusion, and relatively linear kinetics were obtained with increasing doses. Linear kinetics were also observed in reproductive studies in rats and rabbits.

In vitro binding of labeled-treprostinil in human plasma was 91.0%, with the compound having no significant effect on the plasma protein binding of digoxin or warfarin.

Tissue distribution studies in rats with tritium or carbon-labeled treprostinil indicated that radioactivity was widely distributed into tissues and was preferentially distributed to organs of the central compartment, including the stomach and intestinal tract.

Metabolic studies in rats and humans indicated that less than 5% of treprostinil was eliminated unchanged. Five metabolites were identified by LC/MS in human urine with no single metabolite exceeding 15% of the dose.

Balance/excretion studies of labeled-treprostinil in rats and dogs showed that the dose was found in the feces (65-80%) and urine (13-26%). In contrast, human volunteers excreted 13.4% and 78.6% of the dose in feces and urine, respectively. The reason for this difference is not known, but biliary excretion/enterohepatic recirculation may be significant in animals.

Treprostinil showed no inhibitory potential toward cytochrome P450 isozymes when tested in vitro.

TOXICOLOGY

The preclinical toxicology of treprostinil has been extensively evaluated in a series of in vitro and in vivo genetic toxicology studies, reproductive toxicology studies in rats and rabbits, and single and repeated dose toxicity studies in mice, rats and dogs.

Acute Toxicity Studies

Treprostinil has low oral and intravenous acute toxicity in mice and rats (Table 10).

Table 10: Incidence of Death in Acute Toxicity Studies

MLD = Minimum lethal dose *Median lethal dose

In acute subcutaneous toxicity studies in rats and dogs, the maximum dose that did not produce adverse clinical signs was approximately 400 and 500 ng/kg/min, respectively. In the rat, slight ataxia occurred at approximately 490 ng/kg/min and reversed during the infusion period.

Long-term Toxicity Studies

In repeated dose toxicity studies, treprostinil was well tolerated in rats and dogs when given continuously by subcutaneous infusion for up to 6 months or intravenous infusion for up to 3 months. In dogs, dose-limiting toxicity characterized by gastrointestinal changes (emesis, loose stools, intestinal intussusception, hypoactivity, rectal prolapse) contributing to moribundity and death was observed at doses of ≥300 ng/kg/min. This spectrum of gastrointestinal changes has not been observed in the clinical studies.

In both rats and dogs given treprostinil doses up to 450 ng/kg/min and 200 ng/kg/min, respectively, treprostinil-related toxicity was limited to reversible, dose-related reactions at the infusion site and included lumps, masses/nodules, swellings, erythema and/or intermittent pain (dogs only). Microscopic evaluation demonstrated these areas to have local inflammation (abscess or cellulitis), edema, fibrosis or hemorrhage. Although these changes were also observed in saline control animals, the higher incidence and greater severity in the vehicle control and treated groups suggested that these reactions were related to pump implantation, catheterization technique, and/or irritability of the vehicle that was enhanced when administered in combination with treprostinil.

In rats given treprostinil in repeated dose toxicity studies, other treatment-related findings have included reversible redness of extremities (due to the vasodilatory pharmacological activity of treprostinil) observed at all doses and minimal, reversible increases in mean white blood cell counts, total bilirubin and splenic weights (no histological correlation) observed at 450 ng/kg/min. In dogs, there were minimal, transient and reversible decreases in body weight and food consumption, and reversible increases in mean white blood cell counts.

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.

Table 11: Long-term Toxicity Studies - Continuous Subcutaneous (s.c.) or Intravenous (i.v.) Infusion

S-D = Sprague-Dawley *Saline.

Mutagenicity

Treprostinil is not mutagenic or clastogenic in in vitro and in vivo genetic toxicological assays (Table 12).

Table 12: In Vivo and In Vitro Mutagenicity Studies

Reproduction and Teratology

Treprostinil had no effect on adult reproduction, conceptus, early development and growth in rats given up to 450 ng/kg/min by continuous subcutaneous infusion. Administration of treprostinil by continuous subcutaneous infusion during major organogenesis was not teratogenic in pregnant rats at doses up to 900 ng/kg/min (Table 13).

In pregnant rabbits, developmental toxicity characterized by minimal increases in fetal skeletal variations/litter was observed at doses of 150 and 300 ng/kg/min and was associated with maternal toxicity. No developmental toxicity was seen in rabbits at 50 ng/kg/min.

In the Pre- and Postnatal Developmental Study in rats given treprostinil by continuous subcutaneous infusion at doses of 50, 150 or 450 ng/kg/min, the F1 mating index was reduced (not statistically significant) at 450 ng/kg/min. There were no other treatment-related changes in this study and the no observable adverse effect level (NOAEL) for F0 maternal toxicity was 450 ng/kg/min, the conservative NOAEL for F1 male and female reproductive toxicity was 150 ng/kg/min, and the NOAEL for F0 reproductive toxicity and for F1 and F2 developmental toxicity was 450 ng/kg/min.

Table 13: Reproduction and Teratology Studies - Continuous Subcutaneous Infusion

GD = Gestational Day

REFERENCES

1. 1. Simonneau, G., Barst, R.J., Galie, N., Naeije, R., Rich, S., Bourge, R., Keogh, A., Oudiz, R., Frost, A., Blackburn, S., Crow, J.W., Rubin, L.J. Continuous Subcutaneous Infusion of Treprostinil, a Prostacyclin Analogue, in Patients with Pulmonary Arterial Hypertension A Double-Blind, Randomized, Placebo-Controlled Trial. Am J Respir Crit Care Med 2002;165:800-804.
2. 2. Vachiery, JL., Hill, N., Zwicke, D., Barst, R.J., Blackburn, S., Naeije, R. Transitioning From IV Epoprostenol to Subcutaneous Treprostinil in Pulmonary Arterial Hypertension. Chest 2002;121:1561-1565
3. 3. REMODULIN^® solution, 1 mg / mL, 2.5 mg / mL, 5 mg / mL and 10 mg / mL of treprostinil (as treprostinil sodium), Submission Control #203551, Product Monograph, United Therapeutics Corporation. June 13, 2017.