REMODULIN^® (treprostinil sodium) Injection

Remodulin^® (treprostinil sodium) Injection is a sterile sodium salt formulated for subcutaneous or intravenous administration. Remodulin is supplied in 20 mL multi-use vials in four strengths, containing 1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL of treprostinil. Each mL also contains 5.3 mg sodium chloride (except for the 10 mg/mL strength which contains 4.0 mg sodium chloride), 3.0 mg metacresol, 6.3 mg sodium citrate, and water for injection. Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2.

Treprostinil is chemically stable at room temperature and neutral pH.

Treprostinil sodium is (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 monosodium salt. Treprostinil sodium has a molecular weight of 412.49 and a molecular formula of C₂₃H₃₃NaO₅.

The structural formula of treprostinil sodium is:

General: 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. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed.

The pharmacokinetics of continuous subcutaneous Remodulin are linear over the dose range of 1.25 to 22.5 ng/kg/min (corresponding to plasma concentrations of about 0.03 to 8 mcg/L) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 22.5 ng/kg/min has not been studied.

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

Two 12-week, multicenter, randomized, double-blind studies compared continuous subcutaneous infusion of Remodulin to placebo in a total of 470 patients with NYHA Class II-IV pulmonary arterial hypertension (PAH). PAH was primary in 58% of patients, associated with collagen vascular disease in 19%, and the result of congenital left to right shunts in 23%. The mean age was 45 (range 9 to 75 years). About 81% were female and 84% were Caucasian. Pulmonary 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 Remodulin 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. Remodulin was administered as a subcutaneous infusion, described in DOSAGE AND ADMINSTRATION, 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. The two studies were identical in design and conducted simultaneously, and the results were analyzed both pooled and individually.

As shown in Table 1, chronic therapy with Remodulin resulted in small hemodynamic changes consistent with pulmonary and systemic vasodilation.

The effect of Remodulin on 6-minute walk, the primary end point of the 12-week studies, was small and did not achieve conventional levels of statistical significance. For the combined populations, the median change from baseline on Remodulin was 10 meters and the median change from baseline on placebo was 0 meters from a baseline of approximately 345 meters. Although it was not the primary endpoint of the study, the Borg dyspnea score was significantly improved by Remodulin during the 6-minute walk, and Remodulin also had a significant effect, compared with placebo, on an assessment that combined walking distance with the Borg dyspnea score. Remodulin also consistently improved indices of dyspnea, fatigue and signs and symptoms of pulmonary hypertension, but these indices were difficult to interpret in the condiv of incomplete blinding to treatment assignment resulting from infusion site symptoms.

In an 8-week, multicenter, randomized, double-blind, placebo-controlled study, patients on stable doses of Flolan were randomly withdrawn from Flolan to placebo or Remodulin. Fourteen Remodulin and 8 placebo patients completed the study. The primary endpoint of the study was the time to clinical deterioration, defined as either an increase in Flolan dose, hospitalization due to PAH, or death. No patients died during the study.

During the study period, Remodulin effectively prevented clinical deterioration in patients transitioning from Flolan therapy compared to placebo (Figure 1). Thirteen of 14 patients in the Remodulin arm were able to transition from Flolan successfully, compared to only 1 of 8 patients in the placebo arm (p=0.0002).

Figure 1: Time to Clinical Deterioration for PAH Patients Transitioned from Flolan to Remodulin or Placebo in an 8-Week Study

Remodulin^® is indicated as a continuous subcutaneous infusion or intravenous infusion (for those not able to tolerate a subcutaneous infusion) for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms (see CLINICAL PHARMACOLOGY: Clinical Effects) to diminish symptoms associated with exercise.

Remodulin is indicated to diminish the rate of clinical deterioration in patients requiring transition from Flolan^®; the risks and benefits of each drug should be carefully considered prior to transition.

Remodulin is contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

Remodulin is indicated for subcutaneous or intravenous use only.

Remodulin should be used only by clinicians experienced in the diagnosis and treatment of PAH.

Remodulin is a potent pulmonary and systemic vasodilator. Initiation of Remodulin must be performed in a setting with adequate personnel and equipment for physiological monitoring and emergency care. Therapy with Remodulin may be used for prolonged periods, and the patient’s ability to administer Remodulin and care for an infusion system should be carefully considered.

Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be decreased for excessive pharmacologic effects or for unacceptable infusion site symptoms (see DOSAGE AND ADMINISTRATION).

Abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of PAH symptoms and should be avoided.

Patients receiving Remodulin should be given the following information: Remodulin is infused continuously through a subcutaneous or surgically placed indwelling central venous catheter, via an infusion pump. Therapy with Remodulin will be needed for prolonged periods, possibly years, and the patient's ability to accept and care for a catheter and to use an infusion pump should be carefully considered. In order to reduce the risk of infection, aseptic technique must be used in the preparation and administration of Remodulin. Additionally, patients should be aware that subsequent disease management may require the initiation of an alternative intravenous prostacyclin therapy, Flolan^® (epoprostenol sodium).

Caution should be used in patients with hepatic or renal impairment (see CLINICAL PHARMACOLOGY, Special Populations).

Long-term studies have not been performed to evaluate the carcinogenic potential of treprostinil. 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 infusions at rates of up to 450 ng treprostinil/kg/min [about 59 times the recommended starting human rate of infusion (1.25 ng/kg/min) and about 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.

No treprostinil sodium treatment-related effects on labor and delivery were seen in animal studies. The effect of treprostinil sodium on labor and delivery in humans is unknown.

It is not known whether treprostinil is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Remodulin is administered to nursing women.

Safety and effectiveness in pediatric patients have not been established. Clinical studies of Remodulin 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.

Clinical studies of Remodulin 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.

Table 3 uls adverse events that occurred at a rate of at least 3% and were more frequent in patients treated with subcutaneous Remodulin than with placebo in controlled trials in PAH.

Reported adverse events (at least 3%) are included except 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.

Remodulin is administered by continuous infusion. Remodulin 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, the infusion rate should be reduced to 0.625 ng/kg/min.

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

The infusion rate should be increased in increments of no more than 1.25 ng/kg/min per week for the first four weeks and then no more than 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. There is little experience with doses >40 ng/kg/min. Abrupt cessation of infusion should be avoided (see PRECAUTIONS).

Transition from Flolan to Remodulin is accomplished by initiating the infusion of Remodulin and increasing it, while simultaneously reducing the dose of intravenous Flolan. The transition to Remodulin should take place in a hospital with constant observation of response (e.g., walk distance and signs and symptoms of disease progression). During the transition, Remodulin is initiated at a recommended dose of 10% of the current Flolan dose, and then escalated as the Flolan dose is decreased (see Table 4 for recommended dose titrations).

Patients are individually titrated to a dose that allows transition from Flolan therapy to Remodulin while balancing prostacylin-limiting adverse events. Increases in the patient’s symptoms of PAH should be first treated with increases in the dose of Remodulin. Side effects normally associated with prostacyclin and prostacyclin analogs are to be first treated by decreasing the dose of Flolan.