Treprostinil Sodium

Pulmonary Arterial Hypertension

Remodulin 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%) [see Clinical Studies].

It may be administered as a continuous subcutaneous infusion or continuous intravenous (IV) infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections (BSIs), reserve continuous intravenous infusion for patients who are intolerant of the subcutaneous route, or in whom these risks areconsidered warranted [see WARNINGS AND PRECAUTIONS].

Pulmonary Arterial Hypertension In Patients Requiring Transition from Flolan®

In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol sodium), Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration [see WARNINGS AND PRECAUTIONS].

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.

Patients receiving Remodulin 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 Remodulin, infusion site pain and reaction were the most common adverse events among those treated with Remodulin. 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 Remodulin, whether administered subcutaneously or intravenously.

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

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

Reported adverse reactions (at least 3% more frequent on drug than on placebo) 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.

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

The safety of Remodulin 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.

In controlled studies of Remodulin 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% Remodulin, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 Remodulin, 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 Remodulin (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 [see WARNINGS AND PRECAUTIONS].

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of Remodulin. 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 Remodulin. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia bone pain, pruritus and dizziness. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.

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. Patients receiving intravenous infusion should use an infusion set with an inline filter. 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).

Vasodilator; a synthetic analog of prostacyclin.2 3 15

Pulmonary Arterial Hypertension

Used parenterally (as a continuous sub-Q or IV infusion) for treatment of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension) to reduce symptoms associated with exercise; efficacy established principally in patients with NYHA/WHO functional class II–III PAH (idiopathic, heritable, associated with connective tissue diseases or congenital systemic-to-pulmonary shunts).1 2 3 Also used parenterally to reduce rate of clinical deterioration in PAH patients who require conversion from epoprostenol therapy; carefully consider risks and benefits of each drug prior to transition.1

Used by oral inhalation to improve exercise ability in patients with PAH; efficacy established principally in patients with NYHA/WHO functional class III PAH (idiopathic, heritable, or associated with connective tissue diseases).15 16 17 Controlled clinical experience with orally inhaled treprostinil is based primarily on short-term trials in patients receiving the drug as add-on therapy to bosentan or sildenafil.13 15 16 17

Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class III or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.13 40

Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.13 40

In patients with inadequate response to initial monotherapy, may consider combination therapy with an endothelin-receptor antagonist, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially).40 By targeting different pathophysiologic pathways of the disease, combination therapy may provide additive and/or synergistic benefits.40 41 42 43

Has been designated an orphan drug by FDA for treatment of PAH.31

Extensively metabolized in liver, principally by CYP2C8.1 29 Does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A in vitro.1 15 Does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A in vitro.1 15 Pharmacokinetic interactions with drugs metabolized by the CYP enzyme system are considered unlikely.1

Specific Drugs