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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Chronic intravenous infusions 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. ( 5.1 ) • Do not abruptly lower the dose or withdraw dosing. ( 5.2 ) • Treprostinil injection may cause symptomatic hypotension. ( 5.4 ) • Treprostinil injection inhibits platelet aggregation and increases the risk of bleeding. ( 5.5 ) 5.1 Risk of Catheter-Related Bloodstream Infection Chronic intravenous infusions of treprostinil injection are 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 treprostinil injection 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. 5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction Avoid abrupt withdrawal or sudden large reductions in dosage of treprostinil injection, which may result in worsening of PAH symptoms. 5.3 Patients with Hepatic Insufficiency Titrate treprostinil injection slowly in patients with hepatic insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic function [see Dosage and Administration ( 2.5 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . 5.4 Risk of Symptomatic Hypotension Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with treprostinil injection may produce symptomatic hypotension. 5.5 Risk of Bleeding Treprostinil injection inhibits platelet aggregation and increases the risk of bleeding.
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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration [see Warnings and Precautions ( 5.1 )] . Most common adverse reactions (incidence >3%) reported in clinical studies with treprostinil injection: subcutaneous infusion site pain and reaction, headache, diarrhea, nausea, jaw pain, vasodilatation, edema, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 Treprostinil Injection Patients receiving treprostinil injection 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 treprostinil injection, infusion site pain and reaction were the most common adverse events among those treated with treprostinil injection. 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 Reaction Pain Placebo Treprostinil Injection Placebo Treprostinil Injection Severe 1 38 2 39 Requiring narcotics* NA † NA † 1 32 Leading to discontinuation 0 3 0 7 * based on prescriptions for narcotics, not actual use † medications used to treat infusion site pain were not distinguished from those used to treat site reactions Other adverse events included diarrhea, jaw pain, edema, vasodilatation, and nausea, and these are generally considered to be related to the pharmacologic effects of treprostinil injection, whether administered subcutaneously or intravenously. Adverse Reactions during Chronic Dosing Table 4 lists adverse reactions that occurred at a rate of at least 3% m...
adverse reactions table
Table 3: Percentages of Subjects Reporting Subcutaneous Infusion Site Adverse EventsReactionPainPlaceboTreprostinil InjectionPlaceboTreprostinil InjectionSevere138239Requiring narcotics*NA†NA†132Leading to discontinuation0307