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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.
Adverse Events with Subcutaneously Administered Remodulin
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
|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 Remodulin, whether administered subcutaneously or intravenously.
Adverse Reactions during Chronic Dosing
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
Percent of Patients
Percent of Patients
|Infusion Site Pain||85||27|
|Infusion Site Reaction||83||27|
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.
Adverse Events Attributable to the Drug Delivery System
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].
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.
Read the Remodulin (treprostinil sodium) Side Effects Center for a complete guide to possible side effects
Pharmacokinetic/pharmacodynamic interaction studies have been conducted with treprostinil administered subcutaneously (Remodulin) and orally (treprostinil diethanolamine).
Antihypertensive Agents Or Other Vasodilators
Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulants.
In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between treprostinil and bosentan were observed.
In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between treprostinil and sildenafil were observed.
Effect Of Treprostinil On Cytochrome P450 Enzymes
In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A. Thus Remodulin is not expected to alter the pharmacokinetics of compounds metabolized by CYP enzymes.
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 Cmax 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 [see WARNINGS AND PRECAUTIONS].
Remodulin has not been studied in conjunction with Flolan or Tracleer® (bosentan).
Effect Of Other Drugs On Treprostinil
Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) coadministered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively in healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.
Read the Remodulin Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/5/2016
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Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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