Nicepie may be available in the countries listed below.
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International Drug Name Search
Remodulin® (treprostinil) Injection
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 (14.1)].
It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted.
In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol sodium), Remodulin is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition.
Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). Remodulin can be administered as supplied or diluted for intravenous infusion with Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Flolan® Sterile Diluent for Injection prior to administration.
Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a 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 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 adjustments may be undertaken more often if tolerated. There is little experience with doses >40 ng/kg/min. Abrupt cessation of infusion should be avoided [see Warnings and Precautions (5.4)]. Restarting a Remodulin 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 Remodulin to be re-titrated.
In patients with mild or moderate hepatic insufficiency, the initial dose of Remodulin should be decreased to 0.625 ng/kg/min ideal body weight and should be increased cautiously. Remodulin has not been studied in patients with severe hepatic insufficiency [see Warnings and Precautions (5.5), Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].
No studies have been performed in patients with renal insufficiency. No specific advice about dosing in patients with renal impairment can be given.
[see Clinical Pharmacology (12.3)].
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, Remodulin should not be administered.
Subcutaneous Infusion
Remodulin is administered subcutaneously by continuous infusion, 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. The ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) be adjustable to 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.
For subcutaneous infusion, Remodulin 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 Remodulin being used. During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 37°C. The Subcutaneous Infusion rate is calculated using the following formula:
| ||||||
| Subcutaneous Infusion Rate (mL/hr) | = | Dose (ng/kg/min) | × | Weight (kg) | × | 0.00006* |
| Remodulin Vial Strength (mg/mL) | ||||||
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 Remodulin Vial Strength, the infusion rate would be calculated as follows:
| Subcutaneous Infusion Rate (mL/hr) | = | 1.25 ng/kg/min | × | 60 kg | × | 0.00006 | = | 0.005 mL/hr |
| 1 mg/mL | ||||||||
Example 2:
For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin Vial Strength, the infusion rate would be calculated as follows:
| Subcutaneous Infusion Rate (mL/hr) | = | 40 ng/kg/min | × | 65 kg | × | 0.00006 | = 0.031 mL/hr |
| 5 mg/mL | |||||||
Intravenous Infusion
Remodulin must be diluted with either Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Flolan® Sterile Diluent for Injection and 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 Remodulin. 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 ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better of the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene or glass.
Diluted Remodulin has been shown to be stable at ambient temperature for up to 48 hours at concentrations as low as 0.004 mg/mL (4,000 ng/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 changeovers. 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 Remodulin Concentration (mg/mL) can be calculated using the following formula:
Step 1
| Diluted Intravenous Remodulin Concentration (mg/mL) | = | Dose (ng/kg/min) | × | Weight (kg) | × | 0.00006 |
| Intravenous Infusion Rate (mL/hr) | ||||||
The Amount of Remodulin Injection needed to make the required Diluted Intravenous Remodulin Concentration for the given reservoir size can then be calculated using the following formula:
Step 2
| Amount of Remodulin Injection (mL) | = | Diluted Intravenous Remodulin Concentration (mg/mL) | × | Total Volume of Diluted Remodulin Solution in Reservoir (mL) |
| Remodulin Vial Strength (mg/mL) |
The calculated amount of Remodulin Injection is then added to the reservoir along with the sufficient volume of diluent (Sterile Water for Injection, 0.9% Sodium Chloride Injection, or Flolan® Sterile Diluent for Injection) 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 Remodulin Solution Concentration would be calculated as follows:
Step 1
| Diluted Intravenous Remodulin Concentration (mg/mL) | = | 5 ng/kg/min | × | 60 kg | × | 0.00006 | = 0.018 mg/mL (18,000 ng/mL) |
| 1 mL/hr | |||||||
The Amount of Remodulin Injection (using 1 mg/mL Vial Strength) needed for a total Diluted Remodulin Concentration of 0.018 mg/mL and a total volume of 50 mL would be calculated as follows:
Step 2
| Amount of Remodulin Injection (mL) | = | 0.018 mg/mL | × 50 mL = 0.9 mL |
| 1 mg/mL |
The Diluted Intravenous Remodulin Concentration for the person in Example 3 would thus be prepared by adding 0.9 mL of 1 mg/mL Remodulin 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 Remodulin Solution Concentration would be calculated as follows:
Step 1
| Diluted Intravenous Remodulin Concentration (mg/mL) | = | 30 ng/kg/min | × | 75 kg | × | 0.00006 | = 0.0675 mg/mL (67,500 ng/mL) |
| 2 mL/hr | |||||||
The Amount of Remodulin Injection (using 2.5 mg/mL Vial Strength) needed for a total Diluted Remodulin Concentration of 0.0675 mg/mL and a total volume of 100 mL would be calculated as follows:
Step 2
| Amount of Remodulin Injection (mL) | = | 0.0675 mg/mL | × 100 mL = 2.7 mL |
| 2.5 mg/mL |
The Diluted Intravenous Remodulin Concentration for the person in Example 4 would thus be prepared by adding 2.7 mL of 2.5 mg/mL Remodulin 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.
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 1 for recommended dose titrations).
Patients are individually titrated to a dose that allows transition from Flolan therapy to Remodulin while balancing prostacyclin-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.
| Step | Flolan Dose | Remodulin Dose |
|---|---|---|
| 1 | Unchanged | 10% Starting Flolan Dose |
| 2 | 80% Starting Flolan Dose | 30% Starting Flolan Dose |
| 3 | 60% Starting Flolan Dose | 50% Starting Flolan Dose |
| 4 | 40% Starting Flolan Dose | 70% Starting Flolan Dose |
| 5 | 20% Starting Flolan Dose | 90% Starting Flolan Dose |
| 6 | 5% Starting Flolan Dose | 110% Starting Flolan Dose |
| 7 | 0 | 110% Starting Flolan Dose + additional 5-10% increments as needed |
20-mL vial containing 20 mg treprostinil (1 mg per mL).
20-mL vial containing 50 mg treprostinil (2.5 mg per mL).
20-mL vial containing 100 mg treprostinil (5 mg per mL).
20-mL vial containing 200 mg treprostinil (10 mg per mL).
None
Chronic intravenous infusions of Remodulin 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.
In an open-label study of IV treprostinil (n=47), 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.
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 (2)].
Abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of PAH symptoms and should be avoided.
Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function [see Dosage and Administration (2.4, 2.5), Use In Specific Populations (8.6, 8.7), and Clinical Pharmacology (12.3)].
Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].
The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration [see Warnings and Precautions (5.1)].
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.
| Reaction | Pain | |||
|---|---|---|---|---|
| Placebo | Remodulin | Placebo | Remodulin | |
| ||||
| Severe | 1 | 38 | 2 | 39 |
| Requiring narcotics* | NA† | NA† | 1 | 32 |
| Leading to discontinuation | 0 | 3 | 0 | 7 |
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 Events during Chronic Dosing
Table 3 lists 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.
| Adverse Event | Remodulin (N=236) Percent of Patients | Placebo (N=233) Percent of Patients |
|---|---|---|
| Infusion Site Pain | 85 | 27 |
| Infusion Site Reaction | 83 | 27 |
| Headache | 27 | 23 |
| Diarrhea | 25 | 16 |
| Nausea | 22 | 18 |
| Rash | 14 | 11 |
| Jaw Pain | 13 | 5 |
| Vasodilatation | 11 | 5 |
| Dizziness | 9 | 8 |
| Edema | 9 | 3 |
| Pruritus | 8 | 6 |
| Hypotension | 4 | 2 |
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.
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 (5.1)].
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 due to a combination of their seriousness, frequency of reporting, and potential connection to Remodulin. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia and bone pain. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.
Pharmacokinetic/pharmacodynamic interaction studies have been conducted with treprostinil administered subcutaneously (Remodulin) and orally (treprostinil diethanolamine).
Pharmacodynamics
Concomitant administration of Remodulin with diuretics, antihypertensive agents or other vasodilators may increase the risk of symptomatic hypotension.
Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulants.
Pharmacokinetics
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.
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.
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 (5.6)].
Remodulin has not been studied in conjunction with Flolan or Tracleer® (bosentan).
Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered 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.
Pregnancy Category B - In pregnant rats, continuous subcutaneous infusions of treprostinil during organogenesis and late gestational development, at rates as high as 900 ng treprostinil/kg/min (about 117 times the starting human rate of infusion, on a ng/m2 basis and about 16 times the average rate achieved in clinical trials), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infusions of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at an infusion rate of 150 ng treprostinil/kg/min (about 41 times the starting human rate of infusion, on a ng/m2 basis, and 5 times the average rate used in clinical trials). In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at rates of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. Because animal reproduction studies are not always predictive of human response, Remodulin should be used during pregnancy only if clearly needed.
No treprostinil 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.
Remodulin clearance is reduced in patients with hepatic insufficiency. In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency [see Dosage and Administration (2.4), Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
No studies have been performed in patients with renal insufficiency. No specific advice about dosing in patients with renal impairment can be given. [see Clinical Pharmacology (12.3)].
Signs and symptoms of overdose with Remodulin 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 Remodulin.
In controlled clinical trials, seven patients received some level of overdose and in open-label follow-on treatment seven additional patients received an overdose; these occurrences resulted from accidental bolus administration of Remodulin, errors in pump programmed rate of administration, and prescription of an incorrect dose. In only two cases did excess delivery of Remodulin produce an event of substantial hemodynamic concern (hypotension, near-syncope).
One pediatric patient was accidentally administered 7.5 mg of Remodulin 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.
Remodulin (treprostinil) Injection is a sterile solution of treprostinil formulated for subcutaneous or intravenous administration. Remodulin is supplied in 20 mL multidose vials in four strengths, containing 20 mg, 50 mg, 100 mg, or 200 mg (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 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 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. Treprostinil has a molecular weight of 390.52 and a molecular formula of C23H34O5.
The structural formula of treprostinil is:
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.
Treprostinil produces vasodilation and tachycardia. Single doses of treprostinil up to 84 mcg by inhalation produce modest and short-lasting effects on QTc, but this is apt to be an artifact of the rapidly changing heart rate. Treprostinil administered by the subcutaneous or intravenous routes has the potential to generate concentrations many-fold greater than those generated via the inhaled route; the effect on the QTc interval when treprostinil is administered parenterally has not been established.
The pharmacokinetics of continuous subcutaneous Remodulin are linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250 pg/mL) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 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.
Absorption
Remodulin is relatively 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 2,000 pg/mL.
Distribution
The volume of distribution of the drug in the central compartment is approximately 14L/70 kg ideal body weight. Remodulin at in vitro concentrations ranging from 330-10,000 mcg/L was 91% bound to human plasma protein.
Metabolism and Excretion
Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. In a study conducted in healthy volunteers using [14C] treprostinil, 78.6% and 13.4% of the subcutaneous dose was recovered in the urine and feces, respectively, over 10 days. Only 4% was excreted as unchanged treprostinil in the urine. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% and representing 64.4% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative (treprostinil glucuronide). The identified metabolites do not appear to have activity.
The elimination of treprostinil (following subcutaneous administration) is biphasic, with a terminal elimination half-life of approximately 4 hours using a two compartment model. Systemic clearance is approximately 30 L/hr for a 70 kg person.
Based on in vitro studies treprostinil does not inhibit or induce major CYP enzymes [see Drug Interactions (7.5)].
Special Populations
Hepatic Insufficiency
In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency, Remodulin at a subcutaneous dose of 10 ng/kg/min for 150 minutes had a Cmax that was increased 2-fold and 4-fold, respectively, and an AUC 0-∞ that was increased 3-fold and 5-fold, respectively, compared to healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy adults.
Renal Insufficiency
No studies have been performed in patients with renal insufficiency, so no specific advice about dosing in such patients can be given. Although only 4% of the administered dose is excreted unchanged in the urine, the five identified metabolites are all excreted in the urine.
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 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.
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 (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
Improving heart function and reducing long-term effects of a heart attack. It may also be used for other conditions as determined by your doctor.
Reteplase is a tissue plasminogen activator. It works by activating a substance that helps to break up blood clots. Blood clots can prevent oxygen and nutrients from getting to the heart, which causes tissue death and long-term damage to the heart.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Reteplase. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Reteplase. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Reteplase may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Reteplase as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Reteplase.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Pain, redness, or swelling at the injection site.
Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; bleeding at the injection site; chest pain; severe bleeding; sudden, severe headache; trouble breathing; vomiting blood or material that looks like coffee grounds.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Reteplase side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Reteplase is usually handled and stored by a health care provider. If you are using Reteplase at home, store Reteplase as directed by your pharmacist or health care provider.
This information is a summary only. It does not contain all information about Reteplase. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
In the US, Oravig (miconazole systemic) is a member of the drug class azole antifungals and is used to treat Oral Thrush.
US matches:
Miconazole is reported as an ingredient of Oravig in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Bacitracin methylene disalicylate (a derivative of Bacitracin) is reported as an ingredient of Bacitracin MD in the following countries:
Monensin is reported as an ingredient of Bacitracin MD in the following countries:
Monensin sodium salt (a derivative of Monensin) is reported as an ingredient of Bacitracin MD in the following countries:
International Drug Name Search
Ascorvit may be available in the countries listed below.
Ascorbic Acid is reported as an ingredient of Ascorvit in the following countries:
International Drug Name Search
Subitol may be available in the countries listed below.
Oxolamine phosphate (a derivative of Oxolamine) is reported as an ingredient of Subitol in the following countries:
International Drug Name Search
Nimesulida Inibsa may be available in the countries listed below.
Nimesulide is reported as an ingredient of Nimesulida Inibsa in the following countries:
International Drug Name Search
