HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`REMODULIN safely and effectively. See full prescribing information for
`REMODULIN.
`
`REMODULIN® (treprostinil) Injection, for subcutaneous or intravenous
`use
`Initial U.S. Approval: May 2002
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Remodulin is a prostacyclin mimetic indicated for:
`•
`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%). (1.1)
`Patients who require transition from epoprostenol, to reduce the rate of
`clinical deterioration. The risks and benefits of each drug should be
`carefully considered prior to transition. (1.2)
`
`•
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`PAH WHO Group 1 in patients with NYHA Class II-IV symptoms:
`•
`Initial dose for patients new to prostacyclin infusion therapy:
`1.25 ng/kg/min; increase based on clinical response (increments of
`1.25 ng/kg/min per week for the first 4 weeks of treatment, later
`2.5 ng/kg/min per week). Avoid abrupt cessation. (2.2, 2.4)
`• Mild to moderate hepatic insufficiency: Decrease initial dose to
`0.625 ng/kg/min.
`Severe hepatic insufficiency: No studies performed. (2.5)
`
`Administration:
`Continuous subcutaneous infusion is the preferred mode. Use intravenous (IV)
`infusion if subcutaneous infusion is not tolerated. (2.1, 2.6)
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`•
`Remodulin is supplied in 20-mL vials containing 20, 50, 100, 200, or
`400 mg of treprostinil (1, 2.5, 5, 10, or 20 mg/mL). (3)
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`None
`
`-----------------------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)
`Remodulin may cause symptomatic hypotension. (5.4)
`Remodulin inhibits platelet aggregation and increases the risk of
`bleeding. (5.5)
`
`•
`•
`•
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence >3%) reported in clinical studies
`with Remodulin: subcutaneous infusion site pain and reaction, headache,
`diarrhea, nausea, jaw pain, vasodilatation, edema, and hypotension. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`Therapeutics Corp. at 1-866-458-6479 or contact FDA at 1-800-FDA-1088
`or www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS-------------------------------
`•
`Remodulin dosage adjustment may be necessary if inhibitors or inducers
`of CYP2C8 are added or withdrawn. (7.1)
`
`
`Transition from Epoprostenol:
`Increase the Remodulin dose gradually as the epoprostenol dose is decreased,
`based on constant observation of response. (2.7)
`
`_________________________________________________________________________________________________________________________
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 07/2021
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Pulmonary Arterial Hypertension
`1.2 Pulmonary Arterial Hypertension in Patients Requiring
`Transition from Epoprostenol
`2 DOSAGE AND ADMINISTRATION
`2.1 General
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`2.3 Initial Dose for Patients Transitioning to an Implantable
`Intravenous Infusion Pump
`2.4 Dosage Adjustments
`2.5 Patients with Hepatic Insufficiency
`2.6 Administration
`2.7 Patients Requiring Transition from Epoprostenol
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Catheter-Related Bloodstream Infection
`5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large
`Dose Reduction
`5.3 Patients with Hepatic Insufficiency
`5.4 Risk of Symptomatic Hypotension
`5.5 Risk of Bleeding
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-Marketing Experience
`7 DRUG INTERACTIONS
`_________________________________________________________________________________________________________________________
`
`7.1 Effect of CYP2C8 Inhibitors and Inducers on Treprostinil
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Patients with Hepatic Insufficiency
`8.7 Patients with Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`14.2 Flolan-To-Remodulin Transition Study
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`Interruption of Therapy
`Overdose
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
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`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`1.1 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 (14.1)].
`
`1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from Epoprostenol
`
`In patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish
`the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General
`
`Remodulin can be administered with or without further dilution with Sterile Diluent for
`Remodulin or similar approved high-pH glycine diluent (e.g., Sterile Diluent for Flolan or Sterile
`Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to
`administration. See Table 1 below for storage and administration time limits for the different
`diluents.
`
`Diluted Remodulin has been shown to be stable at ambient temperature when stored for up to
`14 days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL).
`
`Table 1: Selection of Diluent
`
`Diluent
`None
`
`Sterile Diluents for Remodulin,
`Flolan, or Epoprostenol
`
`Sterile Water for Injection
`0.9% Sodium Chloride for
`Injection
`
`Storage Limits
`See Section 16
`
`Administration Limits
`16 weeks at 40°C
`
`14 days at room temperature
`
`48 hours at 40C
`
`4 hours at room temperature
`or 24 hours refrigerated
`
`48 hours at 40°C
`
`
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`
`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, reduce the infusion rate to 0.625 ng/kg/min.
`
`2.3 Initial Dose for Patients Transitioning to an Implantable Intravenous Infusion Pump
`
`The initial dose of Remodulin should be the same as the current dose the patient is receiving
`using the external infusion pump at the time of transition.
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`2.4 Dosage Adjustments
`
`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.
`Avoid abrupt cessation of infusion [see Warnings and Precautions (5.2)]. 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.
`
`2.5 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. Remodulin has not been studied in patients with severe
`hepatic insufficiency [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and
`Clinical Pharmacology (12.3)].
`
`2.6 Administration
`
`Inspect parenteral drug products for particulate matter and discoloration prior to administration
`whenever solution and container permit. If either particulate matter or discoloration is noted, do
`not use.
`
`Preparation
`
`Remodulin is administered by subcutaneous or intravenous infusion at a calculated rate based on
`a patient’s dose (ng/kg/min), weight (kg), and the Remodulin concentration (mg/mL).
`
`For administration of Undiluted Remodulin the rate is calculated using the following formula:
`
`Undiluted Infusion
`Rate (mL/hour)
`
`=
`
`Dose (ng/kg/min) x Weight (kg) x
`
`0.00006*
`
`Remodulin Vial Strength (mg/mL)
`
`*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
`
`
`For administration of Diluted Remodulin, the concentration is calculated using the following
`formula:
`
`Step 1
`
`Dose (ng/kg/min) x Weight (kg)
`
`x
`
`0.00006
`
`Diluted
`Remodulin
`Concentration
`(mg/mL)
`
`=
`
`Infusion Rate
`(mL/hour)
`
`The volume of Remodulin Injection needed to make the required diluted Remodulin
`concentration for the given reservoir size can then be calculated using the following formula:
`
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`Step 2
`
`
`Volume of
`Remodulin
`Injection
`(mL)
`
`=
`
`Diluted Remodulin
`Concentration
`(mg/mL)
`Remodulin Vial
`Strength
`(mg/mL)
`
`x
`
`Total Volume of Diluted Remodulin
`Solution in Reservoir
`(mL)
`
`
`The calculated volume of Remodulin Injection is then added to the reservoir along with the
`sufficient volume of diluent to achieve the desired total volume in the reservoir.
`
`Subcutaneous Infusion
`
`Remodulin is administered subcutaneously by continuous infusion, via a subcutaneous catheter,
`using an infusion pump designed for subcutaneous drug delivery. The infusion pump should:
`(1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery,
`programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better,
`(4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride,
`polypropylene or glass. Alternatively, use an infusion pump cleared for use with Remodulin. To
`avoid potential interruptions in drug delivery, the patient must have immediate access to a backup
`infusion pump and subcutaneous infusion sets.
`
`Intravenous Infusion
`
`External Intravenous Infusion Pump:
`Remodulin is administered intravenously by continuous infusion via a surgically placed
`indwelling central venous catheter using an external 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 increases the risk of thrombophlebitis. The
`infusion pump used to administer Remodulin should: (1) have occlusion/no delivery, low battery,
`programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better,
`(3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride,
`polypropylene or glass. Alternatively, use an infusion pump cleared for use with Remodulin. To
`avoid potential interruptions in drug delivery, the patient must have immediate access to a backup
`infusion pump and infusion sets.
`
`Infusion sets with an in-line 0.22- or 0.2-micron pore size filter should be used.
`
`Implantable Intravenous Infusion Pump:
`Use an implantable intravenous infusion pump approved for use with Remodulin, such as the
`Implantable System for Remodulin® (ISR). Refer to the pump manufacturer’s manual for specific
`instructions regarding preparation, programing, implantation, and refilling.
`
`2.7 Patients Requiring Transition from Epoprostenol
`
`Transition from epoprostenol to Remodulin is accomplished by initiating the infusion of
`Remodulin and increasing it, while simultaneously reducing the dose of intravenous
`epoprostenol. 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).
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`Initiate Remodulin at a recommended dose of 10% of the current epoprostenol dose, and then
`escalate as the epoprostenol dose is decreased (see Table 2 for recommended dose titrations).
`
`Patients are individually titrated to a dose that allows transition from epoprostenol therapy to
`Remodulin while balancing prostacyclin-limiting adverse events. Treat increases in the patient’s
`symptoms of PAH first with increases in the dose of Remodulin. Treat side effects normally
`associated with prostacyclin and prostacyclin analogs first by decreasing the dose of
`epoprostenol.
`
`
`Table 2: Recommended Transition Dose Changes
`
`Step
`
`Epoprostenol Dose
`
`Remodulin Dose
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Unchanged
`
`10% Starting Epoprostenol Dose
`
`80% Starting Epoprostenol Dose
`
`30% Starting Epoprostenol Dose
`
`60% Starting Epoprostenol Dose
`
`50% Starting Epoprostenol Dose
`
`40% Starting Epoprostenol Dose
`
`70% Starting Epoprostenol Dose
`
`20% Starting Epoprostenol Dose
`
`90% Starting Epoprostenol Dose
`
`5% Starting Epoprostenol Dose
`
`110% Starting Epoprostenol Dose
`
`0
`
`110% Starting Epoprostenol Dose +
`additional 5-10% increments as needed
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`
`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).
`20-mL vial containing 400 mg treprostinil (20 mg per mL).
`
`4 CONTRAINDICATIONS
`
`None
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Catheter-Related Bloodstream Infection
`
`Chronic intravenous infusions of Remodulin 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.
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`Administration of IV Remodulin 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.
`
`In an open-label study of an implantable pump (n=60), there were two blood stream infections
`(BSIs) related to the implant procedure during approximately 265 patient years.
`
`5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction
`
`Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in
`worsening of PAH symptoms.
`
`5.3 Patients with Hepatic Insufficiency
`
`Titrate Remodulin 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 Remodulin may produce symptomatic hypotension.
`
`5.5 Risk of Bleeding
`
`Remodulin inhibits platelet aggregation and increases the risk of bleeding.
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed elsewhere in labeling: Infections associated with
`intravenous administration [see Warnings and Precautions (5.1)].
`
`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 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
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`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
`Remodulin
`Remodulin
`1
`38
`39
`Severe
`NAb
`NAb
`Requiring narcoticsa
`32
`0
`3
`7
`Leading to discontinuation
`a based on prescriptions for narcotics, not actual use
`b 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
`
`Placebo
`2
`1
`0
`
`Table 4 lists adverse reactions that occurred at 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
`
`Adverse Reaction
`Infusion Site Pain
`Infusion Site Reaction
`Headache
`Diarrhea
`Nausea
`Rash
`Jaw Pain
`Vasodilatation
`Edema
`
`Remodulin
`(N=236)
`Percent of Patients
`85
`83
`27
`25
`22
`14
`13
`11
`9
`
`Placebo
`(N=233)
`Percent of Patients
`27
`27
`23
`16
`18
`11
`5
`5
`3
`
`
`Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included with
`the exception of 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 versus
`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
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`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, paresthesia, hematoma, and pain [see Warnings
`and Precautions (5.1)].
`
`6.2 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, dizziness, arthralgia,
`myalgia/muscle spasm, and pain in extremity. In addition, generalized rashes, sometimes macular
`or papular in nature, and cellulitis have been infrequently reported.
`
`7 DRUG INTERACTIONS
`
`7.1 Effect of CYP2C8 Inhibitors and Inducers on Treprostinil
`
`Dose adjustment of treprostinil may be necessary when co-administered with CYP2C8 inducers
`or inhibitors. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil
`diolamine) 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 changes in exposure of treprostinil with inhibitors or inducers of CYP2C8 observed for the
`oral administration of treprostinil would be similar for treprostinil administered via the parenteral
`route [see Clinical Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summary
`Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-
`associated risk of adverse developmental outcomes. However, there are risks to the mother and
`the fetus associated with pulmonary arterial hypertension (see Clinical Considerations). In animal
`studies, no adverse reproductive and developmental effects were seen in rats at about 123 and
`48 times the human exposure based on Cmax and AUC, respectively. In rabbits, external fetal and
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`soft tissue malformations and skeletal malformations were observed at about 7 and 5 times the
`human exposure based on Cmax and AUC, respectively (see Data).
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`populations is unknown. All pregnancies have a background risk of birth defect, loss, or other
`adverse outcomes. In the U.S. general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
`respectively.
`
`Clinical Considerations
`Disease-associated maternal and embryo-fetal risk
`Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal
`mortality.
`
`Data
`Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous
`administration and with treprostinil diolamine administered orally. In pregnant rats, continuous
`subcutaneous infusions of treprostinil during organogenesis and late gestational development, at
`doses as high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous
`infusion rate, 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 a dose of
`150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous infusion rate, 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 doses of up to 450 ng
`treprostinil/kg/min, did not affect the growth and development of offspring. In studies with orally
`administered treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal
`development (teratogenicity), and postnatal development were determined in rats. In pregnant
`rats, no evidence of harm to the fetus was observed following oral administration of treprostinil
`diolamine at the highest dose tested (20 mg/kg/day), which represents about 123 and 48 times the
`human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate
`achieved in clinical trials, respectively. In pregnant rabbits, external fetal and soft tissue
`malformations and fetal skeletal malformation occurred. The dose at which no adverse effects
`were seen (0.5 mg/kg/day) represents about 7 and 5 times the human exposure, when based on
`Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively.
`No treprostinil treatment-related effects on labor and delivery were seen in animal studies.
`Animal reproduction studies are not always predictive of human response.
`
`8.2 Lactation
`
`Risk Summary
`There are no data on the presence of treprostinil in human milk, the effects on the breastfed
`infant, or the effects on milk production.
`
`8.4 Pediatric Use
`
`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.
`
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`Reference ID: 4834202
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`

`
`
`8.5 Geriatric Use
`
`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.
`
`8.6 Patients with Hepatic Insufficiency
`
`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 (2.5), Warnings and Precautions (5.3), and
`Clinical Pharmacology (12.3)].
`
`8.7 Patients with Renal Impairment
`
`No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by
`dialysis [see Clinical Pharmacology (12.3)].
`
`10 OVERDOSAGE
`
`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 using an external infusion pump, 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.
`
`11 DESCRIPTION
`
`Remodulin (treprostinil) Injection is a sterile solution of treprostinil, a prostacyclin mimetic,
`formulated for subcutaneous or intravenous administration. Remodulin is supplied in 20-mL
`multidose vials in five strengths, containing 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg
`(1 mg/mL, 2.5 mg/mL, 5 mg/mL, 10 mg/mL, or 20 mg/mL) of treprostinil. Each mL also contains
`5.3 mg sodium chloride (except for the 10 mg/mL and 20 mg/mL strengths, which contain 4.0 mg
`sodium chloride), 3 mg metacresol, 6.3 mg sodium citrate dihydrate, 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.
`
`Reference ID: 4834202
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`The structural formula of
`
`treprostinil
`
`is:
`
`OH
`
`
`
`
`H
`
`OCH,CO,H
`
`itOH
`
`in a 50-mL vial
`Sterile Diluent for Remodulin is a
`diluent
`high-pH (pH~10.4) glycine
`supplied
`50 mL ofSterile Diluent for Remodulin. Each vial contains 94 mg glycine,
`73.3 mg
`containing
`and water for
`sodium chloride, sodium
`hydroxide (to adjust pH),
`injection.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`The
`
`actions of
`major pharmacologic
`treprostinil
`arterial vascular beds, and inhibition of
`systemic
`platelet aggregation.
`
`are direct vasodilation of
`
`pulmonary
`
`and
`
`12.2
`
`Pharmacodynamics
`In animals, the
`and left ventricular afterload and increase cardiac
`effects reduce
`right
`vasodilatory
`causes a dose-related
`output and stroke volume. Other studies have shown that
`treprostinil
`effects on cardiac conduction have been
`effect. No
`and
`negative inotropic
`lusitropic
`major
`observed.
`
`treprostinil up to 84 mcg by
`dosesof
`vasodilation and
`tachycardia. Single
`Treprostinil produces
`to be an artifact ofthe
`effects on
`QTc, butthis is apt
`inhalation
`modest and
`short-lasting
`produce
`the subcutaneous or intravenous routes
`heart rate.
`administered
`Treprostinil
`by
`rapidly changing
`to
`hasthe
`generate concentrations
`via the
`many-fold greater than those
`generated
`potential
`inhaled route; the effect on the QTc interval when
`is administered
`treprostinil
`parenterally
`been established.
`
`has not
`
`12.3 Pharmacokinetics
`
`of continuous subcutaneous Remodulin are linear over the dose range of 2.5
`The
`pharmacokinetics
`to
`to 125
`to 18,250 pg/mL)
`concentrations of about 260
`ng/kg/min (corresponding
`plasma
`pg/mL
`and can be described
`a
`at infusion rates
`two-compartment model. Dose
`greater
`by
`proportionality
`has not been studied.
`than 125
`
`ng/kg/min
`
`Subcutaneous and intravenous administration of Remodulin demonstrated
`state at a dose of 10
`
`steady
`
`ng/kg/min.
`
`bioequivalence
`
`at