`
`
`
`
`
`
`•
`
`
`
`
`
`
`
` 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
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`
`
`
`Dosage and Administration (2.3, 2.6)
`07/2018
`
`
`
`
`07/2018
`Warnings and Precautions (5.1)
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`
`
`Remodulin is a prostacyclin vasodilator 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, or 200 mg
`
`
`
`
`
`
`
`•
`of treprostinil (1, 2.5, 5 or 10 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)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`
`Revised: 07/2018
`
`
`
`
`
`
`Transition from Epoprostenol:
`
`
`
`
`
`Increase the Remodulin dose gradually as the epoprostenol dose is decreased,
`
`
`
`based on constant observation of response. (2.7)
`
`_________________________________________________________________________________________________________________________
`
`
`
`
`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 or Renal 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.
`
`Reference ID: 4298821
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Administration Limits
` 16 weeks at 40°C
`
`
` 48 hours at 40°C
`
`
`
`
`
` 48 hours at 40°C
`
` Storage Limits
`
`
` See Section 16
` 14 days at room
`
`
` temperature
`
` 4 hours at room
`
` temperature or
`
`
` 24 hours
` refrigerated
`
` 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
`
`
`
`
`
`
`
`
`
`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.
`
`Reference ID: 4298821
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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:
`
`
`
`
`
`
`Dose (ng/kg/min) x Weight (kg) x
`0.00006*
`
`
`
`
`
`
`
`
`For administration of Diluted Remodulin the rate and concentration is calculated using the
`
`
`
`
`
`following formulas:
`
`
`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:
`
`
`
`
`
`
`
`Reference ID: 4298821
`
`
`
`Undiluted Infusion
`Rate (mL/hour)
`
`
`
`=
`
`
`Remodulin Vial Strength (mg/mL)
`
`*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
`
`
`
`
`
`
`
`
`
` 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 of
`
`
`
`
`the hourly dose, (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).
`
`
`
`
`Reference ID: 4298821
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`Unchanged
`1
`
`
`
`
`
` Remodulin Dose
`
`10% Starting Epoprostenol Dose
`
`
`
`
`2
`
`
`3
`
`
`
`4
`
`
`5
`
`
`6
`
`
`7
`
`
`
`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).
`
`
`
`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.
`
`
`
`Reference ID: 4298821
`
`
`
`
`
`
`
` 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 or Renal Insufficiency
`
`
`Titrate Remodulin 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 (2.5), Use in Specific Populations (8.6, 8.7),
`
`
`
`
`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
`
`
`
`
`
`Reference ID: 4298821
`
`
`
`
`
`
`Table 3: Percentages of Subjects Reporting Subcutaneous Infusion Site Adverse Events
`
`
`
`
`
`
`
` Reaction
`
`
`
` Pain
`
` Remodulin
` Remodulin
`
` Placebo
` Severe
`
`
`
`
` 39
` 1
` 38
`Requiring narcoticsa
`
` NAb
`NAb
`
` 32
`
`
` Leading to discontinuation
`
`
`
`
`
` 0
` 3
` 7
`
`
`
` 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
`
`
`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
`
`
`
`
` Remodulin
`
` (N=236)
` Percent of Patients
`
` 85
`
`
` 83
`
` 27
`
` 25
`
` 22
`
` 14
`
` 13
`
` 11
`
` 9
`
`
`
`
`
`
`
` Adverse Reaction
`
` Infusion Site Pain
` Infusion Site Reaction
`
`
` Headache
`
` Diarrhea
`
` Nausea
`
` Rash
` Jaw Pain
`
` Vasodilatation
`
` Edema
`
`
`
`
`
`
`
` rash. Infusion site reactions were sometimes severe and could lead to discontinuation of
`
` treatment.
`
`
`
`
` Placebo
`
` 2
`
` 1
`
` 0
`
`
`
`
` 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
`
`Reference ID: 4298821
`
`
`
`
`
`
`
` 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 (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
`
`
`
`
`
`Reference ID: 4298821
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`Reference ID: 4298821
`
`
`
`
`
`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 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 c