HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TYVASO safely and effectively. See full prescribing information for
`TYVASO.
`
`
`
`TYVASO (treprostinil) inhalation solution
`Initial U.S. Approval: 2002
`For Oral Inhalation Only
`
`
`
`----------------------------INDICATIONS AND USAGE-------------------------
`Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary
`
`arterial hypertension (WHO Group I) in patients with NYHA Class III
`symptoms, to increase walk distance. (1)
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`----------------------DOSAGE AND ADMINISTRATION----------------------
`
`
`Use only with the Tyvaso Inhalation System. (2.1)
`
`
`•
`
`Administer undiluted, as supplied. A single breath of Tyvaso delivers
`•
`approximately 6 mcg of treprostinil. (2.1)
`
`Administer in 4 separate treatment sessions each day approximately four
`hours apart, during waking hours. (2.1)
`
`Initial dosage: 3 breaths [18 mcg] per treatment session. If 3 breaths are
`not tolerated, reduce to 1 or 2 breaths. (2.1)
`
`Dosage should be increased by an additional 3 breaths at approximately
`
`1-2 week intervals, if tolerated. (2.1)
`
`Titrate to target maintenance dosage of 9 breaths or 54 mcg per
`
`treatment session as tolerated. (2.1)
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg
`
`treprostinil (0.6 mg per mL). (3)
`
`
`
`-------------------------------CONTRAINDICATIONS---------------------------
`None (4)
`
`
`------------------------------DRUG INTERACTIONS---------------------------­
`
`Concomitant diuretics, antihypertensives or other vasodilators may
`
`•
`increase the risk of systemic hypotension. (7.1)
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS--------------------­
`
`Pregnancy: Tyvaso should be used only if clearly needed. (8.1)
`
`
`•
`
`Nursing women: Caution should be exercised when administered to a
`
`•
`nursing woman. (8.3)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`-----------------------WARNINGS AND PRECAUTIONS----------------------
`
`Safety and efficacy have not been established in patients with significant
`•
`underlying lung disease (such as asthma or chronic obstructive
`pulmonary disease). (5.1)
`
`In patients with low systemic arterial pressure, Tyvaso may cause
`symptomatic hypotension. (5.2)
`
`Tyvaso may increase the risk of bleeding, particularly in patients
`
`receiving anticoagulants. (5.4, 7.2)
`Tyvaso dosage adjustments may be necessary if inhibitors or inducers of
`CYP2C8 are added or withdrawn. (5.5, 7.5)
`
`
`Hepatic or renal insufficiency may increase exposure and decrease
`
`
`tolerability. (2.2, 2.3, 5.3)
`------------------------------ADVERSE REACTIONS---------------------------­
`Most common adverse reactions (≥ 10%) are cough, headache, nausea
`dizziness, flushing, throat irritation, pharyngolaryngeal pain and diarrhea. (6)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`
`
`Therapeutics Corp. at 1-866-458-6479 or via e-mail at
`
`drugsafety@unither.com, or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`
`
`
`
`
`
`
`Revised: [July/2009]
`______________________________________________________________________________________________________________________________________
`
`
`8
`
`USE IN SPECIF C POPULATIONSI
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`8.1
`Pregnancy
`
`
`WARNING
`
`8.2
`Labor and Delivery
`
`
`
`
`INDICATIONS AND USAGE
`1
`8.3 Nursing Mothers
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`8.4
`Pediatric Use
`
`
`
`
`2.1 Usual Dosage in Adults
`8.5 Geriatric Use
`
`
`
`
`Patients with Hepatic Insufficiency
`2.2
`8.6
`Patients with Hepatic Insufficiency
`
`
`
`
`2.3
`Patients with Renal Insufficiency
`
`8.7
`Patients with Renal Insufficiency
`
`
`2.4 Administration
`OVERDOSAGE
`
`
`DOSAGE FORMS AND STRENGTHS
`DESCRIPTION
`
`
`CONTRAINDICATIONS
`CLINICAL PHARMACOLOGY
`
`
`
`WARNINGS AND PRECAUTIONS
`12.1 Mechanism of Acti no
`
`
`
`
`Patients with Pulmonary Disease or Pulmonary Infections
`5.1
`
`12.2 Pharmacodynamics
`
`
`
`
`5.2 Risk of Symptomatic Hypotension
`
`12.3 Pharmacokinetics
`
`
`5.3
`Patients with Hepatic or Renal Insufficiency
`NONCLINICAL TOXICOLOGY
`
`
`
`
`5.4 Risk of Bleeding
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`5.5
`Effect of Other Drugs on Treprostinil
`13.3 Developmental Toxicity
`
`
`
`ADVERSE REACTIONS
`13.4
`Inhalational Toxicity
`
`
`
`6.1 Adverse Reactions Identified in Clinical Trials
`CLINICAL STUDIES
`
`
`DRUG INTERACTIONS
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`7.1 Antihypertensive Agents or Other Vasodilators
`
`PATIENT COUNSELING INFORMATION
`
`
`7.2 Anticoagulants
`
`
`7.3 Bosentan
`
`
`7.4
`Sildenafil
`
`
`7.5
`Effect of Cytochrome P450 Inhibitors and Inducers
`
`
`
`
`7.6
`Effect of Other Drugs on Treprostinil
`
`
`
`
`
`3
`4
`5
`
`
`
`
`6
`
`7
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`16
`
`17
`
`
`
`
`1
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`

`FULL PRESCRIBING INFORMATION
`Tyvaso™ (treprostinil) inhalation solution
`
`For Oral Inhalation Only
`
`1
`
`INDICATIONS AND USAGE
`
`Tyvaso is indicated to increase walk distance in patients with WHO Group I pulmonary arterial
`
`hypertension and NYHA Class III symptoms. The effects diminish over the minimum recommended
`dosing interval of 4 hours; treatment timing can be adjusted for planned activities.
`
`While there are long-term data on use of treprostinil by other routes of administration, nearly all
`
`
`controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an
`endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled
`clinical experience was limited to 12 weeks in duration [see Clinical Studies (14)].
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Usual Dosage in Adults
`
`
`Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of the
`
`Optineb-ir Model ON-100/7 (an ultrasonic, pulsed-delivery device) and its accessories.
`
`
`Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. The
`
`treatment sessions should be approximately 4 hours apart.
`
`
`Initial Dosage:
`
`Therapy should begin with 3 breaths of Tyvaso (18 mcg of treprostinil), per treatment session, 4
`
`
`times daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths,
`as tolerated.
`
`Maintenance Dosage:
`
`Dosage should be increased by an additional 3 breaths at approximately 1-2 week intervals, if
`
`tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached per treatment session, 4
`times daily. If adverse effects preclude titration to target dose, Tyvaso should be continued at the highest
`tolerated dose.
`
`If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as
`
`possible at the usual dose.
`
`
`
`The maximum recommended dosage is 9 breaths per treatment session, 4 times daily.
`
`2.2 Patients with Hepatic Insufficiency
`
`
`Plasma clearance of treprostinil is reduced in patients with hepatic insufficiency. Patients with
`
`hepatic insufficiency may therefore be at increased risk of dose-dependent adverse reactions because of
`an increase in systemic exposure [see Warnings and Precautions (5.3), Use in Specific Populations (8.6)
`and Clinical Pharmacology (12.3)].
`
`
`
`
`
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`2.3 Patients with Renal Insufficiency
`
`
`Plasma clearance of treprostinil may be reduced in patients with renal insufficiency, since
`
`treprostinil and its metabolites are excreted mainly through the urinary route. Patients with renal
`insufficiency may therefore be at increased risk of dose-dependent adverse reactions [see Warnings and
`
`Precautions (5.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
`
`
`2.4 Administration
`
`Tyvaso must be used only with the Tyvaso Inhalation System. Patients should follow the
`
`instructions for use for operation of the Tyvaso Inhalation System and for daily cleaning of the device
`
`
`components after the last treatment session of the day. To avoid potential interruptions in drug delivery
`
`because of equipment malfunction, patients should have access to a back-up Optineb-ir device.
`
`Do not mix Tyvaso with other medications in the Optineb-ir device. Compatibility of Tyvaso with
`
`other medications has not been studied.
`
`The Tyvaso Inhalation System should be prepared for use each day according to the instructions for
`
`use. One ampule of Tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a
`single day. Prior to the first treatment session, the patient should twist the top off a single Tyvaso ampule
`and squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions,
`the device should be capped and stored upright with the remaining medication inside.
`
`At the end of each day, the medicine cup and any remaining medication must be discarded. The
`
`device must be cleaned each day according to the instructions for use.
`
`
`
`Avoid skin or eye contact with Tyvaso solution. Do not orally ingest the Tyvaso solution.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg of treprostinil
`(0.6 mg per mL).
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Patients with Pulmonary Disease or Pulmonary Infections
`
`The safety and efficacy of Tyvaso have not been established in patients with significant underlying
`
`lung disease (e.g., asthma or chronic obstructive pulmonary disease). Patients with acute pulmonary
`
`
`infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect.
`
`5.2 Risk of Symptomatic Hypotension
`
`
`Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial
`
`pressure, treatment with Tyvaso may produce symptomatic hypotension.
`
`
`
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`5.3 Patients with Hepatic or Renal Insufficiency
`
`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 (2.2, 2.3), Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology
`
`(12.3)].
`
`
`5.4 Risk of Bleeding
`
`
`Since Tyvaso inhibits platelet aggregation, there may be an increased risk of bleeding, particularly
`
`
`
`among patients receiving anticoagulant therapy.
`
`
`5.5 Effect of Other Drugs on Treprostinil
`
`
`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)].
`
`6 ADVERSE REACTIONS
`
`The following potential adverse reactions are described in Warnings and Precautions (5):
`Decrease in systemic blood pressure [see Warnings and Precautions (5.2)].
`
`-
`Bleeding [see Warnings and Precautions (5.4)].
`
`-
`
`
`
`
`
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`
` 6.1 Adverse Reactions Identified in Clinical Trials
`
`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.
`
`In a 12-week placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group I and
`
`nearly all NYHA Functional Class III), the most commonly reported adverse reactions on Tyvaso
`included: cough and throat irritation; headache, gastrointestinal effects, muscle, jaw or bone pain,
`flushing and syncope. Table 1 lists the adverse reactions that occurred at a rate of at least 4% and were
`more frequent in patients treated with Tyvaso than with placebo.
`
`
`
`
`
` Table 1: Adverse Events in ≥ 4% of PAH Patients Receiving
`Tyvaso and More Frequent∗ than Placebo
`
`
`Adverse Event
`
`
`
`Treatment
`n (%)
`
`Tyvaso
`n = 115
`
`62 (54)
`47 (41)
`29 (25)
`
`22 (19)
`17 (15)
`7 (6)
`
`Placebo
`n = 120
`35 (29)
`27 (23)
`17 (14)
`
`13 (11)
`1 (<1)
`1 (<1)
`
`Cough
`Headache
`Throat Irritation /
`Pharyngolaryngeal Pain
`Nausea
`Flushing
`Syncope
` *More than 3% greater than placebo
`
`
`
`
`The safety of Tyvaso was also studied in a long-term, open-label extension study in which 206
`
`
`patients were dosed for a mean duration of one year. The adverse events during this chronic dosing study
`
`were qualitatively similar to those observed in the 12-week placebo controlled trial.
`
`
`Adverse Events Associated with Route of Administration
`
`Adverse events in the treated group during the double-blind and open-label phase reflecting
`
`irritation to the respiratory tract included: cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis
`and wheezing. Serious adverse events during the open-label portion of the study included pneumonia in
`8 subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label
`experience.
`
`
`7
`
`DRUG INTERACTIONS
`
`Pharmacokinetic/pharmacodynamic interaction studies have not been conducted with inhaled
`
`treprostinil (Tyvaso); however, some of such studies have been conducted with orally (treprostinil
`diethanolamine) and subcutaneously administered treprostinil (Remodulin®).
`
`
`
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`Pharmacodynamics
`
`
`7.1 Antihypertensive Agents or Other Vasodilators
`
`
`Concomitant administration of Tyvaso with diuretics, antihypertensive agents or other vasodilators
`may increase the risk of symptomatic hypotension.
`
`7.2 Anticoagulants
`
`
`
`
`Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding,
`particularly among patients receiving anticoagulants.
`
`Pharmacokinetics
`
`7.3 Bosentan
`
`
`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.
`
`7.4 Sildenafil
`
`
`
`
`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.
`
`
`7.5 Effect of Cytochrome P450 Inhibitors and Inducers
`
`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.
`
`
`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 is unclear if the safety and efficacy of
`treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and
`
`Precautions (5.5)].
`
`
`7.6 Effect of Other Drugs on Treprostinil
`
`
`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.
`
`
`
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`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
`8.1 Pregnancy
`
`Pregnancy Category B
`
`
`There are no adequate and well controlled studies with Tyvaso in pregnant women. Animal
`reproduction studies have not been conducted with treprostinil administered by the inhalation route.
`
`However, studies in pregnant rabbits using continuous subcutaneous (sc) infusions of treprostinil sodium
`
`at infusion rates higher than the recommended human sc infusion rate resulted in an increased incidence
`of fetal skeletal variations associated with maternal toxicity [see Developmental Toxicity (13.3)]. Animal
`
`reproduction studies are not always predictive of human response; Tyvaso should be used during
`
`pregnancy only if clearly needed.
`
`
`8.2 Labor and Delivery
`
`
`No treprostinil treatment-related effects on labor and delivery were seen in animal studies. The
`effect of treprostinil on labor and delivery in humans is unknown.
`
`8.3 Nursing Mothers
`
`It is not known whether treprostinil is excreted in human milk. Because many drugs are excreted in
`
`human milk, caution should be exercised when treprostinil is administered to nursing women.
`
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established. Clinical studies of Tyvaso
`
`did not include patients younger than 18 years to determine whether they respond differently from older
`
`patients.
`
`8.5 Geriatric Use
`
`Clinical studies of Tyvaso did not include sufficient numbers of patients aged 65 years 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 hepatic, renal, or cardiac
`
`
`dysfunction, and of concomitant diseases or other drug therapy.
`
`
`8.6 Patients with Hepatic Insufficiency
`
`
`Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects with
`
`mild-to-moderate hepatic insufficiency. Uptitrate slowly when treating patients with hepatic
`insufficiency because of the risk of an increase in systemic exposure which may lead to an increase in
`
`dose-dependent adverse effects. Treprostinil has not been studied in patients with severe hepatic
`
`insufficiency [see Clinical Pharmacology (12.3), Dosage and Administration (2.2) and Warnings and
`
`Precautions (5.3)].
`
`
`8.7 Patients with Renal Insufficiency
`
`
`No studies have been performed in patients with renal insufficiency. Since treprostinil and its
`
`metabolites are excreted mainly through the urinary route, patients with renal insufficiency may have
`decreased clearance of the drug and its metabolites and consequently, dose-related adverse outcomes
`may be more frequent [see Clinical Pharmacology (12.3), Dosage and Administration (2.3) and
`Warnings and Precautions (5.3)].
`
`
`
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`10 OVERDOSAGE
`
`In general, symptoms of overdose with Tyvaso include flushing, headache, hypotension, nausea,
`
`vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have resolved.
`
`11 DESCRIPTION
`
`Tyvaso is a sterile formulation of treprostinil intended for administration by oral inhalation using
`
`
`the Optineb-ir device. Tyvaso is supplied in 2.9 mL low density polyethylene (LDPE) ampules,
`containing 1.74 mg treprostinil (0.6 mg/mL). Each ampule also contains 18.9 mg sodium chloride, 18.3
`mg sodium citrate, 0.58 mg sodium hydroxide, 11.7 mg 1 N hydrochloric acid, and water for injection.
`Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2.
`
`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 390.51 and a molecular
`formula of C23H34O5.
`
`
`
`The structural formula of treprostinil is:
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`
`Treprostinil is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct
`
`vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.
`
`12.2 Pharmacodynamics
`
`In a clinical trial of 240 healthy volunteers, single doses of Tyvaso 54 mcg (the target maintenance
`
`dose per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by
`
`approximately 10 ms. The QTc effect dissipated rapidly as the concentration of treprostinil decreased.
`
`12.3 Pharmacokinetics
`
`Pharmacokinetic information for single doses of inhaled treprostinil was obtained in healthy
`
`
`volunteers in three separate studies. Treprostinil systemic exposure (AUC and Cmax) post-inhalation was
`shown to be proportional to the doses administered (18 mcg – 90 mcg).
`
`Absorption and Distribution
`
`
`
`In a three-period crossover study, the bioavailability of two single doses of Tyvaso (18 mcg and 36
`mcg) was compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the
`
`
`
`8
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`absolute systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and
`72% (36 mcg).
`
`
`Treprostinil plasma exposure data were obtained from two studies at the target maintenance dose,
`54 mcg. The mean Cmax at the target dose was 0.91 and 1.32 ng/mL with corresponding mean Tmax of
`
`0.25 and 0.12 hr, respectively. The mean AUC for the 54 mcg dose was 0.81 and 0.97 hr·ng/mL,
`
`respectively.
`
`Following parenteral infusion, the apparent steady state volume of distribution (Vss) of treprostinil
`
`is approximately 14 L/70 kg ideal body weight.
`
`
`In vitro treprostinil is 91% bound to human plasma proteins over the 330-10,000 mcg/L
`
`concentration range.
`
`
`Metabolism and Excretion
`
`Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. Treprostinil is
`
`
`substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%)
`
`
`and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each
`accounting for 10-15% 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 elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic,
`
`with a terminal elimination half-life of approximately 4 hours using a two compartment model.
`
`
`Special Populations
`
`Hepatic Insufficiency
`
`Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects
`
`presenting with mild-to-moderate hepatic insufficiency. Treprostinil has not been studied in patients with
`severe hepatic insufficiency [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and
`
`Use in Specific Populations (8.6)].
`
`
`Renal Insufficiency
`
`No studies have been performed in patients with renal insufficiency; therefore, since treprostinil
`
`and its metabolites are excreted mainly through the urinary route, there is the potential for an increase in
`both parent drug and its metabolites and an increase in systemic exposure [see Dosage and
`
`Administration (2.3), Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`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 sodium did not affect fertility or mating performance of male or female rats
`given continuous subcutaneous (sc) infusions at rates of up to 450 ng treprostinil/kg/min [about 59 times
`the recommended starting human sc infusion rate (1.25 ng/kg/min) and 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.
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`
`
` 13.3 Developmental Toxicity
`
`In pregnant rats, continuous sc infusions of treprostinil sodium during organogenesis and late
`
`gestational development, at rates as high as 900 ng treprostinil/kg/min (about 117 times the
`recommended starting human sc infusion rate and about 16 times the average rate achieved in clinical
`trials, on a ng/m2 basis), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of
`continuous sc infusions of treprostinil during organogenesis were limited to an increased incidence of
`fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar vertebra 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 sc infusion rate and 5 times the average rate
`achieved in clinical trials, on a ng/m2 basis).
`
`13.4 Inhalational Toxicity
`
`Rats and dogs that received daily administrations of treprostinil by inhalation for 3 months
`
`developed respiratory tract lesions (respiratory epithelial degeneration, goblet cell
`hyperplasia/hypertrophy, epithelial ulceration, squamous epithelial degeneration and necrosis, and lung
`
`hemorrhage). Some of the same lesions seen in animals sacrificed at the end of treatment (larynx, lung
`and nasal cavity lesions in rats, and lesions of the larynx in dogs) were also observed in animals
`sacrificed after a 4-week recovery period. Rats also developed cardiac changes (degeneration/fibrosis). A
`no-effect dose level for these effects was not demonstrated in rats (doses as low as 7 µg/kg/day were
`administered); whereas 107 µg/kg/day was a no-effect dose level in dogs.
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`14 CLINICAL STUDIES
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`TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled multi-center study of
`
`patients with PAH. The study population included 235 clinically stable subjects with pulmonary arterial
`hypertension (WHO Group I), nearly all with NYHA Class III symptoms who were receiving either
`bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase-5 inhibitor) for at least
`three months prior to study initiation. Concomitant therapy also could have included anticoagulants,
`other vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digitalis, but not a
`
`prostacyclin. These patients were administered either placebo or Tyvaso in four daily treatment sessions
`
`with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Patients were
`predominantly female (82%), had the origin of PAH as idiopathic/familial (56%), secondary to collagen
`vascular disease (33%) or secondary to HIV or previous use of anorexigens (12%); bosentan was the
`concomitant oral medication in 70% of those enrolled, sildenafil in 30%.
`
`
`The primary efficacy endpoint of the trial was the change in six-minute walk distance (6MWD)
`
`
`relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes
`after dosing), and 3-5 hours after bosentan or 0.5-2 hours after sildenafil. Patients receiving Tyvaso had a
`placebo-corrected median change from baseline in peak 6MWD of 20 meters at Week 12 (p<0.001). The
`distribution of these 6MWD changes from baseline at Week 12 were plotted across the range of
`observed values (Figure 1). 6MWD measured at trough exposure (defined as measurement of 6MWD at
`least 4 hours after dosing) improved by 14 meters. There were no placebo-controlled 6MWD
`
`assessments made after 12 weeks.
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Tyvaso (N=115)
`Placebo (N=120)
`
`52%
`
`32%
`
`% of patients with a greater 6MWD change
`
`
`
`
`
`0
`-160
`
`
`
`140≤-140-
`
`-120
`
`-100
`
`-80
`
`-60
`
`40
`20
`0
`-20
`-40
`6MWD change from baseline (m)
`
`60
`
`80
`
`100
`
`120
`
`140
`
`160
`
`
`
`
`
` Figure 1: Distributions of 6MWD Changes from Baseline at Week 12 during Peak Plasma Concentration of Tyvaso
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`The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges-
`
`Lehmann estimator) within various subpopulations defined by age quartile, gender, geographic region of
`the study site, disease etiology, baseline 6MWD quartile, and type of background therapy (Figure 2).
`
`
`
` Figure 2. Placebo Corrected Median Treatment Effect (Hodges-Lehmann estimate with 95% CI) on 6MWD Change from
`
`Baseline at Week 12 During Peak Plasma Concentration of Tyvaso for Various Subgroups
`
`
`
`
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
` Tyvaso (treprostinil) inhalation solution is supplied in 2.9 mL clear LDPE ampules packaged as
`
`
`
` four ampules in a foil pouch. Tyvaso is a clear colorless to slightly yellow solution containing 1.74 mg
`treprostinil per ampule at a concentration of 0.6 mg/mL.
`
`
`
`Ampules of Tyvaso are stable until the date indicated when stored in the unopened foil pouch at
`
`25°C (77°F), with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
`Once the foil pack is opened, ampules should be used within 7 days. Because Tyvaso is light-sensitive,
`
`unopened ampules should be stored in the foil pouch.
`
`
`
`One ampule of Tyvaso should be used each day in the Tyvaso Inhalation System. After a Tyvaso
`ampule is opened and transferred to the medicine cup, the solution should remain in the device for no
`
`more than one day (24 hours). Any remaining solution should be discarded at the end of the day.
`
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` Tyvaso Inhalation System Starter Kit containing 28 ampule carton of Tyvaso [seven foil pouches
`
`
`
` each containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL)] and
`the Tyvaso Inhalation System. (NDC 66302-206-01)
`
` Tyvaso Inhalation System Refill Kit containing 28 ampule carton of Tyvaso [seven foil pouches
`
`
`
` each containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL)] and
`accessories. (NDC 66302-206-02)
`
`2.9 mL LDPE ampule containing 1.74 mg treprostinil (0.6 mg per mL), carton containing 1 foil
`
`pouch with 4 ampules. (NDC 66302-206-03)
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`Patients should be properly trained in the administration process for Tyvaso, including dosing,
`
`Optineb-ir device set up, operation, cleaning, and maintenance, according to the instructions for use [see
`
` Dosage and Administration (2.1)].
`
` To avoid potential interruptions in drug delivery because of equipment malfunction, patients should
`
`
`
` have access to a back-up Optineb-ir device [see Dosage and Administration (2.4)].
`
`
`
` In the event that a scheduled treatment session is missed or interrupted, therapy should be resumed
`
`
` as soon as possible [see Dosage and Administration (2.1)].
`
`Patients should avoid skin or eye contact with Tyvaso. If Tyvaso comes in contact with the skin or
`
`
` eyes, instruct patients to rinse immediately with water [see Dosage and Administration (2.4)].
`
`
`
`US Patent No. 5,153,222
`US Patent No. 6,765,117
`US Patent No. 6,521,212
`US Patent No. 6,756,033
`
`United Therapeutics Corp.
`Research Triangle Park, NC 27709
`
`©Copyright 2009 United Therapeutics Corp. All rights reserved.
`
`Tyvaso manufactured by:
`
`Catalent Pharma Solutions
`Woodstock, IL 60098
`
`For United Therapeutics Corp.
`Research Triangle Park, NC 27709
`
`July 2009
`
`
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`1
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`PATIENT PACKAGE INSERT
`
`Tyvaso (Tī-vāsō)
`
`(treprostinil)
`
`Inhalation Solution
`
`Read this Patient Package Insert before you start taking Tyvaso and each time you get a refill.
`There may be new inform