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TYVASO (treprostinil) inhalant
[United Therapeutics Corp.]


Category DEA Schedule Marketing Status
HUMAN PRESCRIPTION DRUG LABEL New Drug Application
Drug Label Sections

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, for oral inhalation only
Initial U.S. Approval: 2002

INDICATIONS AND USAGE

Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). (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)

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  • Tyvaso dosage adjustments may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.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 1-877-UNITHER (1-877-864-8437) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Concomitant diuretics, antihypertensives or other vasodilators may increase the risk of systemic hypotension. (7.1)

USE IN SPECIFIC POPULATIONS

  • Pregnancy: No experience. (8.1)
  • Nursing women: No experience. (8.3)

See 17 for PATIENT COUNSELING INFORMATION, FDA-approved patient labeling and FDA-approved patient labeling.

Revised: 8/2014

Back to Highlights and Tabs

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Usual Dosage in Adults

2.2 Patients with Hepatic Insufficiency

2.3 Patients with Renal Insufficiency

2.4 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Patients with Pulmonary Disease or Pulmonary Infections

5.2 Risk of Symptomatic Hypotension

5.3 Patients with Hepatic or Renal Insufficiency

5.4 Risk of Bleeding

5.5 Effect of Other Drugs on Treprostinil

6 ADVERSE REACTIONS

6.1 Adverse Reactions Identified in Clinical Trials

6.2 Adverse Reactions Identified in Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Antihypertensive Agents or Other Vasodilators

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Hepatic Insufficiency

8.7 Patients with Renal Insufficiency

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

13.3 Developmental Toxicity

13.4 Inhalational Toxicity

14 CLINICAL STUDIES

14.1 Pulmonary Arterial Hypertension (WHO Group I)

14.2 Long-term Treatment of PAH

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

Tyvaso® (treprostinil) inhalation solution

For Oral Inhalation Only

1 INDICATIONS AND USAGE

Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

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 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)].

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 Tyvaso Inhalation System device.

Do not mix Tyvaso with other medications in the Tyvaso Inhalation System. 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.

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)].

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 1 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
Placebo
n = 120
*
More than 3% greater than placebo
Cough62 (54)35 (29)
Headache47 (41)27 (23)
Throat Irritation / Pharyngolaryngeal Pain29 (25)17 (14)
Nausea22 (19)13 (11)
Flushing17 (15)1 (<1)
Syncope7 (6)1 (<1)

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 2.3 years, with a maximum exposure of 5.4 years. Eighty-nine (89%) percent of patients achieved the target dose of nine breaths, four times daily. Forty-two (42%) percent achieved a dose of 12 breaths four times daily. 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 fifteen subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label experience.

6.2 Adverse Reactions Identified in Post-Marketing Experience

The following adverse reaction has been identified during the postapproval use of Tyvaso. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure:

Angioedema.

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 diolamine) and subcutaneously administered treprostinil (Remodulin®).

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 diolamine), 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 diolamine), 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 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 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.

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 Nonclinical Toxicology (13.3)]. Animal reproduction studies are not always predictive of human response.

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.

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)].

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 Tyvaso Inhalation System. 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:

Chemical Structure

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 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)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year rat carcinogenicity study was performed with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential associated with treprostinil inhalation in rats at systemic exposure levels up to 35 times the clinical exposure at the target maintenance dose of 54 mcg. 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.

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.

In a 2-year rat study with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day, there were more deaths (11) in the mid and high dose treprostinil groups during the first 9 weeks of the study, compared to 1 in control groups. At the high dose level, males showed a higher incidence of inflammation in teeth and preputial gland, and females showed higher incidences of inflammation and urothelial hyperplasia in the urinary bladder. The exposures in rats at mid and high dose levels were about 15 and 35 times, respectively, the clinical exposure at the target maintenance dose of 54 mcg.

14 CLINICAL STUDIES

14.1 Pulmonary Arterial Hypertension (WHO Group I)

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 1), nearly all with NYHA Class III (98%) 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/heritable (56%), secondary to connective tissue diseases (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.

Figure 1

Figure 1: Distributions of 6MWD Changes from Baseline at Week 12 during Peak Plasma Concentration of Tyvaso

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

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

14.2 Long-term Treatment of PAH

In long-term follow-up of patients who were treated with Tyvaso in the pivotal study and the open-label extension (N=206), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 97%, 91%, and 82%, respectively. These uncontrolled observations do not allow comparison with a control group not given Tyvaso and cannot be used to determine the long-term effect of Tyvaso on mortality.

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.

Tyvaso Inhalation System Starter Kit containing a 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 a 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)

Tyvaso 4 Pack Carton with one foil pouch containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL). (NDC 66302-206-03).

Tyvaso Inhalation System Institutional Starter Kit containing a 4 ampule carton of Tyvaso [one foil pouch 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 04).

17 PATIENT COUNSELING INFORMATION

Patients should be properly trained in the administration process for Tyvaso, including dosing, Tyvaso Inhalation System 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 Tyvaso Inhalation System 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)].

©Copyright 2014 United Therapeutics Corp. All rights reserved.

Tyvaso manufactured for:

United Therapeutics Corp.
Research Triangle Park, NC 27709

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 information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is Tyvaso?

Tyvaso is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. Tyvaso can improve the ability to do exercise in people who also take bosentan (an endothelin receptor antagonist (ERA)) or sildenafil (a phosphodiesterase-5 (PDE-5) inhibitor). Your ability to do exercise decreases 4 hours after taking Tyvaso.

It is not known if Tyvaso is safe or effective in people under 18 years of age.

What should I tell my healthcare provider before taking Tyvaso?

Before taking Tyvaso, tell your healthcare provider about all of your medical conditions, including if you:

  • have lung disease, such as asthma or chronic obstructive pulmonary disease (COPD)
  • have a lung infection
  • have liver problems or kidney problems
  • have low blood pressure
  • are pregnant or plan to become pregnant. It is not known if Tyvaso will harm your unborn baby. Women who can become pregnant should use effective birth control while taking Tyvaso.
  • are breast-feeding or plan to breast-feed. It is not known if Tyvaso passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Tyvaso.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tyvaso and other medicines may affect each other.

Especially tell your healthcare provider if you take any of these medicines:

  • medicines that decrease blood clotting
  • water pills (diuretics)
  • medicines used to treat high blood pressure or heart disease
  • gemfibrozil (Lopid) (for high cholesterol)
  • rifampin (Rimactane, Rifadin, Rifamate, Rifater) (for infection)

Know the medicines you take. Keep a list of them and show it to your healthcare provider and specialty pharmacist when you get a new medicine.

How should I take Tyvaso?

  • Take Tyvaso each day exactly as your healthcare provider tells you.
  • See the detailed Tyvaso Inhalation System Instructions for Use.
  • Tyvaso is breathed in (inhaled) through your mouth into your lungs. Tyvaso should only be used with the Tyvaso Inhalation System.
  • Tyvaso is taken in 4 treatment sessions each day during waking hours. The sessions should be at about 4 hours apart.
  • At the beginning of each day, it will take about 5 minutes to prepare the Tyvaso Inhalation System. Each treatment session will take 2 to 3 minutes.
  • Take your first Tyvaso treatment session in the morning and take your last treatment session before bedtime.
  • Your healthcare provider may change your dose if needed.
  • If you miss a dose of Tyvaso take it as soon as you remember.
  • Do not let Tyvaso solution get into your eyes or onto your skin. If it does, rinse your skin or eyes right away with water.
  • Using the Treatment Tracker, record the number of breaths you inhale during each treatment session (4 times a day). You should bring your Treatment Tracker to your medical appointments, as your doctor may want to review it with you.

What are the possible side effects of Tyvaso?

Tyvaso can cause serious side effects, including:

  • Tyvaso may increase the risk of bleeding in people who take blood thinners (anticoagulants).
  • If you have low blood pressure, Tyvaso may lower your blood pressure further.

Ask your healthcare provider if you are not sure if this applies to you.

The most common side effects of Tyvaso include:

  • coughing
  • headache
  • nausea
  • reddening of your face and neck (flushing)
  • throat irritation and pain
  • fainting or loss of consciousness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Tyvaso. For more information, ask your healthcare provider or specialty pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Tyvaso?

  • Store Tyvaso ampules in the unopened foil pack between 59°F to 86°F (15°C to 30°C) until ready to use.
  • When the foil pouch is opened, Tyvaso ampules should be used within 7 days.
  • Tyvaso is sensitive to light. The unopened Tyvaso ampules should be stored in the foil pouch.
  • After a Tyvaso ampule is opened and put into the medicine cup in the Tyvaso Inhalation System, Tyvaso can be kept in the medicine cup for no more than 1 day (24 hours).
  • Tyvaso that is left in the medicine cup at the end of the day must be thrown away.
  • The Tyvaso Inhalation System can be stored in the carrying case when not in use (Example: between treatment sessions or overnight). If storing between treatment sessions, ensure that the plugs are firmly in place in the dome assembly to prevent spillage of Tyvaso. See the Instructions for Use for additional information regarding storage of your Tyvaso Inhalation System.

Keep Tyvaso and all medicines out of the reach of children.

General information about the safe and effective use of Tyvaso.

Medicines are sometimes prescribed for conditions that are not mentioned in a patient information leaflet. Do not use Tyvaso for a condition for which it was not prescribed. Do not give Tyvaso to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about Tyvaso. You can ask your healthcare provider or specialty pharmacist for information about Tyvaso that is written for health professionals.

For more information, go to www.tyvaso.com or call 1-877-UNITHER (1-877-864-8437)..

What are the ingredients in Tyvaso?

Active ingredient: treprostinil
Inactive ingredients: sodium chloride, sodium citrate, sodium hydroxide, hydrochloric acid, and water for injection.

Tyvaso is a registered trademark of United Therapeutics Corporation.

Literature issued July 2012.

United Therapeutics Corp.
Research Triangle Park, NC 27709 USA

Copyright © 2012, United Therapeutics Corp. All rights reserved.

TYVASO®
INHALATION SYSTEM
Instructions for Use

TYVASO®
(treprostinil)
INHALATION
SOLUTION

Table of Contents

General Instructions2
Introduction3
Preparing for Treatment With TYVASO3
  Preparing the Use Environment for Treatment3
  Markings, Indicators, and Symbols4
  Gathering Supplies6
Setting Up Your TYVASO Inhalation System8
  Filling the Inhalation Device Chamber and Medicine Cup8
  Assembling the Inhalation Device10
  Turning On the Inhalation Device13
Setting the Number of Breaths in a Treatment Session14
Inhaling Your Medicine (TYVASO)16
Storing the TYVASO Inhalation System Between Treatment Sessions20
Cleaning and Maintenance of the TYVASO Inhalation System24
  End of Day Cleaning of the Accessories24
  Weekly Cleaning27
  Monthly Refill Kit27
  Device Replacement27
Charging Your TYVASO Inhalation System28
  Rechargeable Battery28
Troubleshooting the TYVASO Inhalation System30
Specifications36
Glossary38
Warranty Information40

General Instructions

The TYVASO Inhalation System should be handled with care.

Follow these important instructions to ensure proper use:

  • Always unplug the device after each use.
  • Do not immerse the device in water or other liquids.
  • Do not place the device in a microwave or regular oven.
  • Do not place the device or use the device in the presence of strong electric or magnetic fields (eg, microwave oven, magnetic imaging equipment).
  • Do not leave the device alone with a small child.
  • Do not use the device near flammable liquids and materials or heated surfaces.
  • Read the instructions carefully and completely to prevent damage to your TYVASO Inhalation System and help you get the best results.
  • This device should only be used on the order of your doctor or licensed healthcare practitioner.
  • Ensure the breath counter is correctly programmed prior to beginning a treatment (see page 14).
  • Do not peel or remove the labels from device.
  • Do not drop the device.

Introduction

Your doctor has prescribed TYVASO® (treprostinil) Inhalation Solution. Please see the accompanying Patient Package Insert for important safety information on TYVASO.

TYVASO is breathed in (inhaled) using the TYVASO Inhalation System, which consists of the inhalation device and its accessories.

These Instructions for Use (IFU) for the TYVASO Inhalation System provide important safety information. It is important that you read these instructions and the TYVASO Patient Package Insert (PPI) before setting up and using the TYVASO Inhalation System. If you have any questions, talk to your doctor or specialty pharmacy provider.

Before beginning treatment with TYVASO, you will receive either a Patient Starter Kit containing a 28-day supply of TYVASO or an Institutional Starter Kit containing a 4-day supply of medication. Both kits include two (2) complete inhalation devices (all accessories and supplies included). When you refill your prescription for TYVASO each month, you will receive a Refill Kit that contains a 28-day supply of TYVASO and new accessories. You will receive a replacement device every two (2) years.

Inhalation Device

Preparing for Treatment With TYVASO

Preparing the Use Environment for Treatment

Follow these important instructions before setting up your treatment:

  • Use the device in a quiet, distraction-free area.
  • Try to use the device at times when your treatment will not be interrupted. If you encounter any distractions during treatment, you can pause your treatment (see page 19).
  • Use the device in a comfortable space where you can stand or sit in an upright position that allows you to take deep breaths.
  • Use the device in an area that provides enough space for the TYVASO Inhalation System and its accessories.
  • Gather all necessary supplies before starting to prepare for treatment (see pages 6 and 7).
  • The TYVASO Inhalation System is recommended for use indoors. Be sure to use and store the inhalation device in environments that match the specified temperature and humidity ranges (see Specifications on page 36).

Markings, Indicators, and Symbols

Figure

Device markings

FigureThe TYVASO Inhalation System complies with the requirements of Protection Class II. Class II equipment provides additional precautions, over and above basic insulation, to provide protection against electric shock.
FigurePlease read the accompanying instructions and labels for important information regarding the TYVASO Inhalation System.
FigureThe TYVASO Inhalation System has a Type B Applied part. Type B Applied parts comply with specific requirements to provide protection against shock and are not suitable for direct cardiac applications.
FigureThe TYVASO Inhalation System should only be used on the order of your doctor or licensed healthcare provider.
FigureThe TYVASO Inhalation System requires a 12V DC power supply.

Gathering Supplies

Gather the following supplies before starting treatment. Use only the parts and accessories that are provided with your starter kit or in the monthly refill kit. Note: supplies are not shown to scale.

1. Inhalation device2. Water Level Cup with 45 mL of distilled water3. Pack of TYVASO ampules

Figure

FigureFigure
Use only distilled water to fill your inhalation device once per day.Use one (1) ampule per day.
4. One of the provided power sources

Figure

Note: Supplies are not shown to scale.
*
These accessories are replaced every month. Replacement accessories are included in the Monthly Refill Kit.
5. Accessories
FigureFigureFigureFigureFigure
Medicine cups*Dome assembly with baffle plate inside*Inhalation piece*Mouthpiece*Two (2) Filter shells*
FigureFigureFigureFigureFigure
Filter membranes (use two (2) per day)*Plugs*Treatment Tracker*Carrying caseDistilled water carrier (optional)

Setting Up Your TYVASO Inhalation System

Filling the Inhalation Device Chamber and Medicine Cup

Before using the TYVASO Inhalation System, you should:

  • Wash your hands

    Figure

  • Make sure the device is NOT connected to a power source
  • Make sure the device is resting on a stable, flat surface during assembly

ONLY USE DISTILLED WATER in the device. Distilled water is highly purified water that can be purchased at most grocery stores and pharmacies. It is necessary for the device to function properly. If you use another type of water (such as bottled or tap water), the device may not function properly.

1
Fill the white chamber inside the device with approximately 45 mL of distilled water (about 1.5 ounces), using the water level cup provided. Fill the cup until water level is between the two arrow markings.

Figure

There is a silver sensor on the inside wall of the chamber. The water level should be above the silver sensor and below the blue ring in the device chamber. DO NOT OVERFILL the chamber, or the medicine cup will not fit correctly. Check the water level after filling the chamber.

Figure

2
Obtain one (1) medicine cup and inspect it for any damage, holes, cracks, or dents. Do not use the medicine cup if it is damaged.

Insert the empty medicine cup into the chamber of the device, making sure that the cup's bottom tip is in the distilled water. The cup will sit on the blue ring.

Figure
Figure

3
Carefully cut open the top of the foil pouch, making sure not to cut the ampules. Each pouch contains four (4) ampules.

Remove one (1) ampule of TYVASO. Keep unused ampules in the foil pouch because the TYVASO medicine is sensitive to light.

One (1) ampule contains enough medicine for one (1) day of treatment no matter how many breaths your doctor has prescribed.

Figure
Figure

4
Gently hold the ampule in the upright (topup) position and twist off its top.

Figure
Figure

5
Point the ampule straight down toward the medicine cup's center to avoid spills.

Gently squeeze the medicine out of the ampule into the medicine cup. Squeeze until it is empty. Check to see that all of the medicine is in the medicine cup.

Figure

Assembling the Inhalation Device

The TYVASO Inhalation System is designed so the parts only fit together properly one way.

When the device is assembled correctly, the parts should fit together easily.

Do not force the parts together.

Figure

1
Visually check to make sure the blue plastic baffle plate and black ring are correctly placed in the dome assembly. They should appear as they do in the images below.

In the unlikely event that the baffle plate is loose or disconnected, use a new dome assembly. If you need to order a new dome assembly, contact your specialty pharmacy provider.

Figure

2
Align the raised circle on the side of the dome assembly with the circle on the side of the device. Push down and screw the dome assembly onto the device clockwise (right) until you hear a click, indicating the dome assembly is fully connected to the medicine cup. When the dome assembly is properly aligned, the filter shell port will point to the back of the device.

Figure
Figure

3
Insert the inhalation piece into the upper opening of the dome assembly and rotate toward the front of the device. Gently push down the inhalation piece to make sure it is securely inserted in the dome assembly.

Figure

4
Insert the mouthpiece into the inhalation piece.

Figure

5
Each day you will need to use a new filter membrane in each filter shell.

To install a new filter membrane:

  • Open the filter shell by unscrewing the two (2) halves.
  • Place a new filter membrane in one (1) of the filter shell halves.
  • Close the filter shell by screwing the two (2) halves together until you can twist no further.

Note: New filter shells come with fresh filter membranes already installed.

Figure

6
Insert one (1) of the filter shells into the filter shell port on the side of the dome assembly and insert the other filter shell into the port on the bottom of the inhalation piece. The two (2) filter shells are identical and can be used in either opening.

Make sure to insert the filter shells straight into their ports, rather than at an angle. If necessary, rotate the inhalation piece so you can insert the filter shell without the device getting in the way.

Figure

7
When the device is fully assembled, it should appear as it does in the photo below.

For convenience, rotate the inhalation piece so you can best see the indicator lights and display screen, which provide important prompts during your treatment.

Figure

Turning On the Inhalation Device

1
Connect your device to one (1) of the power source options by plugging one end of the power cord into the back of the inhalation device and the other end into the power source.

If using the AC wall plug, make sure to plug the output cable into the device before plugging adapter into the power source.

If using the rechargeable battery, make sure it is not also plugged into the AC wall plug.

Figure

2
To turn on the device, press and hold the ON/OFF button for approximately three (3) seconds. When you hear a short beep and the yellow status light is illuminated, release the ON/OFF button. Remember to press the center of the ON/OFF button when powering the device on or off.

When the power is on, the display screen will show the last number of breaths programmed and a yellow light will appear next to the screen.

Make sure the number matches the prescribed number of breaths for that treatment session. If it does not match, see the next page for instructions on setting the number of breaths in a treatment session.

Figure

Setting the Number of Breaths in a Treatment Session

You will inhale TYVASO during four (4) treatment sessions each day. During each treatment session, you will take a series of breaths through the mouthpiece of the TYVASO Inhalation System.

Your doctor will prescribe the number of breaths you should inhale in each treatment session.

You should record the number of breaths in your Treatment Tracker.

Figure

1
Make sure the device is powered off. To power off the device, press and hold the ON/OFF button for three (3) seconds. When you hear a short beep and the display screen turns off, release the ON/ OFF button.

To set the number of breaths, press and hold both the START/STOP and ON/OFF buttons at the same time until the display flashes and the device emits three (3) short beeps.

The flashing display indicates the inhalation device is in breath programming mode. You cannot begin a treatment while the display is flashing.

Figure

2
To increase the number of breaths press the + (ON/OFF) button.

To decrease the number of breaths press the (START/STOP) button.

Remember to press in the center of the buttons.

Figure

3
Once you have entered your prescribed number of breaths, remove your hands from the device and wait approximately 15 seconds.

After approximately 15 seconds, the display will stop flashing and the device will emit three (3) short beeps, indicating that it has saved the new number of breaths. The new number of breaths will appear on the display.

Make sure the number of breaths on the display matches the number of breaths in your prescription. If the numbers do not match, repeat steps 1-3.

Figure

Inhaling Your Medicine, TYVASO® (treprostinil) Inhalation Solution

You will inhale TYVASO during four (4) treatment sessions each day. During each treatment session, you will take a series of breaths through the mouthpiece of the TYVASO Inhalation System.

Figure

Inhalation Tips

Technique:

When breathing each TYVASO treatment, be sure to keep the device level, directing the flow of medicine into the throat and not toward the roof of the mouth.

Seal your lips around the mouthpiece to ensure that you can inhale the full amount of TYVASO after it is produced by the device.

Inhalation:

Each breath should last approximately three (3) seconds, breathing "normal full breaths." Do not hold your breath. Exhale normally and prepare for the next breath.

1
Hold the device upright as shown below. Make sure you can see the display screen and lights clearly and that your hands do not cover the display screen or lights while holding device. If the inhalation piece or mouthpiece block your view of the display screen or lights, move the inhalation piece so you can best see them.

Figure

2
Perform steps A-G to complete one (1) treatment session.
Follow the instructions exactly to make sure you receive the correct medication dose.

AFigureBFigureCFigureDFigure
Press the START/STOP button to begin treatment.The status light turns green and the device emits two (2) short beeps.While the device emits one (1) long beep, exhale completely.After the device emits a short beep and while the inhalation indicator light is flashing green, place your lips securely around the mouthpiece and inhale slowly for the duration of the beep (at least three (3) seconds). Exhale normally, mark a circle in the Treatment Tracker and prepare for the next breath.
Figure
EFigureFFigureGFigure
Repeat steps B through D for the number of prescribed breaths and until the display counts down to "00".After the final breath, the display screen will show "00" then "En," indicating the treatment session is complete.

Check the number of breaths you inhaled on the Treatment Tracker.
To turn off the device, press and hold the ON/OFF button for three (3) seconds and then release.

If the device is left in "En" mode for more than 60 seconds, it will turn off automatically.

3
To pause the treatment between breaths, press the START/STOP button. The display screen will show "PA."

Figure

To resume treatment, press START/ STOP again. "PA" will disappear and the display screen will show the number of breaths remaining.

If the device is disconnected from its power source for any reason (for example, a power failure), reconnect the device to a power source. Follow the instructions on page 13 to turn on the device. The display will show how many breaths are left in that treatment session. Press the START/STOP button to continue your treatment session.

Storing the TYVASO Inhalation System Between Treatment Sessions

If you have more treatment sessions left in the day, perform the following steps.

If you have completed your last treatment session of the day, skip to Cleaning and Maintenance of the TYVASO Inhalation System (see page 24).

Be sure to pack all parts, including a backup power supply, in the carry case whenever transporting your device.

1
Disconnect the device from its power source.

Figure

2
Remove both filter shells.

Do NOT remove the filter membranes from filter shells until after the last treatment session of the day.

Figure
Figure

3
Remove the mouthpiece.

Figure

4
Remove the inhalation piece.

Figure

5
Leave the dome assembly and medicine cup (with the medicine still in it) connected to the device.

Figure

6
Insert a plug into each of the open holes on the dome assembly to prevent the medicine from spilling out.

Figure
Figure

7
The inhalation device with the plugged dome assembly and all the accessories can be stored in the carrying case between treatment sessions.

Figure
Figure

Cleaning and Maintenance of the TYVASO Inhalation System

End of Day Cleaning of the Accessories

1
Disconnect the device from the power source.

Figure

2
Remove both filter shells.

Figure

3
Open the filter shells by twisting in opposite directions.

Remove and discard the used filter membranes.

Figure

4
Remove the mouthpiece.

Figure

5
Remove the inhalation piece.

Figure

6
Remove the dome assembly by turning it counter-clockwise (to the left). The medicine cup should stay attached to the dome assembly.

Figure
Figure

7
Remove the medicine cup by gently squeezing on the sides where it is attached to the dome assembly. Empty the medicine cup into a sink or waste basket, then discard the medicine cup.

Be careful not to spill the medicine when removing or discarding the medicine cup.

Figure
Figure

8
Empty the distilled water from the chamber and let the inhalation device air dry upside down. You can wipe the chamber with a soft cloth or paper towel to collect water.

Figure

9
Clean the accessories (pictured below) by hand in mild, soapy, warm water, then rinse them thoroughly with water. Allow accessories to air dry.

Figure
Figure

10
Once all the items are dry, the filter shells, inhalation piece, mouthpiece, dome assembly, and inhalation device can be stored in the carrying case until the next day's treatment sessions.

Figure

Weekly Cleaning

  • Once a week, use a clean cloth to wipe the interior of the inhalation device chamber, be sure to wipe the disc in the bottom of the device. You may wipe the exterior of the device with a damp cloth if the lights or buttons become difficult to see. Proper cleaning will help to avoid corrosion and leaks and keep your device working properly.

Monthly Refill Kit

  • Once a month, you will receive a refill kit that will come with a new set of accessories from your specialty pharmacy provider. Inspect the shipment to be sure all parts are included (see page 7). Once the new kit has arrived, discard the used dome assembly, inhalation piece, mouthpiece, and two (2) filter shells. Do not recycle the used accessories.

Device Replacement

  • The inhalation device should be replaced every two (2) years from your first day of use. Replacement inhalation devices will be supplied by your specialty pharmacy provider.
Figure

Charging Your TYVASO Inhalation System

Rechargeable Battery

The rechargeable battery is supplied with its own instructions for use. Refer to these instructions for more information.

  • Your TYVASO Inhalation System is supplied with a portable, rechargeable battery. Do NOT use other batteries.
    Figure
  • Your battery can only be charged by using one (1) of the AC wall plugs that comes with your inhalation device.
    Figure
  • To check the battery's voltage level, press and hold the blue button on the front of the battery. You can only check the battery's voltage level when the battery is not plugged into a power source.

    The light below the button will turn on and indicate the battery's voltage level. A red light indicates the battery needs to be charged. A green light indicates the battery is ready to operate the device.
    Figure
Figure
  • To charge the battery, connect the AC wall plug to the battery pack and plug the AC wall plug into an outlet.
    Figure
    A yellow light on the front of the battery will turn on, indicating that the battery is charging.
  • Your battery may take up to 40 hours to fully charge. It is not possible to use the TYVASO Inhalation System with the battery while it is recharging.

    A fully charged battery will typically last up to 200 inhalations. A battery charged for one (1) night (about 10 hours) will typically last up to one (1) day of therapy (about 40 inhalations).
Figure
  • You should connect the charged battery to the TYVASO Inhalation System only for your treatment. When using the battery pack to power the device, make sure the battery is not plugged into a power source.
    Figure
  • After your treatment session is complete, remove the power plug of the battery from the device.
  • Charge the battery whenever you are not using it to power the inhalation device.
  • Always have your AC wall plug or 12V DC adapter available for backup, in case the battery is not charged.
Figure

Troubleshooting the TYVASO Inhalation System

ProblemPossible causesCorrective actions
Low battery (LB)Figure
  • Low battery
  • Unplug the battery from the device. Charge the battery by attaching it to the AC wall plug and outlet.
  • Use an alternative power source, such as the AC wall plug or 12V DC adapter, for treatment.
  • Defective adapter (AC wall plug or 12V DC adapter)
  • Ensure that the plug is properly connected to an outlet.
  • AC wall plug is still plugged into battery and battery is connected to device.
  • Turn off device (see page 14).
  • Disconnect AC wall plug from battery.
  • Check battery status, following instructions on page 28.
  • If device is properly powered and still does not function, contact your specialty pharmacy provider for a replacement.
Low hydrogen (LH)Figure
  • Device chamber is empty or distilled water level in the device chamber is too low.Figure
  • Unplug the device from its power source.
    Remove the dome assembly carefully, making sure not to spill its medicine. Empty the device chamber then refill it with distilled water (see page 8) and reconnect the dome assembly (see page 10).
  • The distilled water you are using is too purified
  • Empty device chamber. Add one (1) teaspoon of tap water to the water fill cup. Fill cup with distilled water up to level between the two arrow markings on cup (see page 8). Pour cup's contents into device chamber.
  • The sensor has a thin layer of build-up
  • Clean sensor and interior surfaces of water chamber with a clean cloth.
  • If device is properly powered and still does not function, contact your specialty pharmacy provider for a replacement.
No medicine comes out of the device during a treatment session
  • No TYVASO® (treprostinil) Inhalation Solution in the medicine cupFigure
  • Unplug the device from its power source. Fill medicine cup with one (1) ampule of TYVASO.
  • Damaged medicine cupFigure
  • Unplug the device from its power source. Replace the medicine cup.
  • Distilled water level in the device chamber is too highFigure
  • Unplug the device from its power source. Empty the device chamber then refill it with 45 mL of distilled water.Figure
  • Multiple medicine cups attached to the dome assemblyFigure
  • Unplug the device from its power source. Remove and dispose of all medicine cups in the device. Insert a single, new medicine cup into device chamber and fill with one (1) ampule of TYVASO.
Difficult to breathe in medicine through the mouthpiece
  • Filter membrane is clogged
  • Unplug the device from its power source. Replace filter membrane (see page 11).Figure
No "click" was heard when attaching the dome assembly
  • No medicine cup in the chamber of the device
  • Insert an empty medicine cup into the chamber of the device and fill it with one (1) ampule of TYVASO.
  • Multiple medicine cups attached to the dome assemblyFigure
  • Unplug the device from its power source. Remove and dispose of all medicine cups in the device. Insert a single, new medicine cup into device chamber and fill with one (1) ampule of TYVASO.
  • Dome assembly is not securely in placeFigure
  • Unplug the device from its power source. Align the circle on the side of the dome assembly with the circle on the side of the device. Push down and screw the dome assembly onto the device clockwise (right) until you hear a click, indicating the dome assembly is fully connected to the medicine cup.
Loss of power during treatment
  • Device is disconnected from its power source
  • Reconnect the device to a power source and press the ON/OFF button to turn on the device. The display will show how many breaths are left in that treatment session. Press the START/STOP button to continue your treatment session.
  • Power source is temporarily disrupted (for example, electricity interruption due to a storm)
  • Reconnect the device to a power source and turn on the device (see page 13). The display will show how many breaths are left in that treatment session. Press the START/ STOP button to continue your treatment session.

Specifications

Inhalation Device

ModelTD-100/A
Size98 × 66 × 105 mm
Weight, inhalation device280 g (9.9 ounces)
Types of power supplyAC wall plug
12V DC adapter
Rechargeable battery
Power input12V DC, 1.5A maximum
Operating power consumption18 Watt maximum
Ultrasonic frequency2.4 MHz (nominal)
Nebulization rate0.50 - 0.55 mg/min (0.9% Saline)
Medicine cup capacity6 mL, nominal
Contact fluid chamber capacity45 mL, nominal
Electric protection classII Type B
Storage temperature/humidity-5 to 40°C/20-80% relative humidity
Operating temperature/humidity15 to 25°C/40-75% relative humidity

Packaging Dimensions (Approximate Length × Width × Height)

Patient Starter Kit (PSK)12.2" × 14.3" × 16.0"
Monthly Refill Kit (MRK)9.9" × 6.1" × 16.1"
Institutional Starter Kit (ISK)12.2" × 14.3" × 16.0"

TYVASO Mass and Particle Specifications for 9 breaths

*
n=108 data points from r=3 inhalation devices. Each data point was 9 breaths.
n=216 data points from r=6 inhalation devices. Each data point was 1 breath.
Mass Median Aerosol Diameter (MMAD)*mean = 2.0 μm
SD = 0.3
Total Emitted Dose per Breathmean = 6.0 μg
SD = 0.4
Total Aerosol Mass*mean = 58 μg
SD = 5.9
Total Respirable Dose*mean = 44.6 μg
SD = 3.5
Respirable Fraction*mean = 73%
SD = 5%
Geometric Standard Deviation (GSD)*mean = 2.6 μm
SD = 0.4

Accessories

Note: Part number subject to change.
ON-110HPARechargeable battery
ON-100Z12V DC adapter
ON-100N-USAC wall plug
ON-102/1/CMedicine cup, Quantity-16
ON-109Filter membranes
ON-120/CPlugs
ON-101/CFilter shell
TD-103/CDome assembly with baffle plate
ON-104/CInhalation piece
ON-105/CMouthpiece
TD-118Water level cup
TD-153Carrying case
TD-155Distilled water carrier

Glossary

Accessories: Parts of the TYVASO Inhalation System. See pages 6 and 7.

Ampule: A sealed, lightweight clear plastic vial containing a 1-day supply of TYVASO® (treprostinil) Inhalation Solution.

Control light for inhalation: A green LED on the top surface of the inhalation device that signals when you should inhale.

Baffle plate: A blue plastic piece that is inside the dome assembly. The baffle plate helps turn TYVASO into particles that are the correct size to inhale.

Black ring: A round seal that fits on the bottom of the dome assembly. The seal helps ensure that TYVASO does not mix with the distilled water in the device chamber.

Display screen: A small area on the inhalation device that displays number and letter prompts to guide you through your treatment sessions.

Distilled water: Water that is highly purified so that it contains only essential elements.

Dome assembly: The plastic accessory that contains the baffle plate and connects the mouthpiece, inhalation piece, and filter shells to the base of the inhalation device.

Filter membrane: The white pad that goes into the filter shells.

Filter shells: Plastic accessories that hold the filter membranes.

Inhalation piece: The plastic accessory that connects the mouthpiece with the dome assembly.

Inhalation device: The base of the TYVASO Inhalation System to which the accessories connect. The inhalation device contains the display screen and lights.

Inhale: How you will breathe in TYVASO with the TYVASO Inhalation System.

Medicine cup: The disposable plastic cone-shaped cup into which TYVASO is poured. The medicine cup fits inside the inhalation device chamber.

Mouthpiece: The plastic part that you will breathe through (using your mouth) to inhale TYVASO.

ON/OFF button: A manually activated control on the front of the device that switches between fully on and fully off power states.

Plugs: Plastic accessories that are inserted into the openings of the dome assembly between treatment sessions. Plugs help keep TYVASO from spilling if the inhalation device tips over.

Prompts: The audio and visual signals that help guide you through the treatment sessions.

Sensor: The silver object on the inside wall of the device chamber. The sensor must be covered with distilled water for the TYVASO Inhalation System to function properly.

Status light: A multicolored LED on the front of the inhalation device that indicates the device's operational status.

Start/Stop treatment button: A manually activated control on the front of the device that begins or pauses treatment.

Specialty pharmacy provider: A pharmacy that carries only specialized medicines and medical devices. Your specialty pharmacy provider is a good source of information about TYVASO and the TYVASO Inhalation System.

Treatment session: One (1) of four (4) daily sessions during which you will take TYVASO with a specific number of inhalations.

TYVASO: The prescription medicine that you will use with the TYVASO Inhalation System.

Water chamber: The white hollow portion in the center of the inhalation device into which distilled water and the medicine cup are placed.

Warranty Information

Your TYVASO Inhalation System is granted a full replacement or repair warranty good for two (2) years from your date of receipt of the TYVASO Inhalation System Starter Kit or five (5) years from the date of manufacture, whichever comes first. This warranty applies to the TYVASO Inhalation System device only. Accessory components are not covered under warranty.

Circumstances that may void your warranty include:

  • Modification or disassembly of the TYVASO Inhalation System device by anyone other than a factory-authorized technician
  • Failure to comply with the written Instructions for Use manual when operating the TYVASO Inhalation System
  • Unapproved use of the TYVASO Inhalation System

For all inquiries relating to service or warranty for your TYVASO Inhalation System, contact your specialty pharmacy provider. You should have the following information available:

  • Device serial number (located on bottom of TYVASO Inhalation System)
  • Date TYVASO Inhalation System was acquired
  • Nature of the problem and any steps taken to fix it

Graphics in IFU are for representation only. Images may not be shown to scale

TYVASO®
INHALATION SYSTEM
Instructions for Use

TYVASO Inhalation Solution is for prescription use only.

TYVASO is a registered trademark of United Therapeutics Corporation.

Literature issued November, 2013

For further questions and information, or to report an adverse reaction, please call 1-877-UNITHER (1-877-864-8437).

Emergency contact information

Clinician: ___________________________________

Nurse educator: ______________________________

Specialty pharmacist: __________________________

United Therapeutics: ___________________________

Distributed by:
United Therapeutics Corporation
Research Triangle Park, North Carolina 27709

TYVASO®
(treprostinil)
INHALATION
SOLUTION

© 2013, United Therapeutics Corporation. All rights reserved.
RTP 3089 Rev. 03

PRINCIPAL DISPLAY PANEL - 4 Ampule Carton

TYVASO®
(treprostinil)
INHALATION
SOLUTION

Treprostinil 1.74 mg / 2.9 mL (0.6 mg/mL)

Four 2.9 mL ampules

For oral inhalation use only

See package insert and
Instructions For Use manual
for dosage and administration

Principal Display Panel - 4 Ampule Carton

PRINCIPAL DISPLAY PANEL - 28 Ampule Carton

TYVASO®
(treprostinil)
INHALATION
SOLUTION

Treprostinil 1.74 mg / 2.9 mL (0.6 mg/mL)

Seven foil pouches each containing four
2.9 mL ampules

For oral inhalation use only

See package insert and
Instructions For Use manual
for dosage and administration.

Principal Display Panel - 28 Ampule Carton

PRINCIPAL DISPLAY PANEL - Starter Kit

TYVASO®
(treprostinil)
INHALATION
SOLUTION

Treprostinil 1.74 mg/2.9 mL (0.6 mg/mL)

TYVASO is for oral inhalation use only and is intended for administration with the TYVASO Inhalation System.

See package insert and Instructions for Use manual for dosage and administration.

TYVASO Inhalation System Starter Kit

CONTENTSQTYCONTENTSQTY
  • 28 ampule carton of TYVASO (seven foil pouches
    each containing four 2.9 mL ampules)
1
  • AC wall plugs
2
  • TYVASO Inhalation Device
2
  • Rechargeable battery
1
  • TYVASO Inhalation System Instructions for Use
    manual
1
  • 12V DC adapter
1
  • Treatment Tracker
1
  • Water level cup
1
  • Sets of Dome assembly, Inhalation piece,
    Mouthpiece, and 2 Filter shells
2
  • Plugs for storage between treatment sessions
2
  • Medicine cups
32
  • Carrying case
1
  • Filter membranes
65
  • Distilled water carrier
1

Each ampule of TYVASO contains: treprostinil 1.74 mg. Each ampule also contains 18.9 mg sodium chloride,
18.3 mg sodium citrate, 0.6 mg sodium hydroxide, 11.7 mg 1N hydrochloric acid, and water for injection.
Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

One new ampule should be used each day. Each ampule of TYVASO (once opened and transferred to
the medicine cup) should remain in the device for no more than 1 day. Any remaining TYVASO and the
medicine cup should be discarded at the end of each day.
Once a foil pouch is opened, use ampules within 7 days.
Store unused ampules of TYVASO in the foil pouch until use, protected from light.
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)
[see USP Controlled Room Temperature].

Keep out of the reach of children.

NDC 66302-206-01
Rx only

Manufactured by United Therapeutics Corporation
Research Triangle Park, NC 27709

United
Therapeutics

CORPORATION

EXP
LOT
RTP3087 Rev.00

PRINCIPAL DISPLAY PANEL - Starter Kit

PRINCIPAL DISPLAY PANEL - Refill Kit

TYVASO®
(treprostinil)
INHALATION
SOLUTION

Treprostinil 1.74 mg/2.9 mL (0.6 mg/mL)

TYVASO is for oral inhalation use only and is intended for administration with the TYVASO Inhalation System

See package insert and Instructions for Use manual for dosage and administration

TYVASO Inhalation System Refill Kit

CONTENTSQTY
  • 28 ampule carton of TYVASO (seven foil pouches each containing
    four 2.9 mL ampules)
1
  • Set of dome assembly, inhalation piece, mouthpiece, and
    2 filter shells
1
  • Medicine cups
32
  • Filters
65
  • Plugs for storage between treatment sessions
2
  • Treatment Tracker
1

Each ampule of TYVASO contains: treprostinil 1.74 mg. Each ampule also contains 18.9 mg sodium chloride,
18.3 mg sodium citrate, 0.6 mg sodium hydroxide, 11.7 mg 1N hydrochloric acid, and water for injection.
Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

One new ampule should be used each day. Each ampule of TYVASO (once opened and transferred to
the medicine cup) should remain in the device for no more than 1 day. Any remaining TYVASO and the
medicine cup should be discarded at the end of each day
Once a foil pouch is opened, use ampules within 7 days
Store unused ampules of TYVASO in the foil pouch until use, protected from light
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)
[see USP Controlled Room Temperature]

Keep out of the reach of children.

NDC 66302-206-02
Rx only

Manufactured for United Therapeutics Corporation
Research Triangle Park, NC 27709

United
Therapeutics

CORPORATION

EXP
LOT
RTP3088 Rev. 00

PRINCIPAL DISPLAY PANEL - Refill Kit

PRINCIPAL DISPLAY PANEL - Institutional Starter Kit

TYVASO Inhalation System
Institutional Starter Kit

TYVASO®
(treprostinil)
INHALATION
SOLUTION

Treprostinil 1.74 mg/2.9 mL (0.6 mg/mL)

TYVASO is for oral inhalation use only and is intended for administration with the TYVASO Inhalation System.
See package insert and Instructions for Use manual for dosage and administration.

CONTENTSQTYCONTENTSQTY
+
4 ampule carton of TYVASO
(one foil pouch containing four 2.9 mL ampules)
1
+
AC wall plugs
2
+
TYVASO Inhalation Device
2
+
Rechargeable battery
1
+
TYVASO Inhalation System Instructions for Use manual
1
+
12V DC adapter
1
+
Treatment Tracker
1
+
Water level cup
1
+
Sets of Dome assembly, Inhalation piece,
Mouthpiece, and 2 Filter shells
2
+
Plugs for storage between treatment sessions
2
+
Medicine cups
32
+
Carrying case
1
+
Filter membranes
65
+
Distilled water carrier
1

Each ampule of TYVASO contains: treprostinil 1.74 mg. Each ampule also contains 18.9 mg sodium chloride,
18.3 mg sodium citrate, 0.6 mg sodium hydroxide, 11.7 mg 1N hydrochloric acid, and water for injection.
Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

+
One new ampule should be used each day. Each ampule of TYVASO (once opened and transferred to the
medicine cup) should remain in the device for no more than 1 day. Any remaining TYVASO and the medicine
cup should be discarded at the end of each day.
+
Once a foil pouch is opened, use ampules within 7 days.
+
Store unused ampules of TYVASO in the foil pouch until use, protected from light.
+
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room
Temperature].

Institutional Starter Kit For Single Patient Use Only.

Keep out of the reach of children.

NDC 66302-206-04 Rx only

Manufactured by United Therapeutics Corporation
Research Triangle Park, NC 27709

United
Therapeutics

CORPORATION

EXP
LOT

PRINCIPAL DISPLAY PANEL - Institutional Starter Kit
TYVASO 
treprostinil inhalant
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:66302-206
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
treprostinil (treprostinil) treprostinil1.74 mg  in 2.9 mL
Inactive Ingredients
Ingredient NameStrength
sodium chloride18.9 mg  in 2.9 mL
sodium citrate18.3 mg  in 2.9 mL
sodium hydroxide0.6 mg  in 2.9 mL
hydrochloric acid11.7 mg  in 2.9 mL
water 
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:66302-206-011 in 1 KIT
128 in 1 BOX
12.9 mL in 1 AMPULE; Combination Product Type = C102842
2NDC:66302-206-021 in 1 KIT
228 in 1 BOX
22.9 mL in 1 AMPULE; Combination Product Type = C102842
3NDC:66302-206-034 in 1 BOX
32.9 mL in 1 AMPULE; Combination Product Type = C102842
4NDC:66302-206-041 in 1 KIT
44 in 1 BOX
42.9 mL in 1 AMPULE; Combination Product Type = C102842
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02238708/14/2009
Labeler - United Therapeutics Corp. (965460025)
Establishment
NameAddressID/FEIBusiness Operations
United Therapeutics Corp.015718364MANUFACTURE(66302-206), LABEL(66302-206)
Establishment
NameAddressID/FEIBusiness Operations
United Therapeutics Corporation965460025MANUFACTURE(66302-206), LABEL(66302-206), ANALYSIS(66302-206), API MANUFACTURE(66302-206)
Establishment
NameAddressID/FEIBusiness Operations
Catalent Pharma Solutions, LLC043911403MANUFACTURE(66302-206)

Revised: 8/2014
 
United Therapeutics Corp.

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