TYVASO

TYVASO- treprostinil inhalant
United Therapeutics Corporation

1 INDICATIONS AND USAGE

1.1 Pulmonary Arterial Hypertension

Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies establishing effectiveness predominately included 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)].

1.2 Pulmonary Hypertension Associated with ILD

Tyvaso is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%) [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. Each treatment session will take 2 to 3 minutes. 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 per treatment session, 4 times daily at approximately 1- to 2-week intervals. Studies establishing effectiveness in patients with PAH and PH-ILD have used target doses of 9 to 12 breaths 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.

2.2 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 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.

5.2 Risk of Bleeding

Tyvaso inhibits platelet aggregation and increases the risk of bleeding.

5.3 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 (7.3) and Clinical Pharmacology (12.3)].

5.4 Bronchospasm

Like other inhaled prostaglandins, Tyvaso may cause acute bronchospasm. Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with Tyvaso Inhalation Solution.

6 ADVERSE REACTIONS

The following potential adverse reactions are described in Warnings and Precautions (5):

Decrease in systemic blood pressure [see Warnings and Precautions (5.1)].
Bleeding [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Pulmonary Arterial Hypertension

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, dizziness, 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 in TRIUMPH I
Adverse Event Treatment n (%)
Tyvason=115 Placebon=120
*
More than 3% greater than placebo
Cough 62 (54) 35 (29)
Headache 47 (41) 27 (23)
Throat Irritation / Pharyngolaryngeal Pain 29 (25) 17 (14)
Nausea 22 (19) 13 (11)
Flushing 17 (15) 1 (<1)
Syncope 7 (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 percent (89%) of patients achieved the target dose of 9 breaths, 4 times daily. Forty-two percent (42%) achieved a dose of 12 breaths, 4 times daily. The adverse events during this chronic dosing study were qualitatively similar to those observed in the 12-week placebo-controlled trial.

In a prospective, observational study comparing patients taking Tyvaso (958 patient-years of exposure) and a control group (treatment with other approved therapies for PAH; 1094 patient-years), Tyvaso was associated with a higher rate of cough (16.2 vs. 10.9 per 100 patient-years), throat irritation (4.5 vs. 1.2 per 100 pt-years), nasal discomfort (2.6 vs. 1.3 per 100 pt-years), and hemoptysis (2.5 vs. 1.3 per 100 pt-years) compared to the control group.

Pulmonary Hypertension Associated with ILD

In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions were similar to the experience in studies of PAH.

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