Tyvaso

Treprostinil inhalation should be taken when you wake up and also before any physical activity, but not more than every 4 hours. Do not change your dose without talking to your doctor.

Treprostinil is breathed into your lungs with Tyvaso® Inhalation System. This system consists of the Tyvaso® Inhalation System device and its accessories. Carefully follow your doctor's instructions for using the medicine and operating and cleaning the equipment. Do not put other medicines into this equipment.

Do not drink this medicine. Do not allow the inhalation solution to come into contact with your skin or eyes. If it does, rinse it off with water right away.

To avoid missing a dose or any possible problems with the drug delivery device you are using, you should have a back-up with Tyvaso® Inhalation System device.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For inhalation dosage form (solution):
  • For pulmonary arterial hypertension:
    • Adults—At first, 18 micrograms (mcg) or three breaths, per treatment session at least 4 hours apart, 4 times a day. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 9 breaths per treatment session, 4 times a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Protect the medicine from direct light. Keep your medicine in the unopened foil pouch until you are ready to use it. Once the foil pack is opened, the ampules should be used within 7 days.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Tyvaso affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Do not stop taking this medicine all of a sudden without calling your doctor. Signs of high pressure in the lungs like shortness of breath, dizziness, or weakness may get worse. Talk with your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Tyvaso while you are pregnant.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Very bad dizziness or passing out.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Trouble breathing that is new or worse.
• Cough that does not go away.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Flushing.
• Jaw pain.
• Dizziness.
• Loose stools (diarrhea).
• Upset stomach.
• Cough.
• Throat irritation.
• Muscle pain.
• Bone pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Store unused containers in foil pouch until use.
• Protect from light.
• Throw away any part of opened pouch that is not used after 7 days.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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.

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)].

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)].

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.

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

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.

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.

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 per 100 patient-years vs. 10.9 per 100 pt-years), throat irritation (4.5 per 100 pt-years vs. 1.2 per 100 pt-years), nasal discomfort (2.6 per 100 pt-years vs. 1.3 per 100 pt-years), and haemoptysis (2.5 per 100 pt-years vs. 1.3 per 100 pt-years) compared to the control group.

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.

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.

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. Also, a study in pregnant rabbits administered oral treprostinil diolamine at exposures higher than those in humans resulted in external fetal and soft tissue malformations and fetal skeletal malformations [see Nonclinical Toxicology (13.3)]. Animal reproduction studies are not always predictive of human response.

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.

Nursing Mothers

It is not known whether treprostinil is excreted in human milk.

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.

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.

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)].

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)].

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.

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).