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SELECT IMPORTANT SAFETY INFORMATION

• Orenitram is Contraindicated in patients with severe hepatic impairment (Child Pugh Class C).
• Remodulin has a Warning and Precaution for chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter, as they are associated with the risk of blood stream infections (BSI) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.
• ADCIRCA is contraindicated in patients taking medicines that contain nitrates or guanylate cyclase stimulators (such as riociguat), as the combination could cause a sudden, unsafe drop in blood pressure. Do not use nitrates within 48 hours of the last dose of ADCIRCA.
• TYVASO and TYVASO DPI have a Warning and Precaution for patients with low systemic arterial pressure, as either product may produce symptomatic hypotension.

Please see below for Indication, Important Safety Information, and links to the Full Prescribing Information for Orenitram, Remodulin, ADCIRCA, TYVASO, and TYVASO DPI.

Orenitram^® (treprostinil) Extended-Release Tablets

INDICATION

Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).

IMPORTANT SAFETY INFORMATION FOR ORENITRAM

CONTRAINDICATIONS

• Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.

WARNINGS AND PRECAUTIONS

• Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
• The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

ADVERSE REACTIONS

• In the 12-week, placebo-controlled, monotherapy study, and an event-driven placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.

DRUG INTERACTIONS

• Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.

SPECIFIC POPULATIONS

• Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
• It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
• Safety and effectiveness of Orenitram in pediatric patients have not been established.
• Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
• There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.

Please see Full Prescribing Information and Patient Information at www.orenitram.com or call 1-877-UNITHER (1-877-864-8437).

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Remodulin^® (treprostinil) Injection

INDICATION

Remodulin is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).

In patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

IMPORTANT SAFETY INFORMATION FOR REMODULIN

WARNINGS AND PRECAUTIONS

• Chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.
• Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.
• 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.
• Remodulin is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.
• Remodulin inhibits platelet aggregation and increases the risk of bleeding.

ADVERSE REACTIONS

• In clinical studies of SC Remodulin infusion, the most common adverse events reported were infusion site pain and infusion site reaction (redness, swelling, and rash). These symptoms were sometimes severe and sometimes required treatment with narcotics or discontinuation of Remodulin. The IV infusion of Remodulin with an external infusion pump has been associated with a risk of blood stream infections, arm swelling, paresthesias, hematoma, and pain. Other common adverse events (≥3% more than placebo) seen with either SC or IV Remodulin were headache (27% vs. 23%), diarrhea (25% vs. 16%), nausea (22% vs. 18%), rash (14% vs. 11%), jaw pain (13% vs. 5%), vasodilatation (11% vs. 5%), edema (9% vs. 3%), and hypotension (4% vs. 2%).

DRUG INTERACTIONS

• Remodulin dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.

SPECIFIC POPULATIONS

• In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min of ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency.
• Safety and effectiveness of Remodulin in pediatric patients have not been established.
• It is unknown if geriatric patients respond differently than younger patients. Caution should be used when selecting a dose for geriatric patients.
• There are no adequate and well-controlled studies with Remodulin in pregnant women. It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.

Please see accompanying Full Prescribing Information for Remodulin.

For additional information, visit www.RemodulinPro.com or call Customer Service at 1-877-UNITHER (1-877-864-8437).

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Important Safety Information for ADCIRCA^® (tadalafil) tablets

CONTRAINDICATIONS

• Nitrates and Guanylate Cyclase (GC) Stimulators: Do not use ADCIRCA in patients taking medicines that contain nitrates or guanylate cyclase stimulators (such as riociguat), as the combination could cause a sudden, unsafe drop in blood pressure. Do not use nitrates within 48 hours of the last dose of ADCIRCA.
• Hypersensitivity Reactions: Patients with a known serious hypersensitivity to tadalafil should not take ADCIRCA

WARNINGS AND PRECAUTIONS

• Cardiovascular: Patients who experience anginal chest pain after taking ADCIRCA should seek immediate medical attention
• Hypotension: Phosphodiesterase 5 inhibitors (PDE-5is), including tadalafil, have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Before prescribing ADCIRCA, carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such actions.
• Worsening Pulmonary Vascular Occlusive Disease: Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD) and administration of ADCIRCA to these patients is not recommended
• Vision/Hearing: Patients who experience a sudden loss of vision in one or both eyes, which could be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), or sudden decrease or loss of hearing after taking ADCIRCA should seek immediate medical attention
• Prolonged Erection: In rare instances, men taking PDE-5is (including tadalafil) for ED reported an erection lasting more than four hours. Male patients who experience a prolonged erection should seek immediate medical attention

SPECIAL POPULATIONS AND POTENTIAL DRUG INTERACTIONS:

• Special Populations (Pregnant or Expecting Pregnancy): Limited data from case series with tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.
• Special Populations (Renal or Hepatic Impairment): The use of ADCIRCA is not recommended for patients with severe renal or hepatic impairment. Please see Full Prescribing Information for dosing recommendations for patients with mild to moderate renal or hepatic impairment
• Potential Drug Interactions: The use of ADCIRCA with alpha blockers, blood pressure medications, or alcohol may lower blood pressure significantly and may lead to symptomatic hypotension (light-headedness or fainting)
• Potential Drug Interactions: Tadalafil is metabolized predominately by CYP3A in the liver. Use of ADCIRCA with potent CYP3A inhibitors, such as ketoconazole and itraconazole, should be avoided. For patients on ADCIRCA therapy that require treatment with ritonavir, ADCIRCA should be discontinued at least 24 hours prior to starting ritonavir. For patients on ritonavir therapy that require treatment with ADCIRCA, start ADCIRCA at 20 mg once a day. Use of ADCIRCA with potent inducers of CYP3A, such as rifampin, should be avoided
• Potential Drug Interactions: ADCIRCA contains the same ingredient (tadalafil) as Cialis^®, which is used to treat erectile dysfunction (ED) and the signs and symptoms of benign prostatic hyperplasia (BPH). The safety and efficacy of combinations of ADCIRCA with Cialis or other PDE-5is have not been studied. Therefore, the use of such combinations is not recommended

ADVERSE REACTIONS

• Adverse Reactions: The most common adverse event with ADCIRCA is headache (42% ADCIRCA vs 15% placebo). Other common adverse events (reported by ≥9% of patients on ADCIRCA and more frequent than placebo by 2%) include myalgia (14% vs 4%), nasopharyngitis (13% vs 7%), flushing (13% vs 2%), respiratory tract infection (13% vs 6%), extremity pain (11% vs 2%), nausea (11% vs 6%), back pain (10% vs 6%), dyspepsia (10% vs 2%), and nasal congestion (9% vs 1%)

ADC.ISI.HCP.SEP2020

For more information about ADCIRCA, please see the Full Prescribing Information and
Patient Information or call 1-800-545-5979.

TYVASO^® (treprostinil) Inhalation Solution and TYVASO DPI™ (treprostinil) Inhalation Powder

INDICATION

TYVASO (treprostinil) Inhalation Solution and TYVASO DPI (treprostinil) Inhalation Powder are prostacyclin mimetics indicated for the treatment of:

• Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with TYVASO 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 clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with TYVASO was limited to 12 weeks in duration.
• Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with TYVASO 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%).

IMPORTANT SAFETY INFORMATION FOR TYVASO AND TYVASO DPI

WARNINGS AND PRECAUTIONS

• TYVASO and TYVASO DPI are pulmonary and systemic vasodilators. In patients with low systemic arterial pressure, either product may produce symptomatic hypotension.
• Both products inhibit platelet aggregation and increase the risk of bleeding.
• Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both C_max 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.
• Like other inhaled prostaglandins, TYVASO and TYVASO DPI 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 and TYVASO DPI.

DRUG INTERACTIONS/SPECIFIC POPULATIONS

• The concomitant use of either product with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension.
• 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 C_max 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.
• Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.
• Safety and effectiveness in pediatric patients have not been established.
• Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to 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.

ADVERSE REACTIONS

• Pulmonary Arterial Hypertension (WHO Group 1)
  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 common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea.
  
  In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of TYVASO who switched to a corresponding dose of TYVASO DPI, the most commonly reported adverse events seen with TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase included cough (35.3%), headache (15.7%), dyspnea (7.8%), and nausea (5.9%).
• Pulmonary Hypertension Associated with ILD (WHO Group 3)
  In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO were similar to the experience in studies of PAH.

Please see Full Prescribing Information for TYVASO or TYVASO DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO^® Inhalation System and TYVASO DPI™ Inhalation Powder, and additional information at www.TYVASOhcp.com or call 1-877-UNITHER (1-877-864-8437).

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