Orenitram Er (treprostinil diolamine)

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Treprostinil is administered parenterally (by continuous subcutaneous or IV infusion) using a controlled-infusion device. Treprostinil also is available as an inhalation solution that is administered by oral inhalation using the Tyvaso(R) Inhalation System or as a dry powder formulation for oral inhalation using the Tyvaso DPI(R) inhaler.

Treprostinil diolamine is administered orally as extended-release tablets (Orenitram(R)).

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There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

Treprostinil/Strong Cyp2c8 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of treprostinil.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C8 inhibitor may increase levels and effects of treprostinil, including severe headache, nausea, diarrhea, and hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When initiating oral treprostinil in patient maintained on a strong CYP2C8 inhibitor, the initial dose should be 0.125 mg twice daily, with dosage increases limited to 0.125 mg twice daily every 3 to 4 days.(1) When initiating a strong CYP2C8 inhibitor in patients maintained on oral treprostinil, consider halving the dose of oral treprostinil.(1) Since it is unknown how strong CYP2C8 inhibitors will affect treprostinil administered intravenously or via inhalation, it would be prudent to initiate and titrate treprostinil doses cautiously in patients maintained on CYP2C8 inhibitors and monitor patients maintained on treprostinil in whom CYP2C8 inhibitors are discontinued.

DISCUSSION: Concurrent use of a strong CYP2C8 inhibitor (gemfibrozil, 600 mg twice daily for 4 days) doubled the maximum concentration (Cmax) and area-under-curve (AUC) of treprostinil (1 mg).(1) The extent to which intravenous(2) and inhaled treprostinil(3) would be affected by a CYP2C8 inhibitor is unknown. Strong inhibitors of CYP2C8 includes gemfibrozil.(4,5)

*The manufacturer states that there are no known contraindications to the use of parenteral or orally inhaled treprostinil.

*Oral treprostinil is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment

• Child-pugh class A hepatic impairment
• Disease of liver
• Diverticular disease

There are no moderate contraindications for this drug.

Infusion site pain and reactions (excluding bleeding/bruising but including reactions such as erythema, induration, and rash) are the most common adverse effects reported in patients receiving subcutaneous infusions of treprostinil; in some cases, these reactions may be severe or require discontinuance of the drug. Adverse effects attributed specifically to the IV route of administration of treprostinil include arm swelling, paresthesias, hematoma, and pain. Headache, diarrhea, nausea, rash, jaw pain, and vasodilation are other common adverse effects frequently reported in clinical trials of patients receiving either subcutaneous or IV treprostinil.

Common adverse effects associated with orally inhaled treprostinil solution include cough, throat irritation, headache, GI effects, muscle pain, jaw pain, bone pain, flushing, and syncope.

Common adverse effects associated with orally inhaled treprostinil powder include cough, headache, shortness of breath, and nausea.

Common adverse effects associated with oral treprostinil include headache, diarrhea, nausea, flushing, jaw pain, extremity pain, hypokalemia, and abdominal discomfort.

Less Frequent

• Hypokalemia

More Frequent

• Diarrhea
• Headache disorder
• Nausea

Less Frequent

• Acute abdominal pain
• Flushing
• Jaw pain
• Pain

Rare or Very Rare

• Arthralgia
• Dizziness
• Dyspepsia
• Myalgia
• Vomiting

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Safety and efficacy of parenteral treprostinil have not been established in children <=16 years of age. Clinical studies of parenteral treprostinil did not include sufficient numbers of patients 16 years of age and younger to determine whether pediatric patients respond differently than adults. In general, dosage should be titrated carefully in pediatric patients.

Safety and efficacy of oral or orally inhaled treprostinil have not been established in pediatric patients younger than 18 years of age.

There are limited case reports of the use of treprostinil in pregnant women and this is insufficient to evaluate the risk associated with adverse developmental outcomes. Consideration also must be given to the risks to the mother and the fetus associated with PAH. In studies in rats, no adverse reproductive and developmental effects were seen at dosages about 123 and 48 times the human exposure. In rabbits, external fetal and soft tissue malformations and skeletal malformations were observed at dosages about 7 and 5 times the human exposure.

It is not known whether treprostinil is distributed into milk, the effects on the breastfed infant, or the effects on milk production.

Dosage of treprostinil should be selected with caution in geriatric patients because of the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy observed in such patients.

Clinical studies of parenteral treprostinil did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger patients.

In clinical studies of orally inhaled treprostinil solution in patients with PAH and PH-ILD, 47.8% of the patients were >=65 years of age. The treatment effects and safety profile observed in geriatric patients were similar to younger patients.

Clinical studies of oral treprostinil in patients >=65 years of age demonstrated slightly higher absolute and relative adverse event rates compared to younger patients.

In general, dosage should be selected carefully in geriatric patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered.