Dosing and uses of Tyvaso, Remodulin, Orenitram (treprostinil)
Adult dosage forms and strengths
injectable solution (Remodulin)
- 1mg/mL
- 2.5mg/mL
- 5mg/mL
- 10mg/mL
inhalation solution (Tyvaso)
- 600mcg/mL
tablet, extended-release (Orenitram)
- 0.125mg
- 0.25mg
- 1mg
- 2.5mg
Pulmonary Arterial Hypertension
Injectable
- Initial: 1.25 ng/kg/min continuous SC/IV infusion (0.625 ng/kg/min if not tolerated)
- Titrate by no more than 1.25 ng/kg/min qWeek x first 4 weeks, then no more than 2.5 ng/kg/min qWeek
- Little experience with doses >40 ng/kg/min
- Must carefully titrated dose
- Avoid abrupt withdrawal
- If infusion is stopped and then restarted within a few hours after discontinuing it, may use the same rate; interruptions for long periods may require retitration
Oral inhalation
- Initial: 18 mcg (3 breaths), per treatment session, QID; if 3 breaths not tolerated, decrease to 1-2 breaths and later increase to 3 breaths as tolerated
- If tolerated, increase by 3 breaths/dose (18 mcg) q1-2Weeks
- Target maintenance: 54 mcg (9 breaths), per treatment session QID
Oral tablet
- Initial: 0.25 mg PO BID with food, taken ~12 hr apart
- Increase dose as tolerated to achieve optimal clinical response by increments or 0.25-0.5 mg BID q3-4 days; if 0.25 mg BID dose increments are not tolerated consider titrating slower
- Total daily dose can be divided and given TID with food (~8 hr apart), titrating by increments of 0.125 mg TID
- Maximum dose: Determined by tolerability; mean dose in a controlled clinical trial at 12 weeks was 3.4 mg BID; maximum doses studied were 12 mg BID in the 12-week blinded study and up to 21 mg BID in an open-label long-term study
- If intolerable adverse effects occur, decrease dose by 0.25 mg increments
- Transition from SC/IV to oral
- Decrease the dose of the SC or IV treprostinil while simultaneously increasing the oral dose
- The SC/IV dose can be reduced up to 30 ng/kg/min per day and the oral dose simultaneously increased up to 6 mg/day (2 mg TID) if tolerated
- The following equation can be used to estimate a comparable total daily dose of oral treprostinil in mg using a patient’s dose of SC/IV treprostinil (in ng/kg/min) and weight (in kg)
- Oral total daily dose (mg) = 0.0072 x SC/IV dose (ng/kg/min) x weight (kg)
Dosage modifications
Coadministration with strong CYP2C8 inhibitors: Initiate at 0.125 mg PO BID; may increase by 0.125 mg BID dose increments every 3-4 days
Renal impairment
- Titrate slowly with moderate renal insufficiency
- Monitor for greater systemic concentrations relative to that of normal renal function
Hepatic impairment
- Injectable
- Mild-to-moderate (Child-Pugh A or B): Initiate SC dose at 0.625 ng/kg/min (ideal body weight)
- Severe (Child Pugh C): Not studied
- Oral inhalation
- Mild-to-moderate (Child-Pugh A or B): Titrate dose slowly
- Severe (Child Pugh C): Not studied
- Extended-release tablets
- Mild (Child-Pugh Class A): Initiate at 0.125 mg PO BID; may increase by 0.125 mg BID dose increments every 3-4 days
- Moderate (Child-Pugh Class B): Avoid use
- Severe (Child-Pugh Class C): Contraindicated
Pediatric dosage forms and strengths
injectable solution (Remodulin)
- 1mg/mL
- 2.5mg/mL
- 5mg/mL
- 10mg/mL
inhalation solution (Tyvaso)
- 600mcg/mL
tablet, extended-release (Orenitram)
- 0.125mg
- 0.25mg
- 1mg
- 2.5mg
Pulmonary Arterial Hypertension
<16 years (injectable): Safety and efficacy not established
<18 years (oral inhalation, oral tablet): Safety and efficacy not established
Injectable (≥16 years)
- Initial: 1.25 ng/kg/min continuous SC/IV infusion (0.625 ng/kg/min if not tolerated)
- Titrate by no more than 1.25 ng/kg/min qWeek x first 4 weeks, then no more than 2.5 ng/kg/min qWeek
- Little experience with doses >40 ng/kg/min
- Must carefully titrated dose
- Avoid abrupt withdrawalIf infusion is stopped and then restarted within a few hours after discontinuing it, may use the same rate; interruptions for long periods may require retitration
Oral inhalation (≥18 years)
- Initial: 18 mcg (3 breaths), per treatment session, QID; if 3 breaths not tolerated, decrease to 1-2 breaths and later increase to 3 breaths as tolerated
- If tolerated, increase by 3 breaths/dose (18 mcg) q1-2Weeks
- Target maintenance: 54 mcg (9 breaths), per treatment session QID
Oral tablet (≥18 years)
- Initial: 0.25 mg PO BID with food, taken ~12 hr apart
- Increase dose as tolerated to achieve optimal clinical response by increments or 0.25-0.5 mg BID q3-4 days; if 0.25 mg BID dose increments are not tolerated consider titrating slower
- Total daily dose can be divided and given TID with food (~8 hr apart), titrating by increments of 0.125 mg TID
- Maximum dose: Determined by tolerability; mean dose in a controlled clinical trial at 12 weeks was 3.4 mg BID; maximum doses studied were 12 mg BID in the 12-week blinded study and up to 21 mg BID in an open-label long-term study
- If intolerable adverse effects occur, decrease dose by 0.25 mg increments
- Transition from SC/IV to oral
- Decrease the dose of the SC or IV treprostinil while simultaneously increasing the oral dose
- The SC/IV dose can be reduced up to 30 ng/kg/min per day and the oral dose simultaneously increased up to 6 mg/day (2 mg TID) if tolerated
- The following equation can be used to estimate a comparable total daily dose of oral treprostinil in mg using a patient’s dose of SC/IV treprostinil (in ng/kg/min) and weight (in kg)
- Oral total daily dose (mg) = 0.0072 x SC/IV dose (ng/kg/min) x weight (kg)
Dosage modifications
Coadministration with strong CYP2C8 inhibitors: Initiate at 0.125 mg PO BID; may increase by 0.125 mg BID dose increments every 3-4 days
Renal impairment
- Titrate slowly with moderate renal insufficiency
- Monitor for greater systemic concentrations relative to that of normal renal function
Hepatic impairment
- Injectable
- Mild-to-moderate (Child-Pugh A or B): Initiate SC dose at 0.625 ng/kg/min (ideal body weight)
- Severe (Child Pugh C): Not studied
- Oral inhalation
- Mild-to-moderate (Child-Pugh A or B): Titrate dose slowly
- Severe (Child Pugh C): Not studied
- Extended-release tablets
- Mild (Child-Pugh Class A): Initiate at 0.125 mg PO BID; may increase by 0.125 mg BID dose increments every 3-4 days
- Moderate (Child-Pugh Class B): Avoid use
- Severe (Child-Pugh Class C): Contraindicated
Tyvaso, Remodulin, Orenitram (treprostinil) adverse (side) effects
>10%
Infusion site reaction, pain (80-85%)
Headache (27-41%)
Nausea (19-22%)
Diarrhea (20-30%)
Vasodilation (10-20%)
Jaw pain (13%)
Rash (10-20%)
1-10%
Dizziness 9%)
Edema (9%)
Pruritis (8%)
Hypotension (4%)
inhalation solution
- Flushing
- Headache
- Nausea
- Throat Irritation
- Cough
Frequency not defined
Angioedema
Bone pain
Restlessness
Cellulitis
Haemoptysis
Inhalation solution
- Flushing
- Headache
- Nausea
- Throat irritation
- Nasal discomfort
Warnings
Contraindications
Extended-release tablets: Severe hepatic impairment (Child Pugh Class C)
Cautions
Hepatic/renal impairment (titrate up slowly), concomitant anticoagulants (increased bleeding risk), lung infections, asthma/COPd
Dosage adjustment may be necessary if CYP2C8 inhibitors (eg, atazanavir, gemfibrozil, ritonavir) or inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin ) are added or withdrawn
Use caution in patients with low areterial blood pressure (may produce symptomatic hypotension)
Do not take oral tablets with alcohol; faster release of treprostinil from the tablet may occur
The tablet shell does not dissolve and can lodge in a diverticulum in patients with diverticulosis
Use a lower dose for the initial dose in patients with mild-to-moderate hepatic insufficiency and titrate dose slowly
Not studied in renal impairment; use caution; titrate dose slowly
Abrupt withdrawal may worsen pulmonary arterial hypertension symptoms
Inhalation therapy not studied in patients with other types of pulmonary diseases (eg, COPD, asthma); monitor closely patients with pulmonary infections
Inhibits platelet aggregation and increases risk of bleeding; use caution in patients receiving concurrent anticoagulant/antiplatelet therapy
Indwelling central venous catherer associated with serious blood stream infections; use this method only in patients intolerant to the SC therapy
Experienced personnel required to administer therapy
Pregnancy and lactation
Pregnancy category: B
Lactation: Unknown if excreated in breast milk; use caution
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Tyvaso, Remodulin, Orenitram (treprostinil)
Mechanism of action
Peripheral prostacyclin vasodilator of both pulmonary and systemic arterial vascular bed; decreases ventricular afterload; also inhibits platelet aggregation
Absorption
Bioavailability: ~100% (SC); 64-72% (inhalation)
Peak plasma time: 10 hr
Peak plasma concentration: 2 mcg/L
Distribution
Protein bound: 91%
Vd: 14 L/70 kg (ideal body weight)
Metabolism
Metatoblized by liver
Metabolites: HU1-HU5
Elimination
Half-life: 2-4 hr
Total body clearance: 30 L/hr
Excretion: Urine (79% ); feces (13%)
Administration
SC/IV Administration
Administration by continuous SC infusion (undiluted) is preferred
May administer by IV infusion (dilution required) if SC infusion not tolerated
IV administration following dilution with a high pH glycine diluent (eg, sterile diluent for Flolan or sterile diluent for epoprostenol sodium) has been associated with a lower incidence of catheter-related infections compared to neutral diluents (sterile water, 0.9% sodium chloride) when used along with catheter care guidelines
Avoid abrupt discontinuation
Oral Administration Extended-release tablets
Administer with food
Swallow tablets whole; do not chew, crush, or split
Avoid abrupt discontinuation; when discontinuing, reduce dose by 0.5-1 mg/day increments
Missed doses
- If 1 dose is missed, take the missed dose as soon as possible, with food
- If ≥2 doses are missed, restart at a lower dose and retitrate
- In the event of a planned short-term treatment interruption for patients unable to take oral medications, consider a temporary infusion of SC or IV treprostinil
- Calculate the total daily dose (mg) of treprostinil for the parenteral route using the following equation
- SC/IV dose (ng/kg/min) = 139 x oral daily dose (mg) ÷ weight (kg)
