treprostinil (Rx)

Brand and Other Names:Remodulin, Orenitram
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution (Remodulin)

  • 1mg/mL
  • 2.5mg/mL
  • 5mg/mL
  • 10mg/mL

tablet, extended-release (Orenitram)

  • 0.125mg
  • 0.25mg
  • 1mg
  • 2.5mg

Pulmonary Arterial Hypertension

Injectable

  • Indicated for treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise
  • Patients who require transition from epoprostenol, to reduce the rate of clinical deterioration; carefully consider the risks and benefits of each drug prior to transition
  • Initial: 1.25 ng/kg/min continuous SC/IV infusion (0.625 ng/kg/min if not tolerated)  
  • Initial dose should be the same as the current dose the patient is receiving using the external infusion pump at the time of transition
  • 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

Extended-release tablets

  • Indicated for treatment of PAH (WHO Group 1) to delay disease progression and to improve exercise capacity
  • Initial: 0.125 mg PO TID or 0.25 mg PO BID
  • Titrate by 0.125 mg TID or 0.25 or 0.5 mg BID not more frequently than every 3-4 days
  • Increase dose to the highest tolerated dose
  • If dose increments are not tolerated, consider titrating slower
  • If intolerable pharmacologic effects occur, decrease dose in increments of 0.125 mg TID or 0.25 mg BID
  • Avoid abrupt discontinuation
  • 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%)

Transition from epoprostenol to treprostinil

  • Remodulin only
  • Initiate treprostinil infusion and begin increasing it, while simultaneously reducing the IV epoprostenol dose
  • Transition should take place in a hospital with constant observation of response (eg, walk distance and signs and symptoms of disease progression)
  • Individually titrate dose that allows transition from epoprostenol therapy to treprostinil while balancing prostacyclin-limiting adverse events
  • Treat increases in the patient’s symptoms of PAH first with increases in the dose of treprostinil
  • Treat side effects normally associated with prostacyclin and prostacyclin analogs first by decreasing the dose of epoprostenol.
  • Recommended transition dose changes
    • Step 1: Epoprostenol dose remains unchanged; treprostinil is 10% of epoprostenol dose
    • Step 2: Epoprostenol dose is 80% of starting epoprostenol dose; treprostinil is 30% of epoprostenol dose
    • Step 3: Epoprostenol dose is 60% of starting epoprostenol dose; treprostinil is 50% of epoprostenol dose
    • Step 4: Epoprostenol dose is 40% of starting epoprostenol dose; treprostinil is 70% of epoprostenol dose
    • Step 5: Epoprostenol dose is 20% of starting epoprostenol dose; treprostinil is 90% of epoprostenol dose
    • Step 6: Epoprostenol dose is 5% of starting epoprostenol dose; treprostinil is 110% of epoprostenol dose
    • Step 7: Epoprostenol dose is discontinued; treprostinil is 110% starting epoprostenol dose + additional 5-10% increments as needed

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

  • Injectable
    • No dose adjustment necessary
  • Extended-release tablets
    • No dosage adjustment necessary
    • Not removed by dialysis

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
  • 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

Dosing considerations

Transition from SC/IV to oral

  • Decrease SC/IV dose while simultaneously increasing the oral dose
  • May reduce SC/IV dose up to 30 ng/kg/min per day and simultaneously increase oral dose 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 Forms & Strengths

injectable solution (Remodulin)

  • 1mg/mL
  • 2.5mg/mL
  • 5mg/mL
  • 10mg/mL

Pulmonary Arterial Hypertension

<16 years (injectable): Safety and efficacy not established

<18 years (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

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
  • 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
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Interactions

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            Adverse 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%)

            Frequency Not Defined

            Angioedema

            Bone pain

            Restlessness

            Cellulitis

            Haemoptysis

            Postmarketing Reports

            Dyspepsia

            Vomiting

            Myalgia/muscle spasm

            Arthralgia

            Syncope

            Pain extremity

            Gastrointestinal effects

            Injectable

            • Thrombophlebitis associated with peripheral IV infusion, thrombocytopenia, bone pain, pruritus, dizziness, arthralgia, myalgia/muscle spasm, and pain in extremity
            • Generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported
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            Warnings

            Contraindications

            Extended-release tablets: Severe hepatic impairment (Child Pugh Class C)

            Injectable: None

            Cautions

            Hepatic/renal impairment (titrate up slowly), concomitant anticoagulants (increased bleeding risk), lung infections, asthma/COPD

            Use caution in patients with low arterial 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

            Abrupt withdrawal may worsen pulmonary arterial hypertension symptoms

            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

            Drug interactions overview

            • Dosage adjustment may be necessary if CYP2C8 inhibitors (eg, atazanavir, gemfibrozil, ritonavir) or inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin ) are added or withdrawn
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            Pregnancy & Lactation

            Pregnancy

            Limited case reports of treprostinil insufficient to inform a drug-associated risk of adverse developmental outcomes; however, there are risks to mother and fetus associated with pulmonary arterial hypertension associated with an increased risk of maternal and fetal mortality; in animal studies, no adverse reproductive and developmental effects observed

            Animal data

            • Animal reproductive studies have shown an adverse effect on fetus; in rats, administration to pregnant rats during period of organogenesis at doses greater than or equal to 10 mg/kg/day (approximately 15 times the human exposure at the dose of 3.5 mg BID on an AUC basis) resulted in decreased pregnancy rate, increased post-implantation loss, and decreased fetal viability and growth
            • In rabbits, teratogenicity and decreased fetal viability and growth were observed at doses greater than or equal to 1.5 mg/kg/day (approximately 7 times the human exposure at dose of 3.5 mg BID on an AUC basis)

            Lactation

            There are no data on presence of treprostinil in human milk, effects on breastfed infant, or on milk production

            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.

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            Pharmacology

            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 infusion)

            Peak plasma time: ~10 hr (SC infusion)

            Concentrations in patients treated with an average dose of 9.3 ng/kg/min SC were ~2000 ng/L

            Distribution

            Protein bound: 91%

            Vd: 14 L/70 kg (ideal body weight)

            Metabolism

            Metabolized by liver, primarily by CYP2C8

            Metabolites: HU1-HU5

            Elimination

            Half-life: ~4 hr

            Total body clearance: 30 L/hr (based on 70 kg person)

            Excretion: Urine (79%); feces (13%)

            Five metabolites were detected in the urine (10-16%) and representing 64% of the dose administered

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            Administration

            SC/IV Preparation

            Visually inspect for particulate matter and discoloration prior to administration

            Administer by SC or IV infusion only

            Refer to Remodulin prescribing information for dosing calculations

            SC/IV Administration

            SC infusion

            • Treprostinil is preferably infused SC, but can be administered by a central IV line if the SC route is not tolerated because of severe site pain or reaction
            • Administer SC by continuous infusion, via a SC catheter, using an infusion pump designed for SC drug delivery
            • Infusion pump should be adjustable to ~0.002 mL/hour, have occlusion/no delivery, low battery, programming error and motor malfunction alarms, have delivery accuracy of ±6% or better, be positive pressure-driven, and have a reservoir made of polyvinyl chloride, polypropylene or glass
            • Alternatively, use an infusion pump cleared for use with treprostinil
            • Avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and SC infusion sets

            External IV infusion pump

            • Administer IV by continuous infusion via a surgically placed indwelling central venous catheter using an external infusion pump designed for IV drug delivery
            • If clinically necessary, a temporary peripheral IV cannula, preferably placed in a large vein, may be used for short term administration
            • Use of a peripheral IV infusion for more than a few hours increases the risk of thrombophlebitis
            • Infusion pump should have occlusion/no delivery, low battery, programming error and motor malfunction alarms, have delivery accuracy of ±6% or better of the hourly dose, be positive pressure driven, and have a reservoir made of polyvinyl chloride, polypropylene or glass
            • Alternatively, use an infusion pump cleared for use with treprostinil
            • To avoid potential interruptions in drug delivery, patient must have immediate access to a backup infusion pump and infusion sets Use infusion sets with an in-line 0.22 or 0.2 micron pore size filter

            Implantable IV infusion pump

            • Use an implantable IV infusion pump approved for use with treprostinil (eg, Implantable System for Remodulin [ISR])
            • Refer to the pump manufacturer’s manual for specific instructions regarding preparation, programing, implantation, and refilling

            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 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

            Storage

            Tablets

            • Store at 25°C (77°F); excursions are permitted between 15-30°C (59-86°F)

            SC/IV

            • Unopened vials
              • Store at 25°C (77°F), with excursions permitted to 2-30°C (36-86°F)
              • A single vial should be used for ≤30 days after the initial introduction into the vial
            • Diluted solutions
              • Sterile diluents for Remodulin: Store at room temperature for up to 14 days and can be used within 48 hr at 40°C
              • Sterile water for injection or 0.9% NaCl: Store at room temperature for up to 4 hr or 24 hr refrigerated and can be used within 48 hr at 40°C
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.