Treprostinil (extended-release tablet)

Treprostinil (extended-release tablet)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

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Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

1.1 Pulmonary Arterial Hypertension Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. The study that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (75%) or PAH associated with connective tissue disease (19%).

When used as the sole vasodilator, the effect of Orenitram on exercise is about 10% of the deficit, and the effect, if any, on a background of another vasodilator is probably less than this. Orenitram is probably most useful to replace subcutaneous, intravenous, or inhaled treprostinil, but this use has not been studied.

Dosage

Recommended Dosing Individualize dosing of Orenitram according to clinical response.

Take Orenitram with food. Swallow Orenitram tablets whole; do not crush, split, or chew.

The recommended starting dose of Orenitram is 0.25 mg twice daily (BID) with food, taken approximately 12 hours apart or 0.125 mg three times daily (TID) with food, taken approximately 8 hours apart. Increase the dose as tolerated to achieve optimal clinical response. The recommended increment is 0.25 or 0.5 mg BID or 0.125 mg TID every 3-4 days. If dose increments are not tolerated consider titrating slower.

The maximum dose is determined by tolerability. The 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 pharmacologic effects occur, decrease the dose in increments of 0.25 mg. Avoid abrupt discontinuation [see WARNINGS AND PRECAUTIONS (5.1)]. Concomitant Administration with CYP2C8 Inhibitors When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil) the initial dose is 0.125 mg BID with 0.125 mg BID dose increments every 3 to 4 days.

2.4 Interruptions and Discontinuation If a dose of medication is missed, the patient should take the missed dose as soon as possible, with food. If a patient misses two or more doses, restart at a lower dose and re-titrate.

In the event of a planned short-term treatment interruption for patients unable to take oral medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To calculate the total daily dose (mg) of treprostinil for the parenteral route divide the oral total daily dose by 5.

When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see WARNINGS AND PRECAUTIONS (5.1)].

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Treprostinil (extended-release tablet) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Treprostinil (extended-release tablet) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Treprostinil (extended-release tablet) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Treprostinil (extended-release tablet) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Treprostinil (extended-release tablet) in pediatric patients.

Contraindications

Severe hepatic impairment (Child Pugh Class C) [see USE IN SPECIFIC POPULATIONS (8.6) and CLINICAL PHARMACOLOGY (12.3)].

Warnings

Worsening PAH Symptoms upon Abrupt Withdrawal Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.

5.2 Risk of Bleeding Orenitram inhibits platelet aggregation and increases the risk of bleeding.

5.3 Increased Exposure with Alcohol Do not take Orenitram with alcohol as release of treprostinil from the tablet may occur at a faster rate than intended.

5.4 Use in Patients with Blind-end Pouches The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

Adverse Reactions

Clinical Trials Experience

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 clinical practice.

In a 12-week placebo-controlled monotherapy study (Study 1; WHO Group 1; functional class II-III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, nausea, and diarrhea. Table 1 lists the adverse reactions that occurred at a rate on Orenitram at least 5% higher than on placebo.

Orenitram patients in Table 1 for Study 1 (N = 151) had access to 0.25 mg tablets at randomization. Approximately 91% of such patients experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). The overall discontinuation rate for any reason was 17% for active and 14% for placebo.

Postmarketing Experience

There is limited information regarding Treprostinil (extended-release tablet) Postmarketing Experience in the drug label.

Drug Interactions

Antihypertensive Agents or Other Vasodilators Concomitant administration of Orenitram with diuretics, antihypertensive agents or other vasodilators increases the risk of symptomatic hypotension.

7.2 Anticoagulants Treprostinil inhibits platelet aggregation; there is increased risk of bleeding, particularly among patients receiving anticoagulants.

7.3 Effect of CYP2C8 Inhibitors Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult volunteers increases exposure to treprostinil. Reduce the starting dose of Orenitram to 0.125 mg BID and use 0.125 mg BID increments every 3 to 4 days [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3)].

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Animal reproductive studies with treprostinil diolamine have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in humans.

In rats, treatment with treprostinil diolamine had no effect on reproductive performance or sperm motility at doses up to 10 mg/kg/day. The exposures at this dose level are about 10- (male) to 18- (female) fold the usual human exposure at the mean dose of 3.4 mg BID.

In pregnant rats, reversible, dose-dependent decreases in body weight gain and food consumption were observed during the first four days of dosing in animals administered 10, 20 and 30 mg/kg/day treprostinil diolamine. In a dose range-finding study, there was a 17% decrease in the pregnancy rate in the animals administered 20 and 30 mg/kg/day. One dam in each of the 20 and 30 mg/kg/day had litters with no viable fetuses. In the definitive study (0, 5, 10 and 20 mg/kg/day), there were four treatment-related deaths, and a 32% decrease in the pregnancy rate for rats administered 20 mg/kg/day. There was an 8% decrease in the pregnancy rate in the animals administered 10 mg/kg/day. Across both studies, an increase in post-implantation loss was observed in animals administered 10 to 30 mg/kg/day, and a significant decrease in the mean number of live births was seen at dose levels ≥10 mg/kg/day. The no observed adverse effect level was 5 mg/kg/day (maternal, fetal viability and growth), and 20 mg/kg/day (teratogenicity), the highest dose tested in the definitive study. The exposures at 5 and 20 mg/kg/day doses represent 13 and 55 times, respectively, the human exposure.

For F1 progeny, a decreased copulation index was observed at the 5 and 10 mg/kg/day treprostinil diolamine dose levels in rats. The no observed effect levels for physical development, reflex development, exploratory behavior, learning and memory, and sexual maturation was 10 mg/kg/day. The no observed effect level for F1 progeny general development (based on body weight) was 10 mg/kg/day for females and ≤ 2.5 mg/kg/day for males; the no observed effect level for F1 reproductive performance was 2.5 mg/kg/day or 6 times the human exposure.

In pregnant rabbits, the primary maternal adverse effects were gastrointestinal disturbance; dose-dependent decreases in mean body weight, body weight gain, and food consumption were observed. During the post-dose phase, the effect was reversed. In a dose range-finding study, there was a 17% decrease in the pregnancy rate for animals administered 4 mg/kg/day. A dose-dependent increase in post-implantation loss was observed. Two dams administered 4 mg/kg/day had litters with no viable fetuses; the mean fetal weight was slightly decreased in animals administered 4 mg/kg/day. In the definitive study, mean fetal weights were significantly decreased in animals administered 0.5 to 3 mg/kg/day of treprostinil diolamine. At doses of 1.5 and 3 mg/kg/day, external fetal and soft tissue malformations were observed in a few fetuses, and the total fetal skeletal malformations were significantly increased. The no observed adverse effect level was less than 0.5 mg/kg/day (maternal), 1.5 mg/kg/day (fetal viability and growth), and 0.5 mg/kg/day (teratogenicity). The 0.5 mg/kg/day dose represents about 5 times the human exposure.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Treprostinil (extended-release tablet) in women who are pregnant.

Labor and Delivery

The effect of Orenitram on labor and delivery in humans is unknown. No treprostinil treatment-related effects on labor and delivery were seen in animal studies.

Nursing Mothers

It is not known whether treprostinil is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, choose Orenitram or breastfeeding.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

Clinical studies of Orenitram 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 decreased hepatic or cardiac function, and of concomitant disease or other drug therapy.

Gender

There is no FDA guidance on the use of Treprostinil (extended-release tablet) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Treprostinil (extended-release tablet) with respect to specific racial populations.

Renal Impairment

No dose adjustments are required in patients with renal impairment. Orenitram is not removed by dialysis [see CLINICAL PHARMACOLOGY (12.3)].

Hepatic Impairment

There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients [see DOSAGE AND ADMINISTRATION (2.2), CONTRAINDICATIONS (4), and CLINICAL PHARMACOLOGY (12.3)].

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Treprostinil (extended-release tablet) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Treprostinil (extended-release tablet) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Treprostinil (extended-release tablet) Administration in the drug label.

Monitoring

There is limited information regarding Treprostinil (extended-release tablet) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Treprostinil (extended-release tablet) and IV administrations.

Overdosage

Signs and symptoms of overdose with Orenitram during clinical trials reflect its dose-limiting pharmacologic effects and include severe headache, nausea, vomiting, diarrhea, and hypotension. Treat supportively.

Pharmacology

There is limited information regarding Treprostinil (extended-release tablet) Pharmacology in the drug label.

Mechanism of Action

The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation, and inhibition of smooth muscle cell proliferation.

Structure

There is limited information regarding Treprostinil (extended-release tablet) Structure in the drug label.

Pharmacodynamics

In a clinical trial of 240 healthy adult volunteers, single doses of inhaled treprostinil 54 µg (the target clinical dose) and 84 µg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 msec. The QTc effect dissipated rapidly as the concentration of treprostinil decreased. Orenitram has not been evaluated in a thorough QTc study.

Pharmacokinetics

In patients with PAH, pharmacokinetics of treprostinil is dose-proportional for systemic exposure (AUC0-t) over the dose range of 0.5 and 15 mg BID. Upon repeat administration with a BID regimen, the accumulation in the systemic exposures to treprostinil is minimal and results in a peak-to-trough ratio of approximately 7. However, a TID regimen will reduce the peak-to-trough fluctuations to approximately 2.5 for the same total daily dose.

Absorption

The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil concentrations occur between approximately 4 and 6 hours following Orenitram administration.

The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by 49% and the Cmax was increased by an average of 13% when Orenitram was administered following a high-fat, high-calorie meal compared to fasting conditions in healthy volunteers. The relative bioavailability of treprostinil following oral administration of Orenitram 1 mg is not significantly altered by meal types ranging from 250 to 500 calories in healthy volunteers.

Distribution

The treprostinil component of Orenitram is highly bound to human plasma proteins, approximately 96% over a treprostinil concentration range of 0.01-10 µg/mL.

Metabolism and Excretion

In a study conducted in healthy volunteers using [14C] treprostinil, treprostinil was extensively metabolized on the side chain of the molecule via oxidation, oxidative cleavage, dehydration, and glucuronic acid conjugation. Treprostinil is primarily metabolized by CYP2C8 and to a lesser extent by CYP2C9. No new metabolites are found upon oral administration compared to parenteral administration of treprostinil. Only 1.13% and 0.19% is excreted as unchanged parent drug in the feces and urine, respectively. Based on in vitro studies treprostinil does not inhibit or induce major CYP enzymes [see DRUG INTERACTIONS (7.3)].

Special Populations

Hepatic Impairment: In subjects with mild (n=8) hepatic impairment, administration of a single 1 mg dose of Orenitram resulted in a mean Cmax and an AUC0-inf that were 1.6- and 2.1-fold, respectively values seen in healthy subjects. With moderate impairment (n=8), the corresponding ratios were 4.0- and 4.8-fold, and with severe impairment (n=6), they were 4.8- and 7.6-fold [see DOSAGE AND ADMINISTRATION (2.2), CONTRAINDICATIONS (4), and USE IN SPECIFIC POPULATIONS (8.6)].

Renal Impairment: In patients with severe renal impairment requiring dialysis (n=8), administration of a single 1 mg dose of Orenitram pre- and post-dialysis resulted in an AUC 0-inf that was not significantly altered compared to healthy subjects.

Drug Interactions

Results of drug interaction studies are shown in Figure 1. Only for the strong CYP2C8 inhibitor does the interaction affect dosing.

Figure 1: Impact of Co-Administered Drugs on the Systemic Exposure of Treprostinil 1 mg Compared to Orenitram Administered Alone

Nonclinical Toxicology

There is limited information regarding Treprostinil (extended-release tablet) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Treprostinil (extended-release tablet) Clinical Studies in the drug label.

How Supplied

There is limited information regarding Treprostinil (extended-release tablet) How Supplied in the drug label.

Storage

There is limited information regarding Treprostinil (extended-release tablet) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Treprostinil (extended-release tablet) Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Treprostinil (extended-release tablet) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Treprostinil (extended-release tablet) Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Treprostinil (extended-release tablet) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.