Orenitram

ORENITRAM- treprostinil tablet, extended release
United Therapeutics Corporation

1 INDICATIONS AND USAGE

1.1 Pulmonary Arterial Hypertension

Orenitram is indicated for the 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%).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

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

The recommended starting dose of Orenitram is 0.125 mg three times daily (TID) with food, taken approximately 8 hours apart or 0.25 mg twice daily (BID) with food, taken approximately 12 hours apart.

Titrate by 0.125 mg TID or 0.25 or 0.5 mg BID not more frequently than every 3 to 4 days. Increase the dose to the highest tolerated dose.

If dose increments are not tolerated, consider titrating slower. If intolerable pharmacologic effects occur, decrease the dose in increments of 0.125 mg TID or 0.25 mg BID. Avoid abrupt discontinuation [see Warnings and Precautions (5.1)].

2.2 Transitioning from Subcutaneous or Intravenous Routes of Administration of Treprostinil

Decrease the dose of Remodulin while simultaneously increasing the dose of Orenitram. The dose of Remodulin can be reduced up to 30 ng/kg/min per day and the dose of Orenitram simultaneously increased up to 6 mg per day (2 mg TID) if tolerated. The following equation can be used to estimate a target total daily dose of Orenitram in mg using a patient’s dose of intravenous (IV)/subcutaneous (SC) treprostinil (in ng/kg/min) and weight (in kg).

Orenitram total daily dose (mg) = 0.0072 × Remodulin dose (ng/kg/min) × weight (kg)

2.3 Dose Adjustment in Patients with Hepatic Impairment

In patients with mild hepatic impairment (Child Pugh Class A) start at 0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days. Avoid use of Orenitram in patients with moderate hepatic impairment (Child Pugh Class B). Orenitram is contraindicated in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure [see Contraindications (4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.4 Dose Adjustment for Use 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 not more frequently than every 3 to 4 days.

2.5 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 use the following equation:

Remodulin (ng/kg/min) = 139 × Orenitram total daily dose (mg)
weight (kg)

When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS AND STRENGTHS

Orenitram (treprostinil) extended-release tablets are available in the following five strengths:

0.125 mg [White tablet imprinted with UT 0.125]
0.25 mg [Green tablet imprinted with UT 0.25]
1 mg [Yellow tablet imprinted with UT 1]
2.5 mg [Pink tablet imprinted with UT 2.5]
5 mg [Red tablet imprinted with UT 5]

4 CONTRAINDICATIONS

Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5 WARNINGS AND PRECAUTIONS

5.1 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 Use in Patients with Blind-end Pouches

The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

6 ADVERSE REACTIONS

6.1 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), and an event-driven, placebo-controlled, combination therapy study (Study 4; WHO Group 1; functional class I-III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, diarrhea, nausea, and flushing.

Orenitram patients in Study 1 (N=151) had access to 0.25 mg tablets at randomization. Approximately 91% of such patients in Study 1 experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). Study 4 enrolled a total of 690 patients, 346 received Orenitram and 344 received placebo. Overall, 19% of patients treated with Orenitram discontinued treatment in Study 4 due to an adverse event (compared to 4% of patients receiving placebo). The exposure to Orenitram in Study 4 was up to 5.1 years with a median duration of exposure of 1.2 years. Table 1 summarizes adverse events with rates at least 5% higher on Orenitram therapy than on placebo that were reported in either Study 1 or 4.

Table 1: Adverse Events with Rates at Least 5% Higher on Orenitram Therapy than on Placebo in Either Study 1 or Study 4
Reaction Study 1N=228* Study 4N=690
Orenitramn=151 Placebon=77 Orenitramn=346 Placebon=344
*
Includes all subjects in the Primary Analysis Population
Headache 63% 19% 75% 35%
Diarrhea 30% 16% 69% 29%
Nausea 30% 18% 40% 23%
Vomiting 17% 16% 36% 10%
Flushing 15% 6% 45% 8%
Pain in jaw 11% 4% 18% 3%
Pain in extremity 14% 8% 18% 9%
Hypokalemia 9% 3% 4% 3%
Abdominal discomfort 6% 0% 8% 4%
Upper abdominal pain 5% 3% 12% 5%

Orenitram was studied in a long-term, open-label, extension study in which 824 patients were dosed for a mean duration of approximately 2 years. About 70% of patients continued treatment with Orenitram for at least a year. The mean dose was 4.2 mg BID at one year. The adverse reactions were similar to those observed in the placebo-controlled trials.

The safety of Orenitram was also evaluated in an open-label study transitioning patients from Remodulin. The safety profile during this study was similar to that observed in the three pivotal studies.

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