United Therapeutics Corp.

United Therapeutics Corp. Drugs

• Unituxin
  

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  Unituxin

  

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  Verify that patients have adequate hematologic, respiratory, hepatic, and renal function prior to initiating each course of Unituxin [see Clinical Studies (14)]. Administer required premedication and hydration prior to initiation of each Unituxin infusion [see Dosage and Administration (2.2)].

  2.1 Recommended Dose

  The recommended dose of Unituxin is 17.5 mg/m2/day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles (Tables 1 and 2 ) [see Dosage and Administration (2.4), Clinical Studies (14)]. Initiate at an infusion rate of 0.875 mg/m2/hour for 30 minutes. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75 mg/m2/hour. Follow dose modification instructions for adverse reactions [see Dosage and Administration (2.3)]. Table 1: Schedule of Unituxin Administration for Cycles 1, 3, and 5 Cycle Day 1 through 3 4 5 6 7 8 through 24* * Cycles 1, 3, and 5 are 24 days in duration. Unituxin X X X X Table 2: Schedule of Unituxin Administration for Cycles 2 and 4 Cycle Day 1 through 7 8 9 10 11 12 through 32* * Cycles 2 and 4 are 32 days in duration. Unituxin X X X X

  2.2 Required Pre-treatment and Guidelines for Pain Management

  Intravenous Hydration

  Administer 0.9% Sodium Chloride Injection, USP 10 mL/kg as an intravenous infusion over one hour just prior to initiating each Unituxin infusion.

  Analgesics

  Administer morphine sulfate (50 mcg/kg) intravenously immediately prior to initiation of Unituxin and then continue as a morphine sulfate drip at an infusion rate of 20 to 50 mcg/kg/hour during and for two hours following completion of Unituxin. Administer additional 25 mcg/kg to 50 mcg/kg intravenous doses of morphine sulfate as needed for pain up to once every 2 hours followed by an increase in the morphine sulfate infusion rate in clinically stable patients. Consider using fentanyl or hydromorphone if morphine sulfate is not tolerated. If pain is inadequately managed with opioids, consider use of gabapentin or lidocaine in conjunction with intravenous morphine.

  Antihistamines and Antipyretics

  Administer an antihistamine such as diphenhydramine (0.5 to 1 mg/kg; maximum dose 50 mg) intravenously over 10 to 15 minutes starting 20 minutes prior to initiation of Unituxin and as tolerated every 4 to 6 hours during the Unituxin infusion. Administer acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to each Unituxin infusion and every 4 to 6 hours as needed for fever or pain. Administer ibuprofen (5 to 10 mg/kg) every 6 hours as needed for control of persistent fever or pain.

  2.3 Dosage Modifications

  Manage adverse reactions by infusion interruption, infusion rate reduction, dose reduction, or permanent discontinuation of Unituxin (Table 3 and Table 4) [see Warnings and Precautions (5), Adverse Reactions (6), Clinical Studies (14)].

  Table 3: Adverse Reactions Requiring Permanent Discontinuation of Unituxin Grade 3 or 4 anaphylaxis Grade 3 or 4 serum sickness Grade 3 pain unresponsive to maximum supportive measures Grade 4 sensory neuropathy or Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks Grade 2 peripheral motor neuropathy Subtotal or total vision loss Grade 4 hyponatremia despite appropriate fluid management Table 4: Dose Modification for Selected Unituxin Adverse Reactions * Symptomatic hypotension, systolic blood pressure (SBP) less than lower limit of normal for age, or SBP decreased by more than 15% compared to baseline. Infusion-related reactions [see Warnings and Precautions (5.1)] Mild to moderate adverse reactions such as transient rash, fever, rigors, and localized urticaria that respond promptly to symptomatic treatment Onset of reaction: Reduce Unituxin infusion rate to 50% of the previous rate and monitor closely. After resolution: Gradually increase infusion rate up to a maximum rate of 1.75 mg/m2/hour. Prolonged or severe adverse reactions such as mild bronchospasm without other symptoms, angioedema that does not affect the airway Onset of reaction: Immediately interrupt Unituxin. After resolution: If signs and symptoms resolve rapidly, resume Unituxin at 50% of the previous rate and observe closely. First recurrence: Discontinue Unituxin until the following day. If symptoms resolve and continued treatment is warranted, premedicate with hydrocortisone 1 mg/kg (maximum dose 50 mg) intravenously and administer Unituxin at a rate of 0.875 mg/m2/hour in an intensive care unit. Second recurrence: Permanently discontinue Unituxin. Capillary leak syndrome [see Warnings and Precautions (5.3)] Moderate to severe but not life-threatening capillary leak syndrome Onset of reaction: Immediately interrupt Unituxin. After resolution: Resume Unituxin infusion at 50% of the previous rate. Life-threatening capillary leak syndrome Onset of reaction: Discontinue Unituxin for the current cycle. After resolution: In subsequent cycles, administer Unituxin at 50% of the previous rate. First recurrence: Permanently discontinue Unituxin. Hypotension* requiring medical intervention [see Warnings and Precautions (5.4)] Onset of reaction: Interrupt Unituxin infusion. After resolution: Resume Unituxin infusion at 50% of the previous rate. If blood pressure remains stable for at least 2 hours, increase the infusion rate as tolerated up to a maximum rate of 1.75 mg/m2/hour. Severe systemic infection or sepsis [see Warnings and Precautions (5.5)] Onset of reaction: Discontinue Unituxin until resolution of infection, and then proceed with subsequent cycles of therapy. Neurological Disorders of the Eye [see Warnings and Precautions (5.6)] Onset of reaction: Discontinue Unituxin infusion until resolution. After resolution: Reduce the Unituxin dose by 50%. First recurrence or if accompanied by visual impairment: Permanently discontinue Unituxin.

  2.4 Instructions for Preparation and Administration

  Preparation

  Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the outer carton. DO NOT FREEZE OR SHAKE vials. Inspect visually for particulate matter and discoloration prior to administration. Do not administer Unituxin and discard the single-use vial if the solution is cloudy, has pronounced discoloration, or contains particulate matter. Aseptically withdraw the required volume of Unituxin from the single-use vial and inject into a 100 mL bag of 0.9% Sodium Chloride Injection, USP. Mix by gentle inversion. Do not shake. Discard unused contents of the vial. Store the diluted Unituxin solution under refrigeration (2°C to 8° C). Initiate infusion within 4 hours of preparation. Discard diluted Unituxin solution 24 hours after preparation.

  Administration

  Administer Unituxin as a diluted intravenous infusion only [see Dosage and Administration (2.1)]. Do not administer Unituxin as an intravenous push or bolus.

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• Orenitram
  

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  Orenitram

  

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  2.1 Recommended Dosing

  Orenitram is supplied as extended release tablets. Individualize dosing of Orenitram according to clinical response.

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

  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)].

  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 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) [see Contraindications (4), Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

  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.

  Take Orenitram with food. Swallow Orenitram intact; use only intact tablets.

  2.2 Interruptions and Discontinuation

  If a dose of medication is missed, 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)].

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• Tyvaso
  

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  Tyvaso

  

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  2.1 Usual Dosage in Adults

  Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of an ultrasonic, pulsed delivery device and its accessories.

  Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. The treatment sessions should be approximately 4 hours apart.

  Initial Dosage:

  Therapy should begin with 3 breaths of Tyvaso (18 mcg of treprostinil), per treatment session, 4 times daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated.

  Maintenance Dosage:

  Dosage should be increased by an additional 3 breaths at approximately 1-2 week intervals, if tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached per treatment session, 4 times daily. If adverse effects preclude titration to target dose, Tyvaso should be continued at the highest tolerated dose.

  If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible at the usual dose.

  The maximum recommended dosage is 9 breaths per treatment session, 4 times daily.

  2.2 Patients with Hepatic Insufficiency

  Plasma clearance of treprostinil is reduced in patients with hepatic insufficiency. Patients with hepatic insufficiency may therefore be at increased risk of dose-dependent adverse reactions because of an increase in systemic exposure [see Warnings and Precautions (5.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

  2.3 Patients with Renal Insufficiency

  Plasma clearance of treprostinil may be reduced in patients with renal insufficiency, since treprostinil and its metabolites are excreted mainly through the urinary route. Patients with renal insufficiency may therefore be at increased risk of dose-dependent adverse reactions [see Warnings and Precautions (5.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  2.4 Administration

  Tyvaso must be used only with the Tyvaso Inhalation System. Patients should follow the instructions for use for operation of the Tyvaso Inhalation System and for daily cleaning of the device components after the last treatment session of the day. To avoid potential interruptions in drug delivery because of equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device.

  Do not mix Tyvaso with other medications in the Tyvaso Inhalation System. Compatibility of Tyvaso with other medications has not been studied.

  The Tyvaso Inhalation System should be prepared for use each day according to the instructions for use. One ampule of Tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a single day. Prior to the first treatment session, the patient should twist the top off a single Tyvaso ampule and squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions, the device should be capped and stored upright with the remaining medication inside.

  At the end of each day, the medicine cup and any remaining medication must be discarded. The device must be cleaned each day according to the instructions for use.

  Avoid skin or eye contact with Tyvaso solution. Do not orally ingest the Tyvaso solution.

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