Actelion Pharmaceuticals Us, Inc.

Actelion Pharmaceuticals Us, Inc. Drugs

• Veletri
  

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  Veletri

  

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  Important Note: Reconstitute VELETRI only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not dilute reconstituted solutions of VELETRI or administer it with other parenteral solutions or medications [see Warnings and Precautions (5.1)].

  2.1 Dosage

  Prepare continuous chronic infusion of VELETRI as directed, and administer through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of VELETRI at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until VELETRI is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, use a lower dose.

  In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

  2.2 Dosage Adjustments

  Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of VELETRI. In general, expect increases in dose from the initial chronic dose.

  Consider increments in dose if symptoms of pulmonary hypertension persist or recur. Adjust the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

  During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of VELETRI or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of VELETRI should be adjusted only under the direction of a physician.

  In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.

  2.3 Administration

  VELETRI, once prepared as directed [see Reconstitution (2.4)], is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, VELETRI may be administered peripherally.

  The ambulatory infusion pump used to administer VELETRI should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver VELETRI. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

  To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

  2.4 Reconstitution

  VELETRI is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not reconstitute or mix VELETRI with any other parenteral medications or solutions prior to or during administration. Each vial is for single use only; discard any unused solution.

  Use after storage of the reconstituted solution

  Prior to use, VELETRI solutions reconstituted with 5 mL diluent must be protected from light and can be refrigerated at 2° to 8°C (36° to 46°F) for as long as 5 days or held at up to 25°C (77°F) for up to 48 hours prior to use. Do not freeze reconstituted solutions of VELETRI. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 5 days, or if held at room temperature for more than 48 hours.

  Before administration, reconstituted solutions are further diluted to the final concentration.

  During use, a single reservoir of diluted solution of 15000 ng/mL or above of VELETRI prepared as directed can be administered at room temperature for up to 24 hours. (If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.) Do not expose this solution to direct sunlight.

  Use after reconstitution and immediate dilution to final concentration

  VELETRI solution reconstituted with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, and immediately diluted to the final concentration in the drug delivery reservoir can be administered per the conditions of use as outlined in Table 1.

  Table 1: Maximum duration of administration (hours) at room temperature (25°C/ 77°F) of fully diluted solutions in the drug delivery reservoir Final concentration range Immediate administration If stored at 2° to 8°C (36° to 46°F) for 1 day If stored at 2° to 8°C (36° to 46°F) for 7 days ≥3,000 ng/mL and <6,000 ng/mL 12 hours "Do not use" "Do not use" ≥ 6,000 ng/mL and < 9,000 ng/mL 24 hours 12 hours "Do not use" ≥ 9,000 ng/mL and < 12,000 ng/mL 24 hours 12 hours 12 hours ≥12,000 ng/mL and < 30,000 ng/mL 24 hours 24 hours 12 hours ≥30,000 ng/mL 72 hours 48 hours 24 hours

  Do not expose this solution to direct sunlight.

  A concentration for the solution of VELETRI should be selected that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. VELETRI, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 2 are directions for preparing different concentrations of VELETRI for up to a 72-hour period. Each vial is for single use only; discard any unused solution.

  Table 2: Reconstitution and Dilution Instructions To make 100 mL of solution with Final Concentration (ng/mL) of: Directions: * Higher concentrations may be prepared for patients who receive VELETRI long-term. 3,000 ng/ml Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, USP.Withdraw 1 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 6,000 ng/mL Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.Withdraw 2 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 9,000 ng/ml Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.Withdraw 3 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 12,000 ng/ml Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.Withdraw 4 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 15,000 ng/mL* Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 30,000 ng/mL* Dissolve contents of two 1.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.

  Infusion rates may be calculated using the following formula:

  Infusion Rate (mL/hr) = [Dose (ng/kg/min) × Weight (kg) × 60 min/hr] Final Concentration (ng/mL)

  Tables 3 to 8 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of VELETRI to be used. These tables may be used to select the most appropriate concentration of VELETRI that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. For infusion/dose rates lower than those listed in Tables 3 to 8, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half life of epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of VELETRI.

  Table 3: Infusion Rates for VELETRI at a Concentration of 3,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 2 3 4 5 Infusion Delivery Rate (mL/hr) 20 --- 1.2 1.6 2.0 30 1.2 1.8 2.4 3.0 40 1.6 2.4 3.2 4.0 50 2.0 3.0 4.0 60 2.4 3.6 70 2.8 80 3.2 90 3.6 100 4.0 Table 4: Infusion Rates for VELETRI at a Concentration of 6,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 2 3 4 5 Infusion Delivery Rate (mL/hr) 20 --- --- --- --- 30 --- --- 1.2 1.5 40 --- 1.2 1.6 2.0 50 1.0 1.5 2.0 2.5 60 1.2 1.8 2.4 3.0 70 1.4 2.1 2.8 3.5 80 1.6 2.4 3.2 4.0 90 1.8 2.7 3.6 100 2.0 3.0 4.0 Table 5: Infusion Rates for VELETRI at a Concentration of 9,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 3 6 9 Infusion Delivery Rate (mL/hr) 20 --- --- --- 30 --- 1.2 1.8 40 --- 1.6 2.4 50 1.0 2.0 3.0 60 1.2 2.4 3.6 70 1.4 2.8 80 1.6 3.2 90 1.8 3.6 100 2.0 4.0 Table 6: Infusion Rates for VELETRI at a Concentration of 12,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 4 6 8 10 Infusion Delivery Rate (mL/hr) 20 --- --- --- --- 30 --- --- 1.2 1.5 40 --- 1.2 1.6 2.0 50 1.0 1.5 2.0 2.5 60 1.2 1.8 2.4 3.0 70 1.4 2.1 2.8 3.5 80 1.6 2.4 3.2 4.0 90 1.8 2.7 3.6 100 2.0 3.0 4.0 Table 7: Infusion Rates for VELETRI at a Concentration of 15,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patientweight (kg) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 20 --- --- --- --- 1.0 1.1 1.3 30 --- --- 1.0 1.2 1.4 1.7 1.9 40 --- 1.0 1.3 1.6 1.9 2.2 2.6 50 --- 1.2 1.6 2.0 2.4 2.8 3.2 60 1.0 1.4 1.9 2.4 2.9 3.4 3.8 70 1.1 1.7 2.2 2.8 3.4 3.9 80 1.3 1.9 2.6 3.2 3.8 90 1.4 2.2 2.9 3.6 100 1.6 2.4 3.2 4.0 Table 8: Infusion Rates for VELETRI at a Concentration of 30,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 6 8 10 12 14 16 30 --- --- --- --- --- 1.0 40 --- --- --- 1.0 1.1 1.3 50 --- --- 1.0 1.2 1.4 1.6 60 --- 1.0 1.2 1.4 1.7 1.9 70 --- 1.1 1.4 1.7 2.0 2.2 80 1.0 1.3 1.6 1.9 2.2 2.6 90 1.1 1.4 1.8 2.2 2.5 2.9 100 1.2 1.6 2.0 2.4 2.8 3.2

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• Tracleer
  

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  Tracleer

  

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  Healthcare professionals who prescribe Tracleer must enroll in the Tracleer Access Program (T.A.P.) and must comply with the required monitoring to minimize the risks associated with Tracleer [see Warnings and Precautions (5.2)].

  2.1 Adult Dosage

  Initiate treatment at 62.5 mg twice daily for 4 weeks and then increase to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.

  Tracleer should be administered in the morning and evening with or without food.

  2.2 Dosage Adjustments for Patients Developing Aminotransferase Elevations

  Measure liver aminotransferase levels prior to initiation of treatment and then monthly. If aminotransferase levels increase, revise the monitoring and treatment plan. The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 × ULN during therapy with Tracleer. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN. There is no experience with the reintroduction of Tracleer in these circumstances.

  Table 1: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3 × ULN ALT/AST levels Treatment and monitoring recommendations * If Tracleer is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above. > 3 and ≤ 5 × ULN Confirm by another aminotransferase test; if confirmed, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values, continue or reintroduce the treatment as appropriate*. > 5 and ≤ 8 × ULN Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, consider reintroduction of the treatment*. > 8 × ULN Treatment should be stopped and reintroduction of Tracleer should not be considered. There is no experience with reintroduction of Tracleer in these circumstances.

  2.3 Patients with Low Body Weight

  In patients with a body weight below 40 kg but who are over 12 years of age, the recommended initial and maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Tracleer in children between the ages of 12 and 18 years [see Use in Specific Populations (8.4)].

  2.4 Use with Ritonavir

  Coadministration of Tracleer in Patients on Ritonavir

  In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or every other day based upon individual tolerability [see Drug Interactions (7.5)].

  Coadministration of Ritonavir in Patients on Tracleer

  Discontinue use of Tracleer at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume Tracleer at 62.5 mg once daily or every other day based upon individual tolerability [see Dosage and Administration (2.6), Drug Interactions (7.5)].

  2.5 Use in Patients with Pre-existing Hepatic Impairment

  Tracleer should generally be avoided in patients with moderate or severe liver impairment. Initiation of Tracleer should generally be avoided in patients with elevated aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

  2.6 Treatment Discontinuation

  There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered.

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• Veletri
  

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  Veletri

  

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  Important Note: Reconstitute VELETRI only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not dilute reconstituted solutions of VELETRI or administer it with other parenteral solutions or medications [see Warnings and Precautions (5.1)].

  2.1 Dosage

  Prepare continuous chronic infusion of VELETRI as directed, and administer through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of VELETRI at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until VELETRI is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, use a lower dose.

  In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

  2.2 Dosage Adjustments

  Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of VELETRI. In general, expect increases in dose from the initial chronic dose.

  Consider increments in dose if symptoms of pulmonary hypertension persist or recur. Adjust the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

  During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of VELETRI or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of VELETRI should be adjusted only under the direction of a physician.

  In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.

  2.3 Administration

  VELETRI, once prepared as directed [see Reconstitution (2.4)], is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, VELETRI may be administered peripherally.

  Infusion sets with an in-line 0.22 micron filter should be used.

  The ambulatory infusion pump used to administer VELETRI should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver VELETRI. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

  To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

  2.4 Reconstitution

  VELETRI is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not reconstitute or mix VELETRI with any other parenteral medications or solutions prior to or during administration. Each vial is for single use only; discard any unused solution.

  Use after reconstitution and immediate dilution to final concentration

  Use at room temperature (77°F/25°C)

  VELETRI solution reconstituted with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, and immediately diluted to the final concentration in the drug delivery reservoir can be administered at room temperature per the conditions of use as outlined in Table 1.

  Table 1: Maximum duration of administration (hours) at room temperature (77°F/ 25°C) of fully diluted solutions in the drug delivery reservoir* Final concentration range Immediate administration If stored for up to 8 days at 36° to 46°F (2° to 8°C) * Short excursions at 104°F (40°C) are permitted for up to:    2 hours for concentrations below15,000 ng/mL   4 hours for concentrations between 15,000 ng/mL and 60,000 ng/mL   8 hours for concentrations above 60,000 ng/mL 0.5mg vial ≥3,000 ng/mL and <15,000 ng/mL 48 hours 24 hours 1.5mg vial ≥15,000 ng/mL and < 60,000 ng/mL 48 hours 48 hours ≥60,000 ng/mL 72 hours 48 hours

  Use at higher temperatures >77°F up to 104°F (>25° to 40°C)

  Temperatures greater than 77°F and up to 86 °F (>25°C to 30°C): A single reservoir of fully diluted solution of 60 000 ng/mL or above of VELETRI prepared as directed can be administered (either immediately or after up to 8 days storage at 36° to 46°F (2° to 8°C))for up to 48 hours. For diluted solutions of less than 60 000 ng/mL, pump reservoirs should be changed every 24 hours.

  Temperatures up to 104°F (40°C): Fully diluted solutions of 60,000 ng/mL or above of VELETRI, prepared as directed, can be immediately administered for periods up to 24 hours.

  Do not expose this solution to direct sunlight.

  A concentration for the solution of VELETRI should be selected that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. VELETRI, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 2 are directions for preparing different concentrations of VELETRI. Each vial is for single use only; discard any unused solution.

  Table 2: Reconstitution and Dilution Instructions To make 100 mL of solution with Final Concentration (ng/mL) of: Directions: * Higher concentrations may be prepared for patients who receive VELETRI long-term. Using the 0.5 mg vial 3,000 ng/ml Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, USP. Withdraw 3 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 5,000 ng/mL Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 10,000 ng/ml Dissolve contents of two 0.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. Using the 1.5 mg vial 15,000 ng/mL* Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 30,000 ng/mL* Dissolve contents of two 1.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.

  Infusion rates may be calculated using the following formula:

  Infusion Rate (mL/hr) = [Dose (ng/kg/min) × Weight (kg) × 60 min/hr] Final Concentration (ng/mL)

  Tables 3 to 7 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of VELETRI to be used. These tables may be used to select the most appropriate concentration of VELETRI that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. For infusion/dose rates lower than those listed in Tables 3 to 7, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half life of epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of VELETRI.

  Table 3: Infusion Rates for VELETRI at a Concentration of 3,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 2 3 4 5 Infusion Delivery Rate (mL/hr) 20 --- 1.2 1.6 2.0 30 1.2 1.8 2.4 3.0 40 1.6 2.4 3.2 4.0 50 2.0 3.0 4.0 --- 60 2.4 3.6 --- --- 70 2.8 --- --- --- 80 3.2 --- --- --- 90 3.6 --- --- --- 100 4.0 --- --- --- Table 4: Infusion Rates for VELETRI at a Concentration of 5,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 2 4 6 8 10 12 14 Infusion Delivery Rate (mL/hr) 20 --- 1.0 1.4 1.9 2.4 2.9 3.4 30 --- 1.4 2.2 2.9 3.6 --- --- 40 1.0 1.9 2.9 3.8 --- --- --- 50 1.2 2.4 3.6 --- --- --- --- 60 1.4 2.9 --- --- --- --- --- 70 1.7 3.4 --- --- --- --- --- 80 1.9 3.8 --- --- --- --- --- 90 2.2 --- --- --- --- --- --- 100 2.4 --- --- --- --- --- --- Table 5: Infusion Rates for VELETRI at a Concentration of 10,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 20 --- --- 1.0 1.2 1.4 1.7 1.9 30 --- 1.1 1.4 1.8 2.2 2.5 2.9 40 1.0 1.4 1.9 2.4 2.9 3.4 3.8 50 1.2 1.8 2.4 3.0 3.6 --- --- 60 1.4 2.2 2.9 3.6 --- --- --- 70 1.7 2.5 3.4 --- --- --- --- 80 1.9 2.9 3.8 --- --- --- --- 90 2.2 3.2 --- --- --- --- --- 100 2.4 3.6 --- --- --- --- --- Table 6: Infusion Rates for VELETRI at a Concentration of 15,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 20 --- --- --- --- 1.0 1.1 1.3 30 --- --- 1.0 1.2 1.4 1.7 1.9 40 --- 1.0 1.3 1.6 1.9 2.2 2.6 50 --- 1.2 1.6 2.0 2.4 2.8 3.2 60 1.0 1.4 1.9 2.4 2.9 3.4 3.8 70 1.1 1.7 2.2 2.8 3.4 3.9 --- 80 1.3 1.9 2.6 3.2 3.8 --- --- 90 1.4 2.2 2.9 3.6 --- --- --- 100 1.6 2.4 3.2 4.0 --- --- --- Table 7: Infusion Rates for VELETRI at a Concentration of 30,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 6 8 10 12 14 16 30 --- --- --- --- --- 1.0 40 --- --- --- 1.0 1.1 1.3 50 --- --- 1.0 1.2 1.4 1.6 60 --- 1.0 1.2 1.4 1.7 1.9 70 --- 1.1 1.4 1.7 2.0 2.2 80 1.0 1.3 1.6 1.9 2.2 2.6 90 1.1 1.4 1.8 2.2 2.5 2.9 100 1.2 1.6 2.0 2.4 2.8 3.2

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• Cough And Cold
  

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  Cough And Cold

  

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  2.1 Recommended Dosage

  The recommended dosage of OPSUMIT is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.

  2.2 Pregnancy Testing in Females of Reproductive Potential

  Initiate treatment with OPSUMIT in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy test during treatment [see Use in Specific Populations (8.6)].

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• Ventavis
  

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  Ventavis

  

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  2.1 Recommended Dosing

  Ventavis is intended to be inhaled using the I-neb® AAD® System. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5.0 mcg and maintained at that dose; otherwise maintain the dose at 2.5 mcg. Ventavis should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).

  Direct mixing of Ventavis with other medications in the I-neb® AAD® System has not been evaluated; do not mix with other medications. To avoid potential interruptions in drug delivery due to equipment malfunctions, the patient should have easy access to a back-up I-neb®AAD® System.

  Ventavis is supplied in 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.

  Delivered dose from ampule of : Nebulizer 10 mcg/mL 20 mcg/mL I-neb® AAD® 2.5 or 5 mcg from one ampule 5 mcg from one ampule

  The 20 mcg/mL concentration is intended for patients who are maintained at the 5 mcg dose and who have repeatedly experienced extended treatment times which could result in incomplete dosing. Transitioning patients to the 20 mcg/mL concentration using the I-neb® AAD® System will decrease treatment times to help maintain patient compliance.

  For each inhalation session, the entire contents of each opened ampule of Ventavis should be transferred into the I-neb® AAD® System medication chamber immediately before use [see Patient Counseling Information (17.1)]. After each inhalation session, any solution remaining in the medication chamber should be discarded. Use of the remaining solution will result in unpredictable dosing. Patients should follow the manufacturer's instructions for cleaning the I-neb® AAD® System components after each dose administration.

  2.2 Monitoring

  Vital signs should be monitored while initiating Ventavis. [see Warnings and Precautions (5.1)].

  2.3 Use in Patients with Pre-existing Hepatic Impairment

  Because iloprost elimination is reduced in patients with impaired liver function [see Special Populations (8.6)], consider increasing the dosing interval (e.g., 3-4 hours between doses depending on the patient's response at the end of the dose interval) in patients with Child-Pugh Class B or C hepatic impairment.

  2.4 Use in Patients with Pre-existing Renal Impairment

  Dose adjustment is not required in patients who are not on dialysis. The effect of dialysis on iloprost is unknown [see Special Populations (8.7)].

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• Valchlor
  

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  Valchlor

  

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  2.1 Dosing and Dose Modification

  For Topical Dermatological Use Only

  Apply a thin film of VALCHLOR gel once daily to affected areas of the skin.

  Stop treatment with VALCHLOR for any grade of skin ulceration, blistering, or moderately-severe or severe dermatitis (i.e., marked skin redness with edema) [see Warnings and Precautions (5.3)]. Upon improvement, treatment with VALCHLOR can be restarted at a reduced frequency of once every 3 days. If reintroduction of treatment is tolerated for at least one week, the frequency of application can be increased to every other day for at least one week and then to once daily application if tolerated.

  2.2 Application Instructions

  VALCHLOR is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

  Patients must wash hands thoroughly with soap and water after handling or applying VALCHLOR.

  Caregivers must wear disposable nitrile gloves when applying VALCHLOR to patients and wash hands thoroughly with soap and water after removal of gloves. If there is accidental skin exposure to VALCHLOR, caregivers must immediately wash exposed areas thoroughly with soap and water for at least 15 minutes and remove contaminated clothing [see Warnings and Precautions (5.2)].

  Patients or caregivers should follow these instructions when applying VALCHLOR:

  Apply immediately or within 30 minutes after removal from the refrigerator. Return VALCHLOR to the refrigerator immediately after each use. Apply to completely dry skin at least 4 hours before or 30 minutes after showering or washing. Allow treated areas to dry for 5 to 10 minutes after application before covering with clothing. Emollients (moisturizers) may be applied to the treated areas 2 hours before or 2 hours after application. Do not use occlusive dressings on areas of the skin where VALCHLOR was applied. Avoid fire, flame, and smoking until VALCHLOR has dried [see Warnings and Precautions (5.6)].

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• Zavesca
  

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  Zavesca

  

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  2.1 Instructions for Administration

  Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease.

  The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next Zavesca capsule should be taken at the next scheduled time.

  It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea.

  2.2 Patients with Renal Insufficiency

  In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73 m2), Zavesca administration should commence at a dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clearance of 30-50 mL/min/1.73 m2), Zavesca administration should commence at a dose of one 100 mg capsule per day. Use of Zavesca in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2) is not recommended [see Use in Specific Populations (8.6)].

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