Notification

Treatment of Pulmonary Artery Hypertension with Intravenous, Subcutaneous, and Inhaled Pharmacologic Agents


Notification Issue Date: 10/03/2019



Policy Attachment


Attachment to Policy # 08.00.25l


Attachment:A

Policy #:08.00.25l

Description:Dosing and Frequency Requirements

Title:Treatment of Pulmonary Artery Hypertension with Intravenous, Subcutaneous, and Inhaled Pharmacologic Agents



DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this Policy to ensure consistency with the most recently published recommendations for the use of epoprostenol (Flolan®) (Veletri®); treprostinil sodium (Remodulin®); iloprost (Ventavis®); and treprostinil (Tyvaso®); and sildenafil (Revatio®). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of epoprostenol (Flolan®) (Veletri®); treprostinil sodium (Remodulin®); iloprost (Ventavis®); treprostinil (Tyvaso®); and sildenafil (Revatio®) outside of the Dosing and Frequency Requirements listed in this Policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the precertification process. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for epoprostenol (Flolan®) (Veletri®); treprostinil sodium (Remodulin®); iloprost (Ventavis®); treprostinil (Tyvaso®); and sildenafil (Revatio®).


DOSING AND FREQUENCY REQUIREMENTS FOR EPOPROSTENOL (FLOLAN®) (VELETRI®)
          Indication
Dosing and Frequency
  • pulmonary arterial hypertension (PAH), in accordance with the World Health Organization (WHO) Group 1 classification. New York Heart Association (NYHA) Functional Classification requirement of Class III-IV
epoprostenol (Flolan®)
  • Initiate intravenous infusion through a central venous catheter at 2 ng/kg/min
  • Change dose in 1-to 2-ng/kg/min increments at intervals of at least 15 minutes based on clinical response.
  • Administration VELETRI® is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump.
  • Infusion Rate (mL/hr) = [Dose (ng/kg/min) x Weight (kg) x 60 min/hr] Final Concentration (ng/mL)
epoprostenol (VELETRI®)
  • Infusion of VELETRI® should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established.
  • If symptoms of pulmonary hypertension persist or recur after improving -the infusion should be increased 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.
  • Administration VELETRI® is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump.
  • Infusion Rate (mL/hr) = [Dose (ng/kg/min) x Weight (kg) x 60 min/hr] Final Concentration (ng/mL)
DOSING AND FREQUENCY REQUIREMENTS FOR TREPROSTINIL SODIUM (REMODULIN®)
Indication
Dosing and Frequency
  • pulmonary arterial hypertension (PAH), in accordance with the World Health Organization (WHO) Group 1 classification. New York Heart Association (NYHA) Functional Classification requirement of Class II-IV
treprostinil sodium (Remodulin®)
  • Initial dose for patients new to prostacyclin infusion therapy:1.25 ng/kg/min; increase based on clinical response (increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment, later 2.5 ng/kg/min per week). Avoid abrupt cessation. Infusion, subcutaneous, continuous/Intravenous route
  • subcutaneous infusion rate (mL/hr) = [dose (ng/kg per minute) × weight (in kg) × 0.00006] ÷ treprostinil vial strength (mg/mL)
  • diluted IV treprostinil concentration (mg/mL) = [dose (ng/kg per minute) × weight (in kg) × 0.00006] ÷ IV infusion rate (mL/hr); amount of treprostinil injection (mL) = [diluted IV treprostinil concentration (mg/mL) ÷ treprostinil vial strength (mg/mL)] × total reservoir volume (mL)
  • Mild to moderate hepatic insufficiency: Decrease initial dose to 0.625 ng/kg/min.
  • Pulmonary arterial hypertension, in individuals requiring transition from epoprostenol (Flolan®)

    Titration:
    StepEpoprostenolTreprostinil
    1Unchanged10% Starting epoprostenol dose
    280% Starting epoprostenol dose30% Starting epoprostenol dose
    360% Starting epoprostenol dose50% Starting epoprostenol dose
    440% Starting epoprostenol dose70% Starting epoprostenol dose
    520% Starting epoprostenol dose90% Starting epoprostenol dose
    65% Starting epoprostenol dose110% Starting epoprostenol dose
    70110% Starting epoprostenol dose plus additional 5% to 10% increments as needed

DOSING AND FREQUENCY REQUIREMENTS FOR ILOPROST (VENTAVIS®)
Indication
Dosing and Frequency
  • pulmonary arterial hypertension (PAH), in accordance with the World Health Organization (WHO) Group 1 classification. New York Heart Association (NYHA) Functional Classification requirement of Class III-IV
iloprost (Ventavis®)
  • Individuals should receive 6 to 9 doses (inhalations) per day (minimum of 2 hours between doses during waking hours) as follows:
    • Starting dose: 2.5 mcg
    • Uptitrate to 5 mcg if 2.5 mcg is well tolerated
    • Maintenance dose: 5 mcg
  • The 20 mcg/mL concentration is for individuals who repeatedly experience extended treatment times
Delivered dose from ampule of :
Nebulizer
10 mcg/mL
20 mcg/mL
I-neb Adaptive Aerosol Delivery (AAD)
System
2.5 or 5 mcg from one ampule
5 mcg from one ampule
  • The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).
DOSING AND FREQUENCY) REQUIREMENTS FOR TREPROSTINIL (TYVASO®)
Indication
Dosing and Frequency
  • pulmonary arterial hypertension (PAH), in accordance with the World Health Organization (WHO) Group 1 classification. New York Heart Association (NYHA) Functional Classification requirement of Class III
treprostinil (Tyvaso®)
  • Administer undiluted, as supplied. A single breath of Tyvaso delivers approximately 6 mcg of treprostinil.
  • Administer in 4 separate treatment sessions each day approximately four hours apart, during waking hours.
  • Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are not tolerated, reduce to 1 or 2 breaths.
  • Dosage should be increased by an additional 3 breaths per session at approximately 1-2 week intervals, if tolerated.
  • Titrate to target maintenance dosage of 9 breaths or 54 mcg per treatment session as tolerated.

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 per treatment session at approximately 1- to 2week intervals, if tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached, 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.
DOSING AND FREQUENCY REQUIREMENTS FOR SILDENAFIL (REVATIO®)
Indication
Dosing and Frequency
  • pulmonary arterial hypertension (PAH), in accordance with the World Health Organization (WHO) Group 1 classification. New York Heart Association (NYHA) Functional Classification requirement of Class II-III
sildenafil (Revatio®)
  • Individuals are currently prescribed oral REVATIO® and who are temporarily unable to take oral medication
  • 2.5 mg or 10 mg three times a day administered as an intravenous bolus injection


References:


Epoprostenol (Flolan®; Veletri®). American Hospital Formulary Service (AHFS). AHFS Drug Information 2019. [Lexicom Web site]. 02/22/2019. Available at: http://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/413206 [via subscription only]. Accessed August 18, 2019.

Epoprostenol (Flolan®). Micromedex® Healthcare Series. [Micromedex® Web site]. 02/20/2019. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed August 18, 2019.

Iloprost (Ventavis®). American Hospital Formulary Service (AHFS). AHFS Drug Information 2019. [Lexicom Web site]. 02/22/2019. Available at:
http://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/413242 [via subscription only]. Accessed August 18, 2019.

Iloprost (Ventavis®). Micromedex® Healthcare Series. [Micromedex® Web site]. Last modified 06/24/2019. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed August 18, 2019.

sildenafil (Revatio®). American Hospital Formulary Service (AHFS). AHFS Drug Information 2019. [Lexicom Web site]. 05/22/2019. Available at:
http://online.lexi.com/lco/action/doc/retrieve/docid/essential_ashp/410719?searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DSildenafil%2520Citrate%26t%3Dname%26va%3Dsildenafil#dosage-admin-nested-0-0. Accessed August 18, 2019.

sildenafil (Revatio®). Micromedex® Healthcare Series. [Micromedex® Web site]. 08/28/2019. Available at: https://www.micromedexsolutions.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch?navitem=headerLogout#. Accessed August 18, 2019.

Treprostinil (Remodulin®; Tyvaso®). American Hospital Formulary Service (AHFS). AHFS Drug Information 2019. [Lexicom Web site]. 02/22/2019. Available at:
http://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/413127[via subscription only]. Accessed August 18, 2019.

Treprostinil (Remodulin®; Tyvaso®). Micromedex® Healthcare Series. [Micromedex® Web site]. Last modified 07/30/2019. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed August 18, 2019.

US Food and Drug Administration. Center for Drug Evaluation and Research. Drugs @FDA. Approval letter for Epoprostenol. [FDA Web site]. 06/27/2008. Available at:http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2008/022260s000ltr.pdf. Accessed August 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Flolan® (epoprostenol sodium). Prescribing information. [FDA Web site]. 12/12/2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020444s024lbl.pdf. Accessed August 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Iloprost (Ventavis®) Inhalation Solution. Prescribing information. [FDA Web site]. October 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021779s018lbl.pdf. Accessed August 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Remodulin® (treprostinil sodium). Prescribing information. [FDA Web site]. May 2002. (Revised July 2018). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208276s000,021272s025lbl.pdf. Accessed August 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Sildenafil (Revatio®) . Prescribing information. [FDA Web site]. 01/17/2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022473s012,203109s012lbl.pdf. Accessed August 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Tyvaso® (treprostinil) inhalation solution. Prescribing information. [FDA Web site]. 2002 (Revised October 2017). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022387s015lbl.pdf. Accessed August 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Veletri® (epoprostenol). Prescribing information. [FDA Web site]. 1995 (Revised June 2012). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022260s005lbl.pdf. Accessed August 18, 2019.



Version Effective Date: 01/01/2020
Version Issued Date: 12/31/2019
Version Reissued Date: N/A

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