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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J1000-27

Original Effective Date: 07/15/10

Reviewed: 05/08/13

Revised: 11/01/15

Subject: Nitisinone (Orfadin®) Capsules

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Position Statement Dosage/ Administration Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates
           

DESCRIPTION:

Nitisinone (Orfadin®) is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in persons with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In persons with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

Since nitisinone inhibits catabolism of tyrosine, use of this drug can result in elevated plasma levels of this amino acid. Treatment with nitisinone, therefore, requires restriction of the daily intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Nitisinone (Orfadin®) meets the definition of medical necessity when used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.

Nitisinone meets the definition of medical necessity when administered for the following Orphan Drug indication (http://www.fda.gov/orphan/designat/list.htm):

Approval duration: 1 year

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved: Nitisinone is indicated for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). The recommended initial dose is 1 mg/kg/day divided into two daily doses. It should be administered at least one hour prior to or two hours after a meal. For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use. The maximum dose is 2 mg/kg/day. Members and their parents/caregivers should be advised of the need to maintain dietary restriction of tyrosine and phenylalanine.

Dosage adjustment: If the biochemical parameters (except plasma succinylacetone) are not normalized within 1 month after start of treatment, the dosage should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to 3 months before the level is normalized after the start of treatment. A dosage of 2 mg/kg/day may be needed once liver function has improved.

Drug Availability: Nitisinone is supplied as 2-, 5- and 10 mg capsules. The product should be stored in the refrigerator (36-46°F). It is available through a single specialty pharmacy, Accredo Health Group.

PRECAUTIONS:

High plasma tyrosine levels: Inadequate restriction of tyrosine and phenylalanine intake can result in elevations in plasma tyrosine. Plasma tyrosine levels should be kept below 500 mcmol/L in order to avoid toxic effects to the eyes (corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin (painful hyperkeratotic plaques on the soles and palms), and nervous system (variable degrees of mental retardation and developmental delay).

Transient thrombocytopenia and leucopenia: Subjects treated with nitisinone and dietary restriction in clinical trials were observed to develop transient thrombocytopenia (3%), leucopenia (3%), or both (1.5%). Monitor platelet and white blood cell counts regularly in persons administered nitisinone therapy.

Monitoring: It is appropriate during regular monitoring to follow urine succinylacetone, ver function tests, alpha-fetoprotein, platelets, white blood cell counts, and serum tyrosine and phenylalanine levels. However, during the initiation of therapy and during acute exacerbations, it may be necessary to follow more closely all available biochemical parameters (e.g., plasma nitisinone concentration, plasma succinylacetone levels, urine 5-ALA levels, and erythrocyte PBG-S activity). Regular liver monitoring by imaging (ultrasound, computerized tomography, magnetic resonance imaging) is recommended. Measure serum phosphate as a screening test for individuals with renal involvement at risk for secondary hypophosphatemia and rickets. Perform slit-lamp examinations of the eyes before initiation of treatment and during any eye adverse reactions (e.g., photophobia, eye pain, signs of inflammation).

BILLING/CODING INFORMATION:

Oral agents are generally administered through the pharmacy benefit.

HCPCS Coding

J8499

Prescription drug, oral, non-chemotherapeutic,

ICD-10 Diagnoses Codes That Support Medical Necessity (Effective 10/01/15)

E70.21

Tyrosinemia

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

Medicare Part D: Florida Blue has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

DEFINITIONS:

Alkaptonuria: a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. It is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase, which participates in the degradation of tyrosine. As a result, homogentisic acid and its oxide, called alkapton, accumulate in the blood and are excreted in urine in large amounts. Excessive homogentisic acid causes damage to cartilage and heart valves as well as precipitating as kidney stones.

Hereditary tyrosinemia type 1: A metabolic disorder in which an enzyme critical for the breakdown of the amino acid tyrosine is missing. This allows abnormal amounts of tyrosine to accumulate in the body and act like as a poison causing damage, especially in the liver.

RELATED GUIDELINES:

None applicable.

OTHER:

None applicable.

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2012. URL www.clinicalpharmacilogy-ip.com Accessed 3/20/13.
  2. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 3/20/13.
  3. Nitisinone. In: McEvoy GK, editor. AHFS drug information 2012 [monograph on the Internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2012 [cited 2013 March 20]. Available from: http://online.statref.com. Subscription required to view.
  4. Nitisinone (Orfadin) [package insert]. Rare Disease Therapeutics, Inc. Franklin (TN): September 2010.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 05/08/13.

GUIDELINE UPDATE INFORMATION:

07/15/10

New Medical Coverage Guideline.

06/15/11

Review and revision to guideline; consisting of updating references.

06/15/12

Review and revision to guideline; consisting of updating coding and references.

06/15/13

Review and revision to guideline; consisting of revising position statement to include orphan drug indication and approval duration, revising dosage/administration and precautions section, adding pertinent definitions, and updating references and program exceptions. No longer reviewed.

11/01/15

Revision: ICD-9 Codes deleted.

Date Printed: June 28, 2017: 11:54 PM