Is ravulizumab-cwvz (Ultomiris) medically indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH)?

Medical Necessity Determination for Ravulizumab-cwvz (Ultomiris) in Paroxysmal Nocturnal Hemoglobinuria

Ravulizumab-cwvz (Ultomiris) is medically indicated and necessary for this patient with documented PNH who has demonstrated significant clinical improvement on therapy, including resolution of hemolysis and abdominal pain, though the current dosing does not meet the weight-based recommendations specified in the FDA label. 1

Primary Indication Assessment

The diagnosis of paroxysmal nocturnal hemoglobinuria (D59.5) is the FDA-approved indication for ravulizumab-cwvz. 1 The patient has documented hemolytic anemia due to PNH with:

• Laboratory evidence of ongoing hemolysis (reticulocyte count 4.93%, haptoglobin <10, LDH 280) 1
• History of severe thrombotic complications (Budd-Chiari syndrome in prior year) requiring completed anticoagulation 2
• Significant clinical improvement since initiating ravulizumab, including resolution of abdominal pain and improved hemoglobin levels (from 5.5-7.1 g/dL pre-treatment to stable 9.1 g/dL) 3, 4

Continuation Criteria Analysis

All three continuation criteria from the plan's medical policy are met:

1. No evidence of unacceptable toxicity or disease progression: The patient has stable hemoglobin (9.1 g/dL), stable platelet count (192), and controlled hemolysis markers with no documented adverse events 3, 5

2. Positive response to therapy: Hemoglobin improved from baseline range of 5.5-7.1 g/dL to stable 9.1 g/dL, LDH normalized to 280 (compared to expected elevation in untreated hemolysis), and complete resolution of abdominal pain that was present prior to treatment 3, 4

3. No concomitant complement inhibitor use: Patient is on ravulizumab monotherapy without other complement inhibitors 1

Critical Dosing Discrepancy

The patient's current dosing regimen does NOT meet FDA-approved weight-based recommendations, which represents a significant medical necessity concern. 1

• Patient weight: 136.8 lbs (62.1 kg) 1
• Current dose: 3000 mg IV every 8 weeks 1
• FDA-recommended dose for 60 to <100 kg: Loading dose 2700 mg, maintenance 3300 mg every 8 weeks 1

The patient is receiving 300 mg LESS than the FDA-recommended maintenance dose for their weight category. 1 This underdosing may explain the persistent signs of ongoing hemolysis (elevated reticulocyte count 4.93%, undetectable haptoglobin <10) despite treatment 4, 5

Clinical Significance of Dosing Error

The treating physician's note acknowledges potential need for dose escalation: "If worsening anemia/hemolysis can increase dose to 3300 mg and/or shorten time frame to every 6-7 weeks." 1 This statement confirms awareness that current dosing may be suboptimal 4

Breakthrough hemolysis events in clinical trials were rare (1.8% associated with suboptimal C5 inhibition) when proper weight-based dosing was maintained. 4 Underdosing increases risk of:

• Breakthrough intravascular hemolysis 4, 5
• Recurrent thrombotic events (particularly concerning given history of Budd-Chiari syndrome) 2
• Loss of clinical benefit requiring transfusion support 3, 5

Long-Term Safety and Efficacy Data

Ravulizumab has demonstrated durable efficacy and safety for up to 6 years in PNH patients, with five-fold reduction in mortality risk compared to untreated patients. 4 Key outcomes include:

• Major adverse vascular events (including thrombosis) rate: 0.7-1.4 per 100 patient-years 4
• Transfusion avoidance maintained in 76.6-86.5% of patients at 52 weeks 3, 5
• Complete and sustained free C5 inhibition when proper dosing maintained 5
• Adverse event rates decreased over time with continued treatment 3, 5

Special Consideration: Budd-Chiari Syndrome History

The patient's history of Budd-Chiari syndrome (I82.0) in the prior authorization strongly supports indefinite complement inhibitor therapy. 2 According to hepatology literature:

• PNH is found in 9-19% of Budd-Chiari syndrome patients 2
• Long-term anticoagulation is warranted due to severity of hepatic vein thrombosis 2
• Indefinite anticoagulation is recommended for venous thrombosis in unusual sites even with complement inhibitor therapy 2

This thrombotic complication history makes optimal dosing of ravulizumab critically important to prevent recurrence. 2, 4

Medical Necessity Determination

APPROVED with required dosing correction:

The ravulizumab-cwvz is medically necessary for this patient with documented PNH and prior life-threatening thrombotic complications, BUT the dose must be corrected to 3300 mg every 8 weeks per FDA weight-based dosing guidelines. 1

Rationale for approval:

• FDA-approved indication (PNH) with documented diagnosis 1
• All three plan continuation criteria met 3, 4
• Demonstrated clinical benefit (hemoglobin improvement, symptom resolution) 3, 5
• History of severe thrombotic complication (Budd-Chiari) requiring indefinite complement inhibition 2
• Long-term safety and efficacy data support continued use 4

Required modification:

• Dose must be increased from 3000 mg to 3300 mg every 8 weeks to align with FDA-approved weight-based dosing for patient weighing 62.1 kg (60 to <100 kg category) 1
• Continued monitoring of hemolysis markers (LDH, haptoglobin, reticulocyte count) to assess adequacy of dose adjustment 4, 5

Common pitfall avoided: Approving continuation without addressing suboptimal dosing that may lead to breakthrough hemolysis or thrombotic recurrence in a patient with established high-risk features 4, 5