Background

Acute hepatic porphyria (AHP) is a rare disease with a prevalence of 5 to 10 cases/100,000 people in the U.S. and effects primarily females (age range 15 to 45 years). The induction of the enzyme amino levulinate synthase 1 (ALAS1) results in increased production and accumulation of toxic heme intermediates delta aminolevulinic acid and porphobilinogen in the plasma and urine. The accumulation of these toxic heme intermediates results in acute attacks characterized by severe abdominal pain, muscle weakness, seizures, psychiatric dysfunction, irreversible neurologic damage, and increased risk of hepatic malignancy.

Givosiran (Givlaari^®) is a double-stranded small interfering RNA that causes degradation of ALAS1 mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to decreased circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of acute hepatic porphyria.

Policy

Givosiran (Givlaari) is considered medically necessary for the treatment of adults (adults (≥18 years) with acute hepatic porphyria (AHP) when ALL  of the following are met:

1. Diagnosis of acute hepatic porphyria (i.e., acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, ALA dehydrase deficient porphyria) AND
2. Patient has active disease with at least two documented porphyria attacks within the past 6 months AND
3. Provider attestation documenting elevated urinary or plasma levels of one of the following within the past 12 months:
   • Porphobilinogen (PBG)
   • Delta-aminolevulinic acid (ALA) AND
4. Patient has not had a liver transplant AND
5. Prescribed by or in consultation with a gastroenterologist, hepatologist, hematologist or a specialist with expertise in the diagnosis and management of acute hepatic porphyria
6. No concurrent prophylactic hemin while on givosiran (use for acute attacks is permitted).

Authorization may be granted for 6 months at a time.

Continuation of Therapy

Continuation of givosiran therapy is considered medically necessary when the following criteria are met:

1. The patient continues to meet the initial eligibility criteria.
2. Documentation demonstrates a positive clinical response to therapy, such as reduction in the frequency or severity of porphyria attacks and or reduced need for intravenous hemin.
3. The patient continues to comply with recommended safety monitoring and specialist oversight.

Reauthorization may be granted for up to 12 months at a time.

Dosing/Administration

2.5 mg/kg subcutaneously once monthly. If severe/clinically significant transaminase elevations resolve after interruption, may resume at 1.25 mg/kg monthly. Split into multiple injections if total volume > 1.5 mL.

Safety & Monitoring

The following monitoring requirements should be incorporated into clinical management consistent with FDA labeling and expert guidance:

• Liver function tests should be obtained at baseline and monitored periodically during treatment. Therapy should be interrupted or discontinued for severe or clinically significant transaminase elevations.
• Renal function should be monitored during treatment as clinically indicated.
• Blood homocysteine levels should be measured at baseline and monitored periodically. In patients with elevated homocysteine levels, supplementation with vitamin B6 may be considered.
• Patients presenting with acute upper abdominal pain during treatment should be evaluated for pancreatitis, particularly if accompanied by elevations in pancreatic enzymes or imaging findings consistent with acute pancreatitis.
• Appropriate medical support should be available at the time of administration to manage potential anaphylactic reactions.
• Concomitant use with sensitive CYP1A2 or CYP2D6 substrates for which minimal concentration changes may result in serious or life‑threatening toxicity should be avoided.

References

1. Bissell DM, Wang B. Acute Hepatic Porphyria. J Clin Transl Hepatol. Mar 2015; 3(1): 17-26. PMID 26357631
2. Wang B, Rudnick S, Cengia B, et al. Acute Hepatic Porphyrias: Review and Recent Progress. Hepatol Commun. Feb 2019; 3(2): 193-206. PMID 30766957
3. Balwani M, Sardh E, Ventura P, et al. Phase 3 Trial of RNAi TherapeuticGivosiran for Acute Intermittent Porphyria. N Engl J Med. Jun 11, 2020; 382(24): 2289-2301. PMID 32521132
4. Ventura P, Bonkovsky HL, Gouya L, et al. Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int. Jan 2022; 42(1): 161-172. PMID 34717041
5. Prescribing Label: Givlaari (givosiran) injection, for subcutaneous use. Initial U.S. Approval: 2019. Available at https://www.alnylam.com/sites/default/files/pdfs/GIVLAARI-Prescribing-Information.pdf. Accessed May 3, 2023.
6. Wang B, Bonkovsky HL, Lim JK, et al. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology. Mar 2023; 164(3): 484-491. PMID 36642627
7. National Institute for Health and Care Excellence. Givosiran for treating acute hepatic porphyria. Highly specialized technologies guidance. Reference number:HST16. Published: 24 November 2021. Available at https://www.nice.org.uk/guidance/hst16. Accessed May 3, 2023.
8. Givlaari (givosiran) Prescribing Information. Updated FDA labeling including pancreatitis warning approved April 10, 2024; DailyMed update September 10, 2025.
9.  Wang B, Bonkovsky HL, Lim JK, et al. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias. Gastroenterology. 2023.
10.  Kuter DJ, Bonkovsky HL, Monroy S, et al. Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial. Journal of Hepatology. 2023.
11.  Sardh E, Balwani M, Rees DC, et al. Long‑term follow‑up of givosiran treatment in patients with acute intermittent porphyria. Orphanet Journal of Rare Diseases. 2024.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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