Givosiran

Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 ( ALAS1 ) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP.

• GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA indicated for the treatment of adults with acute hepatic porphyria (AHP).

• GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis [see Warnings and Precautions (5.1) ].contraindicated

The recommended dose of GIVLAARI is 2.5 mg/kg once monthly by subcutaneous injection. ( 2.1 ) 2.1 Recommended Dosage The recommended dose of GIVLAARI is 2.5 mg/kg administered via subcutaneous injection once monthly. Dosing is based on actual body weight. Missed Dose Administer GIVLAARI as soon as possible after a missed dose. Resume dosing at monthly intervals following administration of the missed dose. Dose Modification for Adverse Reactions In patients with severe or clinically significant transaminase elevations, who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly [see Warnings and Precautions (5.2) ] . In patients who resume dosing at 1.25 mg/kg once monthly without recurrence of severe or clinically significant transaminase elevations, the dose may be increased to the recommended dose of 2.5 mg/kg once monthly. 2.2 Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI [see Warnings and Precautions (5.1) ]. GIVLAARI is intended for subcutaneous use by a healthcare professional only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GIVLAARI is a sterile, preservative-free, clear, colorless-to-yellow solution. It is supplied in a single-dose vial, as a ready-to-use solution that does not require additional reconstitution or dilution prior to administration. Use aseptic technique.

Anaphylactic Reaction: Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms. If anaphylaxis occurs, discontinue GIVLAARI and administer appropriate medical treatment. ( 5.1 ) Hepatic Toxicity: Measure liver function at baseline and periodically during treatment with GIVLAARI. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. ( 2.1 , 5.2 ) Renal Toxicity: Monitor renal function during treatment with GIVLAARI as clinically indicated. ( 5.3 ) Injection Site Reactions: May occur, including recall reactions. Monitor for reactions and manage clinically as needed. ( 5.4 ) Blood Homocysteine Increased: Measure blood homocysteine at baseline and monitor for changes during treatment with GIVLAARI. In patients with elevated blood homocysteine, consider supplementation with vitamin B6 (as monotherapy or multivitamin). ( 5.5 ) Pancreatitis: Consider acute pancreatitis as a potential diagnosis in GIVLAARI-treated patients with acute upper abdominal pain, clinically significant elevation of pancreatic enzymes and/or imaging findings of acute pancreatitis, to ensure appropriate management. ( 5.6 ) 5.1 Anaphylactic Reaction Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials) [see Adverse Reactions (6.1) ] . Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Anaphylactic Reaction [see Warnings and Precautions (5.1) ] Transaminase Elevations [see Warnings and Precautions (5.2) ] Serum Creatinine Increase [see Warnings and Precautions (5.3) ] Injection Site Reactions [see Warnings and Precautions (5.4) ] Blood Homocysteine Increased [see Warnings and Precautions (5.5) ] Pancreatitis [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥20% of patients) included nausea and injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the pivotal placebo-controlled, double-blind study (ENVISION), 48 patients received 2.5 mg/kg GIVLAARI and 46 patients received placebo, administered once monthly via subcutaneous injection for up to 6 months. Patients received GIVLAARI for a median of 5.5 months (range 2.7-6.4 months). Of these, 47 patients received ≥5 months of treatment. The most frequently occurring (≥20% incidence) adverse reactions reported in patients treated with GIVLAARI were nausea (27%) and injection site reactions (25%).

8.1 Pregnancy Risk Summary In animal reproduction studies, subcutaneous administration of givosiran to pregnant rabbits during the period of organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity (see Data ). There are no available data with GIVLAARI use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider the benefits and risks of GIVLAARI for the mother and potential adverse effects to the fetus when prescribing GIVLAARI to a pregnant woman. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24% to 95% of AHP patients, with maternal mortality ranging from 2% to 42%. Pregnancy in AHP patients is associated with higher rates of spontaneous abortion, hypertension and low birth weight infants.

Metabolism

The pharmacokinetics of givosiran and its active metabolite [AS(N-1)3′ givosiran] were evaluated following single and multiple dosing in chronic high excreter subjects and AHP patients as summarized in Table 2. Table 2.

• Nov 20, 2019NDANDA212194Alnylam Pharms Inc

1. 1Porphyria Acute43632%
2. 2Hospitalisation15912%
3. 3Product Dose Omission Issue1037.5%
4. 4Nausea987.2%
5. 5Therapy Interrupted936.8%
6. 6Fatigue906.6%
7. 7Intentional Dose Omission846.1%
8. 8Pain836.1%
9. 9Abdominal Pain654.7%
10. 10Malaise654.7%
11. 11Vomiting614.5%
12. 12Ill-defined Disorder564.1%
13. 13Seizure554.0%
14. 14Unevaluable Event443.2%
15. 15Drug Ineffective433.1%

The 6 most recently updated of 6 ClinicalTrials.gov registrations naming Givosiran as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• ELEVATE, a Registry of Patients With Acute Hepatic Porphyria (AHP)
  Recruiting · Observational · 150 enrolled · Alnylam Pharmaceuticals
  NCT04883905updated 2026-04-27
• Expanded Access Protocol of Givosiran for Patients With Acute Hepatic Porphyria
  Approved for marketing · Expanded access · Alnylam Pharmaceuticals
  NCT04056481updated 2024-05-20
• ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
  Completed · Phase 3 · Interventional · 94 enrolled · Alnylam Pharmaceuticals
  NCT03338816updated 2024-04-22
• A Study to Evaluate Long-term Safety and Clinical Activity of Givosiran (ALN-AS1) in Patient With Acute Intermittent Porphyria (AIP)
  Completed · Phase 1 · Phase 2 · Interventional · 16 enrolled · Alnylam Pharmaceuticals
  NCT02949830updated 2024-03-12
• A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)
  Completed · Phase 1 · Interventional · 10 enrolled · Alnylam Pharmaceuticals
  NCT03505853updated 2019-03-12
• A Phase 1 Study of Givosiran (ALN-AS1) in Patients With Acute Intermittent Porphyria (AIP)
  Completed · Phase 1 · Interventional · 40 enrolled · Alnylam Pharmaceuticals
  NCT02452372updated 2018-06-14

Frequently asked questions

How does Givosiran work?

Givosiran is a double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 ( ALAS1 ) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. This leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP.

What is Givosiran used for?

According to FDA labeling, Givosiran carries indications including: GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA indicated for the treatment of adults with acute hepatic porphyria (AHP).. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Givosiran?

Givosiran is classified as Various alimentary tract and metabolism products, Aminolevulinate Synthase 1-directed RNA Interaction, Small Interfering RNA, Decreased RNA Integrity, Decreased Transcription to RNA.

What are the brand names for Givosiran?

Givosiran is marketed under brand names including Givlaari.

What are the contraindications for Givosiran?

Givosiran labeling lists contraindications including: GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis [see Warnings and Precautions (5.1) ].. Always consult the full prescribing information and a clinician.