Givlaari

GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP).

The recommended dose of GIVLAARI is 2.5 mg/kg once monthly by subcutaneous injection. (

Injection: 189 mg/mL clear, colorless-to-yellow solution in a single-dose vial

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

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.

• 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 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. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.
  )
• 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 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.
  ,
  5.2 Hepatic Toxicity

  Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients treated with GIVLAARI in the placebo-controlled trial

  [see Adverse Reactions (6.1)]

  . Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

  Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. For resumption of dosing after interruption,

  see Dosage and Administration (2.1)

  .
  )
• Renal Toxicity: Monitor renal function during treatment with GIVLAARI as clinically indicated. (
  5.3 Renal Toxicity

  Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI

  [see Adverse Reactions (6.1)]

  . In the placebo-controlled study, 15% of the patients in the GIVLAARI arm experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.
  )
• Injection Site Reactions: May occur, including recall reactions. Monitor for reactions and manage clinically as needed. (
  5.4 Injection Site Reactions

  Injection site reactions have been reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. Among 12 patients with reactions, the highest severity of the reaction was mild among 11 (92%) patients and moderate in one (8%) patient. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration

  [see Adverse Reactions (6.1)]

  .
  )
• 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 Blood Homocysteine Increased

  Increases in blood homocysteine levels have occurred in patients receiving GIVLAARI

  [see Adverse Reactions (6.1)]

  . In the ENVISION study, during the open label extension, adverse reactions of blood homocysteine increased were reported in 15 of 93 (16%) patients treated with GIVLAARI. The clinical relevance of the elevations in blood homocysteine during treatment with GIVLAARI is unknown. Measure blood homocysteine levels prior to initiating treatment and monitor for changes during treatment with GIVLAARI. In patients with elevated blood homocysteine levels, assess folate, vitamins B12 and B6. Consider treatment with a supplement containing vitamin B6 (as monotherapy or a multivitamin preparation).
  )
• 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 Pancreatitis

  Cases of acute pancreatitis, some severe, have been reported in GIVLAARI-treated patients.

  Consider acute pancreatitis as a potential diagnosis in GIVLAARI-treated patients with signs/symptoms of acute pancreatitis including acute upper abdominal pain, clinically significant elevation of pancreatic enzymes, and/or imaging findings of acute pancreatitis, to ensure appropriate management. Consider interruption and/or discontinuation of GIVLAARI treatment for severe cases.
  )