givosiran (Rx)

Brand and Other Names:Givlaari
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, SC solution

  • 189mg/mL (single-dose vial)

Acute Hepatic Porphyria

Indicated for acute hepatic porphyria (AHP)

2.5 mg/kg SC qMonth; dose based on actual body weight

Dosage Modifications

Transaminase elevations

  • Interrupt or discontinue for severe or clinically significant transaminase elevations
  • Severe or clinically significant transaminase elevations: Reduce dose to 1.25 mg/kg qMonth in patients who have dose interruption and subsequent transaminase improvement
  • In patients who resume dosing at 1.25 mg/kg qMonth without recurrence of severe or clinically significant transaminase elevations, may increase dose to 2.5 mg/kg qMonth

Renal impairment

  • Mild, moderate, or severe (eGFR 15 to <89 mL/min/1.73m2): No clinically meaningful differences in pharmacokinetics or pharmacodynamics
  • End-stage renal disease: Unknown

Hepatic impairment

  • Mild (bilirubin ≤1× ULN and AST >1 x ULN, or bilirubin >1-1.5 x ULN): No clinically meaningful differences in pharmacokinetics or pharmacodynamics
  • Moderate-to-severe: Unknown

Dosing Considerations

Measure liver function tests before initiating treatment, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter

Safety and efficacy not established

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Interactions

Interaction Checker

and givosiran

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Nausea (27%)

            Injection-site reactions (25%)

            Rash (17%)

            Increased serum creatinine (15%)

            Elevated transaminases (13%)

            1-10%

            Fatigue (10%)

            <1%

            Anaphylaxis

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            Warnings

            Contraindications

            Severe hypersensitivity, including anaphylaxis

            Cautions

            Anaphylaxis observed; ensure medical support is available to appropriately manage anaphylactic reactions when administering; monitor for signs and symptoms of anaphylaxis

            Transaminase elevations (ALT) of ≥3x ULN observed in the placebo-controlled trial; primarily occurred 3-5 months after initiating treatment; monitor

            Increased serum creatinine levels and decreased eGFR reported; monitor renal function as clinically indicated

            Injection-site reactions reported; symptoms included erythema, pain, pruritus, rash, discoloration, or swelling

            Drug interaction overview

            • In vitro studies indicate that givosiran does not directly inhibit or induce CYP enzymes; however, because of its pharmacological effects on the hepatic heme biosynthesis pathway, givosiran has the potential to reduce the activity of CYP enzymes in the liver
            • Sensitive CYP1A2 or CYP2D6 substrates
              • Sensitive CYP1A2 substrates: Coadministration increased caffeine (sensitive CYP1A2 substrate) AUC by 3.1-fold and Cmax by 1.3-fold
              • Sensitive CYP2D6 substrates: Coadministration increased dextromethorphan (sensitive CYP2D6 substrate) AUC by 2.4-fold and Cmax by 2-fold
              • Avoid use with CYP1A2 or CYP2D6 substrates, for which minimal concentration changes may lead to serious or life-threatening toxicities
              • If concomitant use is unavoidable, decrease CYP1A2 or CYP2D6 substrate dosage in accordance with its prescribing information
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            Pregnancy & Lactation

            Pregnancy

            Data are not available regarding use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Animal studies

            • Administration to pregnant rabbits during organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity

            Clinical considerations

            • Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24-95% of patients with AHP, with maternal mortality ranging from 2-42%
            • Pregnancy in patients with AHP is associated with higher rates of spontaneous abortion, hypertension, and low-birth-weight infants

            Lactation

            Data are not available regarding use in breastfeeding women

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            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

            Absorption

            Peak plasma time: 3 hr (parent drug); 7 hr (metabolite)

            Peak plasma concentration: 321 ng/mL (parent drug); 123 ng/mL (metabolite)

            AUC: 4130 ng⋅hr/mL (parent drug); 1930 ng⋅hr/mL (metabolite)

            Distribution

            Vd: 10.4 L

            Protein bound: 90% (parent drug)

            Organ distribution: Parent drug and metabolite primarily distributed to liver

            Metabolism

            Metabolized by nucleases to oligonucleotides of shorter lengths

            Not a substrate of CYP enzymes

            Active metabolite: AS(N-1)3' givosiran is equipotent to givosiran in plasma; AUC0-24 represents 45% of givosiran AUC at the recommended dosage

            Elimination

            Half-life: 6 hr (parent drug or metabolite)

            Clearance: 35.1 L/hr (18%; parent drug); 64.7 L/hr (33%; metabolite)

            Excretion: Urine 5-14% (parent drug); 4-13% (metabolite)

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            Administration

            SC Preparation

            Ensure that medical support is available to appropriately manage anaphylactic reactions when administering

            Inspect visually for particulate matter and discoloration before administration

            Givosiran is a sterile, preservative-free, clear, colorless-to-yellow ready-to-use solution

            Does not require additional reconstitution or dilution prior to administration

            SC Administration

            Intended for SC administration by a healthcare professional only

            Calculate weight-based dose

            Withdraw volume of solution from vial using ≥21-gauge needle

            Divide doses requiring volumes >1.5 mL equally into multiple syringes

            After withdrawing solution, replace the ≥21-gauge or larger needle with either a 25- or 27-gauge needle with 1/2” or 5/8” needle length

            Avoid having solution on the needle tip until the needle is in the SC space

            Administer SC into abdomen, back or side of upper arms, or thighs; rotate injection sites

            Do not inject into scar tissue or areas that are reddened, inflamed, or swollen

            If injecting into abdomen, avoid 5-cm diameter circle around the navel

            If >1 injection needed for a single dose, the injection sites should be at least 2 cm apart from previous injection locations

            Discard unused portion of the drug

            Missed dose

            • Administer as soon as possible after a missed dose
            • Resume dosing at monthly intervals following administration of the missed dose

            Storage

            Store refrigerated or at controlled room temperature of 2-25°C (36-77°F)

            Store in original container until ready for use

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.