aminolevulinate synthase 1-directed small interfering ribonucleic acids
Indications
Acute hepatic porphyria.
Action
Causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, which subsequently reduces circulating levels of aminolevulinic acid and porphobilinogen, both of which accumulate in acute hepatic porphyria.
Therapeutic Effect(s):
Reduction of porphyria attacks associated with hospitalizations, urgent healthcare visits, or IV hemin administration at home.
Pharmacokinetics
Absorption: Unknown.
Distribution: Distributed primarily to liver.
Protein Binding: 90%.
Metabolism and Excretion: Metabolized by nucleases to oligonucleotides of shorter lengths, including an active metabolite. Primarily excreted in urine (5–14% as unchanged drug; 4–13% as active metabolite).
Half-life: Givosiran– 6 hr. Active metabolite– 6 hr.
TIME/ACTION PROFILE (plasma concentrations)
ROUTE
ONSET
PEAK
DURATION
Subcut
unknown
3 hr (givosiran); 7 hr (active metabolite)
unknown
Contraindication/Precautions
Contraindicated in:
Severe hypersensitivity.
Use Cautiously in:
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Pedi: Safety and effectiveness not established in children.
* CAPITALS indicate life-threatening. Underline indicate most frequent.
Interactions
Drug-Drug
May ↑ levels and risk of toxicity of CYP1A2 substrates, including caffeine ; avoid concurrent use; if concurrent use unavoidable, ↓ dose of CYP1A2 substrate.
May ↑ levels and risk of toxicity of CYP2D6 substrates, including dextromethorphan ; avoid concurrent use; if concurrent use unavoidable, ↓ dose of CYP2D6 substrate.
Route/Dosage
Subcut (Adults): 2.5 mg/kg (actual body weight) once monthly.
Availability
Solution for injection: 189 mg/mL
Assessment
Monitor for signs and symptoms of anaphylactic reactions (rash, hives, dyspnea, swelling of lips, face and throat) during therapy.
Assess for signs and symptoms of injection site reactions (erythema, pain, pruritus, rash, discoloration, swelling around injection site) during therapy.
Lab Test Considerations:
Measure liver function tests before starting therapy, repeat monthly during first 6 mo, and as clinically indicated. If clinically significant transaminase elevations occur, hold or discontinue therapy.
May cause ↑ serum creatinine and ↓ glomerular filtration rate. Monitor renal function periodically during therapy.
Administer by health care professional only. Have medical support available during injections to manage anaphylactic reactions.
Subcut Solution is clear and colorless to yellow; do not inject solutions that are cloudy, discolored, or contain particulate matter. Withdraw dose required using a 21–gauge or larger needle. Divide doses >1.5 mL equally into multiple doses. Replace needle with 25–27 gauge needle with 1/2 or 5/8 inch needle length. Avoid having givosiran on needle tip until needle is in the subcutaneous space. Inject into abdomen, back or side of upper arm, or thigh; rotate injection sites. Avoid scar tissue or areas that are red, inflamed, or swollen; if more than 1 injection needed, keep at least 2 cm between sites. Discard unused solution. Administer missed doses as soon as remembered; resume dosing at monthly intervals after administration of missed dose.
Patient/Family Teaching
Explain purpose of givosiran to patient.
Advise patient to notify health care professional immediately if signs and symptoms of anaphylaxis occur.
Advise patient to notify health care professional if signs and symptoms of injection site reaction occur.
Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding.
Emphasize the importance if routine lab tests to monitor of side effects.
Evaluation/Desired Outcomes
Reduction of porphyria attacks associated with hospitalizations, urgent healthcare visits, or IV hemin administration at home.
givosiran is a sample topic from the Davis's Drug Guide.
Davis’s Drug Guide for Nurses App + Web from F.A. Davis and Unbound Medicine covers 5000+ trade name and generic drugs. Includes App for iPhone, iPad, and Android smartphone + tablet. Handbook covers dosage, side effects, interactions, uses. Davis Drug Guide PDF. Complete Product Information.