General

Pronunciation:
giv-o-si-ran

Trade Name(s)

• Givlaari

Ther. Class.

none assigned

Pharm. Class.

temporary class

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)

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.

Adverse Reactions/Side Effects

Derm: rash

GI: ↑ liver enzymes, nausea

GU: renal impairment

Local: injection site reactions

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis), fatigue

* 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.

Potential Diagnoses

• Deficient knowledge, related to medication regimen (Patient/Family/Teaching) 

Implementation

• 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.