General

Pronunciation:
giv-o-si-ran

Trade Name(s)

• Givlaari

Ther. Class.

none assigned

Pharm. Class.

aminolevulinate synthase 1 directed small interfering ribonucleic acids

Indications

Acute hepatic porphyria.

Action

Causes degradation of aminolevulinate synthase 1 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 health care 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, PANCREATITIS

GU: renal impairment

Hemat: ↑ homocysteine levels

Local: injection site reactions

Misc: fatigue, HYPERSENSITIVITY REACTIONS (including anaphylaxis)

* 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 necessary, ↓ dose of CYP1A2 substrate.
• May ↑ levels and risk of toxicity of  CYP2D6 substrates, including  dextromethorphan ; avoid concurrent use; if concurrent use necessary, ↓ dose of CYP2D6 substrate.

Route/Dosage

SUBQ (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.
• Monitor for signs and symptoms of pancreatitis (acute upper abdominal pain, ↑ amylase/lipase). Therapy should be held or discontinued for severe cases of pancreatitis.

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.
• May cause ↑ blood homocysteine levels. Monitor blood homocysteine levels at baseline and then periodically during therapy. If homocysteine levels become elevated, also assess folate, vitamin B12, and vitamin B6 levels, and consider initiating treatment with a vitamin supplement containing vitamin B6.

Implementation

• Administer by health care professional only. Have medical support available during injections to manage anaphylactic reactions.
• SUBQ 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 ½- or ⅝-inch needle length. Avoid having givosiran on needle tip until needle is in the SUBQ 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 or acute upper abdominal pain occur.
• Advise patient to notify health care professional if signs and symptoms of injection site reaction occur.
• Emphasize the importance of routine lab tests to monitor of side effects.
• Rep:  Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding.

Evaluation/Desired Outcomes

Reduction of porphyria attacks associated with hospitalizations, urgent health care visits, or IV hemin administration at home.