Acute hepatic porphyria: SubQ: 2.5 mg/kg once monthly. Note: Dosing is based on actual body weight.
Missed dose: Administer as soon as possible; then resume dosing at monthly intervals.
eGFR ≥15 to <89 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling; however, no clinically meaningful differences in givosiran pharmacokinetics were observed in patients with eGFR ≥15 to <89 mL/minute/1.73 m2.
eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Preexisting hepatic impairment:
Mild impairment (bilirubin ≤ ULN and AST > ULN, or bilirubin >1 to 1.5 × ULN): There are no dosage adjustments provided in the manufacturer’s labeling; however, no clinically meaningful differences in givosiran pharmacokinetics were observed in patients with mild hepatic impairment.
Moderate or severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Hepatotoxicity during treatment: If severe or clinically significant transaminase elevations occur during therapy, discontinue givosiran. If transaminase levels improve after discontinuing givosiran, may restart at a reduced dose of 1.25 mg/kg once monthly and further increase dose to 2.5 mg/kg once monthly if no recurrence of elevated transaminases on the reduced dose.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous, as sodium [preservative free]:
Givlaari: 189 mg/mL (1 mL)
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous, as sodium:
Givlaari: 189 mg/mL (1 mL)
SubQ: For SubQ administration by a health care professional only. Ensure the availability of proper medical support to appropriately manage anaphylactic reactions during administration. Use a 25-gauge or 27-gauge needle with 1/2-inch or 5/8-inch needle length for administration; avoid givosiran solution on the needle tip until the needle is in the SubQ space. Administer into the abdomen (avoid the 5-cm diameter around the navel), thighs, or the back or side of upper arms. Rotate injection sites; do not inject into scar tissue or inflamed, reddened, or swollen areas. If more than one injection is needed for a single dose, space injection sites ≥2 cm apart. Discard unused portion.
Acute hepatic porphyria: Treatment of adults with acute hepatic porphyria.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Eczema (≤17%), erythema of skin (≤17%), pruritic rash (≤17%), pruritus (≤17%), skin rash (≤17%), urticaria (≤17%)
Endocrine & metabolic: Homocystinemia (16%)
Gastrointestinal: Nausea (27%)
Hepatic: Increased serum alanine aminotransferase (≥3 x ULN: 15%), increased serum transaminases (13%)
Local: Injection site reaction (25%; including transient recall erythema at prior injection site)
Renal: Chronic renal failure (≤15%), decreased estimated GFR (eGFR) (≤15%), increased serum creatinine (≤15%)
1% to 10%: Nervous system: Fatigue (10%)
<1%:
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Immunologic: Antibody development
Severe hypersensitivity (eg, anaphylaxis) to givosiran or any component of the formulation.
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis has occurred; ensure the availability of proper medical support to appropriately manage anaphylactic reactions during administration. Discontinue and administer appropriate medical treatment if anaphylaxis occurs.
• Hepatic toxicity: Transaminase elevations (ALT) of ≥3 times the ULN have occurred, primarily between 3 to 5 months following initiation of therapy. Interrupt or discontinue use if severe or clinically significant transaminase elevations occur during therapy.
• Homocysteine: Increases in blood homocysteine levels have been reported; treat appropriately.
• Injection-site reactions: Injection-site reactions have been reported, including erythema, pain, pruritus, rash, discoloration, and swelling around the injection site; monitor and treat appropriately.
• Renal toxicity: Increases in serum creatinine and decreases in eGFR have been reported.
Inhibits CYP1A2 (moderate), CYP2C19 (weak), CYP2D6 (moderate), CYP3A4 (weak)
Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Risk C: Monitor therapy
Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Risk C: Monitor therapy
Alosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Alosetron. Management: Avoid concomitant use of alosetron and moderate CYP1A2 inhibitors whenever possible. If combined use is necessary, monitor for increased alosetron effects/toxicities. Risk D: Consider therapy modification
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Amitriptyline: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Amitriptyline. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy
Amoxapine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amoxapine. Risk C: Monitor therapy
Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities (including serotonin syndrome) if used with a moderate CYP2D6 inhibitor. Initiate amphetamine therapy at lower doses, monitor frequently, and adjust doses as needed. Discontinue amphetamines if serotoinin syndrome occurs Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Risk C: Monitor therapy
AtoMOXetine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of AtoMOXetine. Risk C: Monitor therapy
Bendamustine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bendamustine. Management: Consider alternatives to moderate CYP1A2 inhibitors during therapy with bendamustine due to the potential for increased bendamustine plasma concentrations and increased bendamustine toxicity. Risk D: Consider therapy modification
Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose when treating indications other than major depressive disorder. Risk C: Monitor therapy
Bromazepam: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Bromazepam. Risk C: Monitor therapy
Caffeine and Caffeine Containing Products: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
CarBAMazepine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Carvedilol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Risk C: Monitor therapy
CloBAZam: CYP2C19 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Weak) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
ClomiPRAMINE: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
ClomiPRAMINE: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of ClomiPRAMINE. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ClomiPRAMINE. Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
Desipramine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Desipramine. Risk C: Monitor therapy
Deutetrabenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Risk C: Monitor therapy
Dextromethorphan: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Dextromethorphan. Risk C: Monitor therapy
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Doxepin (Systemic): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Doxepin (Systemic). Risk C: Monitor therapy
Doxepin (Topical): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Doxepin (Topical). Risk C: Monitor therapy
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DULoxetine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of DULoxetine. Risk C: Monitor therapy
Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Risk D: Consider therapy modification
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flecainide: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Flecainide. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: CYP2C19 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Haloperidol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Haloperidol. Risk C: Monitor therapy
Iloperidone: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Iloperidone. Risk C: Monitor therapy
Imipramine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Imipramine. Concentrations of desipramine may be increased. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Imipramine. Risk C: Monitor therapy
Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Risk C: Monitor therapy
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Lofepramine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Lofepramine. The active metabolite of lofepramine is desipramine. Risk C: Monitor therapy
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification
Melatonin: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Melatonin. Risk C: Monitor therapy
Mequitazine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Mequitazine. Risk X: Avoid combination
Metoclopramide: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Metoclopramide. Risk C: Monitor therapy
Metoprolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Nortriptyline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nortriptyline. Risk C: Monitor therapy
OLANZapine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of OLANZapine. Risk C: Monitor therapy
Oliceridine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Oliceridine. Risk C: Monitor therapy
Olmutinib: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy
PARoxetine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of PARoxetine. Risk C: Monitor therapy
Pentoxifylline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy
Perhexiline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Perhexiline. Risk C: Monitor therapy
Perphenazine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Perphenazine. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Avoid concomitant use of pirfenidone and moderate CYP1A2 inhibitors whenever possible. If combined, decrease the pirfenidone dose to 1,602 mg per day (534 mg three times daily) and monitor for increased pirfenidone toxicities. Risk D: Consider therapy modification
Pitolisant: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Pitolisant. Risk C: Monitor therapy
Pomalidomide: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pomalidomide. Risk C: Monitor therapy
Propafenone: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Risk C: Monitor therapy
Propranolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Propranolol. Risk C: Monitor therapy
Protriptyline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Protriptyline. Risk C: Monitor therapy
Ramelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramelteon. Risk C: Monitor therapy
Ramosetron: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ramosetron. Risk C: Monitor therapy
Rasagiline: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Rasagiline. Management: Limit rasagiline dose to 0.5 mg once daily in patients taking moderate CYP1A2 inhibitors. Risk D: Consider therapy modification
RisperiDONE: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy
ROPINIRole: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Ropivacaine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Ropivacaine. Risk C: Monitor therapy
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
Tacrolimus (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives to the use of moderate CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with reduced clinical effectiveness of tamoxifen. Risk D: Consider therapy modification
Tamsulosin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy
Tasimelteon: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Tasimelteon. Risk C: Monitor therapy
Tetrabenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Theophylline Derivatives. Management: Consider avoidance of this combination. If coadministration is necessary, monitor for increased theophylline serum concentrations and toxicities when combined. Theophylline dose reductions will likely be required. Risk D: Consider therapy modification
Thioridazine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Thioridazine. Risk X: Avoid combination
Timolol (Systemic): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Timolol (Systemic). Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
TraMADol: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Trimipramine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Trimipramine. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Valbenazine: CYP2D6 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Valbenazine. Risk C: Monitor therapy
Vortioxetine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Vortioxetine. Risk C: Monitor therapy
Zuclopenthixol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Adverse events were observed in animal reproduction studies.
Outcome information following exposure to givosiran in pregnancy is limited (Sardh 2019).
It is not known if givosiran is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Signs and symptoms of anaphylaxis; liver function at baseline, every month during the first 6 months of therapy, and as clinically indicated; renal function during therapy and as clinically indicated; homocysteine at baseline and during therapy; folate, vitamins B12 and B6 in patients with elevated homocysteine.
Givosiran causes degradation of aminolevulinate synthase 1 (ALAS1) messenger RNA (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 and porphobilinogen, factors associated with attacks and other disease manifestations of acute hepatic porphyria.
Distribution: Vd: 10.4 L.
Protein binding: 90% (concentration dependent; decreases with increasing concentrations).
Metabolism: Metabolized by nucleases to oligonucleotides of shorter lengths; AS(N-1)3’ is the active metabolite and is equipotent to givosiran.
Half-life elimination: 6 hours.
Time to peak: Givosiran: 3 hours (range: 0.5 to 8 hours); AS(N-1)3’ givosiran: 7 hours (range: 1.5 to 12 hours).
Excretion: Urine (5% to 14% as unchanged drug; 4% to 13% as AS[N-1]3’givosiran).
Solution (Givlaari Subcutaneous)
189 mg/mL (per mL): $46,800.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.