GIVLAARI givosiran sodium 189 mg/mL Injection, Solution, 1 vial
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Small Interfering RNA class.
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🏭 Manufacturer & labeler
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🩺 Clinical
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
1 inactive ingredient listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $42,041.94 | $42,041.94 / 1 ml |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
| Medicare Part B allowsASP · J0223 | $120.915 / J0223 unit | — |
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🧾 Billing & reimbursement
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Givlaari 189 mg/mLthis 71336-1001-01 | Alnylam | 1 vial | — | — | FDA listed | — |
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⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 9631193 ↗ | Method of use | U-2672 | Mar 15, 2033 |
| US 10131907 ↗ | Drug substance | U-2672 | Aug 24, 2028 |
| US 10125364 ↗ | Drug substance | U-2672 | Mar 15, 2033 |
| US 8106022 ↗ | Drug substance | U-2672 | Dec 12, 2029 |
| US 10119143 ↗ | Drug substance | U-2672 | Oct 3, 2034 |
| US 9133461 ↗ | Drug substance | U-2672 | Nov 30, 2033 |
| US 8828956 ↗ | Drug substance | U-2672 | Dec 4, 2028 |
| US 11028392 ↗ | Drug substance | U-2672 | Oct 3, 2034 |
| Code | What it grants | Expires |
|---|---|---|
| ODE-273 | Orphan Drug Exclusivity (7-year) | Nov 20, 2026 |
Is there a generic version of GIVLAARI 189 MG/ML VIAL?
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🗺️ Medicaid utilization & spend
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 71336-1001-01 You're viewing this | 1 VIAL, SINGLE-USE in 1 CARTON (71336-1001-1) / 1 mL in 1 VIAL, SINGLE-USE | 2019-12-12 | Active |
🧭 About this NDC listing & data coverage
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| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | ✓ Available |
| Medicaid utilization (CMS SDUD) | ✓ Available |
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE GIVLAARI is indicated for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA indicated for the treatment of adults with acute hepatic porphyria (AHP). ( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION The recommended dose of GIVLAARI is 2.5 mg/kg once monthly by subcutaneous injection. ( 2.1 )
2.1Recommended Dosage The recommended dose of GIVLAARI is 2.5 mg/kg administered via subcutaneous injection once monthly. Dosing is based on actual body weight. Missed Dose Administer GIVLAARI as soon as possible after a missed dose.
Resume dosing at monthly intervals following administration of the missed dose. Dose Modification for Adverse Reactions In patients with severe or clinically significant transaminase elevations, who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly [see Warnings and Precautions (5.2) ] . In patients who resume dosing at 1.25 mg/kg once monthly without recurrence of severe or clinically significant transaminase elevations, the dose may be increased to the recommended dose of 2.5 mg/kg once monthly.
2.2Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI [see Warnings and Precautions (5.1) ]. GIVLAARI is intended for subcutaneous use by a healthcare professional only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
GIVLAARI is a sterile, preservative-free, clear, colorless-to-yellow solution. It is supplied in a single-dose vial, as a ready-to-use solution that does not require additional reconstitution or dilution prior to administration. Use aseptic technique.
Calculate the required volume of GIVLAARI based on the recommended weight-based dosage [see Dosage and Administration (2.1) ] . Withdraw the indicated injection volume of GIVLAARI using a 21-gauge or larger needle. Divide doses requiring volumes greater than 1.5 mL equally into multiple syringes.
Replace the 21-gauge or larger needle with either a 25-gauge or 27-gauge needle with 1/2" or 5/8" needle length. Avoid having GIVLAARI on the needle tip until the needle is in the subcutaneous space. Administer injection into the abdomen, the back or side of the upper arms, or the thighs.
Rotate injection sites. An injection should never be given into scar tissue or areas that are reddened, inflamed, or swollen. If injecting into the abdomen, avoid a 5 cm diameter circle around the navel.
If more than one injection is needed for a single dose of GIVLAARI, the injection sites should be at least 2 cm apart from previous injection locations. Discard unused portion of the drug.
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Injection: 189 mg/mL clear, colorless-to-yellow solution in a single-dose vial Injection: 189 mg/mL in a single-dose vial. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis [see Warnings and Precautions (5.1) ]. Severe hypersensitivity to givosiran. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Anaphylactic Reaction: Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms. If anaphylaxis occurs, discontinue GIVLAARI and administer appropriate medical treatment.
( 5.1 ) Hepatic Toxicity: Measure liver function at baseline and periodically during treatment with GIVLAARI. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. ( 2.1 , 5.2 ) Renal Toxicity: Monitor renal function during treatment with GIVLAARI as clinically indicated.
( 5.3 ) Injection Site Reactions: May occur, including recall reactions. Monitor for reactions and manage clinically as needed. ( 5.4 ) Blood Homocysteine Increased: Measure blood homocysteine at baseline and monitor for changes during treatment with GIVLAARI.
In patients with elevated blood homocysteine, consider supplementation with vitamin B6 (as monotherapy or multivitamin). ( 5.5 ) Pancreatitis: Consider acute pancreatitis as a potential diagnosis in GIVLAARI-treated patients with acute upper abdominal pain, clinically significant elevation of pancreatic enzymes and/or imaging findings of acute pancreatitis, to ensure appropriate management. ( 5.6 )
5.1Anaphylactic Reaction Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials) [see Adverse Reactions (6.1) ] . Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.
5.2Hepatic Toxicity Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients treated with GIVLAARI in the placebo-controlled trial [see Adverse Reactions (6.1) ] . Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment. Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter.
Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. For resumption of dosing after interruption, see Dosage and Administration (2.1) .
5.3Renal Toxicity Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI [see Adverse Reactions (6.1) ] . In the placebo-controlled study, 15% of the patients in the GIVLAARI arm experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.
5.4Injection Site Reactions Injection site reactions have been reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. Among 12 patients with reactions, the highest severity of the reaction was mild among 11 (92%) patients and moderate in one (8%) patient.
One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration [see Adverse Reactions (6.1) ] .
5.5Blood Homocysteine Increased Increases in blood homocysteine levels have occurred in patients receiving GIVLAARI [see Adverse Reactions (6.1) ] . In the ENVISION study, during the open label extension, adverse reactions of blood homocysteine increased were reported in 15 of 93 (16%) patients treated with GIVLAARI. The clinical relevance of the elevations in blood homocysteine during treatment with GIVLAARI is unknown.
Measure blood homocysteine levels prior to initiating treatment and monitor for changes during treatment with GIVLAARI. In patients with elevated blood…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Anaphylactic Reaction [see Warnings and Precautions (5.1) ] Transaminase Elevations [see Warnings and Precautions (5.2) ] Serum Creatinine Increase [see Warnings and Precautions (5.3) ] Injection Site Reactions [see Warnings and Precautions (5.4) ] Blood Homocysteine Increased [see Warnings and Precautions (5.5) ] Pancreatitis [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥20% of patients) included nausea and injection site reactions.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the pivotal placebo-controlled, double-blind study (ENVISION), 48 patients received 2.5 mg/kg GIVLAARI and 46 patients received placebo, administered once monthly via subcutaneous injection for up to 6 months. Patients received GIVLAARI for a median of 5.5 months (range 2.7-6.4 months).
Of these, 47 patients received ≥5 months of treatment. The most frequently occurring (≥20% incidence) adverse reactions reported in patients treated with GIVLAARI were nausea (27%) and injection site reactions (25%). Permanent discontinuation occurred in one patient due to elevated transaminases.
Table 1: Adverse Reactions that Occurred at Least 5% More Frequently in Patients Treated with GIVLAARI Compared to Patients Treated with Placebo Adverse Reaction GIVLAARI N=48 N (%) Placebo N=46 N (%) Nausea 13 (27) 5 (11) Injection site reactions 12 (25) 0 Rash Grouped term includes pruritus, eczema, erythema, rash, rash pruritic, urticaria 8 (17) 2 (4) Serum creatinine increase Grouped term includes blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease (decreased eGFR) 7 (15) 2 (4) Transaminase elevations 6 (13) 1 (2) Fatigue 5 (10) 2 (4) Adverse reactions observed at a lower frequency occurring in placebo-controlled and open-label clinical studies included anaphylactic reaction (one patient, 0.9%) and hypersensitivity (one patient, 0.9%).
In the ENVISION study, during the open label extension, adverse reactions of blood homocysteine increased were reported in 15 of 93 (16%) patients treated with GIVLAARI [see Warnings and Precautions (5.5) ].
6.2Immunogenicity As with all oligonucleotides, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In placebo-controlled and open-label clinical studies, 1 of 111 patients with AHP (0.9%) developed treatment-emergent anti-drug antibodies (ADA) during treatment with GIVLAARI. No clinically significant differences in the clinical efficacy, safety, pharmacokinetic, or pharmacodynamic profiles of GIVLAARI were observed in the patient who tested positive for anti-givosiran antibodies.
6.3Postmarketing Experience The following additional adverse reactions have been reported during post-approval use. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Sensitive CYP1A2 and CYP2D6 Substrates: Avoid concomitant use with CYP1A2 and CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.1 )
7.1Effect of GIVLAARI on Other Drugs Sensitive CYP1A2 and CYP2D6 Substrates Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates [see Clinical Pharmacology (12.3) ] , which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates, for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary In animal reproduction studies, subcutaneous administration of givosiran to pregnant rabbits during the period of organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity (see Data ). There are no available data with GIVLAARI use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider the benefits and risks of GIVLAARI for the mother and potential adverse effects to the fetus when prescribing GIVLAARI to a pregnant woman.
The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24% to 95% of AHP patients, with maternal mortality ranging from 2% to 42%. Pregnancy in AHP patients is associated with higher rates of spontaneous abortion, hypertension and low birth weight infants. Data Animal Data In an embryo-fetal development study in pregnant rabbits, givosiran was administered subcutaneously at doses of 0.5, 1.5, and 5 mg/kg/day during organogenesis (gestational days 7-19) or 20 mg/kg as a single administration on gestation day 7.
Administration of givosiran was maternally toxic based on decreased body weight gain at all dose levels tested and resulted in increased postimplantation loss starting at 1.5 mg/kg/day. An increased incidence of skeletal variations of the sternebrae was observed at 20 mg/kg. The 1.5 mg/kg/day dose in rabbits is 5 times the maximum recommended human dose (MRHD) of 2.5 mg/kg/month normalized to 0.089 mg/kg/day, based on body surface area.
In a combined fertility and embryo-fetal development study in female rats, givosiran was administered subcutaneously at doses of 0.5 to 5 mg/kg/day during organogenesis (gestational days 6-17). The 5 mg/kg/day dose (9 times the normalized MRHD based on body surface area) was associated with a skeletal variation (incomplete ossification of pubes) and produced maternal toxicity. In a pre- and postnatal development study, givosiran administered subcutaneously to pregnant rats on gestation days 7, 13, and 19 and postnatal days 6, 12, and 18 at doses up to 30 mg/kg did not produce maternal toxicity or developmental effects in the offspring.
8.2Lactation Risk Summary There are no data on the presence of GIVLAARI in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GIVLAARI and any potential adverse effects on the breastfed child from GIVLAARI or from the underlying maternal condition.
8.4Pediatric Use Safety and effectiveness in pediatric patients have not been established.
8.5Geriatric Use Clinical studies of GIVLAARI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary In animal reproduction studies, subcutaneous administration of givosiran to pregnant rabbits during the period of organogenesis resulted in adverse developmental outcomes at doses that produced maternal toxicity (see Data ). There are no available data with GIVLAARI use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Consider the benefits and risks of GIVLAARI for the mother and potential adverse effects to the fetus when prescribing GIVLAARI to a pregnant woman.
The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Porphyria attacks during pregnancy, often triggered by hormonal changes, occur in 24% to 95% of AHP patients, with maternal mortality ranging from 2% to 42%. Pregnancy in AHP patients is associated with higher rates of spontaneous abortion, hypertension and low birth weight infants. Data Animal Data In an embryo-fetal development study in pregnant rabbits, givosiran was administered subcutaneously at doses of 0.5, 1.5, and 5 mg/kg/day during organogenesis (gestational days 7-19) or 20 mg/kg as a single administration on gestation day 7.
Administration of givosiran was maternally toxic based on decreased body weight gain at all dose levels tested and resulted in increased postimplantation loss starting at 1.5 mg/kg/day. An increased incidence of skeletal variations of the sternebrae was observed at 20 mg/kg. The 1.5 mg/kg/day dose in rabbits is 5 times the maximum recommended human dose (MRHD) of 2.5 mg/kg/month normalized to 0.089 mg/kg/day, based on body surface area.
In a combined fertility and embryo-fetal development study in female rats, givosiran was administered subcutaneously at doses of 0.5 to 5 mg/kg/day during organogenesis (gestational days 6-17). The 5 mg/kg/day dose (9 times the normalized MRHD based on body surface area) was associated with a skeletal variation (incomplete ossification of pubes) and produced maternal toxicity. In a pre- and postnatal development study, givosiran administered subcutaneously to pregnant rats on gestation days 7, 13, and 19 and postnatal days 6, 12, and 18 at doses up to 30 mg/kg did not produce maternal toxicity or developmental effects in the offspring.
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness in pediatric patients have not been established.
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of GIVLAARI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Givosiran is a 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.
12.2Pharmacodynamics The pharmacodynamic effects of GIVLAARI were evaluated in chronic high excreters treated with 0.035 to 2.5 mg/kg single dose and AHP patients treated with 2.5 to 5 mg/kg once monthly and 2.5 to 5 mg/kg once quarterly dose via subcutaneous injection. Dose-dependent reduction in urinary ALAS1 mRNA, ALA and PBG levels was observed over the 0.035 to 5 mg/kg dose range (0.14 to 2-fold the approved recommended dosage). Median reductions from baseline in urinary ALA and PBG of 83.7% and 75.1%, respectively, were observed 14 days after the first dose of GIVLAARI 2.5 mg/kg once monthly in AHP patients.
Maximal reductions in ALA and PBG levels were achieved around Month 3, with median reductions from baseline of 93.8% for ALA and 94.5% for PBG, and were sustained thereafter with repeated once monthly dosing. Cardiac Electrophysiology The effect of GIVLAARI on the QTc interval was evaluated in a double-blind, placebo-controlled study and the open-label extension in 94 patients. No large mean increase in QTc (i.e. >20 ms) was detected at the 2.5 mg/kg once monthly dose level.
A dedicated thorough QT study has not been conducted with GIVLAARI.
12.3Pharmacokinetics The pharmacokinetics of givosiran and its active metabolite [AS(N-1)3′ givosiran] were evaluated following single and multiple dosing in chronic high excreter subjects and AHP patients as summarized in Table 2. Table 2. Pharmacokinetic Parameters of Givosiran and Its Active Metabolite Givosiran AS(N-1)3′ Givosiran General Information Steady-State Exposure C max [Mean (CV%)] 321 ng/mL (51%) 123 ng/mL (64%) AUC 24 [Mean (CV%)] 4130 ng∙h/mL (43%) 1930 ng∙h/mL (63%) Dose Proportionality Steady-state maximum plasma concentration (C max ) and area under the curve (AUC) for givosiran and AS(N-1)3′ givosiran increase proportionally over the 0.35 mg/kg to 2.5 mg/kg once monthly dose range (0.14 to 1-fold the approved recommended dosage).
C max and AUC for givosiran and AS(N-1)3′ givosiran increase slightly greater than proportionally at doses greater than 2.5 mg/kg once monthly. Accumulation No accumulation of givosiran or AS(N-1)3′ givosiran was observed following multiple dosing. Absorption T max [Median (range)] 3 (0.5-8) hours 7 (1.5-12) hours Distribution Apparent Central Volume of Distribution (Vz/F) [Mean (RSE%)] Based on population PK model estimation.
10.4L (2.3%) Protein Binding 90% Givosiran plasma protein binding was concentration-dependent and decreased with increasing givosiran concentrations (from 92% at 1 µg/mL to 21% at 50 µg/mL). Not evaluated Organ Distribution Givosiran and AS(N-1)3′ givosiran distribute primarily to the liver after subcutaneous dosing. Elimination Half-Life [Mean (CV%)] 6 hours (46%) 6 hours (41%) Apparent Clearance [Mean (CV%)]
35.1 L/hr (18%)
64.7L/hr (33%) Metabolism Primary Pathway Givosiran is metabolized by nucleases to oligonucleotides of shorter lengths. Givosiran is not a substrate of CYP enzymes Based on in vitro study result. . Active Metabolite The active metabolite, AS(N-1)3′ givosiran, is equipotent to givosiran in plasma and the AUC 0-24 represents 45% of givosiran AUC, at the approved recommended givosiran dosage.
Excretion Primary Pathway The dose recovered in urine was 5%-14% as givosiran and 4%-13% as AS(N-1)3′ givosiran After single and multiple subcutaneous doses of givosiran 2.5 mg/kg and 5 mg/kg. . Specific Populations No clinically meaningful differences in givosiran pharmacokinetics or pharmacodynamics (percent reduction in urinary ALA and PBG) were obs…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Givosiran is a 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.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How Supplied GIVLAARI (givosiran) is a clear, colorless-to-yellow ready-to-use solution available in single-dose vials of 189 mg/mL in cartons containing one vial (NDC 71336-1001-1).
16.2Storage and Handling Store at 2°C to 25°C (36°F to 77°F). Store GIVLAARI in its original container until ready for use.
📦 Storage and Handling ▾
16.2Storage and Handling Store at 2°C to 25°C (36°F to 77°F). Store GIVLAARI in its original container until ready for use.
📋 Description ▾
11 DESCRIPTION GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA (siRNA), covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes. The structural formulas of the givosiran drug substance in its sodium form, and the ligand (L96), are presented below. Abbreviations: Af = adenine 2'-F ribonucleoside; Cf = cytosine 2'-F ribonucleoside; Uf = uracil 2'-F ribonucleoside; Am = adenine 2'-OMe ribonucleoside; Cm = cytosine 2'-OMe ribonucleoside; Gf = guanine 2'-F ribonucleoside; Gm = guanine 2'-OMe ribonucleoside; Um = uracil 2'-OMe ribonucleoside; L96 = triantennary GalNAc (N-acetylgalactosamine) GIVLAARI is supplied as a sterile, preservative-free, 1-mL colorless-to-yellow solution for subcutaneous injection containing 189 mg givosiran in a single-dose, 2-mL Type 1 glass vial with a fluoropolymer-coated rubber stopper and a flip-off aluminum seal.
GIVLAARI is available in cartons containing one single-dose vial each . GIVLAARI is formulated in Water for Injection. Sodium hydroxide and/or phosphoric acid may have been added for pH adjustment during product manufacturing.
The molecular formula of givosiran sodium is C 524 H 651 F 16 N 173 Na 43 O 316 P 43 S 6 with a molecular weight of 17,245.56 Da. The molecular formula of givosiran (free acid) is C 524 H 694 F 16 N 173 O 316 P 43 S 6 with a molecular weight of 16,300.34 Da. Chemical Structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise patients of the potential risks of GIVLAARI treatment: Anaphylactic Reaction: Inform patients about the risk and possible symptoms of severe hypersensitivity reactions that could occur [see Warnings and Precautions (5.1) ] . Hepatic Toxicity: Inform patients that transaminase elevations may occur, and that laboratory testing will be conducted in the first 6 months of treatment and as clinically indicated thereafter [see Warnings and Precautions (5.2) ] . Renal Toxicity: Inform patients that increases in serum creatinine and decreases in eGFR have been reported and that laboratory testing will be conducted as clinically indicated [see Warnings and Precautions (5.3) ] .
Injection Site Reactions: Inform patients of the signs and symptoms of injection site reactions (examples include redness, pain, itching, rash, discoloration, or localized swelling) [see Warnings and Precautions (5.4) ]. Blood Homocysteine Increased : Inform patients that increases in blood homocysteine levels have been reported when using GIVLAARI, and that laboratory testing will be conducted prior to and during treatment with GIVLAARI. Vitamin supplementation may be considered for elevated blood homocysteine levels [see Warnings and Precautions (5.5) ].