GIVLAARI
Generic: GIVOSIRAN SODIUM
Basic Information
Manufacturer
Alnylam Pharmaceuticals, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
SUBCUTANEOUS
FDA Set ID
167e663c-11e1-497b-a3fc-951d65d58eaa
Indications & 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 )
GIVLAARI is an aminolevulinate synthase 1-directed small interfering RNA indicated for the treatment of adults with acute hepatic porphyria (AHP).
( 1 )
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 .
6.1 Clinical 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) ].
6.2 Immunogenicity 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.
6.3 Postmarketing 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 Disorders: Acute pancreatitis
( 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 .
6.1 Clinical 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) ].
6.2 Immunogenicity 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.
6.3 Postmarketing 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 Disorders: Acute pancreatitis