Lanadelumab is a parenteral plasma kallikrein inhibitor, monoclonal antibody indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 2 years and older. Compared to other parenteral therapies for the prophylaxis of angioedema, lanadelumab offers the advantages of less frequent dosing and potentially better safety profile. In a randomized, placebo-controlled trial (RCT) in adult and pediatric patients 12 years and older, the mean reduction in HAE attack rate over 26 weeks was significantly higher in patients treated with lanadelumab compared to placebo. In a rollover, open-label extension of this study, patients receiving lanadelumab 300 mg subcutaneously every 2 weeks had a significantly reduced mean HAE attack rate (reduction vs baseline: 87.4% overall) over 33 months. At week 4, approximately 80% of patients who had been in the lanadelumab 300 mg subcutaneously every 2 weeks treatment group in the RCT remained attack free.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Lanadelumab solution is clear to slightly opalescent and colorless to slightly yellow; do not use if the solution appears discolored or contains visible particles.
-Lanadelumab may be administered by a health care provider or caregiver. Patients 12 years and older may self-administer.
Subcutaneous Administration
-Lanadelumab is available in a single-dose prefilled syringe or a single-dose vial. Additional reconstitution or dilution is not required for the vial or prefilled syringe.
-Take the medication out of the refrigerator 15 minutes before injection to allow it to reach room temperature.
-Avoid vigorous agitation of the vial or prefilled syringe.
Preparation of Single-Dose Vial
-Using an 18-gauge needle, remove prescribed dose from the vial.
-Change the needle to a 27-gauge, 1/2-inch needle or another needle suitable for subcutaneous injection.
-Storage: After preparing the dosing syringe, use within 2 hours if left at room temperature or 8 hours if refrigerated (2 to 8 degrees C or 36 to 46 degrees F). Discard any unused portions of the drug remaining in the vial and syringe.
Administration
-Inject the dose subcutaneously over 10 to 60 seconds into the abdomen, thigh, or upper arm.
Hypersensitivity reactions (1%) have been observed with lanadelumab. In clinical trials, rash, including maculopapular rash and erythematous rash, was reported in 7% of lanadelumab-treated patients. If a severe hypersensitivity reaction occurs, discontinue lanadelumab and institute appropriate treatment.
An injection site reaction, including pain, erythema, bruising or ecchymosis, hematoma, hemorrhage, pruritus, swelling, induration, paresthesias, warmth, edema, and rash, was reported in 52% of lanadelumab-treated patients in clinical trials. Pain, erythema, and bruising were most common.
Upper respiratory infection was reported in 29% of lanadelumab-treated patients in clinical trials.
Headache (21%) and dizziness (6%) were reported in lanadelumab-treated patients in clinical trials.
Myalgia was reported in 5% of lanadelumab-treated patients in clinical trials.
Diarrhea was reported in 5% of lanadelumab-treated patients in clinical trials.
Elevated hepatic enzymes were reported in a lanadelumab clinical trials. Increased aspartate transaminase (AST) and alanine transaminase (ALT) each occurred in 2% of lanadelumab-treated patients. In patients treated with lanadelumab, the incidences of patients with maximum transaminase (ALT or AST) concentrations more than 8, 5, or 3 times the upper limit of normal (ULN) were 1.2%, 0%, and 3.6%, respectively. These transaminase elevations were asymptomatic and transient. No patients receiving placebo experienced increases in hepatic enzymes, and no patients in any treatment group experienced elevated total bilirubin more than 2 times the ULN. A single patient in the lanadelumab group permanently discontinued treatment due to elevated transaminases, specifically AST of 4.1 times the ULN. No patients were reported to have serious adverse reactions of elevated transaminases.
Because lanadelumab is a therapeutic protein, there is a potential for immunogenicity. Among lanadelumab-treated adult and pediatric patients 12 years and older, 10 patients (12%) developed at least 1 anti-drug antibody (ADA)-positive sample during the treatment period compared to 2 placebo-treated patients (5%). The ADA response observed was transient in 2 lanadelumab-treated patients and 1 placebo-treated patient. Pre-existing low titer antibodies were observed in 3 lanadelumab-treated patients and 1 placebo-treated patient with ADAs. In pediatric patients 2 to 11 years, 3 patients (15%) developed ADAs. The ADA response was transient in all 3 patients. None of the pediatric patients had pre-existing antibodies. One patient had neutralizing antibodies. Antibody formation including neutralizing antibodies against lanadelumab did not appear to adversely affect pharmacokinetics, pharmacodynamics, safety, or clinical response.
Lanadelumab may cause laboratory test interference due to an interaction with the activated partial thromboplastin (aPTT) assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by lanadelumab can increase aPTT in this assay. During clinical trials, prolongation of aPTT (more than 1 time the upper limit of normal [ULN]) was observed at 1 or more time points in 11 patients treated with lanadelumab 300 mg every 2 weeks and in 9 patients treated with 300 mg every 4 weeks compared to 5 placebo-treated patients. A single patient receiving lanadelumab 300 mg every 2 weeks experienced transient aPTT elevation more than 1.5 times the ULN, which was confounded by concomitant heparin therapy. None of the increases in aPTT in lanadelumab-treated patients were associated with abnormal bleeding adverse events. There were no differences in INR values between treatment groups.
There are no available data on the use of lanadelumab in human pregnancy to inform any drug associated risks. Monoclonal antibodies such as lanadelumab are transported across the placenta during the third trimester of pregnancy; thus, potential fetal effects are likely to be greater during the third trimester of pregnancy. Lanadelumab crossed the placenta in monkeys. In a pre-and postnatal study, pregnant monkeys were given lanadelumab from gestation day 20, at the beginning of organogenesis, through to parturition at doses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximum recommended human dose. There were no lanadelumab-related effects on embryofetal development, survival, growth, or postnatal development of offspring through 3 months of age.
There are no data on the presence of lanadelumab in human milk, its effects on the breast-fed infant, or its effects on milk production. Lanadelumab is present in the milk of lactating cynomolgus monkeys at approximately 0.2% of the maternal plasma concentration. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for lanadelumab and any potential adverse effects on the breast-fed infant from lanadelumab or the underlying maternal condition.
For angioedema prophylaxis in patients with hereditary angioedema (HAE):
Subcutaneous dosage:
Adults: 300 mg subcutaneously every 2 weeks. Consider a 4-week dosing interval if the patient is well-controlled (e.g., attack free) for more than 6 months.
Children and Adolescents 12 to 17 years: 300 mg subcutaneously every 2 weeks. Consider a 4-week dosing interval if the patient is well-controlled (e.g., attack free) for more than 6 months.
Children 6 to 11 years: 150 mg subcutaneously every 2 weeks. Consider a 4-week dosing interval if the patient is well-controlled (e.g., attack free) for more than 6 months.
Children 2 to 5 years: 150 mg subcutaneously every 4 weeks.
Maximum Dosage Limits:
-Adults
300 mg subcutaneously every 2 weeks.
-Geriatric
300 mg subcutaneously every 2 weeks.
-Adolescents
300 mg subcutaneously every 2 weeks.
-Children
12 years: 300 mg subcutaneously every 2 weeks.
6 to 11 years: 150 mg subcutaneously every 2 weeks.
2 to 5 years: 150 mg subcutaneously every 4 weeks.
1 year: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Lanadelumab products.
Lanadelumab is a non-plasma derived, recombinant, fully human, monoclonal antibody (IgG1/kappa-light chain) that binds to plasma kallikrein and inhibits its proteolytic activity. Kallikrein is a protease that cleaves high molecular weight kininogen to generate cleaved high molecular weight kininogen and bradykinin. Bradykinin, a potent vasodilator, increases vascular permeability resulting in swelling and pain associated with hereditary angioedema (HAE). In patients with HAE due to C1 inhibitor deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present. Uncontrolled increases in plasma kallikrein activity result in angioedema attacks. Lanadelumab decreases kallikrein activity to control excess bradykinin generation in patients with HAE.
Lanadelumab is administered subcutaneously. Concentration-dependent inhibition of plasma kallikrein, measured as a reduction of cleaved high molecular weight kininogen concentrations, was demonstrated after subcutaneous administration of lanadelumab in patients with hereditary angioedema.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
After subcutaneous administration, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is approximately 2 weeks. The anticipated time to reach steady-state is approximately 70 days. At steady-state, the mean accumulation ratio is approximately 2.43 and 1.42 for dosing regimens of 300 mg every 2 weeks and 4 weeks, respectively.
-Special Populations
Renal Impairment
No dedicated studies have been conducted to evaluate the pharmacokinetics of lanadelumab in patients with renal impairment. Based on population pharmacokinetic analysis, mild (CrCl 60 to 89 mL/minute/1.73 m2) and moderate (CrCl 30 to 59 mL/minute/1.73 m2) renal impairment had no effect on the clearance or volume of distribution of lanadelumab.
Pediatrics
Average lanadelumab concentration at steady state was about 25% higher in patients 12 to 17 years compared to adults receiving the same dosage (300 mg subcutaneously every 2 weeks), due to lower body weight in pediatric patients. Exposures in patients 2 to 11 years receiving 150 mg every 2 to 4 weeks were comparable to those in adults receiving 300 mg every 2 weeks. The geometric mean average concentration was approximately 7% higher in patients 6 to 11 years (dose = 150 mg every 2 weeks) and 14% lower in patients 2 to 5 years (dose = 150 mg every 4 weeks) after subcutaneous administration of lanadelumab compared to adult patients (dose = 300 mg every 2 weeks).
Geriatric
After correcting for body weight, age did not meaningfully influence the pharmacokinetics of lanadelumab.
Gender Differences
After correcting for body weight, gender did not meaningfully influence the pharmacokinetics of lanadelumab.
Ethnic Differences
After correcting for body weight, race did not meaningfully influence the pharmacokinetics of lanadelumab.
Obesity
Body weight is a covariate in the variability of lanadelumab clearance and volume of distribution, resulting in higher exposure in lower weight patients; however, the difference is not considered to be clinically relevant.