Dosage & Administration
For intravenous infusion only
PNH Dosage Regimen:
aHUS Dosage Regimen:
gMG Dosage Regimen:
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Bkemv Prescribing Information
Eculizumab products, complement inhibitors, increase the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.
- Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of BKEMV, unless the risks of delaying therapy with BKEMV outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
- Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of serious meningococcal infections, BKEMV is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called BKEMV REMS [see Warnings and Precautions (5.2)].
Paroxysmal Nocturnal Hemoglobinuria (PNH)
BKEMV is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis.
Atypical Hemolytic Uremic Syndrome (aHUS)
BKEMV is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy.
Limitation of Use
BKEMV is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
Generalized Myasthenia Gravis (gMG)
BKEMV is indicated for treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive.
Recommended Vaccination and Prophylaxis for Meningococcal Infection
Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of BKEMV [see Warnings and Precautions (5.1)].
If urgent BKEMV therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.
Healthcare providers who prescribe BKEMV must enroll in the BKEMV REMS [see Warnings and Precautions (5.2)].
Recommended Dosage Regimen – PNH
For patients 18 years of age and older, BKEMV therapy consists of:
- 600 mg weekly for the first 4 weeks, followed by
- 900 mg for the fifth dose 1 week later, then
- 900 mg every 2 weeks thereafter.
Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points [see Warnings and Precautions (5.4)].
Recommended Dosage Regimen – aHUS
For patients 18 years of age and older, BKEMV therapy consists of:
- 900 mg weekly for the first 4 weeks, followed by
- 1,200 mg for the fifth dose 1 week later, then
- 1,200 mg every 2 weeks thereafter.
For patients less than 18 years of age, administer BKEMV based upon body weight, according to the following schedule (Table 1):
| Patient Body Weight | Induction | Maintenance |
|---|---|---|
| 40 kg and over | 900 mg weekly × 4 doses | 1,200 mg at week 5; then 1,200 mg every 2 weeks |
| 30 kg to less than 40 kg | 600 mg weekly × 2 doses | 900 mg at week 3; then 900 mg every 2 weeks |
| 20 kg to less than 30 kg | 600 mg weekly × 2 doses | 600 mg at week 3; then 600 mg every 2 weeks |
| 10 kg to less than 20 kg | 600 mg weekly × 1 dose | 300 mg at week 2; then 300 mg every 2 weeks |
| 5 kg to less than 10 kg | 300 mg weekly × 1 dose | 300 mg at week 2; then 300 mg every 3 weeks |
Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points.
Recommended Dosage Regimen – gMG
For adult patients with generalized myasthenia gravis, BKEMV therapy consists of:
- 900 mg weekly for the first 4 weeks, followed by
- 1,200 mg for the fifth dose 1 week later, then
- 1,200 mg every 2 weeks thereafter.
Administer BKEMV at the recommended dosage regimen time points, or within two days of these time points.
Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion
For adult and pediatric patients with aHUS, and adult patients with gMG, supplemental dosing of BKEMV is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2).
| Type of Plasma Intervention | Most Recent BKEMV Dose | Supplemental BKEMV Dose with Each Plasma Intervention | Timing of Supplemental BKEMV Dose |
|---|---|---|---|
| Plasmapheresis or plasma exchange | 300 mg | 300 mg per each plasmapheresis or plasma exchange session | Within 60 minutes after each plasmapheresis or plasma exchange |
| 600 mg or greater | 600 mg per each plasmapheresis or plasma exchange session | ||
| Fresh frozen plasma infusion | 300 mg or greater | 300 mg per infusion of fresh frozen plasma | 60 minutes prior to each infusion of fresh frozen plasma |
Preparation
Dilute BKEMV to a final admixture concentration of 5 mg/mL using the following steps:
- Withdraw the required amount of BKEMV from the vial into a sterile syringe.
- Transfer the recommended dose to an infusion bag.
- Dilute BKEMV to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, USP; or Ringer's Injection, USP to the infusion bag.
The final admixed BKEMV 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1,200 mg doses (Table 3).
| BKEMV Dose | Diluent Volume | Final Volume |
|---|---|---|
| 300 mg | 30 mL | 60 mL |
| 600 mg | 60 mL | 120 mL |
| 900 mg | 90 mL | 180 mL |
| 1,200 mg | 120 mL | 240 mL |
Gently invert the infusion bag containing the diluted BKEMV solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives.
Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C (64°F to 77°F)]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Administration
Only administer as an intravenous infusion.
Do not administer as an intravenous push or bolus injection.
Administer the BKEMV admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of BKEMV are stable for 64 hours at 2°C to 8°C (36°F to 46°F) or 24 hours at room temperature.
If an adverse reaction occurs during the administration of BKEMV, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction.
Injection: 300 mg/30 mL (10 mg/mL) as a clear to opalescent and colorless to slightly yellow solution in a single-dose vial.
Pregnancy
Risk Summary
Limited data on outcomes of pregnancies that have occurred following eculizumab use in pregnant women have not identified a concern for specific adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy (see Clinical Considerations). Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations 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 defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or fetal/neonatal risk
PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.
aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight.
Data
Human Data
A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to eculizumab have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size.
Animal Data
Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function.
Lactation
Risk Summary
Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab products on the breastfed infant. There are no data on the effects of eculizumab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BKEMV and any potential adverse effects on the breastfed child from BKEMV or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness of BKEMV for the treatment of PNH, or gMG in pediatric patients have not been established.
The safety and effectiveness of BKEMV for the treatment of aHUS have been established in pediatric patients. Use of BKEMV in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1), and Clinical Studies (14.2)].
Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [see Warnings and Precautions (5.1, 5.3)].
Geriatric Use
Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with another indication) were treated with eculizumab in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
BKEMV is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1)].