Adakveo

     Recommended Dosage

Administer ADAKVEO 5 mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 weeks thereafter.

If a dose is missed, administer ADAKVEO as soon as possible.

If ADAKVEO is administered within 2 weeks after the missed dose, continue dosing according to the patient's original schedule.

If ADAKVEO is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter.

Physicians should reevaluate the treatment at least yearly, to assess individual patient’s response to treatment and consider discontinuing therapy with ADAKVEO if no perceived benefit is achieved.

ADAKVEO may be given with or without hydroxyurea.

     Preparation and Administration

ADAKVEO should be prepared and administered by a healthcare professional.

Preparation

• Use aseptic technique to prepare the solution for infusion.
• Calculate the dose (mg) and the total volume (mL) of ADAKVEO solution required, and the number of ADAKVEO vials needed based on the patient’s actual body weight.          
  • Prepare 5 mg of ADAKVEO per kg of actual body weight.
• Calculate the volume of ADAKVEO to be used according to the following equation:

Dilution

Dilute ADAKVEO in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a total volume of 100 mL for intravenous infusion as follows:

1. Obtain the number of vials required. One vial is needed for every 10 mL of ADAKVEO.
2. Bring vials to room temperature for a maximum of 4 hours prior to the start of preparation (piercing the first vial).
3. Visually inspect the vials.           
   • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
   • ADAKVEO is clear to opalescent, colorless or may have a slightly brownish-yellow tint.
   • Do not use if particles are present in the solution.
4. Obtain a 100 mL 0.9% Sodium Chloride Injection or 5% Dextrose Injection infusion bag/container.          
   • Infusion bags/containers must be made of either polyvinyl chloride (PVC), polyethylene (PE), or polypropylene (PP).
5. Remove a volume of 0.9% Sodium Chloride Injection or 5% Dextrose Injection from the infusion bag/container that is equal to the required volume of ADAKVEO solution.
6. Withdraw the necessary amount of ADAKVEO solution and dilute by adding to the infusion bag/container containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection.          
   • The volume of ADAKVEO added to the infusion bag/container should not exceed 96 mL.
7. Gently invert the infusion bag to mix the diluted solution. DO NOT SHAKE.
8. Single-dose vials. Discard unused portion.

Storage Conditions of the Diluted Solution

Administer ADAKVEO diluted solution as soon as possible. If not administered immediately, store the prepared solution either:

• At room temperature up to 25°C (77°F) for no more than 4.5 hours from the start of the preparation (piercing the first vial) to the completion of infusion.
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours, from the start of the time of the preparation (piercing the first vial) to the completion of infusion. This includes the storage of the diluted solution and the time to warm up to room temperature. Protect the diluted solution from light during storage under refrigeration.

Administration

• Administer ADAKVEO diluted solution by intravenous infusion over a period of 30 minutes through an intravenous line, which must contain a sterile, nonpyrogenic 0.2-micron inline filter.
• No incompatibilities have been observed between ADAKVEO and infusion sets composed of PVC, polyethylene (PE-lined PVC), polyurethane (PU), and in-line filter membranes composed of polyethersulfone (PES, neutral and positively charged), positively charged polyamide (PA), and polysulphone (PSU).
• Do not mix or coadminister with other drugs through the same intravenous line.
• After administration of ADAKVEO, flush the line with at least 25 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
• Dispose of any unused product or waste material in accordance with local requirements.

     Pregnancy

Risk Summary

Based on data from animal studies, ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks (see Data).

There are insufficient human data on ADAKVEO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Women with sickle cell disease have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for VOCs, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.

Data

Animal Data

In an enhanced pre- and postnatal development study in cynomolgus monkeys, pregnant animals received intravenous doses of crizanlizumab-tmca at 10 and 50 mg/kg once every 2 weeks during the period of onset of organogenesis through delivery. No maternal toxicity was observed. Maternal exposures at doses of 10 and 50 mg/kg were between 2.8 and 16 times, respectively, the human clinical exposure based on area under the curve (AUC) in patients with sickle cell disease at 5 mg/kg/dose once every 4 weeks. There was an increase in fetal loss (abortions or still births) at both crizanlizumab-tmca doses which was higher in the third trimester.

There were no effects on infant growth and development through 6-months postpartum that were attributable to crizanlizumab-tmca.

Measurable crizanlizumab-tmca serum concentrations were observed in the infant monkeys at postnatal Day 28, confirming that crizanlizumab crosses the placental barrier.

     Lactation

Risk Summary

There is no data on the presence of crizanlizumab-tmca in human or animal milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to crizanlizumab-tmca are unknown.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ADAKVEO and any potential adverse effects on the breastfed child from ADAKVEO or from the underlying maternal condition.

     Pediatric Use

The safety and effectiveness of ADAKVEO for sickle cell disease have been established in pediatric patients aged 16 years and older. Use of ADAKVEO for sickle cell disease is supported by evidence from adequate and well-controlled studies in adults and pediatric patients (SUSTAIN trial). The SUSTAIN trial enrolled one pediatric patient treated with ADAKVEO 5 mg/kg aged 16 years old [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)].

The safety and efficacy of ADAKVEO in pediatric patients below the age of 16 years have not been established.

     Geriatric Use

There were no ADAKVEO-treated patients 65 years of age and older in the clinical studies for sickle cell disease [see Clinical Studies (14)]. Clinical studies of ADAKVEO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

     Infusion-Related Reactions

In the SUSTAIN clinical trial, infusion-related reactions (IRRs) (defined as occurring during/within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. In the STAND clinical trial, IRRs were observed in 6 (7%) patients treated with ADAKVEO 5 mg/kg.

IRRs presented most frequently as pain, nausea, vomiting, fatigue, dizziness, pruritis, diarrhea, and pyrexia. Some IRRs have required hospitalizations. The majority of these IRRs occurred during the first and second infusions.

Monitor for and advise patients to report signs and symptoms of IRRs. Discontinue ADAKVEO infusion for severe IRRs and institute appropriate medical care. Consider permanent discontinuation of ADAKVEO treatment in case of severe IRRs. Manage mild to moderate infusion-related reactions with temporary interruption of infusion, slowing the rate of infusion, symptomatic treatment (e.g., acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), opioids, antihistamines, intravenous fluids, and/or oxygen therapy). For subsequent infusions, consider premedication and/or infusion rate reduction.

Exercise caution with corticosteroids in patients with sickle cell disease unless clinically indicated (e.g., treatment of anaphylaxis). Use of corticosteroids may increase the risk of complications such as acute chest syndrome and fat embolism.

Infusion-Related Reactions and Vaso-occlusive Crises

Infusion-related reactions are sometimes indistinguishable from vaso-occlusive crisis (VOC) events. IRRs and VOCs may occur concomitantly and/or VOCs may occur as a consequence of an IRR.

     Laboratory Test Interference

Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing ethylenediaminetetraacetic acid (EDTA). Mitigation strategies are recommended [see Drug Interactions (7.1)].