ADAKVEO

ADAKVEO- crizanlizumab injection
Novartis Pharmaceuticals Corporation

1 INDICATIONS AND USAGE

ADAKVEO® is indicated to reduce the frequency of vasoocclusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease.

2 DOSAGE AND ADMINISTRATION

2.1 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.

ADAKVEO may be given with or without hydroxyurea.

2.2 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:
Preparation and Administration
(click image for full-size original)

Dilution

Dilute ADAKVEO in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 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 or 5% Dextrose Injection.
  • Dispose of any unused product or waste material in accordance with local requirements.
Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

Injection: 100 mg/10 mL (10 mg/mL) as a clear to opalescent, colorless to slightly brownish-yellow solution in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Infusion-Related Reactions

In the SUSTAIN clinical trial, infusion-related reactions (defined as occurring within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Monitor patients for signs and symptoms of infusion-related reactions, which may include fever, chills, nausea, vomiting, fatigue, dizziness, pruritus, urticaria, sweating, shortness of breath or wheezing. Discontinue ADAKVEO infusion for severe reactions and institute appropriate medical care.

5.2 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)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Infusion-related reactions [see Warnings and Precautions (5.1)]

6.1 Clinical Trials 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.

Sickle Cell Disease

The safety of ADAKVEO was evaluated in the SUSTAIN trial [see Clinical Studies (14.1)]. Eligible patients were diagnosed with sickle cell disease (any genotype including HbSS, HbSC, HbS beta0 -thalassemia, HbSbeta+ thalassemia, and others). Patients received ADAKVEO 5 mg/kg (N = 66) or 2.5 mg/kg (N = 64) or placebo (N = 62) administered by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter. The safety evaluation below is limited to the patients who received the recommended dose of 5 mg/kg.

Among the 66 patients that received the recommended dose (5 mg/kg), 83% were exposed for 6 months or longer and 61% were exposed for approximately one year; forty-two (64%) patients were treated with ADAKVEO in combination with hydroxyurea.

Serious adverse reactions were reported in 2 patients (3%) treated with ADAKVEO 5 mg/kg; both reactions were pyrexia.

Two deaths (3%) occurred in the ADAKVEO 5 mg/kg treatment group. None of the deaths were considered to be related to ADAKVEO.

The most common adverse reactions (≥ 10%) were nausea, arthralgia, back pain, and pyrexia.

Table 1 summarizes the adverse reactions in the SUSTAIN trial.

Table 1: Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in SUSTAIN
ADAKVEO 5 mg/kgN = 66n (%) PlaceboN = 62n (%)
Adverse Reactions All Grades(%) Grade ≥ 3(%) All Grades(%) Grade ≥ 3(%)
Gastrointestinal Disorders
Nausea 12 (18) 0 7 (11) 1 (2)
Musculoskeletal and Connective Tissue Disorders
Arthralgia 12 (18) 1 (2) 5 (8) 1 (2)
Back pain 10 (15) 0 7 (11) 0
General Disorders and Administration Site Conditions
Pyrexia 7 (11) 1 (2) 4 (7) 0

Clinically relevant adverse reactions (all Grades) that were reported in less than < 10% of patients treated with ADAKVEO included: oropharyngeal pain, abdominal pain (abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, and abdominal tenderness), diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.

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