ADAKVEO (Page 3 of 4)

13.2 Animal Toxicology and/or Pharmacology

In the 26-week repeat-dose toxicity study, administration of crizanlizumab-tmca in cynomolgus monkeys at dose levels up to 50 mg/kg/dose once every 4 weeks resulted in inflammation of the vessels in multiple tissues in 2 out of 10 animals.

14 CLINICAL STUDIES

The efficacy of ADAKVEO was evaluated in patients with sickle cell disease in SUSTAIN [NCT01895361], a 52-week, randomized, multicenter, placebo-controlled, double-blind study. A total of 198 patients with sickle cell disease, any genotype (HbSS, HbSC, HbS/beta0 -thalassemia, HbS/beta+ -thalassemia, and others), and a history of 2-10 VOCs in the previous 12 months were eligible for inclusion. Patients were randomized 1:1:1 to ADAKVEO 5 mg/kg (N = 67), ADAKVEO 2.5 mg/kg (N = 66), or placebo (N = 65) administered over a period of 30 minutes by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter for a treatment duration of 52 weeks. Randomization was stratified by patients already receiving hydroxyurea (Y/N) and by the number of VOCs in the previous 12 months (2 to 4, 5 to 10).

Patients received ADAKVEO (with or without hydroxyurea) and were allowed to receive occasional transfusions and pain medications [i.e., acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids] on an as needed basis.

Patients recruited in the study had complications associated with sickle cell disease and other comorbidities including a history of acute chest syndrome (18%); pulmonary hypertension (8%); priapism (7%); psychiatric manifestations (25%) including depression and anxiety; hypertension (17%); cholelithiasis (17%). Demographic and other baseline characteristics were similar among the treatment groups (see Table 2).

Table 2: Demographics and Baseline Characteristics in SUSTAIN Study
Abbreviation: VOCs, vasoocclusive crises.
ADAKVEO 5 mg/kg(N = 67) Placebo(N = 65)
Age (years)
Median 29 26
Range 16, 63 16, 56
Gender, n (%)
Male 32 (48%) 27 (42%)
Female 35 (52%) 38 (59%)
Ethnicity, n (%)
Hispanic or Latino 20 (30%) 11 (17%)
Not Hispanic or Latino 45 (67%) 53 (82%)
Unknown 2 (3%) 1 (2%)
Race
black or African American 60 (90%) 60 (92%)
white 4 (6%) 3 (5%)
Other 3 (5%) 2 (3%)
Sickle cell disease genotype, n (%)
HbSS 47 (70%) 47 (72%)
HbSC 9 (13%) 8 (12%)
HbS/beta0 — thalassemia 3 (5%) 7 (11%)
HbS/beta+ — thalassemia 7 (10%) 1 (2%)
Other 1 (2%) 2 (3%)
Hydroxyurea use, n (%)
Yes 42 (63%) 40 (62%)
No 25 (37%) 25 (39%)
Number of VOCs in previous 12 months, n (%)
2 to 4 42 (63%) 41 (63%)
5 to 10 25 (37%) 24 (37%)

Efficacy was evaluated in the SUSTAIN study by the annual rate of VOCs leading to a healthcare visit. A VOC leading to a healthcare visit was defined as an acute episode of pain with no cause other than a vaso-occlusive event that required a medical facility visit and treatment with oral or parenteral opioids, or parenteral NSAIDs. Acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism (requiring a visit to a medical facility) were also considered VOCs.

Patients with sickle cell disease who received ADAKVEO 5 mg/kg had a lower median annual rate of VOC compared to patients who received placebo (1.63 vs. 2.98) which was statistically significant (p = 0.010). Reductions in the frequency of VOCs were observed among patients regardless of sickle cell disease genotype and/or hydroxyurea use.

Thirty-six percent (36%) of patients treated with ADAKVEO 5 mg/kg did not experience a VOC compared to 17% of placebo-treated patients. The median time to first VOC from randomization was 4.1 months in the ADAKVEO 5mg/kg arm compared to 1.4 months in the placebo.

The main efficacy results of the pivotal study, SUSTAIN, are summarized in Table 3.

Table 3: Efficacy Results from SUSTAIN Trial in Sickle Cell Diseasea
Abbreviations: HL, hodges-lehmann; VOC, vasoocclusive crises. a VOCs were as assessed by an independent review committee.b Standard median.c HL median difference [95% confidence interval (CI)].
Event ADAKVEO, 5 mg/kgb (n = 67) Placebob (n = 65) Treatment Difference Estimatec
Annual rate of VOCa 1.63 2.98 HL = -1.01, (-2.00, 0.00)
Annual rate of days hospitalized 4 6.87

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

ADAKVEO (crizanlizumab-tmca) injection is a sterile, clear to opalescent, colorless to slightly brownish-yellow solution for intravenous infusion supplied as:

Carton containing one 100 mg/10 mL (10 mg/mL) single-dose vial NDC 0078-0883-61

The single-dose vial has a rubber stopper and an aluminum cap with a plastic flip-off disk. Each 10 mL vial is made of Type 1 glass.

Storage and Handling

  • Store and transport refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
  • Do not shake. Do not freeze.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.1)].

Interference With Automated Platelet Counts

Advise patients to inform their healthcare provider that they are receiving ADAKVEO prior to any blood tests due to the potential interference with laboratory tests used to measure platelet counts [see Warnings and Precautions (5.2)].

Manufactured by:
Novartis Pharmaceuticals Corporation
One Health PlazaEast Hanover, New Jersey 07936

US License No. 1244

© Novartis

T2019-119

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: November 2019
PATIENT INFORMATION
ADAKVEO® (ah dak vee oh)(crizanlizumab-tmca)injection, for intravenous use
What is the most important information I should know about ADAKVEO?ADAKVEO may cause serious side effects, including: Infusion reactions. Infusion reactions may happen within 24 hours of receiving an infusion of ADAKVEO. Tell your healthcare provider right away if you get any of the following signs and symptoms of an infusion reaction:
  • fever
  • chills or shivering
  • nausea
  • vomiting
  • tiredness
  • dizziness
  • sweating
  • hives
  • itching
  • shortness of breath or wheezing
Your healthcare provider may monitor you for signs and symptoms of infusion reactions.ADAKVEO may interfere with a certain blood test. Tell your healthcare providers that you are receiving ADAKVEO before having any blood tests. ADAKVEO may interfere with a laboratory test to measure your platelet counts.See “What are possible side effects of ADAKVEO?” for more information about side effects.
What is ADAKVEO? ADAKVEO is used:
  • in people 16 years of age and older who have sickle cell disease
  • to help reduce how often certain episodes (crises) happen.
It is not known if ADAKVEO is safe and effective in children under 16 years of age.
Before receiving ADAKVEO, tell your healthcare provider about all of your medical conditions, including if you:
  • are pregnant or plan to become pregnant. It is not known if ADAKVEO may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if ADAKVEO passes into your breast milk. You and your healthcare provider should decide the best way to feed your baby during treatment with ADAKVEO.
Tell your healthcare provider about all of the medicines you take , including prescription and over-the counter medicines, vitamins, and herbal supplements.
How will I receive ADAKVEO?
  • Your healthcare provider will give you ADAKVEO as an infusion into your vein through an intravenous (IV) line over 30 minutes.
  • You will receive your first infusion, and then a second infusion 2 weeks later. After that, you will receive an infusion every 4 weeks.
  • Your healthcare provider may also prescribe other treatments for you to take during treatment with ADAKVEO.
  • Do not stop receiving ADAKVEO unless your healthcare provider tells you to.
  • If you miss an appointment for infusion, call your healthcare provider as soon as possible to reschedule.
What are the possible side effects of ADAKVEO? ADAKVEO may cause serious side effects. See “What is the most important information I should know about ADAKVEO?” The most common side effects of ADAKVEO include:
  • nausea
  • back pain
  • joint pain
  • fever
These are not all of the possible side effects of ADAKVEO. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of ADAKVEO.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for more information about ADAKVEO.
What are the ingredients in ADAKVEO?
Active ingredient: crizanlizumab-tmcaInactive ingredients: citric acid, polysorbate 80, sodium citrate, and water for injection
Manufactured by: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936U.S. License No. 1244© NovartisT2019-120For more information, go to www.adakveo.com or call 1-877-ADAKVE-0 (1-877-232-5830).

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