Mylotarg - Food and Drug Administration

This label may not be the latest approved by FDA.

For current labeling information, please visit

Mylotarg?

(gemtuzumab ozogamicin for Injection)

FOR INTRAVENOUS USE ONLY

? only

This product¡¯s label may have been revised after this insert was

used in production. For further product information and current

package insert, please visit or call our medical

communications department toll-free at 1-800-934-5556.

WARNINGS

Mylotarg should be administered under the supervision of physicians experienced in the

treatment of acute leukemia and in facilities equipped to monitor and treat leukemia patients.

There are no controlled trials demonstrating efficacy and safety using Mylotarg in combination

with other chemotherapeutic agents. Therefore, Mylotarg should only be used as single agent

chemotherapy and not in combination chemotherapy regimens outside clinical trials.

Severe myelosuppression occurs when Mylotarg is used at recommended doses.

HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS, INFUSION

REACTIONS, PULMONARY EVENTS

Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis),

and other infusion-related reactions which may include severe pulmonary events. Infrequently,

hypersensitivity reactions and pulmonary events have been fatal. In most cases, infusion-related

symptoms occurred during the infusion or within 24 hours of administration of Mylotarg and

resolved. Mylotarg infusion should be interrupted for patients experiencing dyspnea or clinically

significant hypotension. Patients should be monitored until signs and symptoms completely

resolve. Discontinuation of Mylotarg treatment should be strongly considered for patients who

develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome. Since patients

with high peripheral blast counts may be at greater risk for pulmonary events and tumor lysis

syndrome, physicians should consider leukoreduction with hydroxyurea or leukapheresis to

reduce the peripheral white count to below 30,000/?L prior to administration of Mylotarg. (See

WARNINGS.)

1

This label may not be the latest approved by FDA.

For current labeling information, please visit

HEPATOTOXICITY:

Hepatotoxicity, including severe hepatic veno-occlusive disease (VOD), has been reported in

association with the use of Mylotarg as a single agent, as part of a combination chemotherapy

regimen, and in patients without a history of liver disease or hematopoietic stem cell transplant

(HSCT). Patients who receive Mylotarg either before or after HSCT, patients with underlying

hepatic disease or abnormal liver function, and patients receiving Mylotarg in combinations with

other chemotherapy are at increased risk for developing VOD, including severe VOD. Death

from liver failure and from VOD has been reported in patients who received Mylotarg.

Physicians should monitor their patients carefully for symptoms of hepatotoxicity, particularly

VOD. These symptoms can include: rapid weight gain, right upper quadrant pain, hepatomegaly,

ascites, elevations in bilirubin and/or liver enzymes. However, careful monitoring may not

identify all patients at risk or prevent the complications of hepatotoxicity. (See WARNINGS and

ADVERSE REACTIONS sections.)

DESCRIPTION

Mylotarg? (gemtuzumab ozogamicin for Injection) is a chemotherapy agent composed of a

recombinant humanized IgG4, kappa antibody conjugated with a cytotoxic antitumor antibiotic,

calicheamicin, isolated from fermentation of a bacterium, Micromonospora echinospora

subsp. calichensis. The antibody portion of Mylotarg binds specifically to the CD33 antigen, a

sialic acid-dependent adhesion protein found on the surface of leukemic blasts and immature

normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells. The

anti-CD33 hP67.6 antibody is produced by mammalian cell suspension culture using a myeloma

NS0 cell line and is purified under conditions which remove or inactivate viruses. Three separate

and independent steps in the hP67.6 antibody purification process achieves retrovirus

inactivation and removal. These include low pH treatment, DEAE-Sepharose chromatography,

and viral filtration. Mylotarg contains amino acid sequences of which approximately 98.3% are

of human origin. The constant region and framework regions contain human sequences while the

complementarity-determining regions are derived from a murine antibody (p67.6) that binds

CD33. This antibody is linked to N-acetyl-gamma calicheamicin via a bifunctional linker.

Gemtuzumab ozogamicin has approximately 50% of the antibody loaded with 4-6 moles

2

This label may not be the latest approved by FDA.

For current labeling information, please visit

calicheamicin per mole of antibody. The remaining 50% of the antibody is not linked to the

calicheamicin derivative. Gemtuzumab ozogamicin has a molecular weight of 151 to 153 kDa.

Mylotarg is a sterile, white, preservative-free lyophilized powder containing 5 mg of drug

conjugate (protein equivalent) in an amber vial. The drug product is light sensitive and must be

protected from direct and indirect sunlight and unshielded fluorescent light during the

preparation and administration of the infusion. The inactive ingredients are: dextran 40; sucrose;

sodium chloride; monobasic and dibasic sodium phosphate.

CLINICAL PHARMACOLOGY

General

Gemtuzumab ozogamicin binds to the CD33 antigen. This antigen is expressed on the surface of

leukemic blasts in more than 80% of patients with acute myeloid leukemia (AML). CD33 is also

expressed on normal and leukemic myeloid colony-forming cells, including leukemic clonogenic

precursors, but it is not expressed on pluripotent hematopoietic stem cells or on

nonhematopoietic cells.

Mechanism of Action: Mylotarg is directed against the CD33 antigen expressed by

hematopoietic cells. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33

antigen results in the formation of a complex that is internalized. Upon internalization, the

calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released

calicheamicin derivative binds to DNA in the minor groove resulting in DNA double strand

breaks and cell death.

Gemtuzumab ozogamicin is cytotoxic to the CD33 positive HL-60 human leukemia cell line.

Gemtuzumab ozogamicin produces significant inhibition of colony formation in cultures of adult

leukemic bone marrow cells. The cytotoxic effect on normal myeloid precursors leads to

substantial myelosuppression, but this is reversible because pluripotent hematopoietic stem cells

are spared. In preclinical animal studies, gemtuzumab ozogamicin demonstrates antitumor

effects in the HL-60 human promyelocytic leukemia xenograft tumor in athymic mice.

Human Pharmacokinetics

After administration of the first recommended 9 mg/m2 dose of gemtuzumab ozogamicin, given

as a 2 hour infusion, the elimination half lives of total and unconjugated calicheamicin were

about 41 and 143 hours, respectively. After the second 9 mg/m2 dose, the half life of total

calicheamicin was increased to about 64 hours and the area under the concentration-time curve

(AUC) was about twice that in the first dose period. The AUC for the unconjugated

calicheamicin increased 30% after the second dose. Age, gender, body surface area (BSA), and

weight did not affect the pharmacokinetics of Mylotarg.

3

This label may not be the latest approved by FDA.

For current labeling information, please visit

Patients, especially patients previously treated with HSCT, have an underlying risk of VOD. The

AUC of total calicheamicin was correlated with additional risk of hepatomegaly and the risk of

veno-occlusive disease (VOD). There is no evidence that reducing Mylotarg dose will reduce the

underlying risk of VOD. Metabolic studies indicate hydrolytic release of the calicheamicin

derivative from gemtuzumab ozogamicin. Many metabolites of this derivative were found after

in vitro incubation of gemtuzumab ozogamicin in human liver microsomes and cytosol, and in

HL-60 promyelocytic leukemia cells. Metabolic studies characterizing the possible isozymes

involved in the metabolic pathway of Mylotarg have not been performed.

CLINICAL STUDIES

The efficacy and safety of Mylotarg as a single agent have been evaluated in 277 patients in

three single arm open-label studies in patients with CD33 positive AML in first relapse. The

studies included 84, 95, and 98 patients. In studies 1 and 2 patients were ¡Ý 18 years of age with a

first remission duration of at least 6 months. In study 3, only patients ¡Ý 60 were enrolled and

their first remission had to have lasted for at least 3 months. Patients with secondary leukemia or

white blood cell (WBC) counts ¡Ý 30,000/?L were excluded. Some patients were leukoreduced

with hydroxyurea or leukapheresis to lower WBC counts below 30,000/?L in order to minimize

the risk of tumor lysis syndrome. The treatment course included two 9 mg/m2 doses separated by

14 days and a 28-day follow-up after the last dose. Although smaller doses had elicited responses

in earlier studies, the 9 mg/m2 was chosen because it would be expected to saturate all CD33

sites regardless of leukemic burden. A total of 157 patients were ¡Ý 60 years of age and older. The

primary endpoint of the three clinical studies was the rate of complete remission (CR), which

was defined as

a) leukemic blasts absent from the peripheral blood;

b) ¡Ü 5% blasts in the bone marrow, as measured by morphology studies;

c) hemoglobin (Hgb) ¡Ý 9 g/dL, platelets ¡Ý 100,000/?L, absolute neutrophil count (ANC)

¡Ý 1500/?L; and

d) red cell and platelet-transfusion independence (no red cell transfusions for 2 weeks; no

platelet transfusions for 1 week).

In addition to CR, a second response category, CRp, was defined as patients satisfying the

definition of CR, including platelet transfusion independence, with the exception of platelet

recovery ¡Ý100,000/?L. Remission status was determined at approximately 28 days after the last

dose of Mylotarg. This category was added because Mylotarg appears to delay platelet recovery

in some patients. Clinical equivalence between CR and CRp responses has not been established.

Median time to recovery of platelet counts in patients who achieved a CR or a CRp is

summarized in TABLE 4 (see ADVERSE REACTIONS section).

All patients were pre-medicated with acetaminophen 650-1000 mg and diphenhydramine 50 mg

to decrease acute infusion-related symptoms. Growth factors and cytokines were not permitted.

Use of prophylactic antibiotics was not specified.

4

This label may not be the latest approved by FDA.

For current labeling information, please visit

Response Rate

The overall response (OR) rate for the three pooled monotherapy studies was 26% (71/277)

consisting of 13% (35/277) of patients with CR and 13% (36/277) of patients with CRp. The

median time to blast clearance in both CR and CRp patients was 28 days from the first dose of

Mylotarg. The median time to remission was 60 days for both CR and CRp. Remission rates are

shown in Table 1. Of the 157 patients who were ¡Ý 60 years old, the overall remission rate

(OR = CR + CRp) was 24%. For the patients < 60 years old and all 277 patients the OR rates

were 28% and 26%, respectively. Two of the most important determinants of response following

relapse are age and duration of first remission. Remission rates by prognostic category are

outlined in Table 1.

TABLE 1: PERCENTAGE OF PATIENTS BY REMISSION

CATEGORY AND PROGNOSTIC GROUP

Age

Age

First

First

First

Remission

Remission

Remission

< 60

¡Ý 60

6 ¨C 12 months

years

years

< 6 months

¡Ý 12 months

Type of Remission

n = 120

n = 157

n = 37

n = 124

n = 116

CR

13

12

5

10

18

(95% CI)

8, 21

7, 18

1, 18

5, 16

12, 26

CRp

14

12

5

12

16

(95% CI)

8, 22

7, 18

1, 18

7, 19

10, 24

28

24

11

22

35

OR (CR + CRp)

20,

36

18,

32

3,

25

15,

30

26,

44

(95% CI)

The overall response rates were similar for females and males: 27% of females and 25% of males

achieved remission.

In the studies, 95% of the patients were white and 5% of the patients were non-white.

Survival

Overall survival was measured from date of first dose of gemtuzumab ozogamicin to date of

death or data cut-off date (Table 2). Relapse-free survival (duration of remission) for patients in

remission was defined as the time period from date of first documentation of maximum response

(CR or CRp) to the first date of documentation of relapse (pathology report or complete blood

count showing leukemic blast recurrence in peripheral blood or bone marrow), or death, or data

cut-off date.

5

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download