A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Mylotarg Side Effects, and Drug Interactions - Gemtuzumab Ozogamicin
Mylotarg Side Effects, and Drug Interactions - Gemtuzumab Ozogamicin
SIDE EFFECTS
Mylotarg has been administered to 277 patients with relapsed
AML at 9 mg/m2. Mylotarg was generally given as two intravenous infusions
separated by 14 days.
Acute Infusion-Related Events (Table 3)
|
TABLE 3: NUMBER AND PERCENTAGE OF PATIENTS REPORTED TO
HAVE ACUTE INFUSION-RELATED ADVERSE EVENTS (N = 277)
|
|
Adverse Event
|
Any Severity (%)
|
Grade 3 or 4 (%)
|
|
Fever
|
227 (82)
|
17 (6)
|
|
Nausea
|
188 (68)
|
8 (3)
|
|
Chills
|
183 (66)
|
21 (8)
|
|
Vomiting
|
162 (58)
|
3 (1)
|
|
Headache
|
102 (37)
|
2 (< 1)
|
|
Dyspnea
|
73 (26)
|
4 (1)
|
|
Hypotension
|
55 (20)
|
12 (4)
|
|
Hypertension
|
43 (16)
|
5 (2)
|
|
Hyperglycemia
|
29 (10)
|
3 (1)
|
|
Hypoxia
|
15 (5)
|
4 (1)
|
Fever and chills were commonly reported despite prophylactic
treatment with acetaminophen and antihistamines (see WARNINGS
section). Generally, these symptoms occurred at the end of the 2 hour infusion
and resolved after 2 to 4 hours with supportive therapy including acetaminophen,
diphenhydramine, and intravenous fluids. These events all occurred on the same
day as gemtuzumab ozogamicin infusion. Fewer infusion-related events were observed
after the second dose. Methylprednisone given prior to Mylotarg infusion may
ameliorate infusion-related symptoms.
Antibody Formation
Antibodies to gemtuzumab ozogamicin were not detected in any
of the 277 patients, including the 20 patients who received more than 1 course
of study drug, in the Phase 2 clinical studies. Two patients in a Phase 1 study
developed antibody titers against the calicheamicin/calicheamicin-linker portion
of gemtuzumab ozogamicin after three doses. One patient experienced transient
fever, hypotension and dyspnea; the other patient had no clinical symptoms.
No patient developed antibody responses to the hP67.6 antibody portion of Mylotarg.
Myelosuppression
Severe myelosuppression is the major toxicity associated with
Mylotarg.
Neutropenia
During the treatment phase, 267/272 (98%) patients experienced
Grade 3 or Grade 4 neutropenia. For all patients, the median times to ANC recovery
at 500/L for the CR and CRp patients were 40.0 and 43.0 days, respectively.
Anemia, Thrombocytopenia
During the treatment phase, 143/276 (52%) patients experienced
Grade 3 or Grade 4 anemia and 272/276 (99) patients experienced Grade
3 or Grade 4 thrombocytopenia. A summary of the platelet recovery for responding
patients is provided in Table 4.
|
TABLE 4: MEDIAN TIME TO RECOVERY OF PLATELET COUNTS FOR
ALL CR AND CRp PATIENTS (DAYS)
|
| |
CR
|
CRp
|
|
Platelet levels
|
< 60 years of age
|
³ 60 years of age
|
< 60 years of age
|
³ 60 years of age
|
|
> 25,000/mL
|
35
|
38
|
39
|
75
|
|
50,000/mL
|
42
|
40
|
56
|
100
|
|
75,000/mL
|
48
|
42
|
122
|
NA
|
|
100,000/mL
|
56
|
50
|
NA
|
NA
|
|
Abbreviation: NA = Not Available
|
Infection
During the treatment phase, 84/277 (30%) patients experienced
Grade 3 or Grade 4 infections, including opportunistic infections. The most
frequent Grade 3 or Grade 4 infection-related treatment-emergent adverse events
(TEAEs) were sepsis (17%), pneumonia (8%), shock (4%), infection (3%), stomatitis
(2%), and herpes simplex (2%).
Bleeding
During the treatment phase, 36/277 (13%) patients experienced
Grade 3 or Grade 4 bleeding. The most common bleeding events for all patients
were epistaxis (3%), cerebral hemorrhage (2%), intracranial hemorrhage (1%),
melena (1%), petechiae (1%), hematuria (1%), and disseminated intravascular
coagulation (1%).
A greater proportion of NR patients (15%) experienced NCI grade
3 or 4 bleeding events compared with OR patients (7%). Among CR patients, 1
grade 3 bleeding event, epistaxis, was experienced. Bleeding events occurred
in 1/35 CR patients and 4/36 CRp patients.
Transfusions
During the treatment phase, more transfusions were required
in the NR and CRp patients compared with the CRs (Table 5):
|
TABLE 5: NUMBER OF TRANSFUSIONS BY RESPONSE GROUP
|
|
Transfusions
|
All Patients
|
CR
|
CRp
|
NR
|
| |
N = 277
|
N = 35
|
N = 36
|
N = 206
|
|
Platelet transfusions
|
|
|
|
|
|
Mean (SD)
|
NA
|
6.8 (7)
|
23.7 (67)
|
15.7 (20)
|
|
(95% CI)*
|
NA
|
(5.6, 8.0)
|
(12.5, 34.9)
|
(14.3, 17.1)
|
|
RBC transfusions
|
|
|
|
|
|
Mean (SD)
|
NA
|
2.9 (3)
|
5.4 (4)
|
8.1 (22)
|
|
(95% CI)
|
NA
|
(2.4, 3.4)
|
(4.7, 10.1)
|
(8.0, 8.2)
|
|
* calculated - mean ± se where
se = sd/sqr(n)
|
Mucositis
A total of 69/277 (25%) patients were reported to have a TEAE
consistent with oral mucositis or stomatitis. During the treatment phase, 9/277
(3%) patients experienced Grade 3 or 4 stomatitis/mucositis after the first
dose.
Hepatotoxicity
In clinical studies, 80/274 (29%) patients experienced Grade
3 or Grade 4 hyperbilirubinemia. 26/274 (9%) of patients experienced Grade 3
or Grade 4 abnormalities in levels of ALT, and 49/274 (18%) patients experienced
Grade 3 or Grade 4 abnormalities in levels of AST. One patient died with liver
failure in the setting of tumor lysis syndrome and multisystem organ failure
22 days after treatment. Another patient died after an episode of persistent
jaundice and hepatosplenomegaly 156 days after treatment. Ascites, an event
that can be associated with liver damage, was observed in 8 patients. Abnormalities
of liver function were often transient and reversible.
VOD: A total of 299 courses of Mylotarg were administered
in 277 relapsed patients and 16 episodes of VOD (in 15 patients) were identified
(16/299, 5%). The incidence of VOD in patients treated with Mylotarg who had
no prior or subsequent HSCT was 1.0%. The risk of developing VOD was 20% for
patients with a history of HSCT prior to Mylotarg administration. In patients
who received HSCT after Mylotarg administration, the risk of developing VOD
was 15%. (See Table 6). In the 15 patients that developed VOD, 9 patients had
fatal VOD or ongoing VOD at the time of death:
|
TABLE 6: INCIDENCE OF VOD REPORTED BY TREATMENT GROUPS
|
|
|
Number Courses of Mylotarg
|
Number Episodes of VOD
|
Incidence of VOD (episodes per courses)
|
Number Patients in Classification
|
Number Patients with VOD
|
Incidence of VOD (in patients)
|
|
Mylotarg Total
|
299
|
16
|
5%
|
277
|
15
|
5%
|
|
Mylotarg Only
|
215
|
2
|
0.9%
|
200
|
2
|
1%
|
|
HSCT with Mylotarg (total)a
|
84
|
14
|
17%
|
77
|
13
|
17%
|
|
HSCT prior to Mylotargb,c
|
30
|
6
|
20%
|
27
|
6
|
22%
|
|
HSCT following Mylotargb,c
|
54
|
8
|
15%
|
52
|
8
|
15%
|
|
a: 3 patients are included in more than one HSCT category.
|
|
b: 2 patients with a pre-trial history of HSCT each received
HSCT after Mylotarg.
|
|
c: 1 patient received Mylotarg followed by HSCT and then
received a second course of Mylotarg. This patient developed VOD after
HSCT and again after the second course of Mylotarg.
|
Skin
Pruritus was reported in 18/277 (6%) patients, while rash occurred
in 51/277 (18%) patients. Cutaneous herpes simplex was reported in 59/277 (21%)
patients. No patient experienced alopecia.
Early Mortality in Clinical Studies
The overall mortality rate within 28 days of last dose was
16% (44/277). The mortality rate was 14% (17/120) for patients who were <
60 years old, and 17% (27/157) for patients who were ³ 60
years old.
Retreatment Events
Twenty (20) patients received additional courses of Mylotarg
in the studies. One (1) patient received a total of 4 courses of treatment.
Dose Relationship for Adverse Events
Dose-relationship data were generated from a small dose-escalation
study. The most common clinical adverse event observed in this study was an
infusion-related symptom complex of fever and chills. In general, the severity
of fever, but not chills, increased as the dose level increased. Only one dose
level of Mylotarg was studied in the Phase 2 clinical trials in relapsed AML.
Treatment-Emergent Adverse Events (TEAE)
TEAEs (Grades 1-4) that occurred in ³ 10%
of the patients regardless of causality are listed in Table 7.
|
TABLE 7: COMMONLY REPORTED (³
10%) TREATMENT EMERGENT ADVERSE EVENTS BY AGE GROUP: NUMBER (%) OF
PATIENTS
|
|
Body System Adverse Event
|
Patient Age in Years
|
|
Age ³ 60 (n = 157)
|
Age < 60 (n = 120)
|
Any Age (n = 277)
|
|
Any adverse event
|
157 (100)
|
119 (99)
|
276 (100)
|
|
Body as a whole
|
|
Abdominal pain
|
41 (26)
|
47 (39)
|
88 (32)
|
|
Asthenia
|
56 (36)
|
44 (37)
|
100 (36)
|
|
Back pain
|
19 (12)
|
19 (16)
|
38 (14)
|
|
Chills
|
101 (64)
|
82 (68)
|
183 (66)
|
|
Fever
|
122 (78)
|
105 (88)
|
227 (82)
|
|
Headache
|
42 (27)
|
60 (50)
|
102 (37)
|
|
Infection
|
16 (10)
|
10 (8)
|
26 (9)
|
|
Neutropenic fever
|
30 (19)
|
18 (15)
|
48 (17)
|
|
Pain
|
28 (18)
|
21 (18)
|
49 (18)
|
|
Sepsis
|
40 (25)
|
33 (28)
|
73 (26)
|
|
Cardiovascular system
|
|
|
|
|
Hemorrhage
|
14 (9)
|
16 (13)
|
30 (11)
|
|
Hypertension
|
27 (17)
|
16 (13)
|
43 (16)
|
|
Hypotension
|
28 (18)
|
27 (23)
|
55 (20)
|
|
Tachycardia
|
17 (11)
|
11 (9)
|
28 (10)
|
|
Digestive system
|
|
Anorexia
|
43 (27)
|
26 (22)
|
69 (25)
|
|
Constipation
|
36 (23)
|
27 (23)
|
63 (23)
|
|
Diarrhea
|
47 (30)
|
43 (36)
|
90 (32)
|
|
Dyspepsia
|
13 (8)
|
15 (13)
|
28 (10)
|
|
Gum hemorrhage
|
8 (5)
|
17 (14)
|
25 (9)
|
|
Liver function tests abnormal
|
31 (20)
|
35 (29)
|
66 (24)
|
|
Nausea
|
99 (63)
|
89 (74)
|
188 (68)
|
|
Stomatitis
|
34 (22)
|
35 (29)
|
69 (25)
|
|
Vomiting
|
83 (53)
|
79 (66)
|
162 (58)
|
|
Hemic and lymphatic system
|
|
Anemia
|
34 (22)
|
26 (22)
|
60 (22)
|
|
Ecchymosis
|
17 (11)
|
11 (9)
|
28 (10)
|
|
Leukopenia
|
67 (43)
|
62 (52)
|
129 (47)
|
|
Petechiae
|
30 (19)
|
24 (20)
|
54 (19)
|
|
Thrombocytopenia
|
77 (49)
|
62 (52)
|
139 (50)
|
|
Metabolic and nutritional
|
|
Alkaline phosphatase increased
|
15 (10)
|
6 (5)
|
21 (8)
|
|
Bilirubinemia
|
18 (11)
|
15 (13)
|
33 (12)
|
|
Hyperglycemia
|
17 (11)
|
12 (10)
|
29 (10)
|
|
Hypocalcemia
|
15 (10)
|
14 (12)
|
29 (10)
|
|
Hypokalemia
|
38 (24)
|
35 (29)
|
73 (26)
|
|
Hypomagnesemia
|
4 (3)
|
12 (10)
|
16 (6)
|
|
Hypophosphatemia
|
9 (6)
|
12 (10)
|
21 (8)
|
|
Lactic dehydrogenase increased
|
28 (18)
|
17 (14)
|
45 (16)
|
|
Peripheral edema
|
30 (19)
|
10 (8)
|
40 (14)
|
|
Musculoskeletal system
|
|
Myalgia
|
5 (3)
|
13 (11)
|
18 (6)
|
|
Nervous system
|
|
Anxiety
|
15 (10)
|
8 (7)
|
23 (8)
|
|
Depression
|
15 (10)
|
9 (8)
|
24 (9)
|
|
Dizziness
|
15 (10)
|
18 (15)
|
33 (12)
|
|
Insomnia
|
17 (11)
|
16 (13)
|
33 (12)
|
|
Respiratory system
|
|
Cough increased
|
28 (18)
|
19 (16)
|
47 (17)
|
|
Dyspnea
|
41 (26)
|
32 (27)
|
73 (26)
|
|
Epistaxis
|
37 (24)
|
41 (34)
|
78 (28)
|
|
Pharyngitis
|
16 (10)
|
17 (14)
|
33 (12)
|
|
Pneumonia
|
20 (13)
|
15 (13)
|
35 (13)
|
|
Pulmonary physical finding
|
13 (8)
|
12 (10)
|
25 (9)
|
|
Rhinitis
|
11 (7)
|
12 (10)
|
23 (8)
|
|
Skin and appendages
|
|
Herpes simplex
|
29 (18)
|
30 (25)
|
59 (21)
|
|
Pruritus
|
6 (4)
|
12 (10)
|
18 (6)
|
|
Rash
|
29 (18)
|
22 (18)
|
51 (18)
|
|
Urogenital system
|
|
Metrorrhagia
|
1 (2)
|
6 (10)
|
7 (3)
|
|
Vaginal hemorrhage
|
3 (5)
|
9 (15)
|
12 (4)
|
|
Adverse event associated with miscellaneous factors
|
|
Local reaction to procedure
|
27 (17)
|
33 (28)
|
60 (22)
|
TEAEs of NCI grade 3 or 4 severity that occurred in part I
of studies with an incidence of ³ 10% in at least
1 age subgroup, are presented in Table 8.
|
TABLE 8: NUMBER (%) OF PATIENTS REPORTING NCI GRADE 3
OR 4 TREATMENT EMERGENT ADVERSE EVENTS DURING PART I BY AGE GROUP: EVENTS
WITH INCIDENCE ³ 10%
|
|
Body System Adverse Event
|
Patient Age in Years
|
|
Age ³ 60 (n = 157)
|
Age < 60 (n = 120)
|
Any Age (n = 277)
|
|
Any adverse event
|
138 (88)
|
112 (93)
|
250 (90)
|
|
Body as a whole
|
|
Chills
|
17 (11)
|
9 (8)
|
26 (9)
|
|
Fever
|
20 (13)
|
16 (13)
|
36 (13)
|
|
Sepsis
|
23 (15)
|
24 (20)
|
47 (17)
|
|
Digestive system
|
|
Liver function tests abnormal
|
11 (7)
|
12 (10)
|
23 (8)
|
|
Hemic and lymphatic system
|
|
Anemia
|
19 (12)
|
19 (16)
|
38 (14)
|
|
Leukopenia
|
67 (43)
|
60 (50)
|
127 (46)
|
|
Thrombocytopenia
|
75 (48)
|
61 (51)
|
136 (49)
|
|
Respiratory system
|
|
Dyspnea
|
15 (10)
|
8 (7)
|
23 (8)
|
|
Abbreviation: NCI = National Cancer Institute.
|
Clinically important laboratory abnormalities with a Grade
3 or 4 severity are listed in Table 9.
|
TABLE 9: NUMBER (%a) OF PATIENTS WITH LABORATORY
TEST RESULTS OF GRADE 3 OR 4 SEVERITYb
|
|
Efficacy and Safety Studies Grades 3 – 4
|
|
Test
|
Age ³ 60 (n =
157)
|
Age < 60 (n =
120)
|
All Patients (n =
277)
|
|
Hematologic
|
|
|
|
|
Hemoglobin
|
79/157 (50)
|
64/119 (54)
|
143/276 (52)
|
|
WBC
|
149/157 (95)
|
117/119 (98)
|
266/276 (96)
|
|
Total neutrophils, absolute
|
152/155 (98)
|
115/117 (98)
|
267/272 (98)
|
|
Lymphocytes
|
144/155 (93)
|
111/117 (95)
|
255/272 (94)
|
|
Platelet count
|
155/157 (99)
|
117/119 (98)
|
272/276 (99)
|
|
Prothrombin time
|
2/35 (6)
|
4/34 (12)
|
6/69 (9)
|
|
Partial thromboplastin time
|
1/66 (2)
|
1/61 (2)
|
2/127 (2)
|
|
Non-hematologic
|
|
|
|
|
Glucose (hypo/hyper)
|
19/155 (12)
|
13/119 (11)
|
32/274 (12)
|
|
Creatinine
|
1/157 (<1)
|
4/119 (3)
|
5/276 (2)
|
|
Total bilirubin
|
45/156 (29)
|
35/118 (30)
|
80/274 (29)
|
|
AST
|
25/156 (15)
|
24/118 (20)
|
49/274 (18)
|
|
ALT
|
12/156 (8)
|
14/118 (12)
|
26/274 (13)
|
|
Alkaline phosphatase
|
4/156 (3)
|
7/118 (6)
|
11/274 (4)
|
|
Calcium (hypo/hyper)
|
14/157 (9)
|
21/119 (18)
|
35/276 (13)
|
|
a: Percentage is based on the number of patients receiving
a particular laboratory test during the study as is indicated for each
test.
|
|
b: Severity as defined by NCI common toxicity scale version
1.
|
There were considered to be no clinically important differences
in TEAEs between patients < 60 years of age and
those patients ³ 60.
There were considered to be no clinically important differences
in TEAEs between female and male patients.
Other Clinical Experience:
In postmarketing experience and other clinical trials, additional
cases of VOD have been reported, some in association with the use of other chemotherapeutic
agents, underlying hepatic disease/abnormal liver function, or a history of
prior or subsequent HSCT. Renal failure secondary to TLS, hypersensitivity reactions,
anaphylaxis, pulmonary events, and gastrointestinal hemorrhage have also been
reported in association with the use of Mylotarg (gemtuzumab ozogamicin for
Injection). (See WARNINGS section).
DRUG INTERACTIONS
There have been no formal drug-interaction studies performed
with Mylotarg. The potential for drug-drug interaction with drugs affected by
cytochrome P450 enzymes may not be ruled out.
Laboratory Test Interactions
Mylotarg is not known to interfere with any routine diagnostic
tests.
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