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ADVERSE REACTIONS
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. Methylprednisolone 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/μL 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 | ≥ 60 years of age | < 60 years of age | ≥ 60 years of age |
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Abbreviation: NA = Not Available
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| > 25,000/μL | 35 | 38 | 39 | 75 |
| 50,000/μL | 42 | 40 | 56 | 100 |
| 75,000/μL | 48 | 42 | 122 | NA |
| 100,000/μL | 56 | 50 | NA | NA |
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 |
|
* calculated - mean ± se where se = sd/sqr(n)
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| 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) |
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) |
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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.
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| Mylotarg Total | 299 | 16 | 5% | 277 | 15 | 5% |
| Mylotarg Only | 215 | 2 | 1% | 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% |
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 ≥ 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 ≥ 10% of the patients regardless of causality are listed in Table 7.
TABLE 7: COMMONLY REPORTED (≥ 10%) TREATMENT-EMERGENT ADVERSE EVENTS BY AGE GROUP: NUMBER (%) OF PATIENTS | --------------Patient Age in Years------------- |
| Body System | Age ≥ 60 | Age < 60 | Any Age |
| Adverse Event | (n = 157) | (n = 120) | (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 ≥ 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 ≥ 10% | --------------Patient Age in Years-------------- |
| Body System | Age ≥ 60 | Age < 60 | Any Age |
| Adverse Event | (n = 157) | (n = 120) | (n = 277) |
| Abbreviation: NCI = National Cancer Institute. |
| 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) |
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 |
| Age ≥ 60 | Age < 60 | All Patients |
| Test | (n = 157) | (n = 120) | (n = 277) |
|
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.
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| 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 (16) | 24/118 (20) | 49/274 (18) |
| ALT | 12/156 (8) | 14/118 (12) | 26/274 (9) |
| Alkaline phosphatase | 4/156 (3) | 7/118 (6) | 11/274 (4) |
| Calcium (hypo/hyper) | 14/157 (9) | 21/119 (18) | 35/276 (13) |
There were considered to be no clinically important differences in TEAEs between patients < 60 years of age and those patients ≥ 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, renal failure secondary to TLS, renal impairment, hypersensitivity reactions (including bradycardia), anaphylaxis, pulmonary events, pulmonary hemorrhage, gastrointestinal hemorrhage, Budd Chiari Syndrome, portal vein thrombosis, and neutropenic sepsis have also been reported in association with the use of Mylotarg. (See WARNINGS section).
Observational Study: A prospective postmarketing registry study is being conducted to assess the safety of Mylotarg under conditions of routine clinical practice. The primary objectives is to estimate the incidence of hepatic veno-occlusive disease (VOD) among patients treated with Mylotarg. In an interim analysis of 225 patients, SAEs are presented according to an “events of special interest” (ESI) classification comprised of hepatic (including VOD), renal, infusion-related, pulmonary, and hypersensitivity events (Table 10).
There were 816 SAEs reported in 197/225 patients (87.6% of all patients). Of the SAEs, 159 were also ESIs reported in 64 (28.4%) patients. The percentage of patients experiencing a serious ESI was 9.8% (hepatic), 6.7% (renal), 8.0% (infusion-related), and 12.9% (pulmonary). Among the 816 SAEs, 225 (27.6%) were fatal events (multiple concurrent fatal events could be reported for a patient) reported in 134 (59.6%) patients. Using the ESI classification, there were 30 fatal ESIs reported in 19 (8.4%) patients.
In this registry, the incidence of VOD based on an independent review is 10.2% (23/225). Among patients with HSCT before or after Mylotarg infusion the incidence of VOD was 14.9% (10/67 patients). For patients without HSCT the VOD incidence was 8.2% (12/146 patients). HSCT status was not reported in 8.3% (19/225) of patients.
TABLE 10: SERIOUS ADVERSE EVENTS REPORTED IN THE MYLOTARG PROSPECTIVE OBSERVATIONAL STUDY (N=225)a | aBased on interim data, the denominator represents all patients in the registry, including 11 patients for whom no adverse events were reported at the time of database lock for the interim analysis. |
| Reported events | Number events | All events
Number patients | Percent patients (n=225) | Number events | Fatal events
Number patients | Percent patients (n=225) |
| TOTAL | 816 | 197 | 87.6 | 225 | 134 | 59.6 |
| Hepatic | 51 | 22 | 9.8 | 6 | 4 | 1.8 |
| Renal | 21 | 15 | 6.7 | 5 | 5 | 2.2 |
| Infusion-related | 35 | 18 | 8.0 | 4 | 1 | 0.4 |
| Pulmonary | 52 | 29 | 12.9 | 15 | 13 | 5.8 |
| Hypersensitivity | 0 | 0 | - | 0 | 0 | - |
| Other | 657 | 188 | 83.6 | 195 | 130 | 57.8 |
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REPORTS OF SUSPECTED MYLOTARG SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Mylotarg. The information is not vetted and should not be considered as verified clinical evidence.
Possible Mylotarg side effects / adverse reactions in 59 year old male
Reported by a physician from United States on 2011-10-04
Patient: 59 year old male
Reactions: Status Epilepticus, Pyrexia
Suspect drug(s):
Cerubidine
Dosage: 70 mg, qd
Indication: Acute Leukaemia
Start date: 2008-11-14
End date: 2008-11-16
Mylotarg
Dosage: 12 mg, qd
Indication: Acute Leukaemia
Start date: 2008-11-17
End date: 2008-11-17
Ciprofloxacin
Dosage: unk
Indication: Product Used FOR Unknown Indication
Cytarabine
Dosage: 400 mg, qd
Indication: Acute Myeloid Leukaemia
Start date: 2008-11-14
End date: 2008-11-17
Other drugs received by patient: Gentamicin; Rocephin
Possible Mylotarg side effects / adverse reactions in 64 year old male
Reported by a physician from Netherlands on 2011-10-07
Patient: 64 year old male weighing 83.0 kg (182.6 pounds)
Reactions: Cerebral Haemorrhage
Adverse event resulted in: death, hospitalization
Suspect drug(s):
Mitoxantrone Hydrochloride
Dosage: unk
Indication: Acute Myeloid Leukaemia
Start date: 2004-01-20
End date: 2004-01-27
Mylotarg
Dosage: 12 mg, unk
Indication: Acute Myeloid Leukaemia
Start date: 2003-11-29
End date: 2003-12-13
Etoposide
Dosage: unk
Indication: Acute Myeloid Leukaemia
Start date: 2004-01-20
End date: 2004-01-27
Cytarabine
Dosage: unk
Indication: Acute Myeloid Leukaemia
Start date: 2004-01-20
End date: 2004-01-27
Other drugs received by patient: Heparin
Possible Mylotarg side effects / adverse reactions in 61 year old female
Reported by a physician from United Kingdom on 2011-10-13
Patient: 61 year old female
Reactions: Pancytopenia
Adverse event resulted in: life threatening event
Suspect drug(s):
Evoltra (Clofarabine) Solution FOR Infusion
Indication: Acute Myeloid Leukaemia
Start date: 2007-03-14
End date: 2007-03-18
Daunorubicin HCL
Indication: Acute Myeloid Leukaemia
Start date: 2007-03-14
End date: 2007-03-18
Mylotarg
Indication: Acute Myeloid Leukaemia
Start date: 2007-03-14
End date: 2007-03-18
Other drugs received by patient: Alimemazine Tartrate (Alimemazine Tartrate); Potassium Chloride; Chlorhexidine Gluconate; Vancomycin; Combivent Nebuliser; Amphotericin B; Caspofungin Acetate; Calcium Gluconate; Acyclovir; G-CSF (Granulocyte Colony Stimulating Factor); Meropenem; Calcium Carbonate; Oral Balance (Xylitol, Potassium Thiocyanate, Glucose Oxidase, Lysozym; Chlorpheniramine Maleate; Teicoplanin (Teicoplanin); Cotrim; Lorazepam; Loperamide; Clobestasol Propionate; Phosphate Sandoz; Omeprazole; Itraconazole
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Drug label data at the top of this Page last updated: 2008-09-23
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