Gemtuzumab ozogamicin Other names: Gemtuzumab ozogamicin

Gemtuzumab ozogamicin has not been studied in patients with severe renal impairment. Gemtuzumab ozogamicin does not undergo renal clearance, the pharmacokinetics in patients with severe renal impairment is unknown.

There is no information on fertility in patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with gemtuzumab ozogamici. Both men and women should seek advice on fertility preservation before treatment.

In clinical studies infusion related reactions, including anaphylaxis were reported. There have been reports of fatal infusion reactions in the post-marketing setting. Signs and symptoms of infusion related reactions may include fever and chills, and less frequently hypotension, tachycardia, and respiratory symptoms that may occur during the first 24 hours after administration. Infusion of gemtuzumab should be performed under close clinical monitoring, including pulse, blood pressure, and temperature.

Premedication with a corticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to gemtuzumab dosing. Infusion should be interrupted immediately for patients who develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension.

In clinical studies, TLS was reported. Fatal reports of TLS complicated by acute renal failure have been reported in the post-marketing setting. In patients with hyperleukocytic AML, leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC count to below 30,000/mm³ prior to administration of gemtuzumab to reduce the risk of inducing TLS.

Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice. Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemics (e.g. allopurinol) or other agents for treatment of hyperuricaemia (e.g. rasburicase) must be taken.

Hepatotoxicity, including life-threatening, and sometimes fatal hepatic failure and VOD/SOS have been reported in patients treated with gemtuzumab.

Based on an analysis of potential risk factors, adult patients who received gemtuzumab as monotherapy, either before or after an haematopoietic stem cell transplant (HSCT), and patients with moderate or severe hepatic impairment are at increased risk for developing VOD.

Due to the risk of VOD/SOS, signs and symptoms of VOD/SOS should be closely monitored; these may include elevations in ALT, AST, total bilirubin, and alkaline phosphatase, which should be monitored prior to each dose of gemtuzumab, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate. No definitive relationship was found between VOD and time of HSCT relative to higher gemtuzumab monotherapy doses, however, the ALFA-0701 study recommended an interval of 2 months between the last dose of gemtuzumab and HSCT.

Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of gemtuzumab. In patients who experience VOD/SOS, gemtuzumab should be discontinued and patients treated according to standard medical practice.

Dose modification of gemtuzumab is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruptions or permanent discontinuation of gemtuzumab.

The following table shows the dose modification guidelines for non-haematological toxicities.

Dose modifications for non-haematological toxicities:

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; SOS=sinusoidal obstruction syndrome; ULN=upper limit of normal; VOD=venoocclusive disease.

In clinical studies, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening or fatal, were reported. Complications associated with neutropenia and thrombocytopenia may include infections and bleeding/haemorrhagic reactions respectively. Infections and bleeding/haemorrhagic reactions were reported, some of which were life-threatening or fatal.

Complete blood counts should be monitored prior to each dose of gemtuzumab. During treatment, patients should be monitored for signs and symptoms of infection, bleeding/haemorrhage, or other effects of myelosuppression. Routine clinical and laboratory surveillance testing during and after treatment is indicated.

Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of gemtuzumab.

Dose modification of gemtuzumab is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruptions or permanent discontinuation of gemtuzumab.

The following table shows the dose modification guidelines for haematological toxicities.

Dose modifications for haematological toxicities:

Abbreviations: AML=acute myeloid leukaemia; AraC=cytarabine; BMA=bone marrow aspirate, DNR=daunorubicin.

There are no or limited amount of data from the use of gemtuzumab ozogamicin in pregnant women. Studies in animals have shown reproductive toxicity.

Gemtuzumab must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks to the foetus. Pregnant women, or patients becoming pregnant whilst receiving gemtuzumab ozogamicin, or treated male patients as partners of pregnant women, must be apprised of the potential hazard to the foetus.

There is no information regarding the presence of gemtuzumab ozogamicin or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production. Because of the potential for adverse reactions in breast-fed children, women should not breast-feed during treatment with gemtuzumab and for at least 1 month after the final dose.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving gemtuzumab.

Women of childbearing potential, or partners of females of childbearing potential should be advised to use 2 methods of effective contraception during treatment with gemtuzumab for at least 7 months (females) or 4 months (males) after the last dose.

Fertility

There is no information on fertility in patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with gemtuzumab ozogamici. Both men and women should seek advice on fertility preservation before treatment.

Gemtuzumab has moderate influence on the ability to drive and use machines. Patients should be advised they may experience fatigue, dizziness and headache during treatment with gemtuzumab. Therefore, caution should be exercised when driving or operating machines.

Summary of the safety profile

The overall safety profile of gemtuzumab ozogamicin is based on data from patients with acute myeloid leukaemia from the combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. In the combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of gemtuzumab ozogamicin consisted of all grades haemorrhages, all grades VOD, and severe infections. All of these TEAEs were determined to be adverse drug reactions. Because of this limited data collection, laboratory data from the combination therapy study are included in the list below. Information about adverse drug reactions from monotherapy studies and post-marketing experience is presented in order to provide full characterisation of adverse reactions.

In the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatotoxicity, including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). In monotherapy studies, clinically relevant serious adverse reactions also included infusion related reactions (2.5%), thrombocytopenia (21.7%), and neutropenia (34.3%).

The most common adverse reactions (>30%) in the combination therapy study were haemorrhage and infection. In monotherapy studies the most common adverse reactions (>30%) included pyrexia, nausea, infection, chills, haemorrhage, vomiting, thrombocytopenia, fatigue, headache, stomatitis, diarrhoea, abdominal pain, and neutropenia.

The most frequent (≥1%) adverse reactions that led to permanent discontinuation in the combination therapy study were thrombocytopenia, VOD, haemorrhage and infection. The most frequent (≥1%) adverse reactions that led to permanent discontinuation in monotherapy studies were infection, haemorrhage, multi-organ failure, and VOD.

Tabulated list of adverse reactions

The adverse reactions are presented by system organ class (SOC) and frequency categories, defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Selected** adverse reactions in patients who received gemtuzumab ozogamicin in combination therapy study (ALFA-0701):

Abbreviations: N=number of patients; PT =preferred term.
* Including fatal outcome.
** Only selected safety data were collected in this study of newly diagnosed AML.
*** Frequency is based on laboratory values (Grade per NCI CT CAE v4.03).
^a Infection includes Sepsis and Bacteraemia (53.4%), Fungal infection (15.3%), Lower respiratory tract infection (5.3%), Bacterial infection (9.2%), Gastrointestinal infection (8.4%), Skin infection (2.3%), and Other infections (28.4%).
^b Haemorrhage includes Central nervous system haemorrhage (3.1%), Upper gastrointestinal haemorrhage (33.6%), Lower gastrointestinal haemorrhage (17.6%), Subcutaneous haemorrhage (60.3%), Other haemorrhage (64.9%), and Epistaxis (62.6%).
^c Venoocclusive liver disease includes the following reported PT s: Venoocclusive disease and Venoocclusive liver disease*.

Adverse reactions in patients who received gemtuzumab ozogamicin in monotherapy *** studies and post-marketing:

* Including fatal outcome.
** Including fatal adverse reactions in
*** gemtuzumab ozogamicin in the post-marketing setting. the treatment of relapsed AML (9 mg/m 2 ).
# Singular cases.
Abbreviation: PT =preferred term.
^a Infection includes Sepsis and Bacteraemia (25.6%), Fungal infection (10.5%), Lower respiratory tract infection (13.0%), Upper respiratory tract infection (4.3%), Bacterial infection (3.6%), Viral infection (24.2%), Gastrointestinal infection (3.3%), Skin infection (7.9%), and Other infections (19.5%). Post-marketing (frequency category unknown) fungal lung infections including Pulmonary mycosis and Pneumocystis jirovecii pneumonia * ; and bacterial infections including Stenotrophomonas infection were also reported.
^b T hrombocytopenia includes the following reported PT s: Platelet count decreased and T hrombocytopenia*.
^c Neutropenia includes the following reported PT s: Neutropenia, Granulocytopenia and Neutrophil count decreased.
^d Anaemia includes the following reported PT s: Anaemia and Haemoglobin decreased.
^e Leukopenia includes the following reported PT s: Leukopenia and White blood cell count decreased.
^f Pancytopenia includes the following reported PT s: Pancytopenia and Bone marrow failure.
^g Lymphopenia includes the following reported PT s: Lymphopenia and Lymphocyte count decreased.
^h Infusion related reaction includes the following reported PT s: Infusion related reaction, Urticaria, Hypersensitivity, Bronchospasm, Drug hypersensitivity, and Injection site urticaria#.
ⁱ Hyperglycaemia includes the following reported PT s: Hyperglycaemia and Blood glucose increased#.
^j T achycardia includes the following reported PT s: T achycardia, Sinus tachycardia, Heart rate increased#, and Supraventricular tachycardia#.
^k Haemorrhages include Central nervous system haemorrhage (5.1%), Upper gastrointestinal haemorrhage (21.3%), Lower gastrointestinal haemorrhage (15.2%), Subcutaneous haemorrhage (28.5%), Other haemorrhage (32.9%), and Epistaxis (28.5%).
^l Hypotension includes the following reported PT s: Hypotension and Blood pressure decreased.
^m Hypertension includes the following reported PT s: Hypertension and Blood pressure increased.
ⁿ Dyspnoea includes the following reported PT s: Dyspnoea and Dyspnoea exertional.
° Abdominal pain includes the following reported PT s: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal discomfort, and Abdominal tenderness.

Description of selected adverse reactions

Hepatotoxicity, including hepatic VOD/SOS

In the combination therapy study, VOD and hepatic laboratory abnormalities were collected. Additional characterisation of hepatotoxicity adverse reactions is provided from the monotherapy studies. In the combination therapy study (N=131), VOD was reported in 6 (4.6%) patients during or following treatment, 2 (1.5%) of these reactions were fatal. Five (3.8%) of these VOD reactions occurred within 28 days of any dose of gemtuzumab ozogamicin. One VOD event occurred more than 28 days of last dose of gemtuzumab ozogamicin; with 1 of these events occurring a few days after having started an HSCT conditioning regimen. The median time from the last gemtuzumab ozogamicin dose to onset of VOD was 9 days (range: 2-298 days). VOD was also reported in 2 patients who received gemtuzumab ozogamicin as a follow-up therapy following relapse of AML after chemotherapy treatment in the control arm of the combination therapy study. Both of these patients experienced VOD more than 28 days after the last dose of gemtuzumab ozogamicin. One of these patients experienced VOD 25 days after the subsequent HSCT.

Based on an analysis of potential risk factors, adult patients who received gemtuzumab ozogamicin as monotherapy, patients who had received an HSCT prior to gemtuzumab ozogamicin exposure were 2.6 times more likely (95% CI: 1.448, 4.769) to develop VOD compared to patients without HSCT prior to treatment with gemtuzumab ozogamicin; patients who had received an HSCT following treatment with gemtuzumab ozogamicin were 2.9 times more likely (95% CI: 1.502, 5.636) to develop VOD compared to patients without HSCT following treatment with gemtuzumab ozogamicin; and patients who had moderate/severe hepatic impairment at baseline were 8.7 times more likely (95% CI: 1.879, 39.862) to develop VOD compared to patients without moderate/severe hepatic impairment at baseline.

Patients should be monitored for hepatotoxicity. Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of gemtuzumab ozogamicin.

Myelosuppression

In the combination therapy study in patients with previously untreated de novo AML treated with fractionated doses of gemtuzumab ozogamicin in combination with chemotherapy, Grade ¾ decreases in leukocytes, neutrophils, and platelets were observed in 131 (100%), 124 (96.1%), and 131 (100%) patients, respectively.

During the induction phase, 109 (83.2%) and 99 (75.6%) patients had platelet recovery to counts of 50,000/mm³ and 100,000/mm³, respectively. The median times to platelet recovery to counts of 50,000/mm³ and 100,000/mm³ were 34 and 35 days, respectively. During the consolidation 1 phase, 92 (94.8%) and 71 (73.2%) patients had a platelet recovery to counts of 50,000/mm³ and 100,000/mm³, respectively. The median times to platelet recovery to counts of 50,000/mm³ and 100,000/mm³ were 32 and 35 days, respectively. During the consolidation 2 phase, 80 (97.6%) and 70 (85.4%) patients had a platelet recovery to counts of 50,000/mm³ and 100,000/mm³, respectively. The median times to platelet recovery to counts of 50,000/mm³ and 100,000/mm³ were 36.5 and 43 days, respectively.

Thrombocytopenia with platelet counts <50,000/mm³ persisting 45 days after the start of therapy for responding patients (CR and incomplete platelet recovery [CRp]) occurred in 22 (20.4%) of patients. The number of patients with persistent thrombocytopenia remained similar across treatment courses (8 [7.4%] patients at the induction phase and 8 [8.5%] patients at the consolidation 1 phase and 10 [13.2%] patients at the consolidation 2 phase).

During the induction phase, 121 (92.4%) and 118 (90.1%) patients had a documented neutrophil recovery to ANC of 500/mm³ and 1,000/mm³, respectively. The median time to neutrophil recovery to ANC of 500/mm³ and 1,000/mm³ was 25 days. In the consolidation 1 phase of therapy, 94 (96.9%) patients had neutrophil recovery to counts of 500/mm³, and 91 (94%) patients recovered to counts of 1,000/mm³. The median times to neutrophil recovery to ANC of 500/mm³ and 1,000/mm³ were 21 and 25 days, respectively. In the consolidation 2 phase of therapy, 80 (97.6%) patients had neutrophil recovery to counts of 500/mm³, and 79 (96.3%) patients recovered to counts of 1,000/mm³. The median times to neutrophil recovery to ANC of 500/mm³ and 1,000/mm³ were 22 and 27 days, respectively.

In the combination therapy study, in patients with de novo AML treated with fractionated doses of gemtuzumab ozogamicin in combination with chemotherapy (N=131), 102 (77.9%) patients experienced all causality severe (Grade ≥3) infections. Treatment-related death due to septic shock was reported in 1 (0.8%) patients. Fatal severe infection was reported in 2 (1.53%) patients in the gemtuzumab ozogamicin arm and 4 (2.92%) patients in the control arm.

In the combination therapy study (N=131), all grades and Grade ¾ bleeding/haemorrhagic reactions were reported in 118 (90.1%) and 27 (20.6%) patients, respectively. The most frequent Grade 3 bleeding/haemorrhagic reactions were epistaxis (1.5%), haemoptysis (3.1%), and haematuria (2.3%). Grade 4 bleeding/haemorrhagic reactions were reported in 4 (3.1%) patients (gastrointestinal haemorrhage, haemorrhage, and pulmonary alveolar haemorrhage [2 patients]). Fatal bleeding/haemorrhagic reactions were reported in 3 (2.3%) patients (cerebral haematoma, intracranial haematoma, and subdural haematoma).

Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of gemtuzumab ozogamicin.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity.

In clinical studies of gemtuzumab ozogamicin in patients with relapsed or refractory AML, the immunogenicity of gemtuzumab ozogamicin was evaluated using 2 enzyme-linked immunosorbent assays (ELISAs).

Patients in the Phase 2 trials did not develop antidrug antibodies (ADAs) and only 2 patients in a Phase 1 trial developed antibodies against the calicheamicin-linker complex, 1 of whom had reduced hP67.6 plasma concentrations. Overall, the incidence rate of ADA development after gemtuzumab ozogamicin treatment was <1% across the 4 clinical studies with ADA data. Definitive conclusions cannot be drawn between the presence of antibodies and potential impact on efficacy and safety due to the limited number of patients with positive ADAs.

The detection of ADAs is highly dependent on the sensitivity and specificity of the assay. The incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, circulating gemtuzumab ozogamicin concentrations, sample handling, timing of sample collection, concomitant treatments and underlying disease. For these reasons, comparison of incidence of antibodies to gemtuzumab ozogamicin with the incidence of antibodies to other products may be misleading.

Paediatric population

Previously untreated AML

The safety and efficacy of gemtuzumab ozogamicin in children and adolescents with previously untreated AML below the age of 15 years has not been established.

In the completed randomised paediatric Phase 3 Study AAML0531 of gemtuzumab ozogamicin combined with intensive first-line therapy in 1,063 newly diagnosed children (93.7% of patients <18 years of age), and young adults (6.3% of patients) with de novo AML aged 0 to 29 years, the safety profile was similar with that observed in the other studies of gemtuzumab ozogamicin combined with intensive chemotherapy in adult patients with de novo AML. However, the optimal dose of gemtuzumab ozogamicin for paediatric patients was not established, since in Study AAML0531 during the second intensification period after the second dose of gemtuzumab ozogamicin, a larger proportion of patients in the gemtuzumab ozogamicin arm experienced prolonged neutrophil recovery time (>59 days) as compared with the comparator arm (21.0% versus 11.5%), and more patients died during remission (5.5% versus 2.8%).

Relapsed or refractory AML

The safety and efficacy of gemtuzumab ozogamicin in paediatric patients with relapsed or refractory AML has not been established.

Safety results observed in a systematic literature review of studies evaluating gemtuzumab ozogamicin in paediatric patients, are presented in the list below.

Safety results from a systematic literature review in paediatric patients with relapsed or refractory AML who received gemtuzumab ozogamicin:

^a When gemtuzumab ozogamicin was given in combination, cytarabine was part of the combination studied in 8 out of the 9 studies.
^b Fractionated dosing refers to gemtuzumab ozogamicin dose of 3 mg/m² on days 1, 4, 7. Non-fractionated dosing refers to gemtuzumab ozogamicin (total dose ranging 1.8 mg/m²-9 mg/m²) 2 times during a cycle at least 14 days apart.
^c Rates across studies were estimated using inverse variance weighting with fixed effects. Proportions were transformed using Freeman-T ukey double arcsine transformation prior to combining studies, and the estimated combined rate was back-transformed using the harmonic mean of study sample sizes.
^d Within 30 days from the last dose of gemtuzumab ozogamicin.
^e Where analysed, median recovery (defined as 20 × 10⁹/L or 50 × 10⁹/L for platelets and 0.5 × 10⁹/L for neutrophils) ranged from 42-48 days for platelets and 30-37 days for neutrophils.