Tagraxofusp interacts in the following cases:
The passage of tagraxofusp through the blood brain barrier is unknown. Other treatment alternatives should be considered if CNS disease is present.
There are no data from the use of tagraxofusp in pregnant women. Animal reproduction studies have not been conducted with tagraxofusp.
Tagraxofusp should not be used during pregnancy unless the clinical condition of the woman requires treatment with tagraxofusp.
It is unknown whether tagraxofusp/metabolites are excreted in human milk. A risk to breast-feeding newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment with tagraxofusp and for at least one week after the last dose.
In women of childbearing potential, a negative pregnancy test should be obtained within 7 days prior to initiation of therapy. Effective contraception should be used before the first dose is administered and for at least one week after the last dose.
No fertility studies have been conducted with tagraxofusp. There are no data on the effect of tagraxofusp on human fertility.
Tagraxofusp has no or negligible influence on the ability to drive or use machines.
The most serious adverse reaction that may occur during tagraxofusp treatment is CLS which was reported in 18% of patients with a median time to onset of CLS of 6 days.
Adverse reactions occurring in ≥20% of patients treated with tagraxofusp were hypoalbuminemia, increased transaminases, thrombocytopenia, nausea, fatigue and pyrexia.
Adverse reactions grade 3 and above according to the Common Terminology Criteria for Adverse events (CTCAE) and occurring in >5% of patients were increased transaminases, thrombocytopenia and anaemia.
The adverse reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1000 to <1/100).
The adverse reactions described in this section were identified in clinical studies of patients with haematologic malignancies (N=176), including 89 patients with BPDCN. In these studies, tagraxofusp was administered as monotherapy at doses of 7 mcg/kg (12/176, 7%), 9 mcg/kg (9/176, 5%) and 12 mcg/kg (155/176, 88%). Incidence and severity of adverse reaction in patients with BPDCN were similar to those of the entire studied population.
Tabulated list of adverse reactions by MedDRA System Organ Class:
| MedDRA System Organ Class | Frequency of all CTCAE grades | Frequency of CTCAE grade 3 and above |
|---|---|---|
| Infections and infestations | Common Cellulitis Uncommon Pneumonia Urinary tract infection Gingivitis | None |
| Blood and lymphatic system disorders | Very Common Thrombocytopenia Anaemia Common Febrile neutropenia Neutropenia Leukopenia Leukocytosis Lymphopenia | Very Common Thrombocytopenia Common Febrile neutropenia Anaemia Neutropenia Leukopenia Lymphopenia Uncommon Leukocytosis |
| Immune system disorders | Common Cytokine release syndrome | Uncommon Cytokine release syndrome |
| Metabolism and nutrition disorders | Very Common Hypoalbuminemia Common Decreased appetite Tumour lysis syndrome Hyperglycaemia Hyperuricaemia Hypocalcaemia Hypomagnesaemia Hyponatraemia Hypokalaemia Hyperkalaemia Hyperphosphataemia Uncommon Hypophosphataemia Lactic acidosis Acidosis | Common Tumour lysis syndrome Hyperglycaemia Hypoalbuminemia Hyponatraemia Uncommon Hyperuricaemia Hypocalcaemia Hypokalaemia Lactic acidosis Acidosis |
| Psychiatric disorders | Common Confusional state Uncommon Anxiety Depression Insomnia Mental status changes | None |
| Nervous system disorders | Common Syncope Headache Dizziness Uncommon Encephalopathy Metabolic encephalopathy Cerebrovascular accident Facial paralysis Dysgeusia Multiple sclerosis relapse Somnolence Paraesthesia Parosmia Peripheral motor neuropathy Peripheral sensory neuropathy | Common Syncope Uncommon Cerebrovascular accident Metabolic encephalopathy |
| Eye Disorders | Common Vision blurred Uncommon Conjunctival haemorrhage Ocular hyperaemia Vitreous floaters | None |
| Cardiac Disorders | Common Pericardial effusion Tachycardia Sinus tachycardia Uncommon Ventricular fibrillation Supraventricular extrasystoles Atrial fibrillation Bradycardia Myocardial infarction | Uncommon Ventricular fibrillation Pericardial effusion Sinus tachycardia Myocardial infarction |
| Vascular disorders | Very Common Capillary leak syndrome Hypotensiona Common Flushing Uncommon Hypertension Haematoma | Common Capillary leak syndrome Hypotension |
| Respiratory, thoracic and mediastinal disorders | Common Hypoxia Pulmonary oedema Dyspnoea Epistaxis Pleural effusion Cough Uncommon Respiratory failure Wheezing Oropharyngeal pain Tachypnoea | Common Hypoxia Pulmonary oedema Uncommon Respiratory failure Dyspnoea |
| Gastrointestinal Disorders | Very Common Nausea Vomiting Common Dysphagia Diarrhoea Stomatitis Dyspepsia Dry mouth Constipation Uncommon Abdominal distension Abdominal pain Gingival bleeding Tongue blistering Tongue haematoma | Uncommon Nausea |
| Hepatobiliary disorders | Common Hyperbilirubinemia | None |
| Skin and subcutaneous tissue disorders | Common Pruritus Rashb Hyperhidrosis Petechiae Uncommon Angioedema Swelling face Palmar-plantar erythrodysesthesia syndrome Urticaria Alopecia Pain of skin Stasis dermatitis Cold sweat Dry skin | Uncommon Angioedema Rash |
| Musculoskeletal and connective tissue disorders | Common Back pain Bone pain Myalgia Arthralgia Pain in extremity Muscular weakness Uncommon Musculoskeletal pain Coccydynia Muscle spasms Rhabdomyolysis | Uncommon Back pain Arthralgia Rhabdomyolysis |
| Renal and urinary disorders | Common Acute kidney injury Uncommon Renal failure Urinary retention Urinary tract pain Pollakiuria Proteinuria | Uncommon Acute kidney injury |
| General disorders and administration site conditions | Very Common Pyrexia Chills Fatiguec Oedema peripherald Common Influenza-like illness Chest pain Pain Malaise Uncommon Drug intolerance Hypothermia Systemic inflammatory response syndrome | Common Fatigue Uncommon Pyrexia Chills Oedema peripheral Drug intolerance |
| Investigations | Very Common Transaminases increasede Weight increased Common Electrocardiogram QT prolonged Blood alkaline phosphatase increased Blood creatinine increased Blood lactate dehydrogenase increased Blood creatine phosphokinase increased Activated partial thromboplastin time prolonged International normalised ratio increased Uncommon Blood fibrinogen decreased Bacterial test positive Weight decreased | Very Common Transaminases increased Uncommon Electrocardiogram QT prolonged Blood lactate dehydrogenase increased Bacterial test positive |
| Injury, poisoning and procedural complications | Common Infusion related reaction Contusion | Uncommon Infusion related reaction |
a Includes procedural hypotension, orthostatic hypotension
b Includes rash pustular, rash maculo-papular, rash erythematous, rash generalised, rash macular
c Includes asthenia, lethargy
d Includes generalised oedema, oedema, peripheral swelling, fluid retention, fluid overload, periorbital oedema, hypervolaemia
e Includes ALT/AST increased, liver function test increased, hepatic enzyme increased
Capillary leak syndrome was reported in 18% (32/176), with 12% (21/176) Grade 2, 3% (6/176) Grade 3, 1% (2/176) Grade 4, and fatal in 1.7% (3/176). Of the 25 patients that resumed treatment after experiencing an event of CLS, only 1 patient experienced a recurrence of CLS. The median time to onset of CLS was short (6 days), with all but 2 patients experiencing the first onset of CLS in cycle 1. No patient experienced the first onset of CLS after cycle 2. The overall incidence of CLS was similar in patients with BPDCN (20%, 18/89), including 12% (11/89) Grade 2, 2% Grade 3 (2/89), 2% Grade 4 (2/89) and 3 fatal cases (3%). Patients are required to have adequate cardiac function prior to administration of tagraxofusp.
ALT and AST elevations were reported as adverse reactions in 47% (83/176) and 46% (81/176) of patients treated with tagraxofusp monotherapy, respectively. ≥ Grade 3 ALT and AST increased were reported in 23% (40/176) and 23% (40/176), respectively. Elevated liver enzymes occurred in the majority of patients in cycle 1 and were reversible following dose interruptions. Similar onset time and incidence were observed in patients with BPDCN, with 51% (45/89) of patients experiencing adverse events of ALT and AST elevations, with ≥ Grade 3 ALT and AST increased reported in 28% (25/89) and 29% (26/89) respectively. Two patients with BPDCN met the laboratory criteria for Hy's Law; in both cases the laboratory abnormalities were noted during Cycle 1.
Thrombocytopenia was reported in 30% (53/176) of patients treated with tagraxofusp monotherapy and in 35% (31/89) of patients with BPDCN. Thrombocytopenia Grade ≥ 3 was reported in 23% (40/176) of patients treated with tagraxofusp monotherapy and in 26% (23/89) of patients with BPDCN . The majority of thrombocytopenia events were reported in cycle 1 and cycle 2 of treatment. Neutropenia was reported in 9% (15/176) of patients treated with tagraxofusp monotherapy and in 11% (10/89) of patients with BPDCN, with events ≥ Grade 3-reported in 6% (11/176) and 8% (7/89), respectively.
Reactions representative of hypersensitivity were reported in 19% (33/176) of patients treated with tagraxofusp monotherapy and in 17% (15/89) of patients with BPDCN, with events ≥ Grade 3 reported in 3% (6/176) and 4% (4/89), respectively.
Immune response was evaluated by assessment of serum binding reactivity against tagraxofusp (anti-drug antibodies; ADA) and neutralising antibodies by inhibition of functional activity. Immune response was assessed using two immunoassays. The first assay detected reactivity directed against tagraxofusp (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of tagraxofusp. Two cell-based assays were used to investigate the presence of neutralising antibodies by inhibition of a cell-based functional activity.
In 190 patients treated with tagraxofusp in four clinical studies:
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