Progressive multifocal leukoencephalopathy: John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in ADCETRIS-treated patients. PML has been reported in patients who received this treatment after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.
Patients should be closely monitored for new or worsening neurological, cognitive, or behavioural signs or symptoms, which may be suggestive of PML. ADCETRIS dosing should be held for any suspected case of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established. ADCETRIS dosing should be permanently discontinued if a diagnosis of PML is confirmed.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported.
Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis.
ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDs), some with fatal outcomes, have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes) and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections.
Infusion-related reactions: Immediate and delayed infusion-related reactions (IRR), as well as anaphylaxis, have been reported. Patients should be carefully monitored during and after infusion. If anaphylaxis occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered.
If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution.
Patients who have experienced a prior IRR should be premedicated for subsequent infusions. Premedication may include paracetamol (acetaminophen), an antihistamine and a corticosteroid.
IRRs are more frequent and more severe in patients with antibodies to ADCETRIS (see Adverse Reactions).
Tumour lysis syndrome: Tumour lysis syndrome (TLS) has been reported with ADCETRIS. Patients with rapidly proliferating tumour and high tumour burden are at risk of tumour lysis syndrome. These patients should be monitored closely and managed according to best medical practice. Management of TLS may include aggressive hydration, monitoring of renal function, correction of electrolyte abnormalities, anti-hyperuricaemic therapy, and supportive care.
Peripheral neuropathy: ADCETRIS treatment may cause a peripheral neuropathy, both sensory and motor. ADCETRIS-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases. Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and a change in dose of ADCETRIS or ADCETRIS discontinuation (see Dosage & Administration). Neuropathy appeared to be mitigated by dose delay or subsequent reduction or ADCETRIS discontinuation.
Haematological toxicities: Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (≥1 week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose. If Grade 3 or Grade 4 neutropenia develops, manage as needed by dose modifications or discontinuation (see Dosage & Administration). When ADCETRIS is administered in combination with AVD, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose. In the treatment of patients with previously untreated PTCL, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose.
Febrile neutropenia: Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count <1.0 x 109/L, fever ≥38.5°C; ref CTCAE v3) has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of this treatment. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.
Stevens-Johnson syndrome and Toxic Epidermal Necrolysis: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical therapy should be administered.
Gastrointestinal Complications: Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with ADCETRIS. Some cases of GI perforations were reported in patients with GI involvement of underlying lymphoma. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Hepatic function: Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Liver function should be routinely monitored in patients receiving ADCETRIS. Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of ADCETRIS.
Hyperglycaemia: Hyperglycaemia has been reported during clinical trials in patients with an elevated Body Mass Index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycaemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.
Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment and by low serum albumin concentrations (see Pharmacology: Pharmacokinetics under Actions).
Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.
CD30+ CTCL: The size of the treatment effect in CD30+ CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Nevertheless, ADCETRIS should be used with caution in other CD30+ CTCL patients after careful consideration of the potential benefit-risk on an individual basis (see Pharmacology: Pharmacodynamics under Actions).
Effects on ability to drive and use machines: ADCETRIS may have a minor influence on the ability to drive and use machines.