Bavencio

/ Merck

Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.
Recommended Dosage for MCC or UC: The recommended dose is 800 mg or 10 mg/kg body weight, according to treating physician’s discretion, administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage for RCC: The recommended dose is 800 mg or 10 mg/kg body weight, according to treating physician’s discretion, administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.
When combined with axitinib, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for axitinib prior to initiation.
Premedication: Patients have to be premedicated with an antihistamine and with paracetamol prior to the first 4 infusions of avelumab. If the fourth infusion is completed without an infusion-related reaction, premedication for subsequent doses should be administered at the discretion of the physician.
Treatment modifications: Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability.
Elderly: No dose adjustment is needed for elderly patients (≥ 65 years).
Paediatric population: The safety and efficacy in children and adolescents below 18 years of age have not been established.
Renal impairment: No dose adjustment is needed for patients with mild or moderate renal impairment. There are insufficient data in patients with severe renal impairment for dosing recommendations.
Hepatic impairment: No dose adjustment is needed for patients with mild hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations.
See prescribing information for full details.

Treatment of adult patients with metastatic Merkel cell carcinoma (MCC).
Maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy.
Treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:
– Have disease progression during or following platinum-containing  chemotherapy
– Have disease progression within 12 months of neoadjuvant or adjuvant           treatment with platinum-containing chemotherapy.
First-line treatment of patients with advanced renal cell carcinoma (RCC) in combination with axitinib.

Hypersensitivity to the active substance or to any of the excipients.
See prescribing information for full details.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infusion‑related reactions: Infusion‑related reactions, which might be severe, have been reported in patients receiving avelumab. Patients should be monitored for signs and symptoms of infusion‑related reactions including pyrexia, chills, flushing, hypotension, dyspnoea, wheezing, back pain, abdominal pain, and urticaria. See prescribing information for full details.
Immune‑related adverse reactions: including immune‑related pneumonitis, hepatitis, colitis, pancreatitis, myocarditis, endocrinopathies, nephritis and renal dysfunction and others.  Most immune‑related adverse reactions with avelumab were reversible and managed with temporary or permanent discontinuation of avelumab, administration of corticosteroids and/or supportive care. For suspected immune‑related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids administered. If corticosteroids are used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. In patients, whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants may be considered. See prescribing information for full details.
Thyroid disorders (hypothyroidism/hyperthyroidism): Thyroid disorders can occur at any time during treatment. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Hypothyroidism should be managed with replacement therapy and hyperthyroidism with anti‑thyroid medicinal product, as needed. Avelumab should be withheld for Grade 3 or Grade 4 thyroid disorders, see prescribing information for full details.
Adrenal insufficiency: Patients should be monitored for signs and symptoms of adrenal insufficiency during and after treatment. Corticosteroids should be administered (1 to 2 mg/kg/day prednisone intravenously or oral equivalent) for Grade ≥ 3 adrenal insufficiency followed by a taper until a dose of less than or equal to 10 mg/day has been reached. Avelumab should be withheld for Grade 3 or Grade 4 symptomatic adrenal insufficiency. See prescribing information for full details.
Type 1 diabetes mellitus: Avelumab can cause Type 1 diabetes mellitus, including diabetic ketoacidosis. Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Initiate treatment with insulin for Type 1 diabetes mellitus. Avelumab should be withheld and anti-hyperglycaemics in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatment with avelumab should be resumed when metabolic control is achieved on insulin replacement therapy. See prescribing information for full details.
Hepatotoxicity (in combination with axitinib): Hepatotoxicity occurred in patients treated with avelumab in combination with axitinib with higher than expected frequencies of Grade 3 and Grade 4 ALT and AST elevation compared to avelumab alone. Patients should be more frequently monitored for changes in liver function and symptoms as compared to when avelumab is used as monotherapy. Avelumab should be withheld for Grade 2 hepatotoxicity until resolution and permanently discontinued for Grade 3 or Grade 4 hepatotoxicity. Corticosteroids should be considered for Grade ≥ 2 events. See prescribing information for full details.
Patients excluded from clinical studies: Patients with the following conditions were excluded from clinical trials: active central nervous system (CNS) metastasis; active or a history of autoimmune disease; a history of other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C.
Sodium content:  This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium‑free’.

Avelumab is associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of avelumab.
The most common adverse reactions with avelumab were fatigue, nausea, diarrhoea, constipation, decreased appetite, infusion-related reactions,
vomiting, and weight decreased.
The most common Grade ≥ 3 adverse reactions were anaemia, hypertension, hyponatraemia, dyspnoea, and abdominal pain.
See prescribing information for full details.

No interaction studies have been conducted with avelumab.
Avelumab is primarily metabolised through catabolic pathways, therefore, it is not expected that avelumab will have pharmacokinetic drug-drug interactions with other medicinal products.

Women of childbearing potential/Contraception: Women of childbearing potential should be advised to avoid becoming pregnant while receiving avelumab and should use effective contraception during treatment with avelumab and for at least 1 month after the last dose of avelumab.
Pregnancy: There are no or limited data from the use of avelumab in pregnant women. Animal reproduction studies have not been conducted with avelumab. However, in murine models of pregnancy, blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss. These results indicate a potential risk, based on its mechanism of action, that administration of avelumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth. Human IgG1 immunoglobulins are known to cross the placental barrier. Therefore, avelumab has the potential to be transmitted from the mother to the developing foetus. It is not recommended to use avelumab during pregnancy unless the clinical condition of the woman requires treatment with avelumab.
Breast-feeding: It is unknown whether avelumab is excreted in human milk. Since it is known that antibodies can be secreted in human milk, a risk to the newborns/infants cannot be excluded. Breast-feeding women should be advised not to breast-feed during treatment and for at least 1 month after the last dose due to the potential for serious adverse reactions in breast-fed infants.
Fertility: The effect of avelumab on male and female fertility is unknown. Although studies to evaluate the effect of avelumab on fertility have not been conducted, there were no notable effects in the female reproductive organs in monkeys based on 1-month and 3-month repeat-dose toxicity studies.  

Three patients were reported to be overdosed with 5% to 10% above the recommended dose of avelumab. The patients had no symptoms, did not require any treatment for the overdose, and continued on avelumab therapy.
In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions. The treatment is directed to the management of symptoms.

Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original package in order to protect from light.
Once opened, the medicinal product should be diluted and infused immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than a total of 24 hours under refrigerated conditions (2°C to 8°C) or up to 8 hours at room temperature (20°C to 25°C). If refrigerated, allow the vial and/or intravenous bags to come to room temperature prior to use.
See prescribing information for full details.