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.

Metastatic Merkel Cell Carcinoma: Indicated for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC).
Locally Advanced or Metastatic Urothelial Carcinoma
First-Line Maintenance Treatment of Urothelial Carcinoma: Maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy.
Previously-Treated Urothelial Carcinoma: 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.
Advanced Renal Cell Carcinoma
In combination with axitinib is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

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

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: 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. In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable. Reported immune-mediated adverse reactions include pneumonitis, hepatitis, colitis, pancreatitis, myocarditis, endocrinopathies (including hypothyroidism, hyperthyroidism, thyroiditis, adrenal insufficiency and Type 1 diabetes mellitus), nephritis and renal dysfunction, as well as other immune-mediated reactions such as myositis, hypopituitarism, uveitis, myasthenia gravis, myasthenic syndrome, Guillain-Barré syndrome, gastritis, sarcoidosis and non-infective cystitis. Management generally includes withholding avelumab and initiating systemic corticosteroids (prednisone 1–2 mg/kg/day or equivalent), followed by a gradual taper over at least 1 month upon improvement. Based on the severity and recurrence of the adverse reaction, permanent discontinuation of avelumab may be required, and additional immunosuppressive therapy may be considered in cases not adequately controlled with corticosteroids. 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.