Posology : מינונים

4.2   Posology and method of administration

Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.
Posology
Recommended Dosage for MCC
The recommended dose of Bavencio 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 UC
The recommended dose of Bavencio 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 of Bavencio 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 axitinib is used in combination with Bavencio, 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 Bavencio. 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; see Table 1.

Detailed guidelines for the management of immune-mediated adverse reactions are described in section 4.4.

Table 1: Guidelines for withholding or discontinuation of Bavencio

Treatment-related           Severity*                                  Treatment modification adverse reaction
Infusion-related reactions Grade 1 infusion-related reaction           Reduce infusion rate by 50%


Treatment-related         Severity*                                Treatment modification adverse reaction
Grade 2 infusion-related reaction        Withhold until adverse reactions recover to
Grade 0-1; restart infusion with a 50% slower rate
Grade 3 or Grade 4 infusion-related      Permanently discontinue reaction
Pneumonitis               Grade 2 pneumonitis                      Withhold until adverse reactions recover to
Grade 0-1
Grade 3 or Grade 4 pneumonitis or       Permanently discontinue recurrent Grade 2 pneumonitis
Hepatitis                  Aspartate aminotransferase (AST) or       Withhold until adverse alanine aminotransferase (ALT) greater reactions recover to
For Bavencio in            than 3 and up to 5 times upper limit of Grade 0-1 combination with axitinib, normal (ULN) or total bilirubin greater see below                  than 1.5 and up to 3 times ULN
AST or ALT greater than 5 times ULN or Permanently discontinue total bilirubin greater than 3 times ULN
Colitis                    Grade 2 or Grade 3 colitis or diarrhoea Withhold until adverse reactions recover to
Grade 0-1
Grade 4 colitis or diarrhoea or recurrent Permanently discontinue
Grade 3 colitis
Pancreatitis               Suspected pancreatitis                    Withhold Confirmed pancreatitis                    Permanently discontinue
Myocarditis                Suspected myocarditis                     Withhold Confirmed myocarditis                     Permanently discontinue
Endocrinopathies           Grade 3 or Grade 4 endocrinopathies       Withhold until adverse (hypothyroidism,                                                     reactions recover to hyperthyroidism, adrenal                                             Grade 0-1 insufficiency,
hyperglycaemia)
Nephritis and renal        Serum creatinine more than 1.5 and up to Withhold until adverse dysfunction                6 times ULN                               reactions recover to Grade 0-1
Serum creatinine more than 6 times ULN Permanently discontinue
Skin reactions            Grade 3 rash                              Withhold until adverse reactions recover to
Grade 0-1
Grade 4 or recurrent Grade 3 rash or      Permanently discontinue confirmed Stevens–Johnson syndrome
(SJS) or Toxic epidermal necrolysis
(TEN)
Other immune-mediated For any of the following:                     Withhold until adverse adverse reactions         •     Grade 2 or Grade 3 clinical signs reactions recover to (including myositis,            or symptoms of an immune-           Grade 0-1 hypopituitarism, uveitis,       mediated adverse reaction not myasthenia gravis,              described above.
myasthenic syndrome,      For any of the following:                 Permanently discontinue Guillain-Barré syndrome) •      Life threatening or Grade 4 adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy)
Treatment-related           Severity*                                   Treatment modification adverse reaction
•      Recurrent Grade 3 immune- mediated adverse reaction
•      Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks
•      Persistent Grade 2 or Grade 3 immune-mediate adverse reactions lasting 12 weeks or longer
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.03)

Treatment modifications when Bavencio is used in combination with axitinib If ALT or AST ≥ 3 times ULN but < 5 times ULN or total bilirubin ≥ 1.5 times ULN but < 3 times ULN, both Bavencio and axitinib should be withheld until these adverse reactions recover to Grades 0-1. If persistent (greater than 5 days), corticosteroid therapy with prednisone or equivalent followed by a taper should be considered. Rechallenge with Bavencio or axitinib or sequential rechallenge with both Bavencio and axitinib after recovery should be considered. Dose reduction according to the axitinib product information should be considered if rechallenging with axitinib.

If ALT or AST ≥ 5 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN or total bilirubin ≥ 3 times ULN, both Bavencio and axitinib should be permanently discontinued and corticosteroid therapy should be considered.

Dose modification advice for axitinib when used with Bavencio
When Bavencio is administered in combination with axitinib, please refer to the axitinib product information for recommended dose modifications for axitinib.

Special populations

Elderly
No dose adjustment is needed for elderly patients (≥ 65 years) (see sections 5.1 and 5.2).
Paediatric population
The safety and efficacy of Bavencio 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 (see section 5.2).
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 (see section 5.2). There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations.

Method of administration
Bavencio is for intravenous infusion only. It must not be administered as an intravenous push or bolus injection.

Bavencio has to be diluted with either sodium chloride 9 mg/mL (0.9%) or with sodium chloride 4.5 mg/mL (0.45%). It is administered over 60 minutes as an intravenous infusion using a sterile,
non-pyrogenic, low-protein binding 0.2 micrometre in-line or add-on filter.

For instructions on the preparation and administration of the medicinal product, see section 6.6.