Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

Non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus.
AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Non-infectious pneumonitis (including interstitial lung disease) has been frequently reported in patients taking Afinitor and was described very commonly in patients taking Afinitor in the advanced renal cell carcinoma (RCC) setting (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic, and other non-medicinal causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jirovecii (carinii), pneumonia (PJP/PCP) should be ruled out in the differential diagnosis of non-infectious pneumonitis (see section “Infections” below). Patients should be advised to report promptly any new or worsening respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose adjustments.
For oncology patients, if symptoms are moderate (Grade 2) or severe (Grade 3) the use of corticosteroids may be indicated until clinical symptoms resolve.
For TSC patients, if symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Afinitor may be reinitiated at a daily dose approximately 50% lower than the dose previously administered.
For cases of TSC patients where symptoms of non-infectious pneumonitis are severe, Afinitor therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve.
Afinitor may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.
For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP/PCP may be considered.

Infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or PJP/PCP and viral infections including reactivation of hepatitis B virus, have been described in patients taking Afinitor. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], respiratory or hepatic failure) and occasionally fatal in adult and paediatric patients (see section 4.8).
Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor.
If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.
Cases of PJP/PCP, some with fatal outcome, have been reported in patients who received everolimus. PJP/PCP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.


AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5)

Stomatitis
Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse reaction in patients treated with Afinitor (see section 4.8). Stomatitis mostly occurs within the first 8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with Afinitor (everolimus) plus exemestane suggested that an alcohol-free corticosteroid oral solution, administered as a mouthwash during the initial 8 weeks of treatment, may decrease the incidence and severity of stomatitis (see section 5.1). Management of stomatitis may therefore include prophylactic (in adults) and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral solution as a mouthwash. However, products containing alcohol, hydrogen peroxide, iodine and thyme derivatives should be avoided as they may exacerbate the condition. Monitoring for and treatment of fungal infection is recommended, especially in patients being treated with steroid-based medicinal products. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5).

Haemorrhage

Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated with everolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC setting.

Caution is advised in patients taking Afinitor, particularly during concomitant use with active substances known to affect platelet function or that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders. Healthcare professionals and patients should be vigilant for signs and symptoms of bleeding throughout the treatment period, especially if risk factors for haemorrhage are combined.

Renal failure events
Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor (see section 4.8). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring
Renal function
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients treated with Afinitor (see section 4.8).
Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Blood glucose
Hyperglycaemia has been reported in patients taking Afinitor (see section 4.8) Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More frequent monitoring is recommended when Afinitor is co-administered with other medicinal products that may induce hyperglycemia. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor.

Blood lipids

Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported in patients taking Afinitor. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter, as well as management with appropriate medical therapy, is recommended.

Hematological parameters
Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported (see section 4.8).
Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and periodically thereafter.

Functional carcinoid tumours
In a randomised, double-blind, multi-centre trial in patients with functional carcinoid tumours, Afinitor plus depot octreotide was compared to placebo plus depot octreotide. The study did not meet the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and efficacy of Afinitor in patients with functional carcinoid tumours have not been established.

Prognostic factors in neuroendocrine tumours of gastrointestinal or lung origin In patients with non-functional gastrointestinal or lung neuroendocrine tumours and good prognostic baseline factors, e.g. ileum as primary tumour origin and normal chromogranin A values or without bone involvement, an individual benefit-risk assessment should be performed prior to the start of Afinitor therapy. Limited evidence of PFS benefit was reported in the subgroup of patients with ileum as primary tumour origin (see section 5.1).

Interactions
Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, the clinical condition of the patient should be monitored closely. Dose adjustments of Afinitor for oncology patients can be taken into consideration based on predicted AUC, dose adjustments of Afinitor for TSC patients may also be required (see section 4.5).

Concomitant treatment with potent CYP3A4/PgP inhibitors result in dramatically increased blood concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is not recommended.

Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives or carbamazepine), the patient AFI API SEP22 V11                                               REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5).

Hepatic impairment
Oncology patients:
Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment (see section 5.2).


Afinitor is only recommended for use in patients with severe hepatic impairment (Child-Pugh C) if the potential benefit outweighs the risk (see sections 4.2 and 5.2).

No clinical safety or efficacy data are currently available to support dose adjustment recommendations for the management of adverse reactions in oncology patients with hepatic impairment.

TSC patients:

Afinitor is not recommended for use in patients:
•     ≥18 years of age and concomitant severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see sections 4.2 and 5.2).
•     <18 years of age with SEGA and concomitant hepatic impairment (Child-Pugh A, B and C) (see sections 4.2 and 5.2).

Vaccinations
The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5).
For pediatric patients with SEGA who do not require immediate treatment, completion of the recommended childhood series of live virus vaccinations is advised prior to the start of therapy according to local treatment guidelines.

Wound healing complications
Impaired wound healing is a class effect of rapamycin derivatives, including Afinitor. Caution should therefore be exercised with the use of Afinitor in the peri-surgical period.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

Radiation therapy complications

Serious and severe radiation reactions (such as radiation oesophagitis, radiation pneumonitis and radiation skin injury), including fatal cases, have been reported when everolimus was taken during, or shortly after, radiation therapy. Caution should therefore be exercised for the potentiation of radiotherapy toxicity in patients taking everolimus in close temporal relationship with radiation therapy.

AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Additionally, radiation recall syndrome (RRS) has been reported in patients taking everolimus who had received radiation therapy in the past. In the event of RRS, interrupting or stopping everolimus treatment should be considered.

Effects on Driving

4.7       Effects on ability to drive and use machines

Afinitor has minor or moderate influence on the ability to drive and use machines. Patients should be
advised to be cautious when driving or using machines if they experience fatigue during treatment
with Afinitor.