Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Novartis South Africa (Pty) Ltd, Magwa Crescent West, Waterfall City, Jukskei View, Johannesburg, 2090
Hypersensitivity to everolimus, to other rapamycin derivatives or to any of the excipients of AFINITOR (see section 4.4).
Concomitant use of live vaccines.
Pregnancy and lactation (see section 4.6).
Non-infectious interstitial pneumonitis is a class effect of rapamycin derivatives, including everolimus.
Cases of non-infectious interstitial pneumonitis (including interstitial lung disease) have been described in patients taking AFINITOR (see section 4.8). Some of these have been severe and fatalities have occurred.
A diagnosis of non-infectious interstitial 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 Patients should be advised to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious interstitial pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. 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 reintroduced at a daily dose approximately 50 % lower than the dose previously administered.
For cases of grade 3 non-infectious interstitial pneumonitis, interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-initiated at a reduced dose of approximately 50 % lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. For cases of grade 4 non-infectious interstitial pneumonitis, AFINITOR therapy should be discontinued. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non- infectious pneumonitis, prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP/PCP) may be considered. The development of pneumonitis has been reported at a reduced dose.
AFINITOR has immunosuppressive properties and may predispose patients to infections; especially infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, and invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jirovecii (carinii) pneumonia (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] or respiratory failure) and occasionally have had a fatal outcome. Medical practitioners and patients should be aware of the increased risk of infection with AFINITOR, be vigilant for symptoms and signs of infection, and institute appropriate treatment promptly.
Pre-existing invasive fungal infections should be treated prior to starting treatment with AFINITOR. If a diagnosis of invasive systemic fungal infection is made, AFINITOR should be discontinued and treat with appropriate antifungal therapy.
Cases of pneumocystis jirovecii (carinii) pneumonia (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.
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 AFINITOR (see section 4.3).
Angioedema with concomitant use of angiotensin-converting enzyme (ACE) inhibitors Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).
Stomatitis, including mouth ulceration and oral mucositis is the most commonly reported adverse drug reaction in patients treated with AFINITOR (see section 4.8). Stomatitis mostly occurs within the first 8 weeks of treatment. If stomatitis occurs, topical treatments are recommended, but alcohol-, iodine-, thyme- or hydrogen peroxide-containing products should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5).
In a single arm study in 92 postmenopausal breast cancer patients, a topical alcohol-free corticosteroid oral solution was administered as a mouthwash during the initial 8 weeks of starting treatment with AFINITOR plus exemestane. In this study, a clinically meaningful reduction in the incidence and severity of stomatitis was observed.
Cases of renal failure (including acute renal failure), some with 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 (see sections 4.4 and 4.8).
Elevation of serum creatinine, usually mild and proteinurea have been reported in patients taking AFINITOR (see section 4.8). Monitoring of renal function, including measurement of blood urea, urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.
Hyperglycaemia has been reported in patients taking AFINITOR (see sections 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 medicines that may induce hyperglycaemia. Optimal glycaemia control should be achieved before starting a patient on AFINITOR.
Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) 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.
Decreased haemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients treated with AFINITOR (see section 4.8). Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.
Co-administration with strong inhibitors of CYP3A4 or P-glycoprotein (PgP) should be avoided (see sections 4.2 and 4.5). If AFINITOR must be co-administered with a strong CYP3A4 or PgP inhibitor, the patient should be carefully monitored for undesirable effects.
Use caution when administering AFINITOR in combination with moderate CYP3A4 inhibitors or PgP inhibitors. If AFINITOR must be co-administered with a moderate CYP3A4 or PgP inhibitor, the patient should be carefully monitored for undesirable effects and the dose reduced if necessary (see sections 4.2 and 4.5).
Co-administration with strong CYP3A4 or PgP inducers should be avoided (see section 4.5). If AFINITOR must be co-administered with a strong CYP3A4 or PgP inducer, the patient should be carefully monitored for clinical response. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 or PgP if alternative treatment is not possible (see sections 4.2 and 4.5). Exercise caution when AFINITOR is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index, due to the potential for medicine interactions. If AFINITOR is taken with orally administered CYP3A4 substrates with a narrow therapeutic index, the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5).
AFINITOR is not recommended in patients ≥18 years of age with severe hepatic impairment, (Child- Pugh class C) (see sections 4.2 and 5).
The use of live vaccines is contraindicated during treatment with AFINITOR and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR (see sections 4.3 and 4.5). Examples of live vaccines are intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
Impaired wound healing is a class effect of rapamycin derivatives such as everolimus, as in AFINITOR. Caution is advised with the use of AFINITOR in the peri-surgical period (see section 4.8).
Patients with hereditary galactose intolerance (galactosaemia). Lapp lactase deficiency or glucose- galactose malabsorption should not us AFINITOR.
Immunosuppressants may affect the response to vaccination and vaccination during treatment with AFINITOR may therefore be less effective. The use of live vaccines is contraindicated during treatment with AFINITOR (see sections 4.3 and 4.4). Examples of live vaccines are intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines (see section 4.4).
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multi-medicine efflux pump P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of everolimus may be influenced by medicines that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.
Everolimus blood concentrations may be increased by medicines that inhibit CYP3A4 activity and thus decrease everolimus metabolism. Everolimus blood concentrations may be increased by inhibitors of PgP that may decrease the efflux of everolimus from intestinal cells. Concurrent treatment with AFINITOR and strong inhibitors of CYP3A4 or PgP (including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin) should be avoided.
There was a significant increase in exposure to everolimus (Cmax and AUC increased by 3,9- and 15,0-fold, respectively) in healthy subjects when everolimus was co-administered with ketoconazole (a strong CYP3A4 inhibitor and PgP inhibitor).
Concomitant treatment with moderate inhibitors of CYP3A4 including but not limited to erythromycin, verapamil, ciclosporin, fluconazole, diltiazem, amprenavir, fosamprenavir, or aprepitant) and PgP inhibitors requires caution. Reduce the AFINITOR dose if co-administered with moderate CYP3A4/PgP inhibitors (see sections 4.2 and 4.4).
There was an increase in exposure to everolimus in healthy subjects when everolimus was co-administered with:
Other moderate inhibitors of CYP3A4 and PgP that may increase everolimus blood concentrations include certain antifungal medicines (e.g. fluconazole) and calcium channel blockers (e.g. diltiazem).
Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should be avoided during treatment with AFINITOR.
No difference in everolimus Cmin was apparent when administered in the presence or absence of substrates of CYP3A4 and/or PgP following treatment with the 10 mg or 5 mg daily dose.
Co-administration of weak inhibitors of CYP3A4 with or without PgP inhibitors had no apparent impact on everolimus C min following treatment with 10 mg or 5 mg daily dose regimen.
Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.
Concurrent treatment with strong inducers of CYP3A4 or PgP should be avoided. If AFINITOR must be co-administered with a strong CYP3A4 or PgP inducer (e.g. rifampicin and rifabutin), it may be necessary to adjust the dose (see sections 4.2 and 4.4).
Pre-treatment of healthy subjects with multiple doses of rifampicin (a CYP3A4 and PgP inducer) 600 mg daily for 8 days followed by a single dose of everolimus, increased everolimus oral-dose clearance nearly 3-fold and decreased Cmax by 58% and AUC by 63%.
Other inducers of CYP3A4 that may increase the metabolism of everolimus and decrease everolimus blood levels include St. John’s Wort (Hypericum perforatum), anticonvulsants (e.g. carbamazepine, phenobarbitone, phenytoin,) and anti-HIV medicines (e.g. efavirenz, nevirapine). Concomitant treatment with moderate inducers of CYP3A4 or PgP requires caution.
Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.
In vitro, everolimus competitively inhibited the metabolism of the CYP3A4 substrate ciclosporin and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady-state of everolimus Cmax with an oral dose of 10 mg daily or 70 mg weekly is more than 12- to 36-fold below the Ki-values of the in vitro inhibition. An effect of everolimus on the metabolism of CYP3A4 and CYP2D6 substrates is therefore unlikely. Co-administration of weak inhibitors of CYP3A4 with or without PgP inhibitors had no apparent impact on everolimus C min following treatment with 10 mg or 5 mg daily dose regimen.
Co-administration of AFINITOR and exemestane increased exemestane Cmin and C2h by 45% and 71% respectively. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on safety or efficacy.
Co-administration of an oral dose of midazolam with AFINITOR resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC0-int, whereas the metabolic AUC0-int ratio (1-hydroxy- midazolam/midazolam) and the terminal t½ of midazolam were not affected. This suggests that increased exposure to midazolam is due to effects of AFINITOR in the gastrointestinal system when both medicines are taken at the same time. Therefore, AFINITOR may affect the bioavailability of orally administered medicines which are CYP3A4 substrate medicines which are administered by non-oral routes such as intravenous, subcutaneous, and transdermal administrations (see section 4.4).
AFINITOR increased pre-dose concentrations of the antiepileptic medicines (AEMs) carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 10%. The increase in the pre-dose concentrations of these AEMs may not be clinically significant and dose adjustments for AEMs with a narrow therapeutic index, e.g. carbamazepine, may be considered. AFINITOR had no impact on pre-dose concentrations of AEMs that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide). AFINITOR had no impact on the pre-dose concentration of other AEMs, including valproic acid, topiramate, oxcarbazepine, phenobarbital, phenytoin, and primidone.
Co-administration of AFINITOR containing everolimus and depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus /placebo) of 1,47 (90% CI: 1,32 to 1,64) which was unlikely to have clinically significant effects on the efficacy response to everolimus in patients with advanced neuroendocrine tumours.
AFINITOR should not be given to pregnant women (see section 4.3). AFINITOR is contraindicated in pregnancy. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity. The potential risk for humans is unknown.
There are no reported cases of exposure to everolimus during breast-feeding in humans. However, in animal studies everolimus and/or its metabolites readily passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Women taking AFINITOR should therefore not breastfeed their infants during treatment and for 2 weeks after the last dose (see section 4.3).
Women of childbearing potential should be advised that animal studies have been performed showing AFINITOR to be harmful to the developing foetus. Sexually active women of childbearing potential should use highly effective contraception (one that results in an annual pregnancy rate <1% when used correctly) while receiving AFINITOR, and for up to 8 weeks after ending treatment.
Both male and female fertility may be compromised by treatment with AFINITOR.
Caution is advised when driving and using machines, until the effect of AFINITOR on the individual patient has been established.
Adverse drug reaction (ADR, suspected to be related to treatment by the investigator) information is based on pooled safety data in patients receiving AFINITOR (N=2672) in clinical studies including randomised, double-blind, placebo- or active comparator-controlled phase Ill trials and phase-II related to the approved indications in oncology (see section 4.1).
The most common ADRs (incidence >1/10 and suspected to be related to treatment by the investigator) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, peripheral oedema, hyperglycaemia asthenia, pruritus, decreased weight hypercholesterolaemia, epistaxis cough, headache.
The most common grade 3-4 ADRs (incidence >1/100 to <1/10 and suspected to be related to treatment by the investigator) were stomatitis, anaemia, hyperglycaemia, fatigue, infections, pneumonitis, diarrhoea, aesthaenia, thrombocytopenia, neutropenia, dyspnoea, lymphopenia, proteinuria, haemorrhage, hypophosphataemia, rash, hypertension, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), pneumonia and diabetes mellitus.
Table 2 presents the frequency category of ADRs reported in the pooled, safety analysis. ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse reaction: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1000); very rare (<1/10000).
Table 2. Adverse drug reactions from oncology trials:
Very common: Infectionsa
Very common: Anaemia
Common: Thrombocytopenia, neutropenia, leukopenia, lymphopenia
Uncommon: Pancytopenia
Rare: Pure red cell aplasia
Uncommon: Hypersensitivity
Very common: Decreased appetite, hyperglycaemia, hypercholesterolaemia
Common: Hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidaemia, hypokalaemia, dehydration
Common: Insomnia, anxiety, somnolence
Very common: Dysgeusia, headache
Uncommon: Ageusia
Uncommon: Congestive cardiac failure
Common: Haemorrhageb, hypertension
Uncommon: Deep vein thrombosis
Very common: Pneumonitisc, epistaxis, cough
Common: Dyspnoea
Uncommon: Haemoptysis, pulmonary embolism
Rare: Acute respiratory distress syndrome
Very common: Stomatitisd, diarrhoea, nausea
Common: Vomiting, dry mouth, abdominal pain, oral pain, mouth ulcers, dyspepsia, dysphagia
Very common: Rash, pruritus
Common: Dry skin, nail disorder, acne, erythema, hand-foot syndromee, pityriasis rosea
Rare: Angioedema
Common: Arthralgia
Common: Proteinuria, renal failure
Uncommon: Increased daytime urination, acute renal failure
Common: Irregular menstruationf
Uncommon: Amenorrhoeaf
Very common: Fatigue, aesthaenia, peripheral oedema
Common: Pyrexia, mucosal inflammation
Uncommon: Non-cardiac chest pain, impaired wound healing
Very common: Weight decreased
Common: Aspartate aminotransferase increased, alanine aminotransferase increased, blood creatinine increased
a Includes all reactions within the ‘infections and infestations’ system organ class including common: pneumonia, urinary tract infection; uncommon: bronchitis, herpes zoster, sepsis, abscess and isolated cases of opportunistic infections (e.g. aspergillosis, candidiasis, and hepatitis B) and rare: viral myocarditis.
b Includes different bleeding events from different sites not listed individually
c Includes common: pneumonitis, interstitial lung disease, lung infiltration; and rare: alveolitis, pulmonary alveolar haemorrhage, and pulmonary toxicity
d Includes very common: stomatitis; common: aphthous stomatitis, mouth and tongue ulceration; uncommon: glossitis, glossodynia
e reported as palmar-plantar erythrodysaesthesia syndrome
f frequency is based upon number of women 10 to 55 years of age in the safety pool.
In the pooled double-blind phase Ill safety database, the following new or worsening clinically relevant laboratory abnormalities were reported with an incidence of ≥10% (Very common, listed in decreasing frequency):
Haematology: decreased haemoglobin, decreased lymphocytes, decreased white blood cells; decreased platelets, and decreased neutrophils (or collectively as pancytopenia). Clinical chemistry: increased glucose (fasting), increased cholesterol, increased triglycerides, increased aspartate transaminases, decreased phosphate, increased alanine transaminases, increased creatinine and decreased potassium and decreased albumin.
Most of observed abnormalities (≥1/100) were mild (grade 1) or moderate (grade 2). Grade 3/ 4 haematology and chemistry abnormalities include: Haematology: Decreased Iymphocytes, decreased haemoglobin (very common) decreased neutrophils, decreased platelet count, decreased white blood cells (all common).
Clinical chemistry: increased glucose (fasting) (very common); decreased phosphate, decreased potassium, increased AST, increased ALT, increased creatinine, increased cholesterol (total), albumin decreased (all common), increased triglycerides (uncommon).
Adverse drug reaction (ADR) information is based on pooled data from patients with TSC receiving AFINITOR (N=612, including 409 patients <18 years of age) in three randomised, double blind, placebo-controlled, phase Ill studies including blinded and open-label treatment periods, and one non- randomised, open-label, single-arm phase II study which serve as the basis for the listed indications.
The most frequent ADR’s (incidence >1/10 from the pooled database are (in decreasing order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia and hypertension.
The most frequent grade ¾ adverse reactions (incidence >1/100 to <1/10 were pneumonia, stomatitis, amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea and cellulitis.
Table 3 shows the incidence of ADRs based on pooled data in patients receiving everolimus in the TSC studies (including both the double-blind and open-label study and extension periods) covering a duration of exposure of approximately 47 months in TSC-renal angiomyolipoma study. ADRs are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (≥1 /10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing frequency.
Table 3. Adverse drug reactions from clinical trials in TSC reported at a higher rate in the AFINITOR arm than in the placebo arm in TSC studies:
Very common: Nasopharyngitis, upper respiratory tract infection, pneumonia, urinary tract infection, sinusitis, pharyngitis
Common: Otitis media, cellulitis, streptococcal pharyngitis, viral gastroenteritis, gingivitis
Uncommon: Herpes zoster, sepsis, viral bronchitis
Common: Anaemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia
Common: Hypersensitivity
Very common: Decreased appetite, hypercholesterolaemia
Common: Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia
Common: Insomnia, aggression, irritability
Very common: Headache
Uncommon: Dysgeusia
Common: Hypertension, lymphoedema
Very common: Cough
Common: Epistaxis, pneumonitis
Very common: Stomatitisa, diarrhoea, vomiting
Common: Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis
Very common: Rashb, acne
Common: Dry skin, acneiform, dermatitis
Uncommon: Angioedema
Common: Proteinuria
Very common: Amenorrhoeac, irregular menstruationc
Common: Menorrhagia, ovarian cyst, vaginal haemorrhage
Uncommon: Delayed menstruationc
Very common: Pyrexia, fatigue
Common: Increased blood lactate dehydrogenase, increased blood luteinising hormone
Uncommon: Increased blood follicle stimulating hormone
a Includes very common: stomatitis, mouth ulceration, aphthous ulcer; common: tongue ulceration, lip ulceration; uncommon: gingival pain, glossitis.
b Includes very common: rash; common: rash erythematous, erythema; uncommon: rash generalized, rash maculo-papular, rash macular.
c frequency is based upon number of women 10 to 55 years of age while on treatment in the safety pool
In the pooled TSC safety database the following new or worsening clinically relevant laboratory abnormalities reported with an incidence of ≥1/10 (very common, listed in decreasing frequency): Haematology: increased partial thromboplastin time, decreased neutrophils, decreased haemoglobin, decreased white blood cells, decreased platelet count and decreased lymphocytes.
Clinical chemistry: increased cholesterol, increased triglycerides, increased AST, decreased phosphatase, increased ALT, increased alkaline phosphatase and glucose (fasting) increased.
Most of the laboratory abnormalities were mild (grade 1) or moderate (grade 2). Grade ¾ haematology and chemistry abnormalities included:
Haematology: decreased neutrophils, increased partial thromboplastin time, haemoglobin decreased (common); lymphocytes decreased, platelet count decreased, and white blood cells decreased (uncommon).
Clinical chemistry: decreased phosphate, triglycerides increased, increased alkaline phosphatase, increased ALT, increased AST, increased cholesterol (common); and glucose (fasting) increased (uncommon).
AFINITOR has been associated with:
Serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression (see section 4.4). Renal failure events (including fatal ones) and proteinuria. Monitoring of renal function is recommended (see section 4.4).
In clinical trials and post-marketing spontaneous reports, everolimus has been associated with pneumocystis jirovecii (carinii) pneumonia (PJP/PCP), some with fatal outcome (see section 4.4).
In clinical trials and post-marketing spontaneous reports, angioedema has been reported with and without concomitant use of ACE inhibitors (see section 4.4).
In a post-marketing single arm study in postmenopausal women with advanced hormone receptor- positive, HER2-negative breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 mL alcohol-free oral solution (10 mL swished in the mouth for 2 minutes and then spat out, to be repeated 4 times daily for 8 weeks) was administered as a mouthwash to patients at the time of initiating treatment with AFINITOR (10 mg/day) plus exemestane (25 mg/day) to reduce the incidence and severity of stomatitis. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone oral solution. The incidence of grade ≥2 stomatitis at 8 weeks was 2.4% (n=2/85 evaluable patients) which was lower than historically reported at 27.4% (n=132/482) in the phase III study in this patient population (BOLERO-2). The incidence of grade 1 stomatitis was 18.8% (n=16/85) and no grade 3 or 4 stomatitis were reported. The overall safety profile in this study was consistent with that established for everolimus in the oncology and TSC settings, with the exception of oral candidiasis which was reported in 2.2% (n=2/92) of patients in this study compared to 0.2% (n=1/482) of patients in BOLERO-2.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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