Everolimus

Everolimus is a selective inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase that is overactive in many cancers and that drives the proliferation of immune cells. It is a derivative of rapamycin. The same active substance is marketed as three medicinal products with different indications, doses and monitoring: Afinitor (cancer), Votubia (tuberous sclerosis complex) and Certican (transplantation). They are described separately below.

Mechanism of Action

• FKBP-12 complex: everolimus binds the intracellular protein FKBP-12. The complex inhibits mTOR complex 1 (mTORC1), which controls cell growth.
• Protein synthesis and cell cycle: blocking mTORC1 lowers the activity of S6 ribosomal protein kinase (S6K1) and of the eukaryotic elongation factor 4E-binding protein (4EBP-1). These regulate proteins involved in the cell cycle, angiogenesis and glycolysis, so cells stop progressing from G1 into S phase and growth arrests.
• Tumour blood supply: everolimus reduces the expression of hypoxia-inducible factor and of vascular endothelial growth factor (VEGF). It inhibits the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel smooth muscle cells, and reduced glycolysis in solid tumours in laboratory and animal studies.
• Breast cancer: S6K1 is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation.
• Tuberous sclerosis complex: loss of TSC1 or TSC2 function leaves mTOR signalling overactive. The Votubia indications rest on the change in angiomyolipoma or SEGA volume.
• Transplantation: the same mTOR blockade suppresses the cytokine-driven proliferation of T lymphocytes. Certican is therefore used together with a calcineurin inhibitor (ciclosporin or tacrolimus) and corticosteroids.
• Metabolites: the main circulating metabolites are about 100 times less active than everolimus, which provides most of the pharmacological activity.

Pharmacokinetics

• Absorption: peak blood levels occur about 1–2 hours after a dose (median 1 hour in cancer patients taking 5 or 10 mg fasting or with a light fat-free snack). Peak level and exposure are dose-proportional between 5 and 10 mg. Steady state is reached within 2 weeks of once-daily dosing in cancer patients; in transplant patients on twice-daily dosing it is reached by day 4, with blood levels 2 to 3 times those after the first dose.
• Food: in healthy subjects a high-fat meal lowered the AUC of 10 mg by 22% and the peak level by 54%, and a light-fat meal by 32% and 42%; the later part of the concentration curve was unaffected. For Certican tablets a high-fat meal lowered the peak level by 60% and the AUC by 16%, so the tablets are taken consistently, always with or always without food.
• Distribution: the blood-to-plasma ratio is concentration-dependent (17–73% over 5–5,000 ng/mL), and about 20% of the whole-blood concentration is in plasma in cancer patients taking 10 mg daily. Plasma protein binding is about 74% in healthy subjects and in moderate hepatic impairment. In advanced solid tumours the apparent volume of distribution was 191 L (central) and 517 L (peripheral); in kidney-transplant patients on maintenance treatment it was 342 ± 107 L in the terminal phase.
• Metabolism: everolimus is a substrate of CYP3A4 and P-glycoprotein and is the main circulating component in blood. Six main metabolites have been found: three monohydroxylated, two ring-opened hydrolytic products and a phosphatidylcholine conjugate.
• Elimination: mean half-life about 30 hours in cancer patients (oral clearance 24.5 L/h at 10 mg daily) and 28 ± 7 hours in transplant patients (oral clearance 8.8 L/h). After a radiolabelled dose in transplant patients taking ciclosporin, 80% of the radioactivity was in faeces and 5% in urine; unchanged drug was found in neither.
• Hepatic impairment: exposure rises with Child-Pugh class. In one study the AUC was 1.6-, 3.3- and 3.6-fold higher in mild, moderate and severe impairment; in the transplant data the half-life was 52, 59 and 78 hours, which delays steady state. Doses are reduced accordingly (see Administration and Dosage).
• Kidney function, age and ethnicity: creatinine clearance (25–178 mL/min in cancer patients, 11–107 mL/min after transplantation) and age (27–85 years in cancer patients) did not significantly affect clearance. Clearance is similar in Japanese and Caucasian cancer patients with similar liver function and, on average, 20% higher in black transplant patients.

Afinitor — cancer (centrally authorised)

• Hormone receptor-positive advanced breast cancer: HER2/neu-negative disease, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.
• Neuroendocrine tumours of pancreatic origin: unresectable or metastatic, well- or moderately differentiated tumours in adults with progressive disease.
• Neuroendocrine tumours of gastrointestinal or lung origin: unresectable or metastatic, well-differentiated (grade 1 or grade 2), non-functional tumours in adults with progressive disease.
• Renal cell carcinoma: patients with advanced renal cell carcinoma whose disease has progressed on or after VEGF-targeted therapy.

Votubia — tuberous sclerosis complex (TSC) (centrally authorised)

• Renal angiomyolipoma associated with TSC: adults at risk of complications (based on factors such as tumour size, presence of aneurysm, or multiple or bilateral tumours) who do not require immediate surgery. The evidence is based on the change in the sum of angiomyolipoma volume.
• Subependymal giant cell astrocytoma (SEGA) associated with TSC: adults and paediatric patients who need therapeutic intervention but are not amenable to surgery. The evidence is based on the change in SEGA volume; further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.

Certican — transplantation (nationally authorised)

• Kidney and heart transplantation: prophylaxis of organ rejection in adults at low to moderate immunological risk who receive an allogeneic renal or cardiac transplant. Certican is used in combination with ciclosporin for microemulsion and corticosteroids.
• Liver transplantation: prophylaxis of organ rejection in adults who receive a liver transplant. Certican is used in combination with tacrolimus and corticosteroids.

• Hypersensitivity to everolimus, to other rapamycin derivatives (for example sirolimus) or to any of the excipients (Afinitor, Votubia and Certican).

The side-effect profile differs by product and condition. The frequencies below come from the Afinitor SmPC (pooled data from 2,879 patients in eleven cancer studies), the Votubia SmPC (612 patients in tuberous sclerosis complex studies, 409 of them under 18 years) and the Certican SmPC (12-month controlled studies in adult transplant recipients).

Afinitor (Cancer)

The most common reactions (≥1/10), in decreasing order, were stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, peripheral oedema, hyperglycaemia, asthenia, pruritus, weight decrease, hypercholesterolaemia, epistaxis, cough and headache. The most frequent grade 3–4 reactions (≥1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, infections, fatigue, diarrhoea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, haemorrhage, hypophosphataemia, rash, hypertension, pneumonia, raised ALT and AST, and diabetes mellitus.

Very common (≥1/10): infections, anaemia, decreased appetite, hyperglycaemia, hypercholesterolaemia, dysgeusia, headache, pneumonitis, epistaxis, cough, stomatitis, diarrhoea, nausea, rash, pruritus, fatigue, asthenia, peripheral oedema, weight decrease.

Common (≥1/100 to <1/10): thrombocytopenia, neutropenia, leukopenia, lymphopenia, hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidaemia, hypokalaemia, dehydration, hypocalcaemia, insomnia, eyelid oedema, haemorrhage, hypertension, lymphoedema, dyspnoea, vomiting, dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia, dysphagia, raised AST and ALT, dry skin, nail disorder, mild alopecia, acne, erythema, onychoclasis, palmar-plantar erythrodysaesthesia syndrome, skin exfoliation, skin lesion, arthralgia, proteinuria, raised blood creatinine, renal failure, irregular menstruation, pyrexia.

Uncommon (≥1/1,000 to <1/100): pancytopenia, hypersensitivity, ageusia, conjunctivitis, congestive cardiac failure, flushing, deep vein thrombosis, haemoptysis, pulmonary embolism, increased daytime urination, acute renal failure, amenorrhoea, non-cardiac chest pain, impaired wound healing.

Rare (≥1/10,000 to <1/1,000): pure red cell aplasia, acute respiratory distress syndrome, angioedema.

Not known: radiation recall syndrome and potentiation of the radiation reaction.

Important serious reactions are non-infectious pneumonitis (some severe, rarely fatal), serious and opportunistic infections including hepatitis B reactivation (some fatal), renal failure including acute and fatal cases, hypersensitivity including anaphylaxis, angioedema, and severe radiation reactions.

Votubia (Tuberous Sclerosis Complex)

The most frequent reactions (≥1/10), in decreasing order, were stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, irregular menstruation, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia and hypertension. Grade 3–4 reactions in at least 1% of patients were pneumonia, stomatitis, amenorrhoea, neutropenia, pyrexia, irregular menstruation, hypophosphataemia, diarrhoea and cellulitis.

Very common (≥1/10): nasopharyngitis, upper respiratory tract infection, pneumonia, urinary tract infection, sinusitis, pharyngitis, decreased appetite, hypercholesterolaemia, headache, hypertension, cough, stomatitis, diarrhoea, vomiting, rash, acne, amenorrhoea, irregular menstruation, pyrexia, fatigue.

Common (≥1/100 to <1/10): otitis media, cellulitis, streptococcal pharyngitis, viral gastroenteritis, gingivitis, anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia, hypersensitivity, hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia, insomnia, aggression, irritability, lymphoedema, epistaxis, pneumonitis, constipation, nausea, abdominal pain, flatulence, oral pain, gastritis, dry skin, acneiform dermatitis, pruritus, alopecia, proteinuria, menorrhagia, ovarian cyst, vaginal haemorrhage, raised lactate dehydrogenase, raised luteinising hormone, weight decrease.

Uncommon (≥1/1,000 to <1/100): herpes zoster, sepsis, viral bronchitis, dysgeusia, angioedema, rhabdomyolysis, delayed menstruation, raised follicle-stimulating hormone.

Not known: radiation recall syndrome and potentiation of the radiation reaction (identified after marketing).

Menstrual frequencies are based on women aged 10 to 55 years on treatment. Infections were more frequent and more severe in children under 6 years: grade 3–4 infections occurred in 36% (49 of 137) of those aged under 6, 19% (53 of 272) of those aged 6 to under 18 and 13% (27 of 203) of those aged 18 or over, and two fatal infections occurred among 409 patients under 18. Serious hepatitis B reactivation (including fatal cases), renal failure, haemorrhage and Pneumocystis jirovecii pneumonia have also been linked to everolimus.

Certican (Transplantation)

The most frequent reactions are infections, anaemia, hyperlipidaemia, new-onset diabetes mellitus, insomnia, headache, hypertension, cough, constipation, nausea, peripheral oedema and impaired wound healing (including pleural and pericardial effusion). Serum creatinine rose more often with full-dose ciclosporin than with reduced doses.

Very common (≥1/10): viral, bacterial and fungal infections, upper and lower respiratory tract and lung infections including pneumonia, urinary tract infections, leucopenia, anaemia or erythropenia, thrombocytopenia, hyperlipidaemia (cholesterol and triglycerides), new-onset diabetes mellitus, hypokalaemia, insomnia, anxiety, headache, pericardial effusion, hypertension, venous thromboembolic events, pleural effusion, cough, dyspnoea, abdominal pain, diarrhoea, nausea, vomiting, peripheral oedema, pain, impaired wound healing, pyrexia.

Common (≥1/100 to <1/10): sepsis, wound infection, malignant or unspecified tumours, malignant and unspecified skin neoplasms, pancytopenia, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome), tachycardia, lymphocele, epistaxis, renal graft thrombosis, pancreatitis, stomatitis or mouth ulceration, oropharyngeal pain, angioedema, acne, rash, myalgia, arthralgia, proteinuria, renal tubular necrosis, erectile dysfunction, menstrual disorders (including amenorrhoea and menorrhagia), incisional hernia, abnormal liver enzymes (gamma-glutamyl transferase, AST, ALT).

Uncommon (≥1/1,000 to <1/100): lymphomas and post-transplant lymphoproliferative disorders, male hypogonadism (lower testosterone, higher luteinising and follicle-stimulating hormone), interstitial lung disease, non-infectious hepatitis, jaundice, ovarian cyst.

Not known (after marketing): iron deficiency, leukocytoclastic vasculitis, lymphoedema, pulmonary alveolar proteinosis, erythroderma.

Some reactions depend on the transplant type: pericardial effusion was seen in heart transplantation, lymphocele in kidney and heart transplantation, and renal tubular necrosis in kidney transplantation, while angioedema occurred mostly in patients also taking ACE inhibitors. Among 3,256 patients followed for at least a year in controlled studies, 3.1% developed a malignancy (1.0% skin cancer and 0.60% lymphoma or lymphoproliferative disorder). Interstitial lung disease with pneumonitis or fibrosis has occurred, in some cases fatally.

Everolimus is a substrate of CYP3A4 and P-glycoprotein (PgP) and a moderate PgP inhibitor, so medicines and foods that affect either can change its levels. The data below come mainly from the Afinitor SmPC; Certican uses the same principles with blood-level monitoring, and Votubia dosing requires trough checks after any change in CYP3A4 inhibitors or inducers.

• Potent CYP3A4/PgP inhibitors: ketoconazole raised everolimus AUC 15.3-fold and peak level 4.1-fold. Itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, nefazodone and the HIV protease inhibitors ritonavir, atazanavir, saquinavir, darunavir, indinavir and nelfinavir are expected to raise levels greatly. Afinitor should not be combined with potent inhibitors; Certican only if the benefit outweighs the risk, with trough monitoring.
• Moderate inhibitors: erythromycin raised AUC 4.4-fold, imatinib 3.7-fold, verapamil 3.5-fold, oral ciclosporin 2.7-fold and cannabidiol 2.5-fold. Fluconazole, diltiazem, dronedarone, amprenavir and fosamprenavir are expected to raise exposure. With Afinitor, use caution; a reduction to 5 mg or 2.5 mg daily may be considered, although no clinical data support it. After the inhibitor is stopped, allow a washout of at least 2 to 3 days before returning to the previous dose.
• CYP3A4 inducers: rifampicin lowered AUC by 63% and peak level by 58%. Dexamethasone, carbamazepine, phenobarbital, phenytoin, efavirenz and nevirapine are expected to lower exposure. With Afinitor, potent inducers should be avoided; if essential, the dose may be raised from 10 mg up to 20 mg daily in steps of 5 mg or less on days 4 and 8 after starting the inducer (no clinical data), with a washout of at least 3 to 5 days after stopping. For Certican, rifampicin, rifabutin, carbamazepine and phenytoin are not recommended unless the benefit outweighs the risk.
• St John’s wort: a large fall in exposure is expected; preparations containing it should not be used.
• Antiepileptics in tuberous sclerosis: concomitant antiepileptic therapy may affect everolimus metabolism and the dose a patient tolerates. Trough levels are checked 2 to 4 weeks after starting or changing a CYP3A4 inducer, and at least 1 week after starting or changing an inhibitor.
• Grapefruit: grapefruit juice and other foods that affect CYP3A4 or PgP are expected to raise exposure to a widely varying degree; avoid them.
• Ciclosporin and tacrolimus (Certican): Certican is combined with ciclosporin for microemulsion (kidney, heart) or tacrolimus (liver). With full-dose ciclosporin it increases the risk of kidney dysfunction, so reduced ciclosporin doses are used; it has little clinical effect on ciclosporin levels. Everolimus levels can fall if ciclosporin exposure is greatly reduced.
• Statins and fibrates: single doses of atorvastatin or pravastatin did not change either drug’s levels to a clinically relevant extent, but this cannot be extended to other statins. Patients on statins or fibrates should be watched for rhabdomyolysis.
• Oral CYP3A4 substrates with a narrow therapeutic index (pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives): everolimus slightly raised the exposure of an orally given sensitive CYP3A substrate in a study (peak level by 25%, AUC by 30%), probably through gut CYP3A4. Monitor for the side effects of the other medicine.
• Octreotide and exemestane: everolimus raised the trough level of depot octreotide 1.47-fold, and exemestane levels by 45% (trough) and 64% (2 hours after dose) without a change in oestradiol levels or more exemestane-related reactions; neither is thought to matter clinically.
• ACE inhibitors (for example ramipril): higher risk of angioedema.
• Vaccines: the response to vaccination may be weaker; live vaccines should be avoided.
• Radiotherapy: everolimus can potentiate radiation toxicity and cause radiation recall.
• Food: take at the same time every day, with a full glass of water, always with or always without food.

Treatment is started by a specialist, and the three products differ. Afinitor is started and supervised by a physician experienced in anticancer therapy. Votubia is started by a physician experienced in treating tuberous sclerosis complex and in therapeutic drug monitoring. Certican is started and kept under the direction of physicians experienced in immunosuppression after organ transplantation who can monitor everolimus whole-blood concentrations. All are taken by mouth at the same times every day. Afinitor and Votubia tablets are swallowed whole with a glass of water, consistently with or without food, and are not chewed or crushed.

Afinitor: Cancer Indications

• Dose: 10 mg once daily, at the same time every day (tablets of 2.5 mg, 5 mg and 10 mg are available). In breast cancer it is combined with exemestane.
• Duration: as long as clinical benefit is observed or until unacceptable toxicity occurs.

Afinitor: Dose Adjustments for Side Effects

Grade 1 reactions usually need no adjustment. When a reduction is needed the dose is 5 mg daily, and it must not go lower.

• Non-infectious pneumonitis: grade 2 — consider interrupting until symptoms improve to grade 1, restart at 5 mg daily, and stop if there is no recovery within 4 weeks. Grade 3 — interrupt until grade 1, consider restarting at 5 mg daily, and consider stopping if grade 3 recurs. Grade 4 — stop.
• Stomatitis: grade 2 — interrupt until grade 1 and restart at the same dose, but at 5 mg daily if grade 2 recurs. Grade 3 — interrupt until grade 1 and restart at 5 mg daily. Grade 4 — stop.
• Other non-haematological toxicities (excluding metabolic events): grade 2 — no change if tolerable; if intolerable, interrupt until grade 1 and restart at the same dose, but at 5 mg daily if it recurs. Grade 3 — interrupt until grade 1, consider restarting at 5 mg daily, and consider stopping if grade 3 recurs. Grade 4 — stop.
• Metabolic events (for example hyperglycaemia, dyslipidaemia): grade 2 — no change. Grade 3 — interrupt and restart at 5 mg daily. Grade 4 — stop.
• Thrombocytopenia: grade 2 (platelets 50 to below 75 × 10⁹/L) — interrupt until at least 75 × 10⁹/L and restart at the same dose. Grade 3–4 (below 50 × 10⁹/L) — interrupt until at least 75 × 10⁹/L and restart at 5 mg daily.
• Neutropenia: grade 2 (at least 1 × 10⁹/L) — no change. Grade 3 (0.5 to below 1 × 10⁹/L) — interrupt until at least 1 × 10⁹/L and restart at the same dose. Grade 4 (below 0.5 × 10⁹/L) — interrupt until at least 1 × 10⁹/L and restart at 5 mg daily.
• Febrile neutropenia: grade 3 — interrupt until neutrophils reach at least 1.25 × 10⁹/L and there is no fever, then restart at 5 mg daily. Grade 4 — stop.

Afinitor: Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no dose adjustment.
• Hepatic impairment: mild (Child-Pugh A) 7.5 mg daily; moderate (Child-Pugh B) 5 mg daily; severe (Child-Pugh C) only if the benefit outweighs the risk, and then not above 2.5 mg daily. The dose is adjusted if the Child-Pugh status changes.
• Children and adolescents: safety and efficacy from 0 to 18 years have not been established.

Votubia: Renal Angiomyolipoma

10 mg once daily, continued as long as clinical benefit is observed or until unacceptable toxicity occurs. Measuring everolimus blood levels is an option after starting or changing a CYP3A4 inducer or inhibitor, or after any change in hepatic status.

Votubia: SEGA

• Starting dose: dosing is individualised by body surface area (BSA, calculated with the Dubois formula). The recommended starting dose is 4.5 mg/m² once daily, and 7 mg/m² for patients aged 1 to under 3 years. Different tablet strengths can be combined to reach the dose.
• Titration: whole-blood trough concentration is measured at least 1 week after starting, and the dose is titrated to a trough of 5 to 15 ng/mL, in steps of 2.5 mg. The new dose is the current dose multiplied by the target concentration and divided by the current concentration, rounded to the next available tablet strength.
• Follow-up: SEGA volume is evaluated about 3 months after starting. Once the dose is stable, trough levels are checked every 3 to 6 months in patients with changing BSA, or every 6 to 12 months in patients with stable BSA. Treatment continues as long as clinical benefit is observed or until unacceptable toxicity.
• Therapeutic drug monitoring is required: trough levels are also checked at least 1 week after any change in dose or pharmaceutical form, after starting or changing CYP3A4 inhibitors, or after any change in hepatic status, and 2 to 4 weeks after starting or changing CYP3A4 inducers. The same assay and laboratory should be used where possible.

Votubia: Adjustments, Forms and Special Populations

• Side effects: the grade-based rules are those listed for Afinitor, except that treatment restarts at a dose about 50% lower than the previous daily dose. Where this falls below the lowest strength, alternate-day dosing can be considered.
• Pharmaceutical forms: Votubia is available as tablets and dispersible tablets. They are not interchangeable and must not be combined to reach a dose; when switching, the dose is set to the closest milligram strength and the trough is checked at least 1 week later. Patients with SEGA who cannot swallow tablets can stir the tablets in about 30 mL of water until fully dispersed (about 7 minutes) and drink it at once, then rinse out any residue with the same volume of water.
• Hepatic impairment, renal angiomyolipoma: mild (Child-Pugh A) 7.5 mg daily; moderate (B) 5 mg daily; severe (C) only if the benefit outweighs the risk and not above 2.5 mg daily.
• Hepatic impairment, SEGA: not recommended below 18 years. From 18 years, 75% (mild), 50% (moderate) or at most 25% (severe, only if the benefit outweighs the risk) of the BSA-based starting dose.
• Elderly and renal impairment: no dose adjustment.
• Children: safety, efficacy and pharmacokinetics in children under 1 year with SEGA have not been established, nor have efficacy and safety in children with angiomyolipoma without SEGA. Clinical studies showed no effect on growth or pubertal development.
• Missed dose (Afinitor and Votubia): do not take an extra dose; take the next prescribed dose as usual.

Certican: Transplantation

• Kidney and heart transplantation: initial dose 0.75 mg twice daily with ciclosporin for microemulsion, given as soon as possible after transplantation.
• Liver transplantation: 1.0 mg twice daily with tacrolimus, with the first dose about 4 weeks after transplantation.
• How it is taken: for oral use only; the daily dose is divided in two, taken with or without food but always the same way, and at the same time as ciclosporin for microemulsion or tacrolimus. Tablets are swallowed whole with a glass of water and are not split before use. Dispersible tablets exist for patients who cannot swallow tablets (see their SmPC).

Certican: Blood-Level Monitoring and Adjustment

• Doses are adjusted at intervals of 4 to 5 days according to blood levels, tolerability, individual response, changes in co-medication and clinical condition.
• Certican has a narrow therapeutic margin, and routine monitoring of everolimus whole-blood trough levels is recommended. Patients with a trough of at least 3.0 ng/mL had fewer biopsy-confirmed acute rejections in kidney, heart and liver transplantation than those below 3.0 ng/mL. The recommended upper limit is 8 ng/mL, and exposure above 12 ng/mL has not been studied (ranges based on a chromatographic method).
• Monitoring matters most in hepatic impairment, with strong CYP3A4 inhibitors or inducers, when changing formulation, and when the ciclosporin dose is markedly reduced. Everolimus levels may fall if ciclosporin troughs drop below 50 ng/mL.
• Kidney transplantation: Certican should not be used long term with full-dose ciclosporin. Ciclosporin reduction starts immediately after transplantation, with whole-blood trough targets of 100–200 ng/mL in month 1, 75–150 ng/mL in months 2–3, 50–100 ng/mL in months 4–5 and 25–50 ng/mL in months 6–12. Before each reduction, the steady-state everolimus trough must be at least 3 ng/mL. Data below 50 ng/mL are limited; if a patient cannot tolerate reduced ciclosporin, continuing Certican should be reconsidered.
• Heart transplantation: in maintenance, ciclosporin is reduced to the lowest tolerated level to improve kidney function. The regimen is reviewed if kidney function worsens progressively or calculated creatinine clearance falls below 60 mL/min. The everolimus trough must be at least 3 ng/mL before ciclosporin is reduced.
• Liver transplantation: tacrolimus exposure is reduced to limit calcineurin-inhibitor kidney toxicity, starting about 3 weeks after Certican begins, aiming at tacrolimus troughs of 3 to 5 ng/mL. Complete withdrawal of tacrolimus was linked to more acute rejection in a controlled trial, and Certican has not been evaluated with full-dose tacrolimus in controlled trials.

Certican: Special Populations

• Hepatic impairment: trough levels are monitored closely and doses reduced to about two thirds of the usual dose in mild (Child-Pugh A), about half in moderate (B) and about one third in severe (C) impairment. The reduced twice-daily doses are, in kidney and heart transplantation, 0.75 mg (normal liver function), 0.5 mg (mild), 0.5 mg (moderate) and 0.25 mg (severe); in liver transplantation, 1 mg, 0.75 mg, 0.5 mg and 0.5 mg. After starting or adjusting, troughs are checked every 4 to 5 days until two consecutive values are stable, because the longer half-life delays steady state; troughs are preferably in the upper part of the 3–8 ng/mL range.
• Renal impairment: no dose adjustment.
• Elderly (65 years and over): clinical experience is limited; no apparent difference in pharmacokinetics at 65–70 years.
• Black patients: biopsy-confirmed acute rejection was significantly more frequent in black kidney-transplant patients, and there is little information that a higher dose might be needed. Data are insufficient for specific recommendations.
• Children: Certican should not be used in paediatric kidney and liver transplantation. Safety and efficacy in paediatric heart transplantation have not been established.

Non-Infectious Pneumonitis

Non-infectious pneumonitis (including interstitial lung disease) is a class effect of rapamycin derivatives and has been reported frequently with Afinitor; some cases were severe and rarely fatal. It should be considered in patients with non-specific respiratory signs such as hypoxia, pleural effusion, cough or dyspnoea once infectious, neoplastic and other causes have been excluded, and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) should be ruled out. Patients should report new or worsening respiratory symptoms promptly. Those with radiological changes but few or no symptoms can continue without a dose change; corticosteroids may be indicated for moderate (grade 2) or severe (grade 3) symptoms, and PJP prophylaxis may be considered if corticosteroids are needed. Interstitial lung disease has also been reported with Certican; it usually resolves after the medicine is stopped, but fatal cases have occurred.

Infections

Everolimus is immunosuppressive and may predispose to bacterial, fungal, viral and protozoan infections, including opportunistic pathogens. Local and systemic infections have been described, including pneumonia, invasive fungal infections (aspergillosis, candidiasis, PJP) and reactivation of hepatitis B; some were severe, leading to sepsis or respiratory or hepatic failure, and some were fatal. Existing infections should be treated and resolved before starting. Patients and doctors should watch for signs of infection, treat it promptly and consider interrupting or stopping everolimus. An invasive systemic fungal infection requires prompt, permanent discontinuation and antifungal treatment. PJP prophylaxis should be considered if corticosteroids or other immunosuppressants are used with everolimus.

Hypersensitivity and Angioedema

Hypersensitivity reactions, including anaphylaxis, dyspnoea, flushing, chest pain and angioedema (swelling of the airways or tongue), have been observed. Patients taking ACE inhibitors may be at higher risk of angioedema.

Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, is the most commonly reported reaction with Afinitor and mostly occurs within the first 8 weeks. A single-arm study in postmenopausal women with breast cancer suggested that an alcohol-free corticosteroid mouthwash during the first 8 weeks may lower its incidence and severity. Products containing alcohol, hydrogen peroxide, iodine or thyme derivatives should be avoided because they may make it worse. Fungal infection should be looked for and treated, especially in patients on steroid-based medicines; antifungal agents should not be used unless a fungal infection has been diagnosed.

Monitoring: Kidney Function, Glucose, Lipids and Blood Counts

For Afinitor, kidney function (blood urea nitrogen, urinary protein or serum creatinine), fasting blood glucose, cholesterol and triglycerides, and the complete blood count are checked before starting and periodically afterwards. Glucose is checked more often with other medicines that raise it, and glycaemic control should be optimised beforehand where possible. Renal failure, including acute failure and fatal cases, has been observed, particularly in patients with other risk factors for kidney impairment. In transplantation, kidney function, blood glucose and serum lipids are monitored regularly; Certican raises the risk of new-onset diabetes mellitus and of high cholesterol and triglycerides, and patients on statins or fibrates are watched for rhabdomyolysis.

Hepatic Impairment

Exposure to everolimus is higher in mild, moderate and severe hepatic impairment. Afinitor is recommended in severe impairment (Child-Pugh C) only if the benefit outweighs the risk, and no clinical safety or efficacy data support dose adjustments for managing adverse reactions in these patients. Votubia is not recommended in severe hepatic impairment (Child-Pugh C) from 18 years of age unless the benefit outweighs the risk, nor in patients under 18 with SEGA and any hepatic impairment.

Vaccinations

Live vaccines should be avoided during treatment, and vaccination may be less effective. Examples of live vaccines are intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and the oral typhoid vaccine (Ty21a). For children with SEGA who do not need immediate treatment, completing the recommended childhood series of live virus vaccinations before starting Votubia is advised, following local guidelines.

Wound Healing and Surgery

Impaired wound healing is a class effect of rapamycin derivatives, so everolimus is used with caution around surgery. In transplant patients, Certican can worsen wound healing, leading to wound dehiscence, fluid collections and wound infection that may need further surgery. Lymphocele is the most frequently reported effect in kidney-transplant recipients and is more frequent with a higher body mass index; pericardial and pleural effusions are more frequent in heart-transplant recipients and incisional hernias in liver-transplant recipients.

Radiation Therapy

Serious and severe radiation reactions (radiation oesophagitis, radiation pneumonitis, radiation skin injury), including fatal cases, have been reported when everolimus was taken during or shortly after radiotherapy, so caution is needed when the two are close in time. Radiation recall syndrome has occurred in patients who had earlier radiotherapy; interrupting or stopping everolimus should be considered.

Neuroendocrine Tumours (Afinitor)

• Functional carcinoid tumours: in a trial of Afinitor plus depot octreotide against placebo plus depot octreotide, the primary endpoint (progression-free survival) was not met and the interim overall-survival analysis numerically favoured placebo. Safety and efficacy in functional carcinoid tumours have therefore not been established.
• Gastrointestinal or lung neuroendocrine tumours with good prognostic factors: for non-functional tumours with, for example, an ileal primary site and normal chromogranin A or no bone involvement, an individual benefit-risk assessment is needed before starting, because the evidence of benefit was limited in the ileal subgroup.

Transplantation (Certican)

• Immunosuppression: Certican has been used with ciclosporin for microemulsion, basiliximab, or tacrolimus, and corticosteroids. Other combinations have not been investigated adequately, and Certican has not been adequately studied in patients at high immunological risk.
• Rabbit antithymocyte globulin induction: strict caution is advised with the regimen of this induction plus Certican, ciclosporin and steroids. In a heart-transplant trial, serious infections, including fatal ones, were more frequent in the first three months among patients who had received it.
• Serious and opportunistic infections: these include BK virus-associated nephropathy and JC virus-associated progressive multifocal leukoencephalopathy, which should be considered when kidney function worsens or neurological symptoms appear. Fatal infections and sepsis have been reported. Prophylaxis against Pneumocystis jirovecii pneumonia and cytomegalovirus was recommended in trials, mainly for patients at higher risk.
• Kidney function and proteinuria: with full-dose ciclosporin, Certican increases the risk of kidney dysfunction, so reduced ciclosporin doses are required. Proteinuria is more likely at higher everolimus levels; in kidney-transplant patients with mild proteinuria it worsened when a calcineurin inhibitor was replaced by Certican and was reversible on going back. The safety and efficacy of that switch have not been established.
• Renal graft thrombosis: an increased risk of arterial and venous renal thrombosis leading to graft loss has been reported, mostly in the first 30 days after transplantation.
• Thrombotic microangiopathy: used with a calcineurin inhibitor, Certican may increase the risk of calcineurin inhibitor-induced thrombotic microangiopathy, thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome.
• Lymphomas and other malignancies: immunosuppression increases the risk, especially of skin cancer. The risk seems related to the intensity and duration of immunosuppression rather than to one medicine. Skin should be checked regularly, and patients should limit exposure to sunlight and UV light and use suitable sunscreen.
• Other points: angioedema occurred mostly with concomitant ACE inhibitors; immunosuppressants can weaken vaccination, and live vaccines should be avoided; male infertility is a potential risk with prolonged treatment.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use a highly effective method of contraception during Afinitor or Votubia treatment and for up to 8 weeks after it ends. For Certican, effective contraception is advised during treatment and for 8 weeks after. Male patients on Afinitor or Votubia should not be prohibited from attempting to father children.
• Pregnancy: there are no adequate data. Animal studies showed embryotoxicity and foetotoxicity, and the risk for humans is unknown. Afinitor and Votubia are not recommended in pregnancy or in women of childbearing potential not using contraception; Certican should not be given to pregnant women unless the potential benefit outweighs the possible risk to the foetus.
• Breastfeeding: it is not known whether everolimus passes into human milk, but it readily does in rats. Women taking Afinitor or Votubia should not breastfeed during treatment and for 2 weeks after the last dose; women taking Certican should not breastfeed.
• Fertility: the potential to cause infertility is unknown, but secondary amenorrhoea with luteinising hormone and follicle-stimulating hormone imbalance has been seen, and non-clinical findings suggest that male and female fertility may be compromised. With mTOR inhibitors, reversible oligospermia and azoospermia have been reported in the literature.

Lactose

The tablets contain lactose (74 mg, 149 mg or 297 mg per Afinitor 2.5 mg, 5 mg or 10 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

Afinitor and Votubia have a minor or moderate influence on the ability to drive and use machines; patients who feel fatigued should be careful. Certican has no or negligible influence.

Afinitor and Votubia tablets: do not store above 25 °C. Certican tablets need no special temperature. All three are kept in the original package (blister) to protect them from light and moisture, out of the sight and reach of children. Everolimus tablets are not refrigerated and need no cold chain.

3 years for Afinitor, Votubia and Certican tablets. Do not use after the expiry date on the pack.

Prescription only (Rx). Afinitor is subject to restricted medical prescription (Annex II B of its SmPC) and is started and supervised by a physician experienced in anticancer therapy. Votubia is started by a physician experienced in treating tuberous sclerosis complex and in therapeutic drug monitoring, and Certican by a physician experienced in post-transplant immunosuppression who can monitor everolimus whole-blood levels. All three are oral tablets taken at home, so they are supplied to the patient or to the treating clinic or transplant centre on prescription.