Consumer medicine information

Certican

Everolimus

BRAND INFORMATION

Brand name

Certican

Active ingredient

Everolimus

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Certican.

What is in this leaflet

This leaflet answers some common questions about Certican.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine.

You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Certican against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Certican is used for

Certican is used to treat adult patients who have had kidney, heart or liver transplants. It helps to prevent your body from rejecting the transplanted organ.

Certican contains the active ingredient everolimus. It belongs to a group of medicines called immunosuppressants. These medicines help to control your body's immune system.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Certican is available only with a doctor's prescription and is not addictive.

There is not enough information to recommend the use of this medicine in children and adolescents.

Before you take Certican

When you must not take it

Do not take Certican if you have an allergy to:

  • everolimus, the active ingredient in Certican
  • any of the ingredients listed at the end of this leaflet.
  • a similar medicine called Rapamune which contains the active ingredient sirolimus.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; sudden difficulty swallowing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have or have had any of the following medical conditions:

  • problems with your liver
  • high cholesterol

Tell your doctor if you are pregnant or plan to become pregnant. Certican is not recommended for use during pregnancy. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast-feeding. Breastfeeding is not recommended while you are taking Certican. It is not known whether Certican passes into breast milk and could affect your baby.

Tell your doctor if you are male and you want to father children. Certican may reduce sperm production in men, thus reducing the ability to father children. The effect is generally reversible.

Tell your doctor if you are male or female and you want children. Certican may cause infertility in male or female patients.

Tell your doctor if you have intolerance to certain sugars (glucose, galactose, lactose). Certican tablets contain lactose.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes. Your doctor will want to know if you are prone to allergies.

Medicines that suppress the immune system like Certican reduce your body's ability to fight against infections. It is advisable to consult your doctor if you have a fever or generally feel unwell, or have local symptoms such as coughing or a burning sensation when urinating that are severe or persistent over several days. Consult your doctor right away if you feel confused, have problems speaking, memory loss, a headache, impaired vision or seizures, as these may be symptoms of a rare but very serious condition called progressive multiple leukoencephalopathy (PML).

Tell your doctor if you have had recent major surgery, or if you still have an unhealed wound following surgery. Certican may increase the risk of wound-healing problems.

If you have not told your doctor about any of the above, tell him/her before you start taking Certican.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Certican may interfere with each other. These include:

  • Immunosuppressive medicines other than cyclosporin for microemulsion, tacrolimus or corticosteroids.
  • Antibiotics such as rifampicin, clarithromycin, erythromycin and rifabutin
  • Antifungal medicines such as ketoconazole, fluconazole and itraconazole
  • Medicines for high blood pressure or heart problems such as diltiazem and verapamil
  • dronedarone, a medicine used to help regulate your heart beat
  • Medicines used to treat HIV/AIDS such as nelfinavir, indinavir, amprenavir, efavirenz and nevirapine
  • medicines used to lower blood cholesterol, such as atorvastatin, pravastatin or fibrates
  • Midazolam, a medicine used to treat acute seizures, or used as a sedative before or during surgery or other medical procedure.
  • Epilepsy medicines such as carbamazepine, phenobarbitone and phenytoin
  • octreotide, a medicine used to treat acromegaly, a rare hormonal disorder that usually occurs in middle-aged adults
  • Medicines for stomach ulcer or reflux such as cimetidine and cisapride
  • Medicines to prevent nausea and vomiting such as metoclopamide
  • Danazol which is used to treat endometriosis
  • Bromocriptine which is used to treat Parkinson's disease
  • imatinib, a medicine used to inhibit the growth of abnormal cells
  • St John's wort, a herbal product used to treat depression and other conditions.

Such medicines may be affected by Certican or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Some vaccines may be less effective if given when taking Certican.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Certican

Certican tablets are swallowed whole.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label ask your doctor or pharmacist for help.

How much to take

Kidney and heart transplantations
The usual starting dose is 0.75 mg Certican twice daily, taken in the morning and in the evening together with cyclosporine.

The first dose of Certican will be given as soon as possible after transplantation.

Liver transplantation:
The general recommended daily dose is 1 mg Certican twice daily, taken in the morning and in the evening, together with tacrolimus.

The first dose of Certican will be given approximately four weeks after transplantation.

Your doctor will take regular blood tests to measure the amount of Certican in your blood. If needed, your doctor will adjust your dose depending on the results from your blood tests.

When to take it

Always take Certican twice a day. It is best to take the doses 12 hours apart if possible. Taking your doses 12 hours apart and at the same time each day will have the best effect. It will also help you remember when to take them.

Certican can be taken with or without food but should always be taken the same way. (e.g. always with food or always without food).

If you are taking cyclosporine or tacrolimus, you should take it at the same time as Certican.

How to take it

  • Swallow the tablets whole with a full glass of water.
  • Do not crush or chew them.
  • Do not take Certican with grapefruit juice.

How long to take it

Keep taking this medicine for as long as your doctor tells you. You will need to take Certican as long as you have your transplanted organ, or until your doctor changes your immunosuppressive medication.

If you forget to take it

If it is almost time for your next dose skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you miss more than one dose, ask your doctor for advice.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Certican. Do this even if there are no signs of discomfort or poisoning.

While you are taking Certican

Things you must do

Keep all of your doctor's appointments so that your progress can be checked. Regular check-ups with blood and urine tests are essential for your doctor to assess the good function of your transplanted organ, to detect possible unwanted side effects and to adapt the dosages of your medicines to obtain the best treatment.

Blood tests allow your doctor to measure levels of your medicines to check your kidney activity and the levels of sugar and cholesterol in your blood.

Measurement of proteins in a urine sample also helps your doctor to assess kidney activity.

Make sure you use a highly effective contraceptive to prevent pregnancy during treatment with Certican. If you become pregnant while taking this medicine, tell your doctor immediately.

If you develop lumps anywhere in your body, or develop any moles, or you notice changes in existing moles, tell your doctor. This may be an early sign of a cancer. Immunosuppressant medicines, including Certican, may increase the risk of developing certain cancers, including skin cancer and lymphoma (cancer of the lymphatic system).

If you go out in the sun, wear a hat, protective clothing and sunscreen. Do not use a sun lamp. This will help to prevent the development of skin cancer.

If you want to be vaccinated, tell your doctor you are taking Certican before you have the vaccination. Certican may affect your response to vaccination. Some vaccines may not be suitable for you.

If you are experiencing respiratory symptoms (e.g. coughing, difficulty in breathing and wheezing), please inform your doctor. Your doctor may decide whether and how you need to continue Certican, and/or whether you need to receive other medicines to resolve this condition.

Tell your doctor if you experience any swelling of the limbs or around your abdomen.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Certican.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Things you must not do

Do not take Certican to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Certican affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Certican. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • general pain, muscle or joint pain or tenderness
  • weakness, bruising and frequent infections
  • upper and lower respiratory tract infections
  • urinary tract infections
  • slowed wound healing or wound infection
  • nosebleeds
  • acne
  • abdominal pain
  • nausea, vomiting, diarrhoea
  • impotence
  • menstrual disorders (including absent or heavy periods)
  • cold sores, mouth sores
  • pain in the ear, nose or throat
  • jaundice (yellowing of the skin and eyes with darkened urine).
  • difficulty sleeping
  • anxiety
  • headache
  • fever
  • rash
  • increased heart rate
  • breathlessness
  • ovarian cyst

If any of the following happen, tell your doctor immediately:

  • swelling of hands, feet or limbs due to fluid retention
  • symptoms of an allergic reaction such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin
  • burning sensation on urination or increased urgency to urinate
  • severe upper stomach pain, which may be accompanied by nausea and vomiting
  • constant "flu-like" symptoms such as fever (increased temperature), chills/shivering, sore throat, aching joints, swollen glands, cough, or any other signs of infection such as infection of a cut or scratch
  • new lumps or moles, or changes to existing moles, anywhere on the body
  • unusual bleeding or bruising without obvious cause
  • persistent or worsening lung/breathing symptoms like coughing, difficulty breathing, wheezing
  • pain, hernia, unusual warmth, swelling or oozing from the site of surgery
  • tiredness, headaches, shortness of breath when exercising, dizziness and looking pale, which could be signs of anaemia
  • swelling of the face, lips, mouth, tongue, or throat which may cause difficulty in swallowing or breathing
  • sudden reduction in your urine output, especially if accompanied by pain where your transplanted kidney is located.
  • signs that blood clots may have formed, such as severe sudden headache, sudden loss of coordination, blurred vision, loss of vision, slurred speech, numbness in an arm or leg, pain in the calves, thighs or chest, shortness of breath, coughing blood.

The above list includes serious side effects. You may need urgent medical attention or hospitalisation.

In addition, your doctor will do blood tests to check your kidneys to make sure they are not being damaged during treatment with Certican.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed here or not yet known may happen in some people. Some of these side effects can only be found by laboratory testing (e.g. blood level of sugar, fat and cholesterol).

After taking Certican

Storage

  • Keep the tablets in the original packet and foils until it is time to take them.
  • Store the tablets in a cool, dark and dry place at room temperature.
  • Do not store Certican or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

Keep the medicine where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Certican tablets are white to yellowish, round and marbled. Certican tablets are available in four different strengths, supplied in packs of 60 tablets:

  • 0.25 mg: with "C" on one side and "NVR" on the other
  • 0.5 mg: with "CH" on one side and "NVR" on the other
  • 0.75 mg: with "CL" on one side and "NVR" on the other
  • 1.0 mg: with "CU" on one side and "NVR" on the other

Ingredients

Certican tablets contain 0.25, 0.5, 0.75 mg and 1.0 mg of everolimus as the active ingredient. They also contain:

  • butylated hydroxytoluene
  • magnesium stearate
  • lactose
  • hypromellose
  • crospovidone
  • lactose anhydrous

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Contains lactose, galactose, milk, sugars

Sponsor

Certican is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203

® = Registered Trademark

This leaflet was prepared in November 2019.

Australian Registration Number.

0.25 mg tablets - AUST R 97500

0.5 mg tablets - AUST R 97506

0.75 mg tablets - AUST R 97509

1.0 mg tablets - AUST R 97516

(cer011119c.doc) based on PI (cer011119i.doc)

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Certican

Active ingredient

Everolimus

Schedule

S4

 

1 Name of Medicine

Australian Approved Name: everolimus.

2 Qualitative and Quantitative Composition

Certican tablets.

0.25 mg; 0.50 mg; 0.75 mg; 1.0 mg everolimus.

Certican dispersible tablets.

0.10 mg; 0.25 mg everolimus.
Everolimus is a white to faintly yellow powder practically insoluble in water but soluble in organic solvents such as ethanol and methanol.

3 Pharmaceutical Form

Certican tablets.

(White to yellowish, marbled, round, flat with bevelled edge.)
0.25 mg (engraved with "C" on one side and "NVR" on the other): 60's; 0.50 mg (engraved with "CH" on one side and "NVR" on the other): 60's; 0.75 mg (engraved with "CL" on one side and "NVR" on the other): 60's; 1.0 mg (engraved with "CU" on one side and "NVR" on the other): 50's, 60's, 100's, 120's.

Certican dispersible tablets.

(White to yellowish, marbled, round, flat with bevelled edge.)
0.10 mg (engraved with "I" on one side and "NVR" on the other): 0.25 mg (engraved with "JO" on one side and "NVR" on the other): 50's, 60's, 100's, 120's.

List of excipients with known effect.

Lactose, galactose, milk, sugars.
For the full list of excipients, see Section 6.1 List of Excipients.

4 Clinical Particulars

4.1 Therapeutic Indications

Certican is indicated for the prophylaxis of organ rejection in adult patients at mild to moderate immunological risk receiving an allogeneic renal or cardiac transplant and in adult patients receiving an allogeneic hepatic transplant (see Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

Treatment with Certican should only be initiated and maintained by physicians who are experienced in immunosuppressive therapy following organ transplantation. Everolimus should be used in combination with cyclosporin microemulsion and corticosteroids with cyclosporin exposure reduced over time post-transplantation (see Therapeutic drug monitoring).

Kidney and heart transplantation.

An initial dose regimen of 0.75 mg twice a day is recommended for the general kidney and heart transplant population, administered as soon as possible after transplantation.

Liver transplantation.

The dose of 1.0 mg twice a day is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation. A higher Certican dosage regimen (1.5 mg twice daily) was shown to be as effective as the recommended dosage regimen but the overall safety was worse. Therefore this higher dosage regimen is not recommended.

Method of administration.

The daily dose of Certican should always be given orally in two divided doses, consistently either with or without food and at the same time as cyclosporin microemulsion or tacrolimus.
Certican tablets should be taken whole and not crushed before use. For patients unable to swallow whole tablets, Certican dispersible tablets may be used as follows.

Administration in a 10 mL oral syringe.

The maximum amount of Certican that can be dispersed in a 10 mL syringe is 1.25 mg. Place the tablets into the syringe and add water to the 5 mL mark. Shake gently for 90 seconds. After dispersion administer orally directly from the syringe. Rinse the syringe with 5 mL water and administer orally directly from the syringe. If required, a further 10 to 100 mL of water or flavoured drink can be administered.

Administration with a plastic cup.

Place the Certican dispersible tablets in a plastic cup in approximately 25 mL of water. The maximum amount of Certican that can be dispersed in 25 mL of water is 1.5 mg. Allow the tablets to dissolve for approximately 2 minutes. Swirl gently before drinking and immediately rinse the cup with 25 mL of water and drink completely.

Administration via nasogastric tube.

Place the Certican dispersible tablets in a small plastic beaker in 10 mL of water. The maximum amount of Certican that can be dispersed in 10 mL of water is 1.25 mg. Allow the tablets to dissolve for approximately 90 seconds and swirl gently. Place the dispersion into a syringe and inject slowly (within 40 seconds) into the nasogastric tube. Rinse the beaker (and the syringe) 3 times with 5 mL water and inject into the tube. Flush the tube with 10 mL water. The nasogastric tube should be clamped for a minimum of 30 minutes after Certican administration. When cyclosporin microemulsion is administered via nasogastric tube it should be administered before Certican. The two medicines should not be mixed.
The relative bioavailability of the dispersible tablet compared with the tablet is 0.90 based on the AUC ratio of the two forms. Therefore, in the case of a switch from one pharmaceutical form to another, it is recommended to monitor everolimus blood concentrations and to adjust dosages as necessary to achieve the desired target concentration (see Therapeutic drug monitoring).

Paediatric use.

There is insufficient experience to recommend the use of Certican in children and adolescents. Limited information is available in renal transplant paediatric patients.

Use in the elderly.

Clinical experience is limited in patients ≥ 65 years of age.
Nevertheless, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥ 65 to 70 years of age as compared with younger adults.

Use in renal impairment.

No dosage adjustment is required.

Use in hepatic impairment.

Everolimus whole blood trough levels should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh class A), the dose should be reduced to two thirds of the normal dose. For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to one half of the normal dose. For patients with severe hepatic impairment (Child-Pugh class C), the dose should be reduced by at least one half the normal dose with strict attention to therapeutic drug monitoring. Further dose titration should be based on close therapeutic drug monitoring (see Section 5.2 Pharmacokinetic Properties).

Therapeutic drug monitoring.

Certican has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response and safety. Routine everolimus whole blood therapeutic drug level monitoring is recommended. Based on exposure efficacy and exposure safety analysis, patients achieving everolimus whole blood trough levels ≥ 3.0 nanogram/mL have been found to have a lower incidence of biopsy proven acute rejection in renal, cardiac and hepatic transplantation compared with the patients whose trough levels are below 3.0 nanogram/mL. The upper limit to the therapeutic range is recommended at 8 nanogram/mL. Exposure above 12 nanogram/mL has not been studied. These recommended ranges for everolimus are based on chromatographic methods.
It is especially important to monitor everolimus blood concentrations in patients with hepatic impairment, during concomitant administration of strong CYP3A4 inducers and inhibitors, when switching formulation and/or if cyclosporin microemulsion dosing is markedly reduced. Everolimus concentrations may be slightly lower following the dispersible tablet administration.
Optimally, dose adjustments of Certican should be based on trough levels obtained > 4-5 days after the previous dosing change. There is an interaction of cyclosporin on everolimus and, consequently, everolimus levels may decrease if cyclosporin exposure is markedly reduced (i.e. trough concentration < 50 nanogram/mL).

Cyclosporin dose recommendation in renal transplantation.

Certican should not be used long-term together with full doses of cyclosporin. Reduced exposure to cyclosporin in Certican treated renal transplant patients improves renal function. Based on experience gained from study A2309, cyclosporin exposure reduction should be started immediately after initiation of Certican with the following whole blood trough level windows. See Table 1.
Prior to dose reduction of cyclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations (C0) are equal to or above 3 nanogram/mL there are limited data regarding the dosing of Certican with cyclosporin trough concentrations below 50 nanogram/mL, or C2 levels below 350 nanogram/mL, in the maintenance phase. If the patient cannot tolerate reduction of cyclosporin exposure, the continued use of everolimus should be reconsidered.

Cyclosporin dose recommendation in cardiac transplantation.

Cardiac patients in the maintenance period could have their cyclosporin dose reduced beginning one month after transplantation, if Certican is used de novo, as tolerated, in order to improve kidney function. If impairment of renal function is progressive or if the calculated creatinine clearance is < 60 mL/min, the treatment regimen should be adjusted. For cardiac transplant patients, the cyclosporin dose should be guided by the experience in study 2411 and confirmed in study 2310 in which Certican was administered with cyclosporin with recommended reduced target trough concentrations (C0) as follows (see Table 2).
Prior to dose reduction of cyclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations are equal to or above 3 nanogram/mL. In cardiac transplantation there are limited data regarding dosing everolimus with cyclosporin trough concentrations below 50-100 nanogram/mL after 12 months. If the patient cannot tolerate reduction of cyclosporin exposure, the continued use of everolimus should be reconsidered.

Tacrolimus dose recommendation in hepatic transplantation.

In liver transplantation, Certican should be used in combination with tacrolimus and corticosteroids. Hepatic transplant patients should have the tacrolimus exposure reduced to minimize calcineurin related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiation of dosing in combination with Certican based on tacrolimus blood trough levels (C0) targeting 3-5 nanogram/mL. In a controlled clinical trial, complete withdrawal of tacrolimus has been associated with an increased risk of acute rejections, and is not recommended. Certican has not been evaluated with full dose tacrolimus in controlled clinical trials.

4.3 Contraindications

Certican is contraindicated in patients with a known hypersensitivity to everolimus, sirolimus or to any of the excipients.

4.4 Special Warnings and Precautions for Use

The clinical development of Certican has involved use of specific combinations of medicines. In renal and cardiac transplantation, Certican should be used in combination with cyclosporin microemulsion and corticosteroids. In hepatic transplantation, Certican should be used in combination with tacrolimus and corticosteroids. Information about other combinations is lacking.

Management of immunosuppression.

There are limited data regarding the use of Certican without calcineurin inhibitor (CNI) (cyclosporin or tacrolimus). An increased risk of acute rejection was observed in patients who discontinued the administration of CNI compared with those who continued the administration of CNI.
Certican has been administered in clinical trials concurrently with calcineurin inhibitors, basiliximab and corticosteroids. Certican in combination with immunosuppressive agents other than these has not been adequately investigated.
Certican has not been adequately studied in patients at high immunological risk.

Combination with thymoglobulin induction.

Caution is advised with the use of thymoglobulin (rabbit anti-thymocyte globulin) induction and the Certican/ cyclosporin/ steroid regimen. In a clinical study in heart transplant recipients (see Section 5.1 Pharmacodynamic Properties, Study A2310), an increased incidence of serious infections was observed within the first three months after transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin combined with Certican, steroid and cyclosporin at the blood concentration recommended for heart transplantation (higher than in kidney transplantation). This was associated with greater mortality among patients who were both hospitalised and required ventricular assistance device prior to transplantation suggesting that they may have been particularly vulnerable to increased immunosuppression.

Serious and opportunistic infections.

Patients on a regimen of immunosuppressive medicinal products, including Certican, are at increased risk of developing infections especially with opportunistic pathogens (bacterial, fungal, viral, protozoal). Fatal infections and sepsis have been reported in patients treated with Certican. Among opportunistic conditions to which immunosuppressed patients may be vulnerable are polyomavirus infections which include BK virus-associated nephropathy which can lead to kidney graft loss and potentially fatal JC virus-associated progressive multiple leukoencephalopathy (PML). These infections, often related to total immunosuppressive burden, should be considered in the differential diagnosis of immunosuppressed patients with deteriorating kidney graft function or neurological symptoms.
In clinical trials with Certican, antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia was administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis was recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.

Use in hepatic impairment.

Close monitoring of everolimus whole blood trough levels (C0) and everolimus dose adjustment is recommended in patients with impaired hepatic function (see Section 4.2 Dose and Method of Administration).

Interaction with strong inhibitors, inducers of CYP3A4.

Co-administration with strong 3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (e.g. rifampicin, rifabutin) is not recommended unless the benefit outweighs the risk. It is recommended that everolimus whole blood trough levels be monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and following their discontinuation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Lymphomas and other malignancies.

Patients receiving a regimen of immunosuppressive drugs, including Certican, are at increased risk of developing lymphomas or other malignancies, particularly of the skin. The absolute risk seems related to the duration and intensity of immunosuppression rather than to the use of a specific agent. Patients should be monitored regularly for skin neoplasms and advised to minimise exposure to UV light, sunlight and use appropriate sunscreen.

Hyperlipidemia.

In transplant patients, concomitant use of Certican and cyclosporin microemulsion or tacrolimus has been associated with increased serum cholesterol and triglycerides that may require treatment. Patients receiving Certican should be monitored for hyperlipidemia and, if necessary, treated with lipid lowering agents and appropriate dietary adjustments made. The risk/ benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Certican. Similarly the risk/ benefit of continued Certican therapy should be re-evaluated in patients with severe refractory hyperlipidemia.
During Certican therapy with cyclosporin microemulsion, patients administered Certican in conjunction with an HMG-CoA reductase inhibitor and/or fibrates should be monitored for the development of rhabdomyolysis and other adverse effects associated with these agents.

Angioedema.

Certican has been associated with the development of angioedema. In the majority of cases reported patients were receiving ACE inhibitors as co-medication.

Everolimus and calcineurin inhibitor-induced renal dysfunction.

In renal and cardiac transplant Certican may potentiate the renal toxicity of cyclosporin. Certican with full-dose cyclosporin increases the risk of renal dysfunction. Reduced doses of cyclosporin are required for use in combination with Certican in order to avoid renal dysfunction. Appropriate adjustment of the immunosuppressive regimen, in particular reduction of the cyclosporin dose should be considered in patients with elevated serum creatinine levels.
In a liver transplant study Certican with reduced tacrolimus exposure has not been found to worsen renal function in comparison to standard exposure tacrolimus.
Regular monitoring of renal function is recommended in all patients. Appropriate adjustment of the immunosuppressive regimen, in particular reduction of cyclosporin dose, should be considered in patients with elevated serum creatinine levels. In patients receiving renal transplants, everolimus should not be used long-term together with full doses of cyclosporin (see Section 4.2 Dose and Method of Administration). In patients receiving cardiac transplants, cyclosporin dose should be reduced as tolerated during the maintenance period, to prevent renal impairment. Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function.

Proteinuria.

The use of Certican with calcineurin inhibitors in transplant recipients has been associated with increased proteinuria. The risk increases with higher everolimus blood levels.
In renal transplant patients with mild proteinuria while on maintenance immunosuppressive therapy including a calcineurin inhibitor (CNI) there have been reports of worsening proteinuria when the CNI is replaced by Certican. Reversibility has been observed with interruption of Certican and reintroduction of the CNI. The safety and efficacy of conversion from CNI to Certican in such patients have not been established.
Patients receiving Certican should be monitored for proteinuria.

Renal graft thrombosis.

An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, mostly within the first 30 days post-transplantation.

Wound healing complications.

Certican, like other mTOR inhibitors, can impair healing increasing the occurrence of post-transplant complications such as wound dehiscence, fluid collections and wound infection which may require further surgical attention. Lymphocele is the most frequently reported such event in renal transplant recipients and tends to be more frequent in patients with higher body mass index.

Fluid accumulation.

Generalized fluid accumulation, including peripheral edema (e.g., lymphoedema) and other types of localized fluid collection, such as pericardial and pleural effusions and ascites have also been reported. The frequency of pericardial and pleural effusion is increased in cardiac transplant recipients and the frequency of incisional hernias is increased in liver transplant recipients.

Thrombotic microangiopathic disorders.

The concomitant administration of Certican with a calcineurin inhibitor (CNI) may increase the risk of CNI-induced haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and thrombotic microangiopathy.

Interstitial lung disease/ non-infectious pneumonitis.

Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some fatal, have occurred in patients receiving rapamycins and their derivatives, including Certican. A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been discounted through appropriate investigations. Mostly, the condition resolves after discontinuation of Certican and/or addition of glucocorticoids. However, fatal cases have also occurred.

New onset diabetes mellitus.

Certican has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients treated with Certican.

Risk of intolerance to excipients.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

CYP3A4 is the main P450 enzyme involved in the microsomal metabolism of everolimus, and everolimus is a substrate for the multidrug efflux pump, P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by drugs that affect CYP3A4 and/or P-glycoprotein. Concurrent treatment with strong 3A4 inhibitors and inducers is not recommended unless the benefits outweigh the risk. Inhibitors of PgP may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of drugs eliminated by these enzymes. Thus, caution should be exercised when co-administering everolimus with 3A4 and 2D6 substrates with a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant cyclosporin.

Cyclosporin (CYP3A4/PgP inhibitor).

The bioavailability of everolimus was significantly increased by co-administration of cyclosporin microemulsion. In a single-dose study in healthy subjects, cyclosporin increased everolimus AUC by 168% (range 46% to 365%) and Cmax by 82% (range 25% to 158%) compared with administration of everolimus alone. Dose adjustment of everolimus may be necessary if the cyclosporin dose is altered. Certican had a clinically minor influence on cyclosporin pharmacokinetics in renal and heart transplant patients receiving cyclosporin microemulsion. However, everolimus may potentiate the renal toxicity of cyclosporin. Patients should be monitored for decrease in creatinine clearance.

Rifampicin (CYP3A4 inducer).

Pre-treatment of healthy subjects with multiple dose rifampicin followed by a single dose of Certican increased everolimus clearance nearly 3-fold, and decreased Cmax by 58% and AUC by 63%. Combination with rifampicin is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

Atorvastatin (CYP3A4 substrate) and pravastatin (PgP substrate).

Single dose administration of Certican with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, nor, to a clinically relevant extent, the total HMG-CoA reductase bioreactivity in plasma. These results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be monitored for the development of rhabdomyolysis and other adverse events as described in the Product Information of HMG-CoA reductase inhibitors.

Midazolam (CYP3A4 substrate).

In a two period, fixed-sequence, crossover drug interaction study, 25 healthy subjects received a single oral 4 mg dose of midazolam in period 1. In period 2, they received everolimus 10 mg once daily for 5 days and a single 4 mg dose of midazolam with the last dose of everolimus. The Cmax of midazolam increased 1.25-fold (90% CI, 1.14-1.37) and the AUCinf increased 1.30-fold (1.22-1.39). The half-life of midazolam was unaltered. This study indicated that everolimus is a weak inhibitor of CYP3A4.

Other possible interactions.

Inhibitors of CYP3A4 and PgP may increase everolimus blood levels (e.g. antifungal agents: fluconazole, ketoconazole, itraconazole; macrolide antibiotics: clarithromycin, erythromycin; calcium channel blockers: verapamil, nicardipine, diltiazem; protease inhibitors: nelfinavir, indinavir, amprenavir; other substances: cisapride, metoclopramide, bromocriptine, cimetidine, danazol). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood levels (e.g. St John's wort (Hypericum perforatum); anticonvulsants: carbamazepine, phenobarbitone, phenytoin; antibiotics: rifabutin; anti-HIV drugs: efavirenz, nevirapine).
Grapefruit and grapefruit juice affect cytochrome P450 and PgP activity and should therefore be avoided.

Vaccination.

Immunosuppressants may affect response to vaccination and vaccination during treatment with Certican may be less effective. The use of live vaccines should be avoided.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. The potential for everolimus to cause infertility in male and female patients is unknown, however, male infertility and secondary amenorrhoea have been observed. Preclinical toxicology studies having shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican therapy.
Everolimus completely impaired male rat fertility at an everolimus dose that resulted in a drug exposure (blood AUC) that was slightly above the expected maximum human value, and sperm number and motility were reduced. Testicular atrophy was observed in all animal species tested (mouse, rat, minipigs and monkey) at drug exposures similar to or slightly above the expected clinical exposure (blood AUC). There was evidence for partial recovery of fertility over a period approximately equivalent to the treatment period. Female rat fertility could not be assessed at a dose resulting in an adequate drug exposure (blood AUC).

Females and males of reproductive potential.

Women of childbearing potential should be advised to use highly effective contraception methods while they are receiving everolimus and up to 8 weeks after ending treatment.
(Category C)
Risk summary: There are no adequate data from the use of Certican in pregnant women. Studies in animals have shown reproductive toxicity effects including embryo/foetotoxicity. The potential risk to humans is unknown. Everolimus should not be given to pregnant women unless the potential benefit outweighs the potential risk to the foetus.
Animal data: In rats, everolimus crossed the placenta. Oral treatment started before mating and continued to the end of the period of organogenesis, treatment resulted in increased pre- and post-implantation losses. There was a low incidence of fetal cleft sternum, the significance of which is uncertain because it occurred at a dose giving a high fetal resorption rate. Systemic drug exposures (blood AUC) with the doses used in this study were below the expected maximum human value. Treatment of pregnant rabbits during the period of organogenesis slightly increased late fetal resorptions but did not otherwise affect fetal development. The highest dose used in this study gave a systemic drug exposure (blood AUC) that was slightly below the expected maximum human value.
 It is not known whether everolimus is excreted in human milk. In animal studies, everolimus and/or its metabolites were readily transferred into milk of lactating rats. Therefore, women who are taking Certican should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of everolimus on the ability to drive and operate machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Certican combined with cyclosporin, was studied in five trials in renal transplant recipients totalling 2497 patients (including two studies without a non-Certican control group) and three trials in heart transplant recipients totalling 1531 patients (see Clinical trials, ITT population).
Certican, combined with tacrolimus, was studied in one trial which included 719 liver transplant recipients (see Section 5.1 Pharmacodynamic Properties, ITT population). The overall safety profile was not distinct from previous experiences with Certican and expectations in a liver transplant population up to 36 months.
The occurrence of the adverse events may depend on the immunosuppressive regimen (i.e. degree and duration). In the studies, combining Certican with full dose cyclosporin for microemulsion elevated serum creatinine was observed more frequently than in control patients. The overall incidence of adverse events was lower with reduced dose cyclosporin microemulsion (see Section 5.1 Pharmacodynamic Properties).
With the exception of elevation of serum creatinine, the safety profile of Certican in the trials in which it was administered with reduced dose cyclosporin was similar to that described in the 3 pivotal studies in which full dose of cyclosporin was administered, except that elevation of serum creatinine was less frequent, and mean and median serum creatinine values were lower, in the trials in which Certican was administered with reduced dose cyclosporin. A lower rate of viral infections, primarily due to CMV in renal and heart transplant recipients and BK virus in renal transplant recipients, has been shown with the currently recommended Certican based immunosuppressive regimen in renal transplant recipients (see Section 5.1 Pharmacodynamic Properties).
In controlled clinical trials in which a total of 3256 patients receiving Certican in combination with other immunosuppressants were monitored for at least 1 year, a total of 3.1% developed malignancies, with 1.0% developing skin malignancies and 0.6% developing lymphoma or lymphoproliferative disorder.

Tabulated summary of adverse drug reactions from clinical trials.

The frequency rates of the adverse drug reactions listed below are derived from analysis of the 12 month incidences of events reported in multicentre, randomised, controlled trials investigating Certican in combination with calcineurin inhibitors (CNI) and corticosteroids in transplant recipients. All of the trials included non-Certican, CNI based standard therapy arms.
The adverse reactions reported as possibly or probably related to Certican seen in the phase III clinical trials are presented in Tables 3 and 4. Unless noted otherwise, these disorders have been identified by an increased incidence in the phase III studies comparing patients on a Certican-treated patients with patients on a non-Certican standard therapy regimen, or the same incidence in case the event is known as an ADR of the comparator (MPA in renal and heart transplant studies). Except where noted otherwise, the adverse reaction profile is relatively consistent across all transplant indications. Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common > 1/10, common > 1/100 and < 1/10, uncommon > 1/1,000 and < 1/100, rare > 1/10,000 and < 1/1,000, very rare < 1/10,000.

Adverse drug reactions from post-marketing spontaneous reports.

The following adverse drug reactions have been derived from post-marketing experience with Certican via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. See Table 5.

4.9 Overdose

In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats.
Reported experience with overdose in humans is very limited. There is a single case of an accidental ingestion of 1.5 mg everolimus in a 2 year old child where no adverse events were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability.
General supportive measures should be initiated in all cases of overdose. The Poisons Information Centre (telephone 13 11 26) is available for advice.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group, ATC.

Pharmacotherapeutic group: selective immunosuppressive agents. ATC code: L04A A18.

Mechanism of action.

Everolimus, a proliferation signal inhibitor, prevents allograft rejection in rodent and non-human primate models of allotransplantation. It exerts its immunosuppressive effect by inhibiting the proliferation, and thus clonal expansion, of antigen-activated T cells which is driven by T cell specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signalling pathway which is triggered upon binding of these T cell growth factors to their respective receptors, and which normally leads to cell proliferation. The blockage of this signal by everolimus leads to an arrest of the cells at the G1 stage of the cell cycle.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus the growth factor-stimulated phosphorylation of the p70 S6 kinase is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (also called m-TOR), this finding suggests that the everolimus-FKBP-12 complex binds to and thus interferes with the function of FRAP. FRAP is a key regulatory protein which governs cell metabolism, growth and proliferation; disabling FRAP function thus explains the cell cycle arrest caused by everolimus.
Everolimus has a different mode of action than cyclosporin. In preclinical models of allotransplantation, the combination of everolimus and cyclosporin was more effective than either drug alone.
The effect of everolimus is not restricted to T cells. It inhibits, in general, growth factor stimulated proliferation of haematopoietic as well as non-haematopoietic cells like, for instance, that of vascular smooth muscle cells. Growth factor stimulated vascular smooth muscle cell proliferation, triggered by injury to endothelial cells and leading to neointima formation, plays a key role in the pathogenesis of chronic rejection. Preclinical studies with everolimus have shown inhibition of neointima formation in a rat aorta allotransplantation model.

Clinical trials.

Renal transplantation.

Certican in fixed doses of 1.5 mg/day and 3 mg/day, in combination with standard doses of cyclosporin microemulsion and corticosteroids, was investigated in two phase III de novo renal transplant trials (Studies B201 and B251). Mycophenolate mofetil (MMF) 1 g twice a day was used as comparator. The co-primary composite endpoints were efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) at 6 months, and graft loss, death or loss to follow-up at 12 months. Certican was overall non-inferior to MMF in these trials. The incidence of biopsy proven acute rejection at 6 months in the B201 study was 21.6%, 18.2%, and 23.5% for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups, respectively. In the B251 study, the incidences were 17.1%, 20.1%, and 23.5% for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups, respectively.
Reduced allograft function with elevated serum creatinine was observed more frequently among subjects using Certican in combination with full dose cyclosporin microemulsion than in MMF patients. This effect is believed to be due to increased cyclosporin nephrotoxicity. Drug concentration pharmacodynamic analysis showed that renal function could be improved with reduced exposure to cyclosporin while conserving efficacy for as long as blood trough everolimus concentration was maintained above 3 nanogram/mL. This concept was subsequently confirmed in two further phase IIIb studies (A2306 and A2307, including 237 and 256 patients respectively) which evaluated efficacy and safety of Certican 1.5 and 3 mg per day (initial dosing, subsequent dosing based on target trough concentration ≥ 3 nanogram/mL) in combination with reduced exposure to cyclosporin. In both studies, renal function was improved without compromising efficacy. In these studies however there was no non-Certican comparative arm. A phase III, multicentre, randomised, open label, controlled trial A2309, has been completed in which 833 de novo renal transplant recipients were randomised to either one of two Certican regimens, differing by dosage, and combined with reduced dose cyclosporin or a standard regimen of sodium mycophenolate (MPA) + cyclosporin and treated for 12 months. All patients received induction therapy with basiliximab pre-transplant and on Day 4 post-transplant. Steroids could be given as required post-transplant.
Starting dosages in the two Certican groups were 1.5 mg/day and 3 mg/day, given twice a day, subsequently modified from Day 5 onwards to maintain target blood trough everolimus levels of 3 to 8 nanogram/mL and 6 to 12 nanogram/mL respectively. Sodium mycophenolate dosage was 1.44 g/day. Cyclosporin dosages were adapted to maintain target blood trough level windows as shown in Table 6. The actual measured values for blood concentrations of everolimus and cyclosporin (C0 and C2) are shown in Table 7.
Although the higher dosage Certican regimen was as effective as the lower dosage regimen, the overall safety was worse and so the upper dosage regimen is not recommended.
The lower dosage regimen for Certican is that recommended (see Section 4.2 Dose and Method of Administration).
The primary efficacy endpoint was a composite failure variable (biopsy proven acute rejection, graft loss, death or loss to follow-up). The outcome is shown in Table 8.
Changes in renal function, as shown by calculated glomerular filtration rate (GFR) using the MDRD formula are shown in Table 9.
Proteinuria was assessed at scheduled visits by spot analysis of urinary protein/ creatinine and categorized by levels of clinical relevance as represented in Table 10. Few patients in any of the treatment groups reached the nephrotic threshold but a greater proportion of Certican patients were consistently in the subnephrotic category than was the case in the MPA group. A concentration effect was shown relating proteinuria levels to everolimus trough levels particularly at values of C0 above 8 nanogram/mL.
Adverse events reported more frequently in the recommended (lower dosage) Certican regimen than in the MPA control group have been included in Table 3. A lower frequency for viral infection was reported for Certican treated patients resulting principally from lower reporting rates for CMV infection (0.7% versus 5.95%) and BK virus infection (1.5% versus 4.8%).

Cardiac transplantation.

In the phase III cardiac study (B253), both Certican 1.5 mg/day and 3 mg/day in combination with standard doses of cyclosporin microemulsion and corticosteroids, were investigated versus azathioprine (AZA), 1-3 mg/kg/day. The primary endpoint was a composite of incidence of acute rejection ≥ ISHLT grade 3A, acute rejection associated with haemodynamic compromise, graft loss, patient death or loss to follow-up at 6, 12 and 24 months. Both doses of Certican were superior to AZA at 6, 12 and 24 months. The incidence of biopsy proven acute rejection ≥ ISHLT grade 3A at month 6 was 27.8% for the 1.5 mg/day group, 19% for the 3 mg/day group and 41.6% for the AZA group, respectively (p = 0.003 for 1.5 mg versus control, < 0.001 for 3 mg versus control).
Based on coronary artery intravascular ultrasound data obtained from a subset of the study population, both Certican doses were statistically significantly more effective than AZA in preventing allograft vasculopathy (defined as an increase in maximum intimal thickness from baseline ≥ 0.5 mm in at least one matched slice of an automated pullback sequence), an important risk factor for long-term graft loss.
In study B253, cyclosporin doses were based on target trough levels as follows. Weeks 1 to 4: 250-400 nanogram/mL, months 1 to 6: 200-350 nanogram/mL, months 7 to 24: 100-300 nanogram/mL.
Elevated serum creatinine was observed more frequently among subjects using Certican in combination with full dose cyclosporin microemulsion than in AZA patients. This effect suggests that Certican increases the cyclosporin induced nephrotoxicity. However, further analysis suggested that renal function could be improved with cyclosporin dose reduction without loss of efficacy as long as everolimus blood values are maintained above a given threshold. Studies A2411 and A2310 have subsequently been carried out to investigate this.
Study A2411 was a randomised, 12 month, open label study comparing Certican in combination with reduced doses of cyclosporin microemulsion and corticosteroids to mycophenolic mofetil (MMF) and standard doses of cyclosporin microemulsion and corticosteroids in de novo adult cardiac transplant patients. The study included a total of 174 patients. Certican (N = 92) was initiated at 1.5 mg/day and the dose was adjusted to maintain target blood everolimus trough levels between 3-8 nanogram/mL. MMF (N = 84) was initiated at a dosage of 1500 mg twice daily. Cyclosporin microemulsion doses were adjusted to target the trough levels (nanogram/mL) listed in Table 11.
Renal function in study A2411 did not meet the noninferiority criteria (-6 mL/min) vs MMF. Mean creatinine clearance (Cockcroft-Gault formula) at 6 months: Certican: 65.4 v MMF: 72.2 mL/min (difference: -6.85 mL/min, 95% CI: -14.9, 1.2) and at 12 months: Certican: 68.7 v MMF: 71.8 mL/min (difference: -3.10 mL/min, 95% CI (-12.26, 6.06). The change from baseline was: Certican: -6.0 mL/min v MMF: -4.2 mL/min; p = 0.697. Efficacy, expressed as the rate of biopsy proven acute rejection episodes (ISHLT grade ≥ 3A), was maintained as comparable in the two groups at 12 months (Certican: 22.8% v MMF: 29.8%).
Study A2310 is a phase III, multicentre, randomised, open label study comparing the efficacy and safety of two Certican/ reduced dose cyclosporin regimens against a standard mycophenolate mofetil (MMF)/ cyclosporin regimen over 24 months. The use of induction therapy was centre specific, the options being no induction or induction with either basiliximab or thymoglobulin. All patients received corticosteroids.
Starting doses in the two Certican groups were 1.5 mg/day and 3 mg/day, subsequently modified from day 4 onwards to maintain target blood trough everolimus levels of 3 to 8 nanogram/mL and 6 to 12 nanogram/mL respectively. The MMF dose was 3 g/day. Cyclosporin dosages were adapted to maintain the same target blood trough level windows as in study A2411. Blood concentrations of everolimus and cyclosporin are shown in Table 12.
Recruitment to the experimental, upper dosage Certican treatment arm was prematurely discontinued because of an increased rate of fatalities within this treatment group, due to infection and cardiovascular disorders, occurring within the first 90 days postrandomisation. The nature and pattern of the fatalities in this dosage arm did not suggest the difference to be linked to the presence or type of induction therapy.
Statistical comparisons are limited to comparisons between the completed treatment arms. The drug blood concentration levels actually achieved are described in Table 12.
The primary efficacy endpoint was a composite failure variable, implying occurrence of any of the following: Biopsy Proven Acute Rejection (BPAR) episode of ISHLT grade > =3A, acute rejection (AR) episode associated with hemodynamic compromise (HDC), graft loss/ retransplant, death, or loss to follow-up. Efficacy outcome at 12 and 24 months is shown in Table 13.
The higher fatality rate in the Certican arm relative to the MMF arm was mainly the result of an increased rate of fatalities from infection in the first three months among Certican patients in the study subgroup of patients receiving thymoglobulin induction therapy. A notably higher 3 month incidence in severe infections in Certican than MMF patients in the thymoglobulin subgroup appears to reflect greater immunosuppressive potency. The imbalance in fatalities within the thymoglobulin subgroup being particularly evident among patients hospitalised prior to transplantation and with L-ventricular assistance devices, suggests greater vulnerability in such patients to the consequences of infectious complications.
The imbalance in mortality observed during the first 12 months was no longer apparent by month 24.
Intravascular ultrasound (IVUS) studies were performed on a subset of patients to investigate changes post-transplantation (month 12 value relative to a baseline value effected during the first three months post-transplant) in intimal thickness within a segment of the left anterior descending (LAD) coronary artery. The results of the measured change in maximum intimal thickness along with frequency of patients with cardiac allograft vasculopathy (defined as an increase in the maximal intimal thickness of 0.5 mm or more) are described in Table 14.
The reduced increase in intimal coronary thickness in Certican relative to MMF patients was apparent regardless of age, gender, presence or absence of diabetes and maximum level of serum cholesterol observed by month 12.
Renal function over the course of study A2310, assessed by estimated glomerular filtration rate (eGFR) using the MDRD formula, indicates a statistically significant difference of 5.5 mL/min/1.73 m2 (97.5% CI -10.9, -0.2; p = 0.019) lower for the everolimus 1.5 mg group at month 12. The decrease in mean GFR from baseline to month 12 was: Certican -7.1 mL/min vs MMF -2.9 mL/min, p = 0.211.
Post hoc data analyses suggest that the difference observed was mainly associated with the exposure to cyclosporin. This difference was reduced to -3.6 mL/min/1.73 m2 and not statistically significant (97.5% CI -8.9, 1.8) in centres where the mean cyclosporin levels were lower in patients receiving Certican than in patients randomised to the control arm, as recommended.
Additionally, the difference was mainly driven by a difference developed during the first month post-transplantation when patients are still in an unstable hemodynamic situation possibly confounding the analysis of renal function. Thereafter, the decrease in mean GFR from month 1 to month 12 was significantly smaller in the everolimus group than in the control group (-6.4 vs -13.7 mL/min, p = 0.002).
At month 24, the calculated GFR was significantly lower for the everolimus 1.5 mg group (58.8 mL/min 1.73 m2) than for the MMF arm (65.3 mL/min 1.73 m2). The difference in mean GFR (MDRD) at month 24 between the everolimus 1.5 mg group and MMF group was -6.47 mL/min/1.73 m2 (97.5% CI: -11.9, -1.0; p=0.008).
Proteinuria, expressed as urinary protein: urinary creatinine levels measured in spot urine samples tended to be more elevated in the Certican treated patients. Subnephrotic values were observed in 22% of the patients receiving Certican compared to MMF patients (8.6%). Nephrotic levels were also reported (0.8%), representing 2 patients in each treatment group.
However, proteinuria was rarely reported as an AE by month 24 (9 patients [3.2%] in everolimus 1.5 mg group and 5 patients [1.9%] in the MMF group), with no cases of severe intensity. The majority of patients were in the mild proteinuria range and an overall improvement observed between baseline and month 12 and 24 in all groups. A total of 3 and 2 patients had proteinuria values reaching the nephrotic range at month 24 in the everolimus 1.5 mg and MMF groups, respectively.
The adverse reactions for everolimus 1.5 mg group in study A2310 are consistent with adverse drug reactions presented in Table 3. A lower rate of viral infections was reported for Certican treated patients resulting principally from a lower reporting rate for CMV infection compared to MMF (7.2% vs 19.4%).

Hepatic transplantation.

In the phase III adult hepatic transplant study (H2304), reduced exposure tacrolimus and Certican was administered to HCV+ and HCV-patients with the initial Certican dose (1.0 mg/day) starting approximately 4 weeks after transplantation and was investigated versus standard exposure tacrolimus up to 24 months (core study) and for an additional 12 month extension period up to 36 months post-transplant. Certican was dose adjusted to maintain target blood everolimus trough levels between 3-8 nanogram/mL for the Certican + Reduced tacrolimus arm. Mean everolimus trough levels were within the target ranges at all time points ranging from 3.4 to 6.3 nanogram/mL in the Certican + Reduced tacrolimus arm. Tacrolimus doses were subsequently adjusted to achieve target trough levels between 3-5 nanogram/mL through 12 months in the Certican + Reduced tacrolimus arm. A third arm in study H2304 with complete withdrawal of tacrolimus at 4 months post transplantation has been associated with an increased risk of acute rejections and was terminated early.
The primary endpoint of the study was to compare the efficacy failure rate, defined as the composite endpoint of treated biopsy proven acute rejection, graft loss or death with early tacrolimus minimisation, facilitated by introduction of Certican starting approximately 4 weeks after liver transplantation, to standard exposure tacrolimus, at 12 months.
Overall, in the 12 month analysis, the incidence of the composite endpoint (tBPAR, graft loss or death) was lower in Certican + reduced tacrolimus arm (6.7%) compared to the tacrolimus control arm (9.7%) (Table 15). The difference in estimates between Certican + reduced tacrolimus and tacrolimus control was -3.0% with 97.5% CI: (-8.7% to 2.6%). Regarding the rates of graft loss and fatal cases the Certican + reduced tacrolimus arm was noninferior compared to the tacrolimus control arm indicating no increased mortality risk in this population. A statistically significantly lower rate of biopsy proven acute rejection was seen in the Certican + reduced tacrolimus arm (4.1%) compared to tacrolimus control arm (10.7%) (Table 16). Results are similar between HCV+ and HCV-patients.

Extension - primary efficacy results at 36 months.

Of the total 231 patients who entered the extension for Certican + Reduced tacrolimus (n=106) and tacrolimus control (n=125), 84% and 86% of patients completed study medication, 91% and 94% of patients completed study phase with 16% and 14% of patients discontinuing study medication, respectively.
The incidence of patients with composite efficacy failure events (tBPAR, graft loss or death) at month 36 since extension baseline (month 24) was low and similar across the treatment arms at 1.9% (n=2), and 2.4% (n=3) in the Certican + Reduced tacrolimus and tacrolimus control arms respectively.
For the ITT population (all patients randomized in the core study), the Kaplan-Meier estimates of the primary composite efficacy endpoint (tBPAR, graft loss or death) to 36 months was lower in the Certican + Reduced tacrolimus arm (11.5%) than in the tacrolimus control arm (14.6%). The difference between Certican + Reduced tacrolimus and tacrolimus control was -3.2% (97.5% CI: -10.5%, 4.2%; p-value 0.3337).

Renal function.

Comparison between treatment groups for change in eGFR (MDRD4) [mL/min/1.73 m2] from time of randomisation (day 30) to month 12, 24 and 36 for the ITT population is presented in Table 17. The eGFR at 12 months was higher for Certican + Reduced tacrolimus (80.6 mL/min/1.73 m2) in comparison to the tacrolimus control (70.3 mL/min/1.73 m2) and a higher eGFR was also observed throughout the entire study.
Statistically significant between-treatment group difference (Certican + Reduced tacrolimus versus tacrolimus control arm) was observed in favor of Certican + Reduced tacrolimus arm for the mean eGFR from week 6 up to month 36 (including at study endpoint and treatment endpoint). At randomization, mean eGFR was 85.0 and 78.0 mL/min/1.73 m2 for the Certican + Reduced tacrolimus and tacrolimus control arms respectively. At the month 36 time point, the difference in mean eGFR between Certican + Reduced tacrolimus and tacrolimus control was 15.2 mL/min/1.73 m2. The mean eGFR at month 36 was 78.7 and 63.5 mL/min/1.73 m2 for the Certican + Reduced tacrolimus and tacrolimus control arms respectively.

5.2 Pharmacokinetic Properties

Absorption.

After oral dosing, peak everolimus concentrations occur 1 to 2 hours postdose. Everolimus blood concentrations are dose proportional over the dose range 0.25 to 15 mg in transplant patients. The relative bioavailability of the dispersible tablet compared with the tablet is 0.90 (90% CI 0.76-1.07) based on the AUC ratio.

Effects of food.

The Cmax and AUC of everolimus are reduced by 60% and 16% when the tablet formulation is given with a high fat meal. To minimise variability, Certican should be taken consistently with or without food.

Distribution.

The blood to plasma ratio of everolimus is concentration dependent ranging from 17 to 73% over the range of 5 to 5,000 nanogram/mL. Plasma protein binding is approximately 74% in healthy subjects and patients with moderate hepatic impairment. The distribution volume associated with the terminal phase (Vz/F) in maintenance renal transplant patients is 342 ± 107 L.

Metabolism.

Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main metabolic pathways identified in man were monohydroxylations and O-dealkylations. Two main metabolites were formed by hydrolysis of the cyclic lactone. Everolimus was the main circulating component in blood. None of the main metabolites are likely to contribute significantly to the immunosuppressive activity of everolimus.

Excretion.

After a single dose of radiolabelled everolimus to transplant patients receiving cyclosporin the majority (80%) of radioactivity was recovered from the faeces, and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine nor faeces.

Steady-state pharmacokinetics.

Pharmacokinetics were comparable for kidney and heart transplant patients receiving everolimus twice daily simultaneously with cyclosporin. Steady state is reached by day 4 with an accumulation in blood levels of 2 to 3-fold compared with the exposure after the first dose. Tmax occurs at 1 to 2 hours postdose. Cmax averages 11.1 ± 4.6 and 20.3 ± 8 nanogram/mL and AUC averages 75 ± 31 and 131 ± 59 nanogram.hour/mL at 0.75 and 1.5 mg b.i.d., respectively. Predose trough blood levels (Cmin) average 4.1 ± 2.1 and 7.1 ± 4.6 nanogram/mL at 0.75 and 1.5 mg b.i.d., respectively. Everolimus exposure remains stable over time in the first post-transplant year. Cmin is significantly correlated with AUC yielding a correlation coefficient between 0.86 and 0.94. Based on a population pharmacokinetic analysis, oral clearance (CL/F) is 8.8 L/h (27% interpatient variation) and the central distribution volume (Vc/F) is 110 L (36% interpatient variation). Residual variability in blood concentrations is 31%. The elimination half-life is 28 ± 7 h.

Hepatic impairment.

Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh class A) was 1.6-fold higher; in two independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh class B) the average AUC was 2.1-fold and 3.3-fold higher respectively; and in 6 patients with severe hepatic impairment (Child-Pugh class C) the average AUC was 3.6-fold higher. For patients with mild hepatic impairment (Child-Pugh class A), the dose should be reduced to two thirds of the normal dose. For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to one half of the normal dose. For patients with severe hepatic impairment (Child-Pugh class C) the dose should be reduced by at least one half the normal dose with strict attention to therapeutic drug monitoring. Further dose titration should be based on close therapeutic drug monitoring (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Renal impairment.

Post-transplant renal impairment (Clcr range 11-107 mL/min) did not affect the pharmacokinetics of everolimus.

Paediatrics.

Everolimus CL/F increased in a linear manner with patient age (1 to 16 years), body surface area (0.49-1.92 m2), and weight (11-77 kg). Steady-state CL/F was 10.2 ± 3.0 L/hour/m2 and elimination half-life was 30 ± 11 hours. Nineteen paediatric de novo renal transplant patients (1 to 16 years) received Certican dispersible tablets at a dose of 0.8 mg/m2 (maximum 1.5 mg) twice daily with cyclosporin microemulsion. They achieved an everolimus AUC of 87 ± 27 nanogram.hour/mL which is similar to adults receiving 0.75 mg twice daily. Steady-state trough levels were 4.4 ± 1.7 nanogram/mL.

Elderly.

A limited reduction in everolimus oral CL of 0.33% per year was estimated in adults (age range studied was 16-70 years). No dose adjustment is considered necessary.

Exposure-response relationships.

The average everolimus trough concentration over the first 6 months post-transplant was related to the incidence of biopsy confirmed acute rejection and with thrombocytopenia in renal and cardiac transplant patients (see Table 18). In hepatic transplant patients the relationship of everolimus trough concentrations and clinical events is less well defined, however, higher exposures do not correlate with an increase in adverse effects.

5.3 Preclinical Safety Data

Genotoxicity.

Everolimus did not show genotoxicity in in vitro tests for gene mutation (bacteria and mammalian cells), and in an in vitro test and in vivo mouse micronucleus assay for clastogenic activity.

Carcinogenicity.

Long-term carcinogenicity studies have been carried out in mice and rats and no oncogenic responses were observed. Drug exposures (blood AUC) were up to 8 times the expected maximum human value in mice, but were less than the expected maximum human value in rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablets.

Butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone, lactose anhydrous.

Dispersible tablets.

Butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone, lactose anhydrous, colloidal anhydrous silica.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C in the original packaging. Protect from light and moisture.

6.5 Nature and Contents of Container

Certican tablets.

0.25 mg: 60's; 0.50 mg: 60's; 0.75 mg: 60's; 1.0 mg: 50's, 60's, 100's, 120's.

Certican dispersible tablets.

0.10 mg and 0.25 mg: 50's, 60's, 100's, 120's.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The chemical name is 40-O-(2-hydroxyethyl)-rapamycin or 40-O-(2-hydroxyethyl)-sirolimus. Its molecular formula is C53H83NO14 and its molecular weight is 958.2.

Chemical structure.

The structural formula of everolimus is:

CAS number.

159351-69-6.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes