4/4/2018
`
`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
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`Certican Tablets
`
`Novartis Pharmaceuticals UK Ltd
`contact details
`
`Active ingredient
`everolimus
`
`Legal Category
`POM: Prescription only medicine
`
`SmPC (lemclproductl1920lsmpc)
`
`Patient Leaflet (lemclproductl1920/pil)
`
`Last updated on eMC: 02 Oct 2017
`
`G View changtfiuemc/product/1920/smpc/history),
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`I21 Print([emc/product/l920/smp_c[p£nt)l
`
`Show table of contents
`
`This information is intended for use by health professionals
`
`1. Name of the medicinal product
`
`Certican® 0.25 mg tablets
`
`Certican® 0.75 mg tablets
`
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
`
`2. Qualitative and quantitative composition
`
`Each tablet contains 0.25/0.75 mg everolimus.
`
`firm—nus) with known effect:
`
`Each tablet contains 2/7 mg lactose monohydrate and 51/112 mg Anhydrous lactose.
`
`For the full list of excipients, see section 6.1.
`
`3. Pharmaceutical form
`
`Tablet
`
`Tablets are white to yellowish, marbled, round, flat with a bevelled edge.
`
`0.25 mg (diameter of 6 mm): engraved with “C” on one side and “NVR” on the other.
`
`0.75 mg (diameter of 8.5 mm): engraved with “CL” on one side and “NVR” on the other.
`
`4. Clinical particulars
`
`4.1 Therapeutic indications
`
`Kidney and heart transplantation
`
`Certican is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an
`allogeneic renal or cardiac transplant. In kidney and heart transplantation, Certican should be used in combination with
`ciclosporin for microemulsion and corticosteroids.
`
`Liver transplantation
`
`Certican is indicated for the prophylaxis of organ rejection in adult patients receiving a hepatic transplant. In liver
`transplantation, Certican should be used in combination with tacrolimus and corticosteroids.
`
`4.2 Posology and method of administration
`
`Treatment with Certican should only be initiated and maintained by physicians who are experienced in immunosuppressive
`therapy following organ transplantation and who have access to everolimus whole blood concentration monitoring.
`
`Posology
`
`Adults
`
`An initial dose regimen of 0.75 mg twice daily in co-administration with ciclosporin is recommended for the general kidney and
`heart transplant population, administered as soon as possible after transplantation.
`
`The dose of 1.0 mg twice daily in co—administration with tacrolimus is recommended for the hepatic transplant population with
`the initial dose approximately 4 weeks after transplantation.
`
`Patients receiving Certican may require dose adjustments based on blood concentrations achieved, tolerability, individual
`response, change in co-medications and the clinical situation. Dose adjustments can be made at 4-5 day intervals (see
`Therapeutic drug monitoring).
`
`§pecial mpu/ation
`
`Black patients
`
`The incidence of biopsy-proven acute rejection episodes was significantly higher in black renal transplant patients compared
`with non-black patients. There is limited information indicating that black patients may require a higher Certican dose to achieve
`similar efficacy to non-black patients (see section 5.2). Currently, the efficacy and safety data are too limited to allow specific
`recommendations for use of everolimus in black patients.
`
`Paediatric population
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
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`There is insufficient data in children and adolescents to recommend the use of Certican in renal transplantation (see section 5.1
`and 5.2) and no recommendation on a posology can be made. In hepatic transplant paediatric patients, Certican should not be
`used (see section 5.1).
`
`Elderly patients (265 years)
`
`Clinical experience in patients >65 years of age is limited. Although data are limited, there are no apparent differences in the
`pharmacokinetics of everolimus in patients 265-70 years of age (see section 5.2).
`
`Patients with renal impairment
`
`No dosage adjustment is required (see section 5.2).
`
`Patients with impaired hepatic function
`
`Everolimus whole blood trough concentrations should be closely monitored in patients with impaired hepatic function. The dose
`should be reduced to approximately two thirds of the normal dose for patients with mild hepatic impairment (Child-Pugh Class
`A), to approximately one half of the normal dose for patients with moderate hepatic impairment (Child Pugh Class B), and to
`approximately one third of the normal dose for patients with severe hepatic impairment (Child Pugh Class C). Further dose
`titration should be based on therapeutic drug monitoring (see section 5.2). Reduced doses rounded to the nearest tablet
`strength are tabulated below:
`
`Table 1 Certican dose reduction in patients with hepatic impairment
`
`Normal hepatic
`function
`
`Mild hepatic
`impairment (Child-
`Pugh A)
`
`Moderate hepatic
`impairment (Child-
`Pugh B)
`
`Severe hepatic
`impairment (Child-
`Pugh C)
`
`transplantation
`
`Renal and cardiac
`transplantation
`
`0.75 mg b.i.d.
`
`0.5 mg b.i.d.
`
`0.5 mg b.i.d.
`
`0.25 mg b.i.d.
`
`Hepatic
`
`1 mg b.i.d.
`
`0.75 mg b.i.d.
`
`0.5 mg b.i.d.
`
`0.5 mg b.i.d.
`
`Therapeutic drug monitoring,
`
`The use of drug assays with adequate performance characteristics when targeting low concentrations of ciclosporin or
`tacrolimus is recommended.
`
`Certican has a narrow therapeutic index which may require adjustments in closing to maintain therapeutic response. Routine
`everolimus whole blood therapeutic drug concentration monitoring is recommended. Based on exposure-efficacy and
`exposure-safety analysis, patients achieving everolimus whole blood trough concentrations 23.0 ng/ml have been found to
`have a lower incidence of biopsy-proven acute rejection in renal, cardiac and hepatic transplantation compared with patients
`whose trough concentrations are below 3.0 ng/ml. The recommended upper limit of the therapeutic range is 8 ng/ml. Exposure
`above 12 ng/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 ciclosporin closing is markedly
`reduced (see section 4.5). Everolimus concentrations might be slightly lower following dispersible tablet administration.
`
`Ideally, dose adjustments of Certican should be based on trough concentrations obtained >4-5 days after the previous dosing
`change. There is an interaction between ciclosporin and everolimus, and everolimus concentrations may therefore decrease if
`ciclosporin exposure is markedly reduced (i.e. trough concentration <50 ng/ml).
`
`Patients with hepatic impairment should preferably have trough concentrations in the upper part of the 3-8 ng/ml exposure
`range.
`
`After starting treatment or after a dose adjustment, monitoring should be performed every 4 to 5 days until 2 consecutive trough
`concentrations show stable everolimus concentrations, as the prolonged half-lives in hepatically impaired patients delay the
`time to reach steady state (see sections 4.4 and 5.2). Dose adjustments should be based on stable everolimus trough
`concentrations.
`
`Ciclosporin dose recommendation in renal transplantation
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
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`Certican should not be used long-term together with full doses of ciclosporin. Reduced exposure to ciclosporin in Certican-
`treated renal transplant patients improves renal function. Based on experience gained from study A2309, ciclosporin exposure
`reduction should be started immediately after transplantation with the following recommended whole blood trough
`concentration windows:
`
`Table 2 Renal transplantation: recommended target ciclosporin blood trough concentration windows
`
`Target ciclosporin Co
`(nglml)
`
`Month 1
`
`Months 2-3
`
`Months 4-5
`
`Months 6-12
`
`25-50
`
`Certican groups
`
`100-200
`
`75-150
`
`50-100
`
`(Measured Co and 02 concentrations are shown in section 5.1).
`
`Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations
`are equal to or above 3 ng/ml.
`
`There are limited data regarding dosing Certican with ciclosporin trough concentrations below 50 ng/ml, or 02 concentrations
`below 350 ng/ml, in the maintenance phase. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use
`of Certican should be reconsidered.
`
`Ciclosporin dose recommendation in cardiac transplantation
`
`Cardiac transplant patients in the maintenance phase should have their ciclosporin dose reduced 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. In cardiac transplant patients, the ciclosporin dose may be based on ciclosporin
`blood trough concentrations. See section 5.1 for experience with reduced ciclosporin blood concentrations.
`
`In cardiac transplantation, there are limited data regarding dosing Certican with ciclosporin trough concentrations of 50-100
`ng/ml after 12 months.
`
`Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations
`are equal to or above 3 ng/ml.
`
`Tacrolimus dose recommendation in hepatic transplantation
`
`Hepatic transplant patients should have their tacrolimus exposure reduced to minimise calcineurin-related renal toxicity. The
`tacrolimus dose should be reduced starting approximately 3 weeks after initiating co—administration with Certican, based on
`targeted tacrolimus blood trough concentrations (Co) of 3-5 ng/ml. In a controlled clinical trial, complete withdrawal of tacrolimus
`has been associated with an increased risk of acute rejections.
`
`Certican has not been evaluated with full-dose tacrolimus in controlled clinical trials.
`
`Method of administration
`
`Certican is for oral use only.
`
`The daily dose of Certican should always be given orally in two divided doses consistently either with or without food (see
`section 5.2) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic drug monitoring).
`
`Certican tablets should be swallowed whole with a glass of water and not crushed before use. For patients unable to swallow
`whole tablets, Certican dispersible tablets are also available (see Certican dispersible tablets Summary of Product
`Characteristics).
`
`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
`
`Management of immunosuppression
`
`In clinical trials, Certican has been administered concurrently with ciclosporin for microemulsion, basiliximab, or with tacrolimus,
`and corticosteroids. Certican in combination with immunosuppressive agents other than these has not been adequately
`investigated.
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
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`Certican has not been adequately studied in patients at high immunological risk.
`
`Combination with thymglobulin induction
`
`Strict caution is advised with the use of thymoglobulin (rabbit anti-thymocyte globulin) induction and the
`Certican/ciclosporin/steroid regimen. In a clinical study in heart transplant recipients (Study A2310, see section 5.1), an
`increased incidence of serious infections including fatal infections was observed within the first three months after
`transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin.
`
`Serious and opportunistic infections
`
`Patients treated with immunosuppressants, including Certican, are at increased risk for opportunistic infections (bacterial,
`fungal, viral and protozoal). Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive
`multiple leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may
`lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients
`with deteriorating renal function or neurological symptoms. Fatal infections and sepsis have been reported in patients treated
`with Certican (see section 4.8).
`
`In clinical trials with Certican, antimicrobial prophylaxis for Pneumocystisjiroveci (carinii) pneumonia and Cytomegalovirus
`(CMV) was recommended following transplantation, particularly for patients at increased risk for opportunistic infections.
`
`Liver function impairment
`
`Close monitoring of everolimus whole blood trough concentrations (Co) and everolimus dose adjustment is recommended in
`patients with impaired hepatic function (see section 4.2).
`
`Because of longer everolimus half-lives in patients with hepatic impairment (see section 5.2), everolimus therapeutic monitoring
`after starting treatment or after a dose adjustment should be performed until stable concentrations are reached.
`
`Interaction with oral CYP3A4 substrates
`
`Caution should be exercised when Certican is taken in combination with orally administered CYP3A4 substrates with a narrow
`therapeutic index due to the potential for drug interactions. If Certican is taken with orally administered CYP3A4 substrates with
`a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the
`patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4
`substrate (see section 4.5).
`
`Interaction with strong inhibitors or inducers of CYP3A4
`
`Co-administration with strong CYP3A4-inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin,
`ritonavir) and inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin) is not recommended unless the benefit outweighs
`the risk. It is recommended that everolimus whole blood trough concentrations be monitored whenever inducers or inhibitors of
`CYP3A4 are concurrently administered and after their discontinuation (see section 4.5).
`
`Lymphomas and other malignancies
`
`Patients receiving a regimen of immunosuppressive medicinal products, including Certican, are at increased risk of developing
`lymphomas or other malignancies, particularly of the skin (see section 4.8). The absolute risk seems related to the duration and
`intensity of immunosuppression rather than to the use of a specific medicinal product. Patients should be monitored regularly
`for skin neoplasms and advised to minimise exposure to UV light and sunlight, and to use appropriate sunscreen.
`
`Hype—rlipidaemia
`
`The use of Certican with ciclosporin for microemulsion or tacrolimus in transplant patients has been associated with increased
`serum cholesterol and triglycerides that may require treatment. Patients receiving Certican should be monitored for
`hyperlipidaemia and, if necessary, treated with lipid-lowering medicinal products and have appropriate dietary adjustments
`made (see section 4.5). The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an
`immunosuppressive regimen including Certican. Similarly, the risk/benefit of continued Certican therapy should be re—evaluated
`in patients with severe refractory hyperlipidaemia. Patients administered a HMG-CoA reductase inhibitor and/or fibrate should
`be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the Summary of
`Product Characteristics for the medicinal product(s) concerned (see section 4.5).
`
`flgioedema
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
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`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 transplantation, Certican with full-dose ciclosporin increases the risk of renal dysfunction. Reduced doses
`of ciclosporin 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 ciclosporin 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 without Certican. Regular monitoring of renal function is recommended in all
`patients. Caution should be exercised when co-administering other medicinal products that are known to have a negative 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 concentrations. 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 switching from a 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 accumulation 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 a higher body
`mass index. 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.
`
`The concomitant administration of Certican with a calcineurin inhibitor (CNI) may increase the risk of CNI-induced haemolytic
`uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.
`
`Vaccinations
`
`Immunosuppressants may affect the response to vaccination. During treatment with immunosuppressants, including
`everolimus, vaccination may be less effective. The use of live vaccines should be avoided.
`
`Interstitial lung disease/non-infectious pneumonitis
`
`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 ruled out through appropriate investigations. Cases of ILD have been reported with Certican, which generally
`resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred (see section 4.8).
`
`New onset diabetes mellitus
`
`Certican has been shown to increase the risk of new onset diabetes mellitus after transplantation. Blood glucose
`concentrations should be monitored closely in patients treated with Certican.
`
`Male infertility_
`
`There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. As preclinical
`toxicology studies have shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk
`of prolonged Certican therapy.
`
`Risk of intolerance of excipients
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
`
`Certican tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or
`glucose-galactose malabsorption should not take this medicine.
`
`4.5 Interaction with other medicinal products and other forms of interaction
`
`Everolimus is mainly metabolised by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the
`multidrug efflux pump, P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of systemically absorbed
`everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-glycoprotein. Concurrent treatment with
`strong 3A4 inhibitors and inducers is not recommended. Inhibitors of P-glycoprotein may decrease the efflux of everolimus from
`intestinal cells and increase everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and a
`mixed inhibitor of CYP2D6. All in vivo interaction studies were conducted without concomitant ciclosporin.
`
`Table 3 Effects of other active substances on everolimus
`
`Active substance by interaction
`
`Interaction — Change in Everolimus Recommendations concerning co-
`AUC/Cmalx Geometric mean ratio
`administration
`
`(observed range)
`
`Strong CYP3A4/P9P inhibitors
`
`Ketoconazole
`
`AUC T15.3-fold
`(range 11242-5)
`
`Cmax (41-fold
`
`(range 2.6-7.0)
`
`Co-administration with strong
`_
`CYP3A4/PgP-inhibitors is not
`recommended unless the benefit
`
`outweighs the risk.
`
`ltraconazole, posaconazole,
`voriconazole
`
`Not studied. Large increase in
`everolimus concentration is expected.
`
`(range1.3-3.8)
`
`Telithromycin, clarithromycin
`
`Nefazodone
`
`Ritonavir, atazanavir, saquinavir,
`darunavir, indinavir, nelfinavir
`
`Moderate CYP3A4/P9P inhibitors
`
`Erythromycin
`
`Verapamil
`
`AUC (44-fold
`(range 2.04 2.6)
`
`Cmax T2-0-fOId
`(range 0943.5)
`
`AUC T3740“
`Cmax (22-fold
`
`AUC 13.5-fold
`
`(range 2.2-6.3)
`
`Cmax T2.3-fold
`
`Everolimus whole blood trough
`concentrations should be monitored
`whenever inhibitors of CYP3A4/P9P
`are concurrently administered and
`after their discontinuation.
`Use caution when co-administration of
`moderate CYP3A4 inhibitors or PgP
`inhibitors cannot be avoided.
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
`
`Ciclosporin oral
`
`AUC T2.7-fold
`
`(range 1.5-4.7)
`
`Cmax T1.8-fold
`
`(range 1.3-2.6)
`
`Fluconazole
`
`Diltiazem, nicardipine
`
`Not studied. Increased exposure
`expected.
`
`Not studied. Increased exposure
`Dronedarone
`expected.
`
`Amprenavir, fosamprenavir
`
`Not studied. Increased exposure
`expected.
`
`Grapefruitjuice or other food
`affecting CYP3A4/P9P
`
`Not studied. Increased exposure
`expected (the effect varies widely).
`
`Combination should be avoided.
`
`Strong and moderate CYP3A4 inducers
`
`Rifampicin
`
`Carbamazepine
`
`Phenytoin
`
`Phenobarbital
`
`
`
`AUC I63%
`
`(range O-80%)
`
`Cmax i58%
`
`(range 10-70%)
`
`Not studied. Decreased exposure
`expected.
`
`Not studied. Decreased exposure
`expected.
`
`Not studied. Decreased exposure
`expected.
`
`Not studied. Decreased exposure
`expected.
`
`Co—administration with strong
`CYP3A4-inducers is not
`recommended unless the benefit
`
`outweighs the risk.
`
`Everolimus whole blood trough
`concentrations should be monitored
`whenever inducers of CYP3A4 are
`
`Efavirenz, nevirapine
`
`Not studied. Decreased exposure
`expected.
`
`concurrently administered and after
`their discontinuation.
`
`St John's Wort
`
`(Hypericum perforatum)
`
`Not studied. Large decrease in
`exposure expected.
`
`Preparations containing St John's
`Wort should not be used during
`treatment with everolimus
`
`Agents whose plasma concentrations may be altered by everolimus:
`
`Octreotide
`
`Co—administration of everolimus (10 mg daily) with depot octreotide increased octreotide Cmin with a geometric mean ratio
`(everolimus/placebo) of 1 .47-fold.
`
`Ciclosporin
`
`Certican had a minor clinical influence on Ciclosporin pharmacokinetics in renal and heart transplant patients receiving
`Ciclosporin for microemulsion.
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`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
`
`Single-dose administration of Certican with either atorvastatin or pravastatin to healthy subjects did not influence the
`pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a
`clinically relevant extent. However, 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 Summary of Product
`Characteristics of HMG-CoA reductase inhibitors.
`
`Oral CYP3A4A substrates
`
`Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4
`and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy
`subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A4 substrate probe, with
`everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC. The effect is likely to be due
`to inhibition of intestinal CYP3A4 by everolimus. Hence, everolimus may affect the bioavailability of orally co-administered
`CYP3A4 substrates. However, a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is
`not expected. If everolimus is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g.
`pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for
`undesirable effects described in the product information of the orally administered CYP3A4 substrate.
`
`Vaccinations
`
`Immunosuppressants may affect the response to vaccination and vaccination during treatment with Certican may be less
`effective. The use of live vaccines should be avoided.
`
`Paediatric mpulation
`
`Interaction studies have only been performed in adults.
`
`4.6 Fertility, pregnancy and lactation
`
`mgmy.
`
`There are no adequate data from the use of Certican in pregnant women. Studies in animals have shown reproductive toxicity
`effects including embryo/foetotoxicity (see section 5.3). The potential risk for humans is unknown. Certican should not be given
`to pregnant women unless the potential benefit outweighs the potential risk for the foetus. Women of childbearing potential
`should be advised to use effective contraception methods while they are receiving Certican and up to 8 weeks after treatment
`has been stopped.
`
`Breast-feeding
`
`It is not known whether everolimus is excreted in human milk. In animal studies, everolimus and/or its metabolites were readily
`transferred into the milk of lactating rats. Therefore, women who are taking Certican should not breast feed.
`
`Fertility_
`
`There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors (see section
`4.4, 4.8, and 5.3). The potential for everolimus to cause infertility in male and female patients is unknown, however, male
`infertility and secondary amenorrhoea have been observed.
`
`4.7 Effects on ability to drive and use machines
`
`No studies of the effects on the ability to drive and use machines have been performed.
`
`4.8 Undesirable effects
`
`a) Summary of the safety_profile
`
`The frequencies of adverse 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 adult transplant recipients. All but two of the trials (in renal transplantation) included non-Certican, CNl-based
`standard-therapy arms. Certican combined with ciclosporin was studied in five trials in renal transplant recipients totalling 2,497
`patients (including two studies without a non-Certican control group), and three trials in heart transplant recipients totalling
`1,531 patients (ITT populations, see section 5.1).
`
`https://www.medicines.org.uk/emc/product/1920/smpc
`
`9/25
`
`NOVARTIS EXHIBIT 2054
`Breckenridge v. Novartis, IPR 2017-01592
`Page 9 of 32
`
`NOVARTIS EXHIBIT 2054
`Breckenridge v. Novartis, IPR 2017-01592
`Page 9 of 32
`
`

`

`4/4/2018
`
`Certican Tablets - Summary of Product Characteristics (SmPC) - (eMC)
`
`Certican combined with tacrolimus was studied in one trial, which included 719 liver transplant recipients (ITT population, see
`section 5.1).
`
`The most common events are: infections, anaemia, hyperlipidaemia, new onset of diabetes mellitus, insomnia, headache,
`hypertension, cough, constipation, nausea, peripheral oedema, impaired healing (including pleural and pericardial effusion).
`
`The occurrence of the adverse events may depend on the immunosuppressive regimen (i.e. degree and duration). In the
`studies combining Certican with ciclosporin, elevated serum creatinine was observed more frequently in patients administered
`Certican in combination with full-dose ciclosporin for microemulsion than in control patients. The overall incidence of adverse
`events was lower with reduced-dose ciclosporin for microemulsion (see section 5.1).
`
`The safety profile of Certican administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studies
`in which full-dose ciclosporin was administered, except that elevation of serum creatinine was less frequent, and mean and
`median serum creatinine values were lower, than in the Phase III studies.
`
`b) Tabulated summary of adverse reactions
`
`Table 4 contains adverse drug reactions possibly or probably related to Certican seen in Phase III clinical trials. Unless noted
`otherwise, these disorders have been identified by an increased incidence in the Phase III studies comparing Certican-treated
`patients with patients on a non-Certican, standard-therapy regimen, or the same incidence in case the event is a known ADR of
`the comparator MPA in renal and heart transplant studies (see section 5.1). Except where noted othenivise, the adverse
`reaction profile is relatively consistent across all transplant indications. It is compiled according to MedDRA standard organ
`classes.
`
`Adverse reactions are listed according to their frequencies, which are defined as: very common (21/10); common (21/100 to
`<1/10); uncommon (21/1, 000 to <1/100); rare (2 1/10, 000 to < 1/1, 000); very rare (< 1/10, 000).
`
`Table 4 Adverse drug reactions possibly or probably related to Certican
`
`Infections and infestations
`
`Very common
`
`Infections (viral, bacterial, fungal), upper
`respiratory tract infection, lower respiratory
`tract and lung infections (including
`pneumonia)1, urinary tract infections2
`
`Sepsis, wound infection
`
`Neoplasms benign, malignant and
`unspecified
`
`Common
`
`Malignant or unspecified tumours, malignant
`and unspecified skin neoplasms
`
`new onset diabetes mellitus, hypokalaemia
`
`Uncommon
`
`Blood and lymphatic system disorders
`
`Very common
`
`Common
`
`Endocrine disorders
`
`Uncommon
`
`Lymphomas/post-transplant
`lymphoproliferative disorders (PTDL)
`
`Leukopaenia, anaemia/erythropenia,
`thrombocytopenia1
`
`Pan