Expiration date: 10/2025
The composition and form of issue:
Dispersible tablets, 1 tablet contains:
everolimus 0.1 mg
0.25 mg
excipients: butylhydroxytoluene lactose monohydrate hypromellose, magnesium stearate, silicon dioxide colloidal anhydrous lactose anhydrous crospovidone
10 PCs in blister. in cardboard pack 5, 6, 10 or 25 blisters.
Tablets, 1 tablet contains:
everolimus 0.25 mg
0.5 mg
0.75 mg
1 mg
excipients: butylhydroxytoluene lactose monohydrate hypromellose magnesium stearate the lactose anhydrous crospovidone
10 PCs in blister. in cardboard pack 5, 6, 10 or 25 blisters.
Description pharmaceutical form:
Tablets 0,25 mg: round, flat, white to yellowish color, with beveled edges, marbling, on the one hand the marking "C" on the other "NVR".
Tablets 0.5 mg: round, flat, white to yellowish color, with beveled edges, marbling, on the one hand the marking "CH" on the other "NVR".
Tablets 0.75 mg: round, flat, white to yellowish color, with beveled edges, marbling, on the one hand the marking "CL" on the other "NVR".
Tablets 1 mg: round, flat, white to yellowish color, with beveled edges, marbling, on the one hand the marking "CU," on the other "NVR".
Dispersible tablets 0.1 mg: round, flat, white to yellowish color, with beveled edges, marbling, on the one hand the marking "I" on the other "NVR".
Dispersible tablets 0.25 mg: round, flat, white to yellowish color, with beveled edges, marbling, on the one hand the marking "JO" on the other "NVR".
Pharmacokinetics:
Suction. Once inside C max achieved through 1-2 h in patients after transplantation of a concentration of everolimus in blood is proportional to dose in the dose range of 0.25 to 15 mg based On AUC relative bioavailability of the dispersible tablets compared with the tablets is 90%.
Effect of food: the Cmax and AUC of everolimus was decreased by 60 and 16%, respectively, when the pill with a very fatty foods. To reduce variability to a minimum, the drug Certican should be taken either with food or without it.
Distribution. The ratio of the concentration of everolimus in blood and its concentration in plasma is in the range from 17 to 73%, depending on the concentrations in the range of 5 to 5000 ng/ml in healthy volunteers and patients with mild impaired hepatic function the plasma protein binding is approximately 74%. VSS in the final phase in patients after kidney transplantation are on maintenance therapy, is (342±107) L.
Metabolism. Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main routes of metabolism identified in humans was monohydroxylation and O-dealkylation. Two main metabolite formed by hydrolysis of the cyclic lactone. None of them has significant immunosuppressive activity. In the systemic circulation is mainly everolimus.
Excretion. After administration of a single dose of labeled radioactive label everolimus patients after transplantation and receiving cyclosporine, the majority (80%) of radioactivity was determined in the feces, a small amount (5%) stood out with urine. Unchanged substance was not detected neither in urine nor in feces.
Pharmacokinetics at steady state
Pharmacokinetics in patients with renal and cardiac transplant treated with everolimus 2 times per day simultaneously with cyclosporine in the form of a microemulsion were comparable. The equilibrium state was achieved on the 4th day with the accumulation in the blood in concentrations that are 2-3 times higher than the blood concentration after the application of the first dose. After taking the drug, the Tmax is 1-2 h before the drug in doses of 0.75 and 1.5 mg 2 times a day the average value of Cmax is (11,1±4,6) ng/ml (20,3±8,0) ng/ml, average AUC — (75±31) ng×h/ml and (131±59) ng×h/ml, respectively. While taking the drug in doses of 0.75 and 1.5 mg 2 times daily S0 of everolimus in the blood are, on average, (4,1±2,1) ng/m, or (7,1±4,6) ng/ml, respectively (C0 is the basal concentration determined in the morning before taking another dose). Exposure of everolimus remains stable all the time during the first year after transplantation. S0 highly correlated with the AUC with the correlation coefficient ranging between 0.86 and 0.94. Based on the analysis of pharmacokinetics in transplant patients, total clearance is 8.8 l/h (range, — 27%), apparent Central VSS is 110 liters (range, — 36%). T1/2 is (28±7) h
Pharmacokinetics in special clinical cases
Violations liver function. 8 patients with moderately acute violations of the liver (class b on a scale Child-Pough) everolimus AUC was increased approximately 2 times compared to that of 8 healthy volunteers. The AUC positively correlated with the concentration of serum bilirubin and an increase in PV and negatively correlated with the concentration of serum albumin. If the concentration of bilirubin was >34 µmol/l, PV was >1.3 INR (prolongation of >4 sec) and/or albumin concentration was <35 g/l, there was a trend to increased AUC in patients with moderate-to-severe hepatic failure. The impact of severe hepatic impairment (class C Child-Pugh) the AUC has not been studied, but probably it is the same or more pronounced than the impact of moderate hepatic insufficiency.
Violations of kidney function. Post-transplant renal failure (Cl creatinine — 11-107 ml/min) did not affect the pharmacokinetic parameters of everolimus.
Pediatrics. Cl of everolimus was increased in linear dependence on the patient's age (1 to 16) of the body surface area (0,49–1,92 m2) and body mass (11-77 kg). In equilibrium Cl was (10,2±3,0) l/h/m2, T1/2 — (30±11) h
Nineteen de novo patients after kidney transplantation at the age from 1 year to 16 years received the drug Certican in the form of dispersible tablets at a dose of 0.8 mg/m2 (maximum 1.5 mg) 2 rasav day with cyclosporine in the form of a microemulsion. In these patients, the AUC of everolimus was (87±27) ng×h/ml, and corresponded to that of adults receiving 0.75 mg 2 times/day. In equilibrium basal concentration was (4,4±1,7) ng/ml.
Adult patients. Adult patients aged 16 to 70 years, there has been a decrease in the clearance of everolimus by 0.33% per year (dose adjustment required).
Based on the population pharmacokinetics analysis of total Cl was higher in patients of black race, on average, by 20%.
Impact on efficiency. In recipients of kidney and heart for 6 months after transplantation was correlation between basal concentrations of everolimus and frequency of biopsy-proven acute rejection and of thrombocytopenia.
Table
Kidney transplantation | |||||
| ?0, ng/ml | &le3,4 | 3,5–4,5 | 4,6–5,7 | 5,8–7,7 | 7,8–15 |
| No rejection | 68% | 81% | 86% | 81% | 91% |
| Thrombocytopenia (<100·109/?) | 10% | 9% | 7% | 14% | 17% |
| Heart transplantation | |||||
| ?0, ng/ml | &le3,5 | 3,6–5,3 | 5,4–7,3 | 7,4–10,2 | 10,3–21,8 |
| No rejection | 65% | 69% | 80% | 85% | 85% |
| Thrombocytopenia (<75·109/?) | 5% | 5% | 6% | 8% | 9% |
Description pharmacological action:
The active ingredient of the drug Certican — everolimus is an inhibitor of the proliferative signal. Everolimus has immunosuppressive effect through inhibition of antigen-activated proliferation of T cells and, therefore, clonal expansion, called IL specific T cells (e.g. IL-2 and IL-15). Everolimus inhibits an intracellular signaling pathway, which normally leads to cell proliferation triggered by binding of these growth factors T cells with appropriate receptors. Blockade of this signal by everolimus leads to arrest of cell division in the G1 phase of the cell cycle.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus is the inhibition of phosphorylation of P70 S6 kinase stimulated by the growth factor. Because the phosphorylation of P70 S6 kinase is under the control of FRAP (so-called m-TOR), these data suggest that the complex everolimus-F???-12 binds to FRAP. FRAP is a key regulatory protein which governs cell metabolism, growth and proliferation impaired function of the FRAP, thus explains the cell cycle arrest caused by everolimus. Everolimus is thus distinct from cyclosporine mechanism of action. In preclinical models of allograft was shown higher efficacy of the combination of everolimus with cyclosporine, compared with the isolated use of each of them.
The effect of everolimus is not limited to the effect on T cells. It inhibits stimulated by growth factors proliferation of both hematopoietic and negaotiations cells (e.g. smooth muscle cells). Stimulated by the growth factor proliferation of smooth muscle cells of blood vessels, which is triggered when damage to endothelial cells and leading to neointima formation, plays a key role in the pathogenesis of chronic rejection.
The pilot studies have shown inhibition of neointima formation in rats with aortic allograft.
Indications:
Prevention of graft rejection of the kidney and heart in adult recipients with low and medium immunological risk receiving the base immunosuppressive therapy with cyclosporine in the form of a microemulsion and corticosteroids.
Data on the drug Certican in children and adolescents is not sufficient to recommend the use of the drug in these patients. However, there are limited data on the use of the drug in pediatric renal transplantation.
Contraindications:
Hypersensitivity to everolimus, sirolimus or other components of the drug.
With caution:
severe hepatic insufficiency (because the safety and efficacy of everolimus in patients with impaired liver function have not been studied — it is recommended to carefully monitor its concentration in blood plasma)
rare hereditary disorders related to galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption
children and adolescents (data on the drug Certican not sufficient to recommend the use of the drug in these patients). However, there are limited data on the use of the drug in pediatric renal transplantation
the simultaneous use of other drugs, has a negative impact on renal function.
All patients is recommended regular monitoring of renal function. When the concentration of creatinine in the serum should be considered on correction of the mode of immunosuppressive therapy, in particular the reduction in dose of cyclosporine.
Application of pregnancy and breast-feeding:
Data on the drug Certican in pregnancy.
The pilot studies have shown the presence of toxic effects on reproduction, including embryo toxicity and fetotoksicnosti. It is unknown whether there is a potential risk to humans. You should not use the drug Certican in pregnant women except in those cases where the expected benefits of therapy outweighs the potential risk to the fetus.
Women of childbearing age should be advised to use effective methods of contraception during treatment with the drug Certican and for 8 weeks after the end of therapy.
Unknown, selects whether everolimus in breast milk of a person.
In experimental studies it was shown that everolimus and/or its metabolites rapidly penetrated into the milk of lactating rats. Therefore, women receiving the drug Certican, you should not breast-feed.
Side effects:
Data on the frequency of adverse reactions was obtained in the course of 3 clinical trials (combined data from 1199 patients). In these 3 randomized, double-blind, controlled, multicentre clinical studies (2 studies, the patients with kidney transplant de novo and 1 study in patients with heart transplantation de novo) in which the drug Certican used in a dose of 1.5 or 3 mg/day for at least 12 months in combination with cyclosporine in the form of a microemulsion and corticosteroids.
Also data on the frequency of occurrence of adverse reactions received in 2 open studies that have investigated the efficacy and safety of the drug Certican in the dose of 1.5 and 3 mg/day in combination with cyclosporine at a reduced dose in patients with kidney transplant, de novo.
To determine the frequency of adverse reactions used the following criteria: very common (&ge1/10) frequently (&GE. 1/100, <1/10), sometimes (&ge1/1000, <1/100) rare (&ge1/10000, <1/1000) very rare (<1/10000).
Listed below are the undesirable reactions possibly or probably associated with the drug Certican that have been registered in clinical phase III studies (kidney transplantation or heart).
Infectious disease: often viral, bacterial and fungal infections, sepsis and sometimes wound infection.
From the hematopoietic system and lymphatic system: very often — often leukopenia — thrombocytopenia, anemia, coagulopathy, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome sometimes hemolysis.
From the endocrine system: sometimes — hypogonadism in men (low testosterone levels, increased levels of LH).
Metabolic disorders: very often — hypercholesterolemia, hyperlipidemia often hypertriglyceridemia.
From the vascular system: often — increased blood pressure, limfocele, venous thrombosis.
The respiratory system: often — sometimes pneumonia — interstitial lung disease, pulmonary alveolar proteinosis.
From the digestive system: often — pain in the abdomen, diarrhea, nausea, pancreatitis, vomiting.
Hepatobiliary system: rarely — hepatitis, liver function abnormalities, jaundice, increased levels of ALT, ACT , GGT.
The skin and subcutaneous tissue: often — angioneurotic ????4, acne, complications of the surgical wound and sometimes a rash.
From the side of musculoskeletal system: rarely — myalgia.
From the urinary system: often — urinary tract infections sometimes — necrosis of renal tubules, pyelonephritis.
Other: often — swelling, pain.
Note:
1 was installed in a dose-dependent effect or the phenomenon was observed significantly more frequently in patients receiving the drug in a dose of 3 mg/day.
2 in heart transplantation.
3 in kidney transplantation.
4 primarily in patients receiving concurrently ACE inhibitors.
In controlled clinical trials in which patients were observed for at least 1 year, lymphoma or lymphoproliferative disease developed in 1.4% of patients receiving the drug Certican (1.5 or 3 mg/day) in combination with other immunosuppressants. Malignant skin tumors have been reported in 1.3% of patients, other types of malignancy — 1.2% of patients.
The occurrence of these adverse events may depend on the degree and duration of immunosuppressive therapy. In major studies the increase of concentration of serum creatinine was observed more frequently in patients receiving the drug Certican in combination with full dose cyclosporine in the form of a microemulsion than in control patients. The overall incidence of adverse events was lower in the appointment of the reduced doses of cyclosporine in the form of a microemulsion.
The safety profile of the drug Certican in studies using the drug, along with reduced dose of cyclosporine was the same as in the 3 main studies, which were administered a standard dose of cyclosporine. However, when use of the drug Certican along with reduced dose cyclosporine less likely to have an increased concentration of creatinine in plasma was observed lower mean and median creatinine concentration in plasma than in other phase III studies.
When using m-TOR inhibitors, including the drug Certican were rarely observed lesion of the parenchyma of the lungs, such as inflammation of the parenchyma of the lungs (pnevmonity) and/or pulmonary fibrosis non-infectious etiology, in rare cases with fatal outcome. In most cases, after the abolition of drug therapy Certican and/or destination GCS noted the disappearance of data of adverse reactions.
Drug interactions:
Everolimus is metabolized mainly in the liver and to some extent in the intestinal wall, with the participation of isoenzyme CYP3A4. Everolimus is also a substrate for protein-Transporter P-glycoprotein. Therefore, absorption and subsequent elimination of systemically absorbirowawrzayasa of everolimus may be influenced by drugs that interact with CYP3A4 and/or P-glycoprotein. The combined use of the drug Certican with strong inhibitors or inducers of CYP3A4 is not recommended. Inhibitors of P-glycoprotein can reduce the release of everolimus from intestinal cells and increase everolimus concentrations in serum. In vitro, everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing plasma concentrations of drugs that are excreted with the participation of these enzymes. Therefore, caution should be exercised with simultaneous use of Certican with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index. All studies of the interaction in vivo was carried out without the simultaneous application of cyclosporine.
Cyclosporine a (inhibitor of CYP3A4/P-glycoprotein). The bioavailability of everolimus was significantly increased with simultaneous use of cyclosporine. In the study a single dose in healthy volunteers cyclosporine in the form of a microemulsion (Sandimmun Neoral) increased everolimus AUC by 168% (from 46 to 365%) and Cmax by 82% (from 25 to 158%) compared to using only one of everolimus. When changing the dose of cyclosporine may require correction dosing regimen of everolimus.
The clinical significance of the effect of the drug Certican on the pharmacokinetics of cyclosporine minimal in patients with transplant kidneys and hearts, receiving cyclosporine in the form of a microemulsion.
Rifampicin (CYP3A4 inducer). In healthy volunteers who received prior therapy multiple doses of rifampicin, the subsequent use of the drug Certican in a single dose, there was an almost 3-fold increase in Cl and decrease everolimus Cmax by 58% and AUC by 63%. The combined use of Certican with rifampicin is not recommended.
Atorvastatin (a CYP3A4 substrate) or pravastatin (a substrate for P-glycoprotein). When a single dose of the drug Certican with atorvastatin or pravastatin to healthy volunteers clinically meaningful effect on the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as the General bioreactivity HMG-COA reductase in the plasma is not detected. However, these results cannot be extrapolated to other inhibitors of HMG-COA reductase.
Patients receiving inhibitors of HMG-COA reductase inhibitors, should be monitored for the development of rhabdomyolysis and other adverse events in accordance with the instructions on the application of the above funds.
Another possible interaction. Moderate inhibitors of CYP3A4 and P-glycoprotein can increase the concentration of everolimus in blood (e.g. anti-fungal drugs: fluconazole antibiotics the macrolides — erythromycin CCB — verapamil, nicardipine, diltiazem protease inhibitors — nelfinavir, indinavir, amprenavir).
Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus concentration in the blood (such as St. John's wort, anticonvulsants — carbamazepine, phenobarbital, phenytoin medicines for the treatment of HIV efavirenz, nevirapine.)
Grapefruit and grapefruit juice affect the activity of cytochrome P450 and P-glycoprotein, so avoid their use against the background of the drug Certican.
Vaccination. Immunosuppressants may affect the response after vaccination against the background of drug treatment Certican vaccination may be less effective. You should avoid use of live vaccines.
Method of application and dose:
Inside, either always with food or always without it.
Adults. The recommended starting dose in patients with renal and cardiac transplants is 0.75 mg 2 times/day. The drug should start to apply as soon as possible after transplantation. The daily dose Certican always divided into 2 doses. The drug Certican take at the same time with cyclosporine in the form of a microemulsion. May require correction dosing regimen of the drug Certican taking into account the achieved concentrations in plasma, tolerability, individual response to treatment, changes in concomitant drug therapy and the clinical situation. The correction mode can be carried out at intervals of 4-5 days.
Blacks. The incidence of development of acute rejection confirmed by biopsy was higher for blacks compared to the rest. According to the limited information available to the blacks, you may need a higher dose of the drug Certican to achieve the same effect as the other patients receiving the drug at the recommended adult doses. Currently available data on efficacy and safety is insufficient to provide specific recommendations on the use of everolimus for the blacks.
Elderly patients (&ge65 years of age). Clinical experience with the drug Certican in patients aged &ge65 years limited. However, the apparent differences in the pharmacokinetics of everolimus in patients aged &ge65–70 years compared to younger adult patients were observed.
Patients with impaired renal function. In patients with impaired renal function dose adjustment is not required.
Application for violations of liver function. In patients with hepatic impairment should be carefully monitored basal concentrations of everolimus in whole blood. In patients with mild and moderate hepatic insufficiency (class A or b on a scale Child-Pough) dose Certican should be reduced approximately in 2 times compared to the average dose in those cases where there is a combination of 2 indicators of the following: bilirubin is >34 µmol/l (> 2 mg/DL), albumin <35 g/l (<3.5 g/DL), MHO (INR, International Normalized Ratio) — >1.3 (PV prolongation of >4 sec). Further titration of the dose is carried out based on the data therapeutic monitoring. In patients with severe hepatic impairment (class C Child-Pugh) everolimus has not been studied.
Therapeutic monitoring. It is recommended that regular monitoring of therapeutic concentrations of everolimus in whole blood. Based on the analysis of exposure-efficacy and exposure-safety, it was found that in patients with S0 >3 ng/ml, the frequency of biopsy-proven acute rejection as the kidneys and heart were lower than in patients with S0 <3 ng/ml. the Recommended upper range of therapeutic concentrations of everolimus is 8 ng/ml. Concentrations above 12 ng/ml has not been studied. The concentration of everolimus was determined by chromatography.
It is especially important to control the concentration of everolimus in blood in patients with liver failure in the period of simultaneous use of strong inducers and inhibitors of CYP3A4, when switching to another dosage form and/or if the dose of cyclosporine significantly reduced. The concentration of everolimus in blood at use of dispersible tablets can be lower than when using conventional tablets. It is preferable to carry out correction of dosing regimen of the drug Certican based on the values of S0 everolimus, determined more than 4-5 days after your last dosage. Because ciclosporin interacts with everolimus, may decrease concentrations of fluoride if the concentration of cyclosporin is significantly reduced (C0 <50 ng/ml).
Recommendations for the dosing regimen of cyclosporine in combination therapy with the drug Certican in patients after kidney transplantation
Sertican the drug should not be used long-term with cyclosporine in full dose. Reduction of cyclosporine dosage in patients after kidney transplantation treated with medication Certikin led to improvement in renal function. Reduced doses of cyclosporine should be started within 1 month after transplantation. On the basis of data obtained during clinical studies, the recommended concentration ranges of cyclosporine (cyclosporine concentration in blood was determined 2 hours after a dose) defined in the Protocol of this study as follows: 0-4 weeks — 1000-1400 ng/ml 5-8 months — 700-900 ng/ml 9-12 months — 550-650 ng/ml weeks 13-52 — 350-450 ng/ml. In this study the value of basal concentrations (C0) of cyclosporine were (ng/ml): 1st month — (239±114) 3rd month — (131±85) 6th month — (82±60) 12th month (61±28).
It is very important that in the early period after transplantation, concentrations of everolimus and cyclosporine did not decrease below therapeutic range, to minimize the risk of a lack of effect.
Recommendations for the dosing regimen of cyclosporine in combination therapy with the drug Certican in patients after heart transplantation
For patients after heart transplantation in the supportive phase should reduce the dose of cyclosporine to improve kidney function. With the progression of renal dysfunction or in that case, if the calculated value of Cl creatinine is <60 ml/min, the necessary correction of the mode of therapy on the basis of data obtained in clinical trials. In studies of the drug Certican was administered in combination with reduced doses of cyclosporine and values of the basal concentration (C0) of cyclosporine were: 1st month — 200-350 ng/ml, in the 2nd month 150-250 ng/ml in 3-4 months 100-200 ng/ml, in 5-6th month — 75-150 ng/ml, in a 7 to 12-th months — 50-100 ng/ml prior To dose reduction of cyclosporine it should be ascertained that the value of the equilibrium S0 of everolimus is >3 ng/ml.
In heart transplantation, there are limited data regarding drug dosing in cyclosporine C0 Certican 50-100 ng/mg after 12 months after transplantation.
Instructions for use of the drug in tablet form.Tablets should be taken whole, not crushed before use to drink a glass of water.
Instructions for use of the drug in the form of dispersible tablets. Patients who can't swallow pills, prescribed drug Certican in the form of dispersible tablets used to prepare dispersion (a suspension of small solid particles in water).
Reception using the oral syringe 10 ml. When taking dispersible tablets, you can use oral syringe. To do this, place the orodispersible tablet in a syringe. The maximum amount of drug Certican from which it is possible to prepare a dispersion with a volume of water 10 ml (10 ml syringe), is 1.25 mg. Next, add water to the mark of 5 ml, wait for 90 s, while slightly shaking the syringe. After the formation of the dispersion of the injected contents of the syringe directly into the mouth. You should then rinse the syringe by typing 5 ml of water, and to enter the contents into his mouth. After that you should drink 10-100 ml of water.
The reception of a plastic Cup. When taking dispersible tablets, you can use a plastic Cup. To do this, place the dispersible tablets of the drug Certican in a plastic Cup, which is approximately 25 ml of water. The maximum amount of drug Certican from which it is possible to prepare a dispersion with a volume of water 25 ml, 1.5 mg. Then you should leave the Cup for about 2 minutes to form a dispersion before use stir the contents of the Cup to allow the tablets to dissolve. Then immediately rinse Cup, adding 25 ml of water and drink the contents.
Introduction through naso-gastric probe. When taking dispersible tablets, you can use a nasogastric tube. To do this, place the dispersible tablets of the drug Certican in a small plastic medical Cup containing 10 ml of water. Wait 90, slightly rotating the Cup. Then you need to dial the dispersion in the syringe and slowly (over 40) to enter through a nasogastric tube. Then rinse the beaker and the syringe 3 times, gaining 5 ml of water, and enter through the probe. After that you should rinse the probe 10 ml of water. After drug administration Certican nasogastric tube should hold at least 30 min.
If cyclosporin in the form of a microemulsion is also administered through a nasogastric tube, it is necessary to make before drug administration Certican. You should not mix these 2 products.
Overdose:
In experimental studies it was shown that everolimus has a low potential acute toxicity. After ingestion of the drug at a dose of 2000 mg/kg in single administration was not observed deaths or severe toxicity in mice and rats (control range).
Reported cases of overdose in humans is very limited. There is a single fact accidental ingestion of 1.5 mg everolimus in a child 2 years of age, while adverse events were observed. After a single oral administration at doses up to 25 mg in patients after transplantation was noted acceptable tolerability.
Treatment: in all cases of overdose should initiate General supportive measures.
Special instructions:
Drug treatment Certican should start and be done only by doctors with experience in the use of immunosuppressive
