Sertican

Certican has an immunosuppressive effect. Its active ingredient is everolimus, an inhibitor of proliferative signal activity.

Everolimus has immunosuppressive activity, slowing down the process of T-cell proliferation, which has an antigen-activated nature, and along with this, clonal expansion, which develops under the influence of special IL T-cells (for example, such as IL-2 with IL-15). The substance slows down the movement of the signal inside the cells, which normally causes cellular proliferation, which develops during the synthesis of growth factors of these T-cells with suitable endings. When this signal is blocked by everolimus, cell division stops at the G1 stage of the cell cycle.

[ 1 ], [ 2 ]

Indications Serticana

It is used to prevent possible rejection of a transplanted heart or kidney in individuals with moderate or low immunological risk who are undergoing basic immunosuppressive treatment using cyclosporine microemulsion and GCS.

Release form

The component is released in tablets of 0.25, 0.5, and 0.75 or 1 mg - 10 pieces inside a cell plate. In a box - 5, 6, and 10 or 25 plates.

[ 3 ], [ 4 ]

Pharmacodynamics

At the molecular level, everolimus forms a link with a cytoplasmic protein (FKBP-12). Everolimus slows down the phosphorylation of the growth factor-stimulated kinase-p70 S6. Since this process is under the control of the FRAP element (called m-TOR), this information suggests that the everolimus-FKBP-12 link is synthesized with the FRAP element.

The FRAP component is a key regulatory protein that controls cell growth, proliferation, and metabolism; disruption of FRAP may explain the cell cycle arrest induced by everolimus. This suggests that everolimus has a different mode of action than cyclosporine. In preclinical allograft models, everolimus was found to be more effective in combination with cyclosporine than either alone.

Everolimus is not limited to T-cell activity. It inhibits growth factor-stimulated cell proliferation, both hematopoietic and non-hematopoietic (e.g., smooth muscle cells). Growth factor-stimulated proliferation of intravascular smooth muscle cells, triggered by endothelial cell damage and leading to neointima formation, is a key element in the pathogenesis of chronic rejection.

Experimental tests revealed a slowdown in neointima formation in rats that underwent aortic allotransplantation.

[ 5 ]

Pharmacokinetics

Absorption.

When administered orally, the Cmax level is observed after 1-2 hours. In people after transplantation, blood values of everolimus are proportional to the dose in the dosage range of 0.25-15 mg. Taking into account the AUC level, the relative bioavailability of dispersible tablets compared to conventional ones is 90%.

The Cmax and AUC values of the substance decreased by 60% and 16%, respectively, when the drug was taken with very fatty foods. To minimize the variability of these parameters, Certican is recommended to be used either with or without food.

Distribution processes.

The ratio of blood to plasma values of everolimus is in the range of 17-73% and is determined by values in the range of 5-5000 ng/mL.

In volunteers and individuals with moderate hepatic impairment, plasma protein synthesis is approximately 74%. The final VSS in renal transplant recipients undergoing maintenance procedures is 342±107 l.

Exchange processes.

Everolimus is a substrate of the CYP3A4 component together with P-glycoprotein. The key metabolic pathways are monohydroxylation and O-dealkylation. The main metabolic units (there are 2 of them) are formed during hydrolysis of the cyclic lactone. They do not have a noticeable immunosuppressive effect. Everolimus is mostly found inside the circulatory system.

Excretion.

When a single dose of radiolabeled everolimus was administered to transplant recipients receiving cyclosporine, most of the radioactivity (80%) was recovered in the faeces, with only 5% excreted in the urine. No unchanged element was detected in either urine or faeces.

[ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]

Dosing and administration

The drug is used orally - either constantly with food or constantly without it.

At first, people with a transplanted kidney or heart should use 0.75 mg of the drug 2 times a day. You should start using it as soon as possible after the transplant. The daily dosage of the drug is always divided into 2 doses. The drug should be taken at the same time as cyclosporine microemulsion.

It may be necessary to change the dosage regimen of the drug taking into account the obtained plasma parameters, personal response to therapy, tolerance, as well as changes in concomitant drug treatment and clinical picture. Changing the dosage regimen is allowed at 4-5-day intervals.

People representing the Negroid race.

The incidence of acute rejection confirmed by biopsy is higher in this group of patients (compared to others). Based on the limited information currently available, Negroid patients may require an increased dose of Certican to achieve an effect similar to that seen in other patients taking the drug in standard adult doses. The current information regarding the safety and efficacy of the drug does not allow for specific recommendations for the use of everolimus in Negroid patients.

Use for problems with liver function.

In patients with deficiency, basal whole blood everolimus levels should be closely monitored.

In moderate or mild cases of insufficiency, the dose of the drug should be reduced by approximately half in relation to the average dosage in situations where a combination of 2 of the following parameters is used: bilirubin is >34 μmol/L (or >2 mg/dL); albumin is <35 g/L (or <3.5 g/dL); the INR value is >1.3 (PT prolongation >4 seconds). Subsequent titration of the dose is performed taking into account the information from drug monitoring.

There are no studies of everolimus in people with severe disease.

Medical monitoring.

Whole blood everolimus levels should be continuously monitored. Exposure-to-efficacy and exposure-to-safety analyses showed that individuals with C0 values >3 ng/mL are less likely to have acute cardiac or renal rejection diagnosed by biopsy than individuals with C0 values <3 ng/mL. It is recommended that the drug level of everolimus be no greater than 8 ng/mL. Levels greater than 12 ng/mL have not been studied. Everolimus levels were measured by chromatography.

It is important to monitor everolimus blood levels in patients with hepatic impairment when co-administered with strong CYP3A4 inducers or inhibitors, when switching to another therapeutic formulation, or when significantly reducing the cyclosporine dosage.

Everolimus blood levels are slightly lower during administration of dispersible tablets than after administration of conventional tablets. It is recommended that dosage adjustments be made based on everolimus C0 values recorded more than 4-5 days after the previous adjustment. Since cyclosporine interacts with everolimus, the level of the latter may decrease in the case of a significant decrease in cyclosporine levels (C0 < 50 ng/mL).

Dosage regimens for cyclosporine when combined with Certican in people after kidney transplantation.

The drug is prohibited to use for a long time in full dose together with cyclosporine. Reduction of cyclosporine dosage in patients after kidney transplantation who used Certican resulted in improvement of renal function. It is necessary to reduce the dose of cyclosporine immediately after transplantation. In this case, the recommended residual values of cyclosporine in blood plasma after 12 hours from the moment of drug administration (C0 observation) are equal to:

• for the period up to 1 month – 100-200 ng/ml;
• up to 2-3 months – 75-150 ng/ml;
• up to 4-5 months – 50-100 ng/ml;
• up to 0.5-1 year – 25-50 ng/ml.

Before performing a dose reduction of cyclosporine, it is necessary to confirm that the steady-state blood levels of Certican (C0) are ≥3 ng/mL.

Appropriate dosage regimens of cyclosporine when administered with Certican in humans following cardiac transplantation.

In patients who have had a heart transplant, during the maintenance phase, the dose of cyclosporine should be reduced after 1 month from the date of transplantation to improve kidney function. If renal dysfunction progresses or if the calculated Cl creatinine values are <60 ml per minute, the treatment regimen should be changed.

The data obtained from clinical trials suggest that when everolimus is used in this group of patients, target plasma cyclosporine levels based on C0 observations should be:

• 200-300 ng/ml in the 1st month after transplantation;
• 150-250 ng/ml – after 2 months;
• 100-200 ng/ml – after 3-4 months;
• 75-150 ng/ml – after 5-6 months;
• 50-100 ng/ml – after 7-12 months.

Before reducing the cyclosporine dose, it is necessary to ensure that the steady-state blood level of everolimus (C0) is 3 ng/mL or higher.

In cases of cardiac transplantation, there is limited information regarding drug dosing at cyclosporine C0 values of 50-100 ng/mg after 1 year post-transplant.

Schemes for using the tablet form of the drug.

The tablets are taken whole, without crushing, and the medicine is washed down with plain water (1 glass).

Administration via 10 ml oral syringe.

In case of administration of dispersible tablet form, it is allowed to use an oral syringe – the medicine is placed inside it. To prepare dispersion with the volume of liquid inside the syringe of 10 ml (this is its full capacity), a maximum of 1.25 mg of the medicine can be used.

After the tablet is inserted, water is added to the syringe to the level of 5 ml, then wait 1.5 minutes, shaking the syringe a little. When the dispersion is formed, the substance is injected from the syringe directly into the mouth. After this, the syringe is rinsed, 5 ml of plain water is drawn into it, and it is injected into the mouth. Then you need to drink another 10-100 ml of plain water.

Use through a plastic cup.

A plastic cup can also be used to take the dispersible tablet form. With this method, the tablets are placed in a cup into which 25 ml of plain water has been poured. With this volume of liquid, the amount of the medicinal substance from which the dispersion is made may not exceed 1.5 mg. The cup with water and tablets is left for approximately 120 seconds to form a dispersion; before taking, the liquid in the cup must be shaken to dissolve the substance. After this, the cup is rinsed, another 25 ml of plain water is poured into it, and then it is drunk.

Use with a nasogastric tube.

Dispersible tablets can also be administered through a nasogastric tube. The medicine is placed inside a small medical cup, into which 10 ml of plain water is poured. Then wait 1.5 minutes, shaking the cup slightly. After this, the dispersion is drawn into a syringe and administered at low speed (for 40 seconds) through a nasogastric tube. The syringe with the cup is rinsed 3 times, each time drawing 5 ml of plain water, and then inserted through the tube. Then the tube is washed using 10 ml of liquid. After using the medicine, the nasogastric tube must be clamped for at least half an hour.

When administering cyclosporine microemulsion via a nasogastric tube, this procedure should be performed before using Certican. These medications must not be mixed.

[ 12 ]

Use Serticana during pregnancy

There is no information regarding the use of Certican in pregnant women.

During experimental tests, toxic effects on reproduction (feto- and embryotoxicity) were noted. There is no information on whether there is a risk to the human body. It is prohibited to use the drug during the specified period, except in situations where the probable benefit from treatment is more expected than the risk of negative consequences for the fetus.

Patients of reproductive age are required to use reliable contraception during the active phase of Certican therapy and for 2 months after its completion.

It is not known whether everolimus is excreted in human milk.

In experimental tests, it was found that everolimus or its metabolic components rapidly pass into the milk of rats. For this reason, breastfeeding is prohibited during treatment.

Contraindications

Contraindicated for use in cases of severe intolerance to sirolimus with everolimus or other components of the drug.

Caution is required when using in the following situations:

• severe liver failure (because the efficacy and safety of everolimus in people with liver failure have not been studied, its plasma levels should be closely monitored);
• rare hereditary disorders – galactosemia, severe lactose intolerance or glucose-galactose malabsorption;
• a combination of medication with other drugs that have a negative impact on kidney function.

All patients undergoing treatment should have their renal function monitored continuously. If serum creatinine levels increase, the immunosuppressant regimen should be modified, such as by reducing the cyclosporine dosage.

[ 11 ]

Side effects Serticana

Side effects include:

• lesions of infectious nature: often infections of bacterial, viral or fungal origin. Sometimes wound lesions develop;
• ^{disorders associated with lymph and hematopoietic function: leukopenia 1} is most common. Coagulopathy is quite common, as well as anemia ¹ with thrombocytopenia ¹, TTP or HUS. Sometimes hemolysis develops;
• endocrine disorders: sometimes men experience hypogonadism (increased LH levels and decreased testosterone levels);
• problems with metabolic function: mainly hyperlipidemia or -cholesterolemia develops. Hypertriglyceridemia is also quite common;
• vascular disorders: venous thrombosis, increased blood pressure or lymphocele are often observed ³;
• Respiratory system damage: pneumonia is often observed. In addition, interstitial lung pathology or alveolar proteinosis of the lungs may sometimes occur;
• symptoms from the digestive function: vomiting, diarrhea, pain in the abdominal area, pancreatitis and nausea often appear;
• signs associated with hepatobiliary activity: sometimes hepatitis, jaundice, liver dysfunction and an increase in AST with ALT and GGT values are observed;
• disorders in the subcutaneous tissue and epidermis: acne, Quincke's edema ⁴ and complications in the surgical scar area are often observed. Rashes sometimes appear;
• disorders of the musculoskeletal structure: myalgia is sometimes observed;
• Lesions affecting the urinary tract: infections affecting the urinary tract often occur. Sometimes pyelonephritis or necrosis of the renal tubules is observed;
• others: pain or swelling is often noted.

¹ presence of a dose-dependent effect; or such an effect was most often observed in people using the drug at a dose of 3 mg per day.

² in people with heart transplants.

³ in people with kidney transplants.

⁴ mainly in individuals who combine Certican with ACE inhibitors.

Overdose

Everolimus has been shown to have a low potential for acute toxicity in experimental studies. No death or severe toxicity was observed in rats or mice after a single oral dose of 2000 mg/kg.

Information on human intoxication is extremely limited. There is a single report of a 2-year-old child accidentally swallowing 1.5 mg of the drug, but no adverse effects occurred. After a single oral administration of up to 25 mg, normal tolerance of the drug was observed in transplant recipients.

In case of any overdose, general supportive measures are required.

[ 13 ], [ 14 ], [ 15 ], [ 16 ]

Interactions with other drugs

Everolimus is metabolized primarily intrahepatically; some of the process also occurs within the intestinal wall via the CYP3A4 isoenzyme. In addition, the substance acts as a substrate for the protein that carries P-glycoprotein. Therefore, the absorption and subsequent elimination of this component may be affected by drugs that interact with the CYP3A4 element or P-glycoprotein. Combining Certican with potent inducers or inhibitors of the CYP3A4 component is prohibited. Agents that inhibit P-glycoprotein can weaken the process of releasing the drug component from intestinal cells, as well as increase its serum levels.

When used in vitro, the everolimus component was a competitive substance that inhibited the activity of CYP3A4 with CYP2D6, which potentially increased plasma levels of drugs excreted by these enzymes. Therefore, it is necessary to be very careful when combining drugs with substrates of CYP3A4 and CYP2D6 components that have a narrow drug index. All in vivo interaction tests were performed without combination with cyclosporine.

Cyclosporine, which inhibits the activity of CYP3A4 or P-glycoprotein.

The bioavailability of everolimus increases significantly when administered with cyclosporine. When testing a single dose of cyclosporine microemulsion in volunteers, it increased AUC values of everolimus by 168% (from 46% to 365%), and at the same time Cmax values by 82% (from 25% to 158%), compared with the administration of Certican alone. In case of correction of the cyclosporine dose regimen, it may be necessary to change the dosage values of everolimus.

The therapeutic significance of the drug's effect on the pharmacokinetic characteristics of cyclosporine in people with kidney or heart transplants using the latter's microemulsion is minimal.

Rifampicin, which is an inducer of the activity of the CYP3A4 element.

In volunteers who had previously used rifampicin in multiple doses, with subsequent use of Certican in a single dose, an almost threefold increase in Cl everolimus values was observed, as well as a decrease in AUC by 63% and Cmax by 58%. Therefore, combining the drug with rifampicin is prohibited.

People using substances that inhibit HMG-CoA reductase activity should be monitored for the occurrence of rhabdomyolysis and other adverse effects in accordance with the recommendations for the above-described drugs.

Other possible therapeutic interactions.

Substances that moderately inhibit the action of CYP3A4 with P-glycoprotein can increase blood levels of everolimus (for example, antifungals - fluconazole; macrolide antibiotics - erythromycin; and also CCBs - nicardipine with verapamil and diltiazem; protease inhibitors - indinavir with nelfinavir and amprenavir).

Elements that induce CYP3A4 activity are capable of enhancing the metabolic processes of everolimus and reducing its blood level (among these are St. John's wort, anticonvulsants (phenobarbital with carbamazepine and phenytoin) and drugs used for HIV (nevirapine with efavirenz)).

Grapefruit juice and grapefruit itself affect the activity of hemoprotein P450, as well as P-glycoprotein, which is why it is necessary to stop taking them during treatment with Certican.

Vaccination.

Immunosuppressants can affect the body's response to vaccines, so when using drugs, the effect of vaccination may be weakened. It is necessary to refuse the administration of live vaccines.

[ 17 ], [ 18 ]

Storage conditions

Certican should be stored in a dark, dry place, out of the reach of small children. Temperature values should not exceed 25°C.

[ 19 ]

Shelf life

Certican is approved for use for a period of 36 months from the date of sale of the medication.

[ 20 ]

Use in children

There is very little information regarding the use of the drug in pediatrics, so it is usually not recommended for this group of patients. Although there is limited information on the administration of the drug to children during kidney transplantation.

Analogues

The drug's analogues are Arava, Myfortic, Xeljanz and Baxmun with Mofilet and Zenapax, as well as Panimun, Imusporin, Remicade and Imufet with Neolem and Lifemun. Also on the list are Lefno, Cycloral, Mifenax, Cellcept with Ekvoral and Raptiva with Tysabri.

[ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ], [ 27 ]