Certican

Certified has an immunosuppressive effect. Its active element is everolimus, an inhibitor of proliferative signal activity.

Everolimus possesses immunosuppressive activity, slowing down the proliferation of T-cells, which has an antigen-activated character, and with it clonal expansion, which develops under the influence of specific IL-T cells (for example, such as IL-2 with IL-15). The substance slows down the movement of the signal inside the cells, normally causing cell proliferation, which develops during the synthesis of the growth factors of these T-cells with suitable endings. When blocking the specified signal under the action of everolimus, cell division stops at the G1-stage of the cell cycle.

[1], [2]

Indications Sertika

It is used to prevent possible rejection of a transplanted heart or kidney in people with moderate and low immunological risk who undergo basic immunosuppressive treatment using cyclosporine microemulsion, as well as GCS.

Release form

The release of the component is made in tablets with a volume of 0.25, 0.5, and also 0.75 or 1 mg - 10 pieces inside the cell plate. In the box - 5, 6, as well as 10 or 25 records.

[3], [4]

Pharmacodynamics

At the molecular level, everolimus forms a bundle with cytoplasmic protein (FKBP-12). With the help of everolimus, a slowing down of the process of phosphorylation of the object of kinase-p70 S6 is developed, which is stimulated by the growth factor. Because this process is under the control of the FRAP element (called m-TOR), this information makes it possible to assume that a bunch of everolimus-FKVR-12 is synthesized with the FRAP element.

The FRAP component is the main regulatory protein that controls the growth, proliferation and metabolism of cells; FRAP's work disorder can be explained by stopping the activity of the cell cycle, which is caused by the activity of everolimus. From this it follows that everolimus has a different principle of influence than cyclosporin. During the testing of preclinical models of allotransplantation, a more pronounced effectiveness of the combination of everolimus with cyclosporine was found in comparison with the separate use of each of these elements.

The activity of everolimus is not limited to exposure only to T-cells. The substance slows down cell proliferation stimulated by growth factors - both hemopoietic and non-hemopoietic (for example, smooth muscle cells). The proliferation of smooth muscle cells located inside the vessels, stimulated by the growth factor, and triggered by damage to the endothelium cells and leads to the formation of neointima, is a key element in the pathogenesis of developing rejection, which has a chronic form.

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

[5]

Pharmacokinetics

Absorption.

In oral use, the Cmax level is noted after 1-2 hours. In humans, after transplantation, the blood values of everolimus are proportional to the dose in the dosage range of 0.25-15 mg. Taking into account the level of AUC, the relative bioavailability of tablets of dispersible nature in comparison with the usual is 90%.

The Cmax and AUC values of the substance decreased, respectively, by 60%, as well as by 16% if used with very fatty foods. To reduce the variability of these indicators to a minimum, Certikan is recommended to be used either with or without food.

Distribution processes.

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

In volunteers and people with a moderate degree of hepatic impairment, synthesis with intraplasma protein is approximately 74%. At the final stage, the VSS in people after kidney transplantation, staying on supporting procedures, is 342 ± 107 l.

Exchange processes.

Everolimus is a substrate of the component CYP3A4 along with P-glycoprotein. Key exchange pathways are monohydroxylation and O-dealkylation. The main metabolic elements (2 of them) are formed during the hydrolysis of the cyclically shaped lactone. They do not have a noticeable immunosuppressive effect. For the most part, everolimus resides within the circulatory system.

Excretion.

When using a single dose of radiolabeled everolimus in humans after transplantation, using cyclosporine, most of its radioactivity (80%) was recorded inside the feces, and only 5% was excreted in the urine. The unchanged element is not found either inside the urine or inside the feces.

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

Dosing and administration

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

First, people with a transplanted kidney or heart should use 0.75 mg of the drug 2 times a day. You need to start the application as soon as possible after transplantation. Daily dosage of drugs is always divided into 2 uses. You need to take medicine at the same time with cyclosporine microemulsion.

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

People representing the Negroid race.

The frequency of situations with the appearance of acute rejection, which was confirmed on a biopsy, is higher in this group of patients (compared with others). According to the limited information currently available, Negroids may need an increased portion of Sertikan to obtain an effect similar to that seen in other people who take drugs in standard adult dosages. Currently available information regarding the safety and efficacy of the drug does not allow to select special recommendations for the use of everolimus in the Negroids.

Use for problems with hepatic activity.

In individuals with insufficiency, the basal values of everolimus inside whole blood should be closely monitored.

In the moderate or mild deficiency phase, the dose of medication should be reduced approximately by half in relation to the average dosage in situations where a combination of 2 of the following indicators is used: bilirubin is> 34 μmol / L (or> 2 mg / dL); albumin is <35 g / l (or <3.5 g / dl); the MHO value is> 1.3 (lengthening of the PV> 4 seconds). Subsequent titration of the portion is carried out, taking into account the information of drug monitoring.

People with severe impairment have not conducted studies on the effects of everolimus.

Medical monitoring.

It is required to constantly monitor the performance of everolimus inside whole blood. The analysis of exposure-efficacy values as well as exposure-safety made it possible to determine that in people with C0 values> 3 ng / ml the probability of heart or kidney rejection diagnosed during biopsy is acutely lower than in individuals with C0 values <3 x ng / ml It is recommended that the everolimus medication should be a maximum of 8 ng / ml. Indicators of more than 12 ng / ml have not been studied. The level of everolimus was detected by chromatography.

It is extremely important to monitor the blood values of everolimus in people with liver insufficiency when combined with powerful inducers or inhibitors of the CYP3A4 element, when switching to a different therapeutic form or when the amount of cyclosporin is significantly reduced.

The blood indicators of everolimus during the administration of dispersible tablets are slightly lower than in the case of the introduction of conventional tablets. It is recommended to adjust the dosage regimen of the drug, taking into account the C0 values of everolimus, recorded after more than 4-5 days from the moment of the previous adjustment. Because cyclosporine interacts with everolimus, the level of the latter can decrease in the event of a significant decrease in cyclosporine (C0 <50 ng / ml).

Cyclosporine dosing regimen for combination with Certican in humans after kidney transplantation.

The drug is prohibited for a long time to use in full portions with cyclosporine. Reducing the dosage of cyclosporine in individuals after renal transplantation, using Certain, caused an improvement in renal activity. It is necessary to lower a portion of cyclosporine immediately after the transplant. In this case, the recommended residual values of cyclosporine inside the blood plasma after 12 hours from the moment of using the drug (C0 observation) are:

• for the period up to the 1st 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 reduction in the portion of cyclosporin, it is required to confirm that the sertican equilibrium blood values (C0) are ≥3 ng / ml.

Diagrams of suitable dosage portions of cyclosporine when administered with Certikan in humans after cardiac transplantation.

Persons to whom the heart was transplanted, during the supporting stage, need to reduce the amount of cyclosporine after 1 month since the transplantation - in order to improve the functioning of the kidneys. If progression of renal dysfunction is noted, or with calculated creatinine Cl values <60 ml per minute, the treatment regimen needs to be changed.

The data obtained in clinical tests allow us to establish that, in the case of the use of everolimus in this group of patients, the target plasma values of cyclosporine, according to the indications of C0-observations, should be:

• 200-300 ng / ml for the first 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 portion of cyclosporine, it is required to find out exactly that the equilibrium blood index of everolimus (C0) is 3 ng / ml or higher.

In cases of cardiac transplantation, there is limited information regarding the dosing of drugs with C0 cyclosporine values of 50-100 ng / mg, after 1 year after transplantation.

Schemes for using the tablet form of drugs.

Tablets are consumed whole, without grinding; while the medicine is washed down with plain water (1 cup).

Use through an oral syringe with a capacity of 10 ml.

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

After the introduction of the pill, add water to the syringe to the indicator of 5 ml, after which they wait 1.5 minutes, shaking the syringe a little. When a dispersion is formed, the substance is injected directly from the syringe into the mouth. After that, the syringe is rinsed, typed in it with 5 ml of plain water, and injected into the mouth. Then you need to drink another 10-100 ml of plain water.

Use through a plastic cup.

For use dispersible tablet form can also be used plastic cup. With this method, the tablets are placed in a cup, which was pre-poured 25 ml of ordinary water. With this volume of liquid, the indicator of the medicinal substance from which the dispersion is made may not exceed 1.5 mg. A cup of water and tablets are left for about 120 seconds to form a dispersion; Before taking, you need to shake up the liquid in the cup to dissolve the substance. After that, rinse the cup, pour another 25 ml of plain water into it, and then drink it.

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 ordinary water is poured. Next, wait 1.5 minutes, slightly shaking the glass. After that, the dispersion is collected inside the syringe and at a low speed (for 40 seconds) is injected through a nasogastric tube. The syringe with a glass is rinsed 3 times, taking 5 ml of plain water each time, and then injected through the probe. Next, the probe is washed using 10 ml of liquid. After using the drug, the nasogastric tube should be clamped for at least half an hour.

With the introduction and microemulsion of cyclosporine through a nasogastric probe, this procedure should be performed before applying Sertikan. These medicines are prohibited from mixing.

[12]

Use Sertika during pregnancy

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

During the experimental tests, the presence of toxic effects on reproduction (feto-and embryotoxicity) was noted. There is no information whether there is a risk to the human body. It is forbidden to use the medicine during the specified period, excluding situations when the likely benefit of treatment is more expected than the risk of negative consequences for the fetus.

Patients in reproductive age need to use reliable contraception at the active stage of therapy with Certican and for 2 months from the moment of its completion.

There is no evidence whether everolimus can be excreted in human milk.

In experimental tests, it was found that everolimus or its metabolic elements quickly pass into the milk of rats. Because of this, breastfeeding is prohibited during treatment.

Contraindications

It is contraindicated to use in case of strong intolerance against sirolimus with everolimus or other elements of drugs.

Caution is required when used in such situations:

• failure of the liver in the severe stage (because the effectiveness and safety of everolimus in people with disorders of the liver work have not been studied, it is necessary to closely monitor its plasma indicators);
• rare hereditary disorders - galactosemia, severe lactose intolerance, or glucose-galactose malabsorption;
• combination of medication with other drugs that have a negative impact on the work of the kidneys.

All patients need to constantly monitor the work of the kidneys. If an increase in serum creatinine levels is observed, it is necessary to resolve the issue regarding changes in the scheme of immunosuppressive treatment - for example, to reduce the amount of cyclosporine.

[11]

Side effects Sertika

Among the side effects are:

• lesions of an infectious nature: often infections that are bacterial, viral or fungal genesis. Sometimes wound lesions develop;
• disorders associated with lymph and hematopoietic function: leukopenia is the most common ¹. Quite often there is coagulopathy, and in addition to this anemia ¹ with thrombocytopenia ¹, TTP or HUS. Sometimes hemolysis occurs;
• endocrine disorders: hypogonadism is sometimes observed in men (an increase in LH values and a decrease in testosterone levels);
• problems with the exchange function: mainly hyperlipidemia or cholesterolemia develops. Hypertriglyceridemia is also quite common;
• violations of vascular activity: venous thrombosis is often noted, an increase in blood pressure or lymphocele ³;
• lesions of the respiratory organs: pneumonia is often observed. In addition, interstitial pulmonary pathology or alveolar lung proteinosis can sometimes occur;
• symptoms of digestive function: often vomiting, diarrhea, pain in the abdominal area, pancreatitis and nausea;
• signs associated with hepatobiliary activity: sometimes there is hepatitis, jaundice, liver function disorders and an increase in AST values with ALT and GGT;
• abnormalities in the subcutaneous tissue and epidermis: Acne, angioedema ^4, and complications in the surgical scar area are often noted. Sometimes rashes appear;
• disorders of the musculoskeletal structure: myalgia is sometimes observed;
• lesions affecting the urinary tract: infections that often affect the urinary ducts often appear. Sometimes there is pyelonephritis or renal tubular necrosis;
• others: pain or swelling often occur.

^{1 the}  presence of a dose-dependent effect; or this effect was most frequently observed in people who used the drug in a 3 mg dose per day.

²  in persons with a heart transplant.

³  in people with kidney transplantation.

⁴  mainly in persons who combine Certikan with an ACE inhibitor.

Overdose

During experimental tests, a weak potential of everolimus was revealed relative to the acute form of toxicity. When administered orally with a single administration of the drug in 2,000 mg / kg portions, there was no death or severe poisoning in rats with mice.

Information regarding cases of intoxication in humans is extremely limited. There is a single message with unintentional ingestion of 1.5 mg of a drug by a 2-year-old child, but no negative symptoms have occurred. After 1 single oral administration in portions up to 25 mg in humans after transplantation, normal tolerability of the drug was observed.

Any overdose requires the implementation of supporting procedures of a general nature.

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

Interactions with other drugs

The metabolism of everolimus mainly has an intrahepatic pathway; also part of the process takes place inside the intestinal wall using CYP3A4 isoenzyme. At the same time, the substance acts as a substrate of the protein that carries the P-glycoprotein. Therefore, medications that interact with the CYP3A4 element or P-glycoprotein can affect the absorption and further elimination of this component. Combining Sertikan with powerful inducers or inhibitors of the component CYP3A4 is prohibited. P-glycoprotein inhibiting agents can weaken the process of releasing the drug component from intestinal cells, as well as increase its serum indices.

When using the in vitro element, everolimus was a competitive substance that slows down the activity of CYP3A4 with CYP2D6, which potentially increases the plasma values of drugs, whose excretion occurs with the help of these enzymes. Because of this, it is necessary to very carefully combine drugs with the substrates of the components CYP3A4 and CYP2D6, which have a narrow drug index. All in vivo type interaction tests were performed without combination with cyclosporin.

Cyclosporin, slowing down CYP3A4 or P-glycoprotein.

The level of bioavailability of everolimus increases significantly when used together with cyclosporine. When testing a 1-time portion of the cyclosporine microemulsion, in volunteers, it increased the AUC values of everolimus by 168% (from 46% to 365%), and at the same time the Cmax values - by 82% (from 25% to 158%) compared to the administration exclusively Sertikana. In the case of correction of the cyclosporine batch mode, a change in everolimus dosing values may also be necessary.

The therapeutic value of the effect of the drug on the pharmacokinetic characteristics of cyclosporine in people with transplanted kidneys or heart, using the microemulsion of the latter, is minimal.

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

Volunteers who previously used rifampicin in multiple batches, with further use of Sertikan in 1-fold dosage, showed an almost threefold increase in the values of Cl of everolimus, as well as a decrease in AUC by 63% and C max - by 58%. Therefore, to combine the drug with rifampicin is prohibited.

People using substances that slow down the activity of HMG-CoA reductase need to be monitored for the appearance of rhabdomyolysis and other negative signs in accordance with the recommendations for the above-described drugs.

Other possible therapeutic interactions.

Substances that moderately inhibit the effects of CYP3A4 with P-glycoprotein can increase the blood indices of everolimus (for example, antimycotics - fluconazole; macrolide antibiotics - erythromycin; and besides, BPC - nicardipine with verapamil and diltiazem, which slow down protease antif - antifaccin - antifaccin - antifaccin - antifungal - with diltiazem and diltiazem. ).

Elements that induce CYP3A4 activity are capable of enhancing the exchange processes of everolimus and lowering its blood level (such as St. John's wort, anticonvulsants (phenobarbital with carbamazepine and phenytoin) and drugs used in HIV (nevirapine with efavirenz)).

Grapefruit juice and it itself affects the activity of hemoprotein P450, as well as P-glycoprotein, which is why it is required to refuse their intake 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 introduction of live vaccines.

[17], [18]

Storage conditions

The certificate must be kept in a dark, dry place, protected from small children. Temperature values - not more than 25 ° C.

[19]

Shelf life

The certificate is allowed to apply throughout the 36-month term since the sale of the drug.

[20]

Use in children

There is too little information regarding the use of drugs in pediatrics, so it is usually not recommended for this group of patients. Although there is limited information about the introduction of medication to children during kidney transplantation.

Analogs

Analogues of the drug are the means of Arava, Mifortik, Xelianz and Baksmun with Moofilet and Zenapax, as well as Panimmun, Imusporin, Remikeid and Imufet with Neo-Leum and Lifemun. Also on the list are Lefno, Zicloral, Mifenax, Cellcept with Ekvorel and Raptiva with Tizabri.

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