Certican 0.5mg Novartis prophylaxis of transplantation in patients with kidney or heart (6 blisters x 10 tablets)

Dosage form Box of 6 blisters x 10 tablets
Specifications Everolimus
Ingredient Novartis

Ingredient

Composition information	Content
Everolimus	0.5mg

Uses

indications

0.5mg Certican drug is indicated to prevent transplantation in adult patients at risk of immunity from low to medium transplantation that is being transplanted with kidney or heart other species of genes. Everolimus should be used in combination with ciclosporin in the form of emulsion and with corticosteroids.

Pharmacology

Everolimus, a major inhibitor for proliferation, prevention of broken puff in the same species in research models in rodent and elderly animals that are not people in the same species. It has a immunosuppressive effect by inhibiting T-active antigen cell proliferation, thus expanding Clon, which is controlled by specific interleukin for T cells, such as Interleukin-2 and Interleukin-15. Everolimus inhibits the sugar mainly inside cells that often lead to cell proliferation when caused by the cohesion of T -cell growth factors into receptors. This main breaking by Everolimus causes cells to stop in the G1 stage of the cell cycle.

At molecular level, Everolimus forms a complex with the FKBP-12 protein of the cytoplasm. When the presence of Everolimus, the phosphorylation of P70 S6 Kinase stimulates the inhibitory growth factor. Because the phosphorylation of P70 S6 Kinase is subject to FRAP's control (also known as M-Tor), this sign shows that the Everolimus-KFBP-12 complex is attached and thus hinder the function of the FRAP. FRAP is a main regulating protein that controls the metabolism, growth and proliferation of cells; Therefore, FRAP's functional loss explains the cell cycle suspension caused by Everolimus.

so Everolimus has a different way compared to ciclosporin. In the assembly models of the same preclinical species, the combination of Everolimus and Ciclosporin is more effective than using each substance.

The effect of Everolimus is not limited in T. In general, Everolimus inhibits the proliferation of blood and cellular cell cells without hemolysis organs such as smooth muscle cells to stimulate growth factors. The proliferation of blood vessel muscle cells stimulates the growth factor caused by endothelial cell damage and leads to the formation of endothelial vein that plays a major role in the pathology of chronic graft waste. Pre -clinical studies with Everolimus have shown the inhibition of endothelial formation in a transplant model of the same aorta in the rat.

Pharmacokinetics

absorption

Everolimus's peak concentration reaches 1-2 hours after taking a dose of oral. Everolimus concentration in blood in patients with graft proportional to the dose in the dose range from 0.25 - 15 mg. The relative bioavailability of the dispersed tablet compared to the usual tablet is 0.90 (0.76-1.07, 90%reliable range) is based on the ratio of the area below the concentration curve (AUC).

Effect of food: The highest concentration in plasma (CMAX) decreased by 60% and the area under the curve (AUC) of Everolimus decreased by 16% when the tablet formula was used with high -fat meals. To minimize variables, should always use Everolimus with food or always not used with food.

Distribution

Everolimus's plasma/plasma concentration ratio, which depends on the concentration range from 5 - 5000 ng/ml, is 17% to 73%. The cohesion with plasma proteins is about 74% in healthy subjects and medium liver failure patients. The distribution is related to the terminal (VZ/F) on kidney transplant patients at the maintenance stage of 342 ± 107 liters.

Biological/metabolic transformation

Everolimus is a substrate of CYP3A4 and P-Glycoprotein. After drinking, Everolimus is an administrative component in the blood in humans. 6 main metabolites of Everolimus have been detected in human blood, including 3 metabolites Monohydroxylation, 2 opening hydrolysis products and an Everolimus phosphatidylcholine complex. These metabolites are also determined in animals used in toxicity research and shows about 100 times inferior to Everolimus. Therefore, the original substance is considered to be a great contribution to the pharmacological activity of Everolimus.

Elimination

After taking a single dose of radioactive Everolimus on organ transplant patients using ciclosporin, most radioactive activity (80%) is detected in feces and only a small amount (5%) is excreted in urine. No initial drug detection in urine or feces.

Pharmacokinetics in a stable state

Equivalent pharmacokinetics in kidney transplant patients and heart transplant use Everolimus twice a day with micro -form ciclosporin. Stable state is achieved on the 4th day, with the accumulation of blood concentrations in the blood 2-3 times when compared to the exposure to the drug after the first dose. The time to achieve the highest concentration in plasma (TMAX) occurs 1-2 hours after the drug. At the dose of 0.75 mg, 2 times/day, the average cmax is 11.1 ± 4.6ng/ml, at the dose of 1.5 mg, 2 times/day, the average cmax is 20.3 ± 8 ng/ml, and the average AUC is 75 ± 31 ng • hours/ml at the dose of 0.75 mg 2 times/day and the average AUC is 131 ± 59 ng • hours/ml at the dose of 1.5 mg, 2 times. At the dose of 0.75 mg, 2 times/day, the blood bottom concentration before taking the drug (cmin) is average of 4.1 ± 2.1 ng/ml and at the dose of 1.5 mg twice a day, the average cmin is 7.1 ± 4.6 ng/ml. The exposure to Everolimus remains stable over time in the first year after grafting. Cmin is meaningful to AUC, creating a correlation coefficient from 0.86 to 0.94. Based on the pharmacokinetic analysis of the research group, the oral clearance (Cl/F) is 8.8 liters/hour (the variation between patients is 27%) and the central distribution volume (VC/F) is 110 liters (the variable between patients is 36%). The remaining variation of blood concentrations is 31%. The sale time is 28 ± 7 hours.

Hepatic failure: Compared to Everolimus AUC in those with normal liver function, the average AUC of 6 mild liver failure patients (type A child-pgh is 1.6 times higher; The average AUC in 2 independent research groups including 8 and 9 patients with average liver failure (type B child-pgh) is 2.1 and 3.3 times higher; And the average AUC in 6 patients with severe hepatic failure (type C) is 3.6 times higher. The average half -life is 52 hours in patients with mild liver failure, 59 hours in patients with average liver failure and 78 hours in patients with severe liver failure. Prolonged half -life slows down the time to reach the concentration of Everolimus in the blood in a stable state.

Renal failure: Renal failure after transplantation (creatinine clearance (Clcrea from 11 - 107ml/min) does not affect the pharmacokinetics of Everolimus.

Children: The oral clearance (Cl/F) of Everolimus increases linearly with the age of the patient (1-16 years old), the body surface area (0.49-1.92m2) and weight (11-77kg). Cl/F is in a stable state of 10.2 ± 3 liters/hour/m2 and the sale time is 30 ± 11 hours. 19 patients (1 - 16 years old) have been treated with Everolimus dispersed tablets at a dose of 0.8 mg/m2 (maximum 1.5 mg) 2 times/day along with micro -form ciclosporin. These patients achieved the AUC of Everolimus are 87 ± 27 ng • hours/ml similar to adults using 0.75 mg, 2 times/day. The bottom concentration (C0) in a stable state is 4.4 ± 1.7 ng/ml.

Elderly: The reduction in the oral clearance of Everolimus is 0.33% per year is estimated in adults (the age of research is 16-70 years old). No need to consider adjusting the dose.

Race: Based on pharmacokinetics analysis in groups of researchers, oral clearance (Cl/F) on average, 20% higher in organ transplanted black skin.

Before taking Certican 0.5mg Novartis prophylaxis of transplantation in patients with kidney or heart (6 blisters x 10 tablets)

How to use

Certican 0.5mg medication is only for drinking.

Dosage

Everolimus treatment should only start and maintain because physicians with experience in immunosuppressive treatment after organ transplantation and are the one who decides the monitoring of Everolimus concentration in the whole blood.

Adults

The recommended starting dose is 0.75 mg, 2 times/day for kidney transplant group and heart transplant in general, so use as soon as possible after grafting. Everolimus dose daily should always be divided into 2 drinks (2 times/day).

Patients taking Everolimus may need to adjust the dose based on blood concentrations in the blood, tolerance, response of each patient, change in combination drugs and clinical status. The adjustment of the dose can be done 4-5 days apart.

Black skin patients

The rate of rapid transplantation has been significantly higher than a black biopsy in black skin compared to non -black patients. The limited information shows that black skin patients may need a higher dose of Everolimus to achieve the same effect as the effect achieved in non -black patients when taking recommended doses for adults. Currently, data on efficiency and safety is still very limited, not allowed to have special recommendations on the use of Everolimus for black skin patients.

Use in children and teenagers

Not enough data on using Everolimus for children and teenagers to support the use of drugs for patients in these age groups. However, there is some information in kidney transplant.

Elderly patients (≥ 65 years old)

Not much clinical experience in patients ≥ 65 years old. However, there is no clear difference in pharmacokinetics of Everolimus in patients ≥ 65-70 years old when compared to younger adults.

Patients with renal failure

No dose adjustment.

Patients with liver failure

The bottom concentration (C0) of Everolimus in the whole blood should be closely monitored in patients with liver function impairment. For patients with mild or medium liver failure (Child-Pugh group A or B), the dose should be reduced to about ½ of the usual dose if there are 2 of the following conditions: bilirubin> 34 micromol/l (> 2 mg/dl), albumin 1.3 Inr (extension> 4 seconds). Additional benchmarks should be based on the monitoring of treatment (see pharmacokinetic part). Everolimus has not been evaluated in patients with severe liver failure (Child-Pough index of group C, see the attention and caution at use).

Treatment of treatment

Recommendations regularly monitor the concentration of drug treatment in the whole blood. Based on the analysis of the concentration of residual-residual and safe-level-level drug concentration, the patient has achieved the bottom concentration (C0) of Everolimus in the whole blood ≥ 3.0 ng/mL with a lower rate of rapid rehabilitation that has been determined by biopsy in both kidney transplant and cardiac transplant compared to patients with base concentration (C0) below 3.0 ng/mL. The upper limit of the recommended treatment level is 8 ng/mL. There is no research on the level of over 12 ng/mL. These recommendations for Everollimus are based on chromatography method.

It is especially important to monitor Everolimus concentration in the blood in patients with liver failure while using simultaneously with induction substances and strong inhibitors CYP3A4, when switching to other drugs and/or if the doses of ciclosporin are significantly reduced (see the drug interaction part). Everolimus concentration may decrease slightly after using dispersed tablets.

Ideally adjust the Everolimus dose based on bottom concentration (C0) reaches> 4-5 days after changing the dose before. Because ciclosporin interacts with Everolimus, Everolimus concentration may decrease if the residual ciclosporin level decreases significantly (ie the bottom concentration (C0)

Ciclosporin dose recommends in kidney transplant

Do not use Everolimus for a long time with full doses of ciclosporin. Ciclosporin levels decreased in kidney transplant patients treated with Everolimus, improving kidney function. Reducing the level of residual ciclosporin to start after 1 month. Based on the experience achieved from A2306 research (see the pharmacological part), the following dosage ciclosporin is determined by the research outline (the concentration of Ciclosporin in the blood is measured 2 hours after use (C2)) is recommended: week 0 - 4: 1000 - 1400 ng/mL, week 5 - 8: 700 - 900 ng/mL, week 9-12: 550 - 650 ng/65 450 ng/ml. In this study, the bottom concentration (C0) of Ciclosporin in the blood (in/ml) measured is: January: 239 ± 114, March: 131 ± 85; June: 82 ± 60; December: 61 ± 28. It is important to ensure that both Everolimus and Ciclosporin concentrations do not decrease early below the treatment level after grafting to minimize the risk of loss.

Before reducing the dose of ciclosporin, the bottom concentration (C0) of Everolimus in the blood is total in a stable state equal to or over 3 ng/ml.

There is a little data related to the use of Everolimus with bottom concentrations (C0) of ciclosporin below 50 ng/ml, or Ciclosporin levels in the blood measurement for 2 hours after use (C2) below 350 ng/ml, during maintenance. If the patient cannot tolerate the decrease in ciclosporin levels, the continued use of Everolimus should be considered back.

Ciclosporin dose recommends in heart transplant

Patients with heart grafts during maintenance treatment should reduce the dose of ciclosporin when tolerated to improve kidney function. If the renal function fails or if the creatinine clearance coefficient is calculated by

In heart transplant patients, there is a little data related to the use of Everolimus with bottom concentrations (C0) of ciclosporin below 175 ng/ml for the first 3 months, less than 135 ng/ml at 6 months and less than 100 ng/mL after 6 months.

Before reducing the dose of ciclosporin, the bottom concentration (C0) of Everolimus in the blood is equal to or over 3 ng/ml.

In heart transplant patients, the data related to Certican dose with bottom concentrations (C0) of ciclosporin drops to 50 - 100 ng/ml after 12 months is limited. If the patient cannot tolerate the reduction of ciclosprin's residual concentration, the continued use of Certican needs to be reviewed.

Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.What do

do when overdose? Not observing death toxicity or serious toxicity in mice or rats is given single doses of 2000 mg/kg (limited test).

Not much experience overdose in humans. There is a separate case of 1,5 mg Everolimus in a 2 -year -old child, but have not seen any harmful reactions. Single doses of up to 25 mg have been used for patients with highly acceptable tolerances.

start with general supportive treatments in all cases of overdose.

In an emergency, call the 115 emergency center immediately or go to the nearest local health station.

What to do when you forget 1 dose? However, if the time to relax with the next dose is too short, skip the dose and continue the calendar of the drug. Do not use double dose to compensate for missed dose.

Side Effects

The frequency of side effects of the drug is listed below the 3 clinical trials and gross data from 1199 patients. These are 3 tests in many centers, random, double, verified, 2 new kidney transplantation and 1 new heart transplant test, of which Everolimus is used for 1.5 mg or 3.0 mg/day for at least 12 months in combination with ciclosporin micro -form and with corticosteroids, in addition to the frequency of the auxiliary reactions of the drug from 2 researches knowing the drug name. These studies have evaluated the effectiveness and safety of Everolimus 1.5 mg/day and 3 mg/day in combination with reduced ciclosporin levels in new kidney transplant.

Side reactions are listed according to the frequency determined as follows: very common:> 1/10, common:> 1/100 and 1/1,000 and 1/10,000 and

The following side effects may or may be related to Everolimus that have been recorded in phase III clinical trials (kidney transplantation and heart transplant). This table is composed by the agency according to the standard of Med Dra.

Infections and parasites:

common: viral infection, bacterial infection and fungal infection, bacterial infection

Very common: leukemia 1.

Uncommon: Genital disability in men (Testosterone decreases, increases).

Metabolic and nutrient disorders:

Very common: hyperkemoms of blood cholesterol, hyperlipidemia.

common: Hypertension, lymphatic cyst 2, Venous thrombosis.

common: pneumonia.

common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: hepatitis, liver disorders, jaundice, abnormal liver function test 3

Skin and subcutaneous tissue disorders:

Common: Neuroma 4, Acne, complications in the surgical wound.

Uncommon: Ban.

Less: muscle pain.

Kidney and urinary disorders:

common: Urinary tract infections

common: edema, pain.

2: In kidney transplant patients.

3: γ-GT, AST, ALT increases.

4: Mainly in patients with simultaneous use of angiotensin (ACE).

In clinical trials that the patient is monitored for at least 1 year, cell lymphoma or lymphocytic proliferation in 1.4% of patients taking Everolimus (1.5 mg or 3 mg/day) in combination with other immunosuppressive drugs. Malignant skin diseases in 1.3% of patients, and other malignant types in 1.2% of patients.

The appearance of side effects may depend on the degree and duration of immunosuppressive drug treatment. In key studies, serum creatinine has been observed more commonly in patients using Everolimus in combination with ciclosporin micro -type micro form The percentage of side effects is generally lower when reducing the dose of micro -form ciclosporin (see pharmacological part - clinical studies).

Everolimus safety charts in two tests know the name of the drug similar to the chart described in three important studies, except for increased serum creatinine and lower average serum creatinine values than other values in other phase III studies.

Warnings

Before using the drug you need to read the instructions carefully and refer to the information below.

contraindicated

Certican drug 0.5mg contraindicated in the following cases:

Contraindicated to use Everolimus in patients who know hypersensitivity to Everolimus, Sirolimus or with any component of excipients.

Caution when using

immunosuppressive control

In clinical trials, Everolimus has been used in combination with micro -form ciclosporin, Basiliximal and Corticosteroids. There is no complete research on the use of Everolimus with other immunosuppressive drugs compared to these substances.

Everolimus has not been fully studied in patients with high risk of immunity.

Combined with entry therapy with thymoglobulin

Be careful with the use of thymoglobulin (anti -thymocyte rabbit globulin) such as imported therapy and Certican/Ciclosporin/Steroid treatment mode. In a clinical study in a heart transplant, observing the incidence of serious infections increased in the first three months after grafting in the group of patients who used imported therapy with Thymocyte -resistant breathing globe combined with Certican, Steroid and Ciclosporin at the recommended blood level for heart transplantation (higher than renal transplant). This is related to a higher mortality rate in patients who must be hospitalized with the need for ventricular support equipment before transplantation, showing that these patients may be particularly sensitive to enhanced immunosuppressive inhibition.

Serious infections and opportunistic infections

On patients being treated with immunosuppressive drugs, including Certican, there is an increase in the risk of infection, especially infections due to opportunistic pathogens (bacteria, fungi, viruses, single -cell animals). There have been reports on hemorrhage and death infections in rings treated with Certican. In opportunistic infections that patients treated for immunosuppressive infection can include polyomavirus, including kidney disease related to BK virus, which can lead to renal eye and white brain white (PML) related to JC virus is likely to be fatal. These infections are often associated with the total amount of immunosuppressive drugs used, which should be diagnosed distinguished from patients with immunosuppressive patients with impaired kidney function or neurological symptoms.

In clinical trials with Certican, Pneumocystic Jiroveci (Carinii) antibiotic prophylaxis (Carinii) was used in the first 12 months after organ transplantation. Preventive treatment for Cytomegalovirus infection (CMV) is recommended in the first 3 months after organ transplantation, especially for patients with increased risk of cytomegalovirus infection.

Hepatic failure

Advantage to closely monitor the full concentration (CD) of Everolimus in the whole blood and adjust the dose of Everolimus in patients with liver failure.

Interaction with strong inhibitors, CYP3A4 induction substances

It is not recommended to use in combination with strong CYP3A4 inhibitors (for example ketoconazole, iTraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and CYP3A4 induction substances (eg Rifampicin, rifabutin) unless the benefits are risky. Problems monitoring the bottom concentration (CO) of Everolimus in the blood of the whole blood whenever the induction substances or CYP3A4 inhibitors are used in combination or stop use.

lymphoma and other malignant diseases

Patients who are taking immunosuppressive drugs include Certican, high risk of developing lymphoma or other malignant diseases, especially in the skin. The absolute risk seems to be more relevant to the time and immunosuppressive level than the use of specific drugs. Patients should be monitored regularly about the skin in the skin and should avoid the lowest exposure to the ultraviolet light of the sun and use appropriate sun protection.

hyperlipidemia

In organ transplant patients, simultaneous use of Certican and Ciclosporin micro emulsion form is associated with cholesterol and triglycerides serum, may need treatment. Patients who are using Certican should be monitored with hyperlipidemia and, if necessary, treated with drugs that reduce blood lipids and adjust the appropriate diet.

It is necessary to consider the risk of benefits in patients who have been determined to increase blood lipids before starting the immunosuppressive treatment regime including Certican. Similarly, it is necessary to assess the risk of the benefits of continuing Certican treatment in severe hyperlemia rings that do not respond to drugs.

Patients who are taking HMG-Coa Reductase and/or Fibrate inhibitors should be monitored for the possibility of muscle pattern and/or other side effects as described in the corresponding prescription information of these drugs.

Tharma

Certican is associated with veins. In most cases, patients are recorded in combination drugs as Angiotensin (ACE).

Kidney toxicity

Certican in combination with ciclosporin is enough doses that increase the risk of kidney dysfunction. Ciclosporin dose should be reduced when combined with Certican to avoid kidney dysfunction. Regular monitoring of kidney function is recommended in all patients. Adjust the appropriate immunosuppressive drug treatment mode, especially need to consider reducing ciclosporin dose in patients with increased serum creatinine levels. Caution should be careful when used with other drugs that have known harmful effects on kidney function.

proteinuria

The use of ceroican along with ciclosporin in new patients with kidney transplant is associated with increased proteinuria. This risk increases with higher Everolimus concentration in the blood.

In patients with a mild proteinuria during the treatment of immunosuppressive drug maintenance, including Calcineurin inhibitors (CNI), have been recorded worse proteinuria when replacing CNI with Certican. Observed the ability to recover when stopping using Certican and reuse CNI. The safety and effectiveness of conversion from CNI to Certican in these patients have not been determined.

Patients who are using Certican should be monitored proteinuria.

thrombosis in the kidneys

Increased risk of arterial thrombosis and kidney veins, leading to loss of graft, has been recorded, most occurring within the first 30 days after the graft.

complications for wound healing

Certican, like other MTor inhibitors, can affect the healing process, increase the appearance of post -organ transplant complications such as cracks, fluid and wound infections, may need extra care by surgery. Lymphatic cysts are the most commonly recorded side effects in kidney transplant patients and tend to be more common in patients with higher body mass index. The frequency of pericardium and pleural effusion increases in heart transplant patients.

Blood vascular disease/hemorrhage decreased thrombocytopenia/Hemolytic syndrome

Concomitance use of Certican with a calcineurin inhibitor (CNI) may increase the risk of hemolytic hypertrophy syndrome/hemorrhage hemorrhage decreased thrombocytopenia/thrombosis caused by CNI.

Interstitial lung disease/pneumonia is not due to infection

It is necessary to consider the diagnosis of interstitial lung disease (ILD) in patients with symptoms suitable for pneumonia due to infection but does not respond to antibiotic treatment and in patients where the causes of infections, neo -born tumors and the causes are not due to the drugs have been excluded through appropriate polls. CaTican lung disease cases have been recorded, often recovered when stopping the drug, having or untreated with glucocorticoid. However, deaths also occur.

newly started diabetes

Certican has been recorded increasing the risk of newly started diabetes after organ transplantation. Need to closely monitor blood glucose concentration in patients treated with Certican.

Infertility in men

There are reports in literature about non -sperm and few sperm status that can recover in patients treated with MTOR inhibitors. Clinical -clinical studies have shown that Everolimus can reduce sperm and infertility in men must be considered a potential risk of prolonged Certican treatment.

The risk of intolerance to excipients

Patients with dangerous genetic problems are galactose intolerance, serious or abnormal deficiency of glucose-Galactose absorption of glucose-galactose.

The effect of drugs on driving and operating machinery

has no studies have been conducted on the effects on driving and operating machinery.

Use drugs for women during pregnancy and lactation

Pregnant women:

Not enough data on using Certican for pregnant women. Animal studies have shown the effects of reproductive toxicity including embryo toxicity and toxicity for fetuses. The risk is unknown for humans. Certican should not be used for pregnant women unless expected benefits exceed the risk that may be available to the fetus. Pregnant women should recommend using effective contraceptive methods while using Certican and taking up to 8 weeks after stopping treatment with Certican.

breastfeeding women:

It is unclear whether Everolimus is excreted into breast milk, but in animal studies, Everolimus and/or its metabolites go through easily into the milk mouse milk. So women who are using Certican should not breastfeed.

Drug interaction

Everolimus is metabolized mainly in the liver and to a certain extent in the small intestinal wall thanks to CYP3A4. It is also a substance for p-glycoprotein (PGP) is a pump for the release of many drugs. Therefore, Everolimus' absorption and excretion is absorbed by the whole body, which can be affected by drugs that affect CYP3A4 and/or PGP. It is not recommended for simultaneous treatment with inhibitors and/or causing strong CYP3A4.

PGP inhibitors can reduce the release of Everolimus from the small intestine cells and increase the concentration of Everolimus in the blood. In vitro, Everolimus is a competitive inhibitor of CYP3A4 and CYP2D6, which increases the concentration of drugs eliminated by these enzymes. Therefore, it is necessary to be cautious when used in combination with Everolimus with substrates of CYP3A4 and CYP2D6 with narrow treatment index. All studies on Vivo interactive drugs have been conducted without combination with ciclosporin.

ciclosporin (CYP3A4/PGF inhibitor)

Everolimus' bioavailability increases significantly when used in combination with ciclosporin. In a single dosage study in healthy people, ciclosporin formed by emulsion (neoral) has increased the area under the concentration curve (AUC) of Everolimus is 168% (about 46% - 365%), and the highest concentration in plasma (CMAX) is 82% (about 25% - 158%) when compared to using Everolimus merely. Everolimus dose may be adjusted if the dose of ciclosporin is required. Certican only has a mild clinical effect on the pharmacokinetics of ciclosporin in patients with kidney transplant and heart transplant using ciclosporin micro emulsion.

rifampicin (CYP3A4 induction)

Healthy patients were treated earlier with many doses of rifampicin, then used a Certican willow increased the Everolimus clearance coefficient nearly 3 times, reducing the highest concentration in plasma (CMAX) was 58% and reducing the area under the concentration curve (AUC) was 63%. Do not recommend using rifampicin.

Atorvastatin (substrate of CYP3A4) and Pravastatin (Mechanical Mechanics of PGP)

Taking single dose of Certican with Atorvastatin or Pravastatin for healthy people does not affect the pharmacokinetics of Atorvastatin, Pravastatin and Everolimus, as well as the biological reaction of HMG-COA Reductase in plasma to a clinical relevant level. However, these results cannot be inferred to other HMG-CoA Reductase inhibitors.

Patients must be monitored about the development of muscle pilot disease and other side effects as described in the prescription information about HMG-CA Reductase inhibitors.

Midazolam (substrate of CYP3A4A)

In a two -stage cross -interaction study, a fixed sequence, 25 healthy people received a 4 mg of Midazolam single dose in phase 1. In phase 2, they take 10 mg Everolimus, 1 time/day for 5 days and 4 mg of Midazolam with the final dose of Everolimus. Midazolam's cmax increased by 1.25 times (90% CI, 1.14-1.37) and Aucin increased by 1.30 times (1.22-1.39). Midazolam's semi -cancellation time does not change. This study showed that Everolimus was a weak inhibitor of CYP3A4.

Other interactions may meet

Average inhibitors of CYP3A4 and PGP may increase the concentration of Everolimus in the blood (eg antifungal substances. Fluconazole, antibiotics of macrolide erythromycin; Calci channel blockers: Verapamil, Nicardipin, Diltiazem; Protease Nelfinavir, Indinavir, Amprenavir, Amprenavir). CYP3A4 induction substances can increase the metabolism of Everolimus and reduce the concentration of Everolimus in the blood (for example: St. John's Wort (Hypericum Perforatum), Carbamazepine anti -convulsions, phenobarbital, phenytoin, antiviral drugs that cause immunodeficiency in humans (HIV): 'Efavirenz, Nevirapine).

Grapefruit and grapefruit juice affects the activity of Cytochrome P450 and PGP, so avoid use.

vaccination

Immunodive inhibitors can affect response to vaccination and thus vaccination during treatment with Certican IT effectively. Avoid using live vaccines.

Storage

Do not store over 30 ° C. Keep the drug in the original packaging to avoid light and avoid moisture.

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