Advagraf: instructions for using the medicine, structure, Contraindications
Active material: Tacrolimus
When ATH: L04AD02
CCF: Immunosuppressive drugs
ICD-10 codes (testimony): Z94
Manufacturer: ASTELLAS PHARMA EUROPE B.V. (Netherlands)
Advagraf: dosage form, composition and packaging
Capsules of the prolonged action hard gelatin, size №5, Cover light yellow with red ink inscription applied “0.5 mg”, body orange and bears the logo of the company and “647”; contents of capsules – white powder.
| 1 caps. | |
| tacrolimus (monohydrate) | 500 g |
Excipients: gipromelloza, ethyl cellulose, lactose monohydrate, magnesium stearate.
Ingredients of the capsule shell: Titanium dioxide (E171), dye iron oxide yellow (E172), iron oxide red dye (E172), gelatin, sodium lauryl.
Ink composition (Opacode S-1-15083): pharmaceutical glaze 45% (shellac ethanol solution), soy lecithin, simethicone, iron oxide red dye (E172), giproloza.
10 PC. – blisters (5) – aluminum packets (1) – packs cardboard.
Capsules of the prolonged action hard gelatin, size №4, Cap white with drawing in red ink inscription “1 mg”, body orange and bears the logo of the company and “677”; contents of capsules – white powder.
| 1 caps. | |
| tacrolimus (monohydrate) | 1 mg |
Excipients: gipromelloza, ethyl cellulose, lactose monohydrate, magnesium stearate.
Ingredients of the capsule shell: Titanium dioxide (E171), dye iron oxide yellow (E172), iron oxide red dye (E172), gelatin, sodium lauryl.
Ink composition (Opacode S-1-15083): pharmaceutical glaze 45% (shellac ethanol solution), soy lecithin, simethicone, iron oxide red dye (E172), giproloza.
10 PC. – blisters (5) – aluminum packets (1) – packs cardboard.
Capsules of the prolonged action hard gelatin, size №0, Cover gray-red coated with red ink inscription “5 mg”, body orange and bears the logo of the company and “687”; contents of capsules – white powder.
| 1 caps. | |
| tacrolimus | 5 mg |
Excipients: gipromelloza, ethyl cellulose, lactose monohydrate, magnesium stearate.
Ingredients of the capsule shell: Titanium dioxide (E171), dye iron oxide yellow (E172), iron oxide red dye (E172), gelatin, sodium lauryl.
Ink composition (Opacode S-1-15083): pharmaceutical glaze 45% (shellac ethanol solution), soy lecithin, simethicone, iron oxide red dye (E172), giproloza.
10 PC. – blisters (5) – aluminum packets (1) – packs cardboard.
Advagraf: pharmachologic effect
Immunosuppressive drugs. At the molecular level, the effects and the intracellular accumulation of tacrolimus caused by binding to a cytosolic protein (FKBP 12).
FKBP complex 12 – tacrolimus specifically and competitively inhibits calcineurin, providing a calcium-blocking transmission routes of T-cell signals and preventing transcription of a discrete number of lymphokine genes.
Tacrolimus - vыsokoaktivnыy immunodepressant. In in vitro and in vivo experiments, tacrolimus clearly reduced the formation of cytotoxic lymphocytes, which play a key role in graft rejection. Tacrolimus suppresses the formation of lymphokines (interleukin-2, Interleukin-3, c-интерферон), T-cell activation, expression of the IL-2 receptor, and dependent on T-helper cell proliferation.
Advagraf: pharmacokinetics
Absorption
Established, that humans tacrolimus is rapidly absorbed from the gastrointestinal tract. Capsules of the prolonged action - formulation, Provides long-lasting absorption of tacrolimus from the gastrointestinal tract. The average time to reach Cmax is about 2 no. Absorption tacrolimus variabelyna (variability of absorption in adults – 6-43%). The bioavailability of tacrolimus averages 20-25%. Bioavailability, and the rate and extent of absorption of tacrolimus, while taking food falling. Character biliary excretion does not affect the absorption of the drug.
Distribution
After reaching Css when receiving tacrolimus Advagrafa® there is a high correlation between the AUC and minimal (C0) tacrolimus concentrations in blood. Therefore, monitoring of the minimum (FROM0) concentrations of tacrolimus in the blood gives an indication of systemic drug exposure. The distribution of tacrolimus in the human body after i / v administration is biphasic. In the systemic circulation tacrolimus binds well with erythrocytes. The ratio of the concentration of tacrolimus in whole blood and plasma around 20:1. A large proportion of tacrolimus plasma (> 98.8%) It is bound to plasma proteins (serum albumin, a1-acid glycoprotein) a position.
Tacrolimus is widely distributed in the body. Fixed Vd given plasma concentration of about 1300 l (in healthy humans). The same indicator, calculated on whole blood, is the average 47.6 l.
Metabolism
Tacrolimus is extensively metabolised in the liver, mainly, by means of the CYP3A4 isoenzyme. Metabolism tacrolimus intensively flows into the intestinal wall. It identified some metabolites of tacrolimus. In in vitro experiments, it was shown, that only one of the metabolites possess immunosuppressive activity, activity close to tacrolimus. Other metabolites differed weak immunosuppressive activity, or lack thereof. In the systemic circulation only detected one of the metabolites of tacrolimus in low concentrations. Thus, pharmacological activity of the preparation is practically independent of metabolites.
Excretion
Tacrolimus - a substance with low klirensom. In healthy people, the average total body clearance, calculated at concentrations in whole blood, – 2.25 l /. In adult patients after liver transplantation, kidney and heart values clearance made 4.1 l /, 6.7 l / h 3.9 l / hr, respectively. Low hematocrit and hypoproteinemia contribute to an increase in the unbound fraction of tacrolimus, speeding up the clearance of tacrolimus. Corticosteroids, used in transplantation, They can also increase the metabolic rate and speed up the clearance of tacrolimus.
T1/2 tacrolimus long and choppy. In healthy people, the average T1/2 whole blood is approximately 43 no.
After the in / and oral administration 14C-labeled tacrolimus, the main share of radioactivity detected in the faeces. About 2% radioactivity was detected in the urine. In urine and faeces around 1% tacrolimus determined unchanged. Hence, tacrolimus before breeding is almost completely metabolized. The main route of excretion of bile was.
Advagraf: testimony
- Prevention and treatment of liver allograft rejection, kidney in adult patients;
- Treatment of allograft rejection, refractory to standard immunosuppressive regimes therapy in adults.
Advagraf: dosing regimen
Advagraf® - Oral form for receiving tacrolimus 1 time / day. Therapy with Advagraf® It requires careful monitoring by staff, suitably qualified and available the necessary equipment. This drug may appoint a doctor, experienced in immunosuppressive therapy in patients with transplanted organs.
Uncontrolled transfer of patients from one drug to another tacrolimus (including the transition from conventional capsules on Release Capsules) It is unsafe. This can lead to graft rejection or increased incidence of side effects, vklyuçaya hypo- or giperimmunosupressiyu, due to the occurrence of clinically significant differences in exposure of tacrolimus. The patient should take one of the dosage forms of tacrolimus in compliance with the recommended dosing regimen. Changes in the formulation or dosing regimen should be undertaken only under the supervision of a specialist in the field of transplantation. After the transfer is necessary to closely monitor the concentration of tacrolimus in the blood and adjust the dose of the drug to maintain the systemic exposure of tacrolimus at an adequate level.
Initial dose, shown below, It should be viewed only as recommendations. In the early postoperative period Advagraf® typically used in combination with other immunosuppressive. The dose may vary depending on the mode of immunosuppression. Selecting dose Advagraf® It should be based, primarily, in the clinical evaluation of the risk of rejection and individual tolerability, and the result of monitoring of tacrolimus in the blood.
When clinical signs of rejection should consider the need for immunosuppressive therapy correction mode. In stable patients, translated from the drug Prograf® (twice daily intake) of Advagraf® (once daily dosing), with a total daily dose 1:1 (mg:mg), systemic exposure of tacrolimus (AUC0-24) while taking the drug Advagraf® It was approximately 10 % less than the drug Prograf®. The relationship between the minimum levels of tacrolimus (FROM24) and systemic exposure of the drug Advagraf® It was the same, as in the use of the drug Prograf®. In the transition (conversion) with drug Prograf® of Advagraf® shall be measured as the minimum levels of tacrolimus to the conversion from one drug to another, and over the next two weeks. At this dose Advagraf® It should be adjusted to achieve the systemic exposure of tacrolimus similar drug Prograf®.
In patients after kidney transplantation and liver de novo AUC0-24 tacrolimus in the first day of the drug Advagraf® It was respectively 30% and 50% lower compared to equivalent doses of the drug Prograf®.
By the 4 th day systemic exposure of tacrolimus, estimated at C0, when using the drug Prograf® and drug Advagraf® in patients after liver transplantation and kidney were similar. In order to ensure adequate exposure of tacrolimus in the treatment of drug Advagraf® during the first two weeks after transplantation is recommended regular and careful monitoring of the minimum (FROM0) tacrolimus concentrations in blood. Unnecessarily. tacrolimus - a substance with low klirensom, to achieve the equilibrium concentrations after correction dose Advagraf® It may take several days.
Patient, which can not take the drug orally directly after transplantation, tacrolimus may be administered in / in (Prohraf® 5 mg / ml, Concentrate for infusion) dose, of about 1/5 the recommended oral dose for that indication.
Mode of application
The oral daily dose Advagraf® it is recommended to take in the morning 1 time / day. Receiving long-acting capsules made immediately after their removal from the blister. Patients should be warned about the presence of desiccant packaging (sachet of silica gel), which is not intended for receiving. Capsules recommended drink liquid (preferably, water). To achieve maximum absorption of Advagraf® It is encouraged to take on an empty stomach: for 1 hours before or after 2-3 h postprandial. The missed dose should be taken as soon as possible, preferably on the same day; It should not take a double dose the next morning.
Duration of dosing
For the prevention of graft rejection immunosuppression must be maintained constantly; Consequently, duration of therapy is not limited to.
Dosing recommendations
Kidney transplantation
Prophylaxis of transplant rejection
The oral therapy with Advagraf® should start with a daily dose 0.2-0.3 mg / kg body weight, 1 time / day (morning). The drug should be started within 24 hours after transplantation.
Roasted transplant
Prophylaxis of transplant rejection
The oral therapy with Advagraf® should start with a daily dose 0.1-0.2 mg / kg body weight, 1 time / day (morning). The drug should be started through 12-18 hours after transplantation.
Correction doses post-transplant period
With the passage of time after transplantation of kidney or liver dose Advagraf® typically reduce. In some cases the cancellation of concomitant immunosuppressants, ie. transition to Advagraf monotherapy®. Improving the condition of the patient may alter the pharmacokinetics of tacrolimus and require additional adjustments doses Advagraf®.
Treatment of transplant rejection
With a view to the relief of graft rejection following approach is recommended: increasing the dose of tacrolimus, strengthening of corticosteroid therapy, short courses of therapy of mono- / polyclonal antibodies. If you have any signs of toxicity of tacrolimus (eg, pronounced adverse reactions), You may need to reduce doses of Advagraf®. Information about the transition from cyclosporine to Advagraf® , see “Conversion (transition) with cyclosporine to Advagraf®“.
Kidney and liver transplantation
When switching from other immunosuppressive drugs to Advagraf® treatment should begin with the initial oral dose, described above in section “Prophylaxis of transplant rejection” the transplantation of kidneys and liver.
Heart transplant
When you go to therapy with Advagraf® in Adult, Initial oral daily dose is 0.15 mg / kg body weight, 1 time / day (morning).
Transplantation of other organs
The clinical experience with the drug Advagraf® for the treatment of patients after lung transplantation, pancreas, no bowel. Odnako tacrolimus (Prohraf®) used in patients with lung transplants in the initial oral dose of 0.1-0.15 mg / kg / day, after pancreas transplantation at the initial oral dose of 0.2 mg / kg / day, after intestinal transplantation in the initial oral dose of 0.3 mg / kg / day.
Conversion (transition) with cyclosporine to Advagraf®
When switching from ciclosporin to Advagraf® Caution should be exercised. Treatment with Advagraf® It recommended to begin after determining the concentration of cyclosporine in the blood and assess the clinical condition of the patient. The conversion should be delayed in the presence of elevated concentrations of cyclosporine in the blood. In practice, tacrolimus therapy begins 12-24 h after discontinuation of cyclosporine. After the transition is recommended to monitor the concentration of cyclosporine in the blood, as may slow clearance of cyclosporine.
Conversion (transition) with drug Prograf® of Advagraf®
If patients after allotransplantation, taking Prograf® 2 times / day, must be translated into the drug Advagraf® 1 time / day, the ratio of the daily doses in a period of transition should be 1:1 (mg:mg). Advagraf® it is recommended to take in the morning. After the transition to Advagraf® the minimum necessary to control (FROM0) the concentration of tacrolimus in the blood and to carry out the correction dose to maintain the systemic exposure of tacrolimus at the same level.
Correction doses in certain categories of patients
In Patients with severe hepatic dysfunction to maintain a minimum (C0) concentration of tacrolimus in the blood within the therapeutic range recommended may require dose reduction Advagraf®.
As renal function It did not affect the pharmacokinetics of tacrolimus, need to adjust the dose missing. However, due to the nephrotoxic potential of tacrolimus is recommended to carefully monitor renal function (including determination of serum creatinine, QC calculation and control the amount of urine).
In black patients to achieve similar minimum (C0) tacrolimus concentrations in blood can require higher doses, than patients Caucasians.
For information about, that men and women require different doses to achieve equal minimum (C0) tacrolimus concentrations in blood are not.
For information about, what elderly patients require special dose Advagraf®, no.
Recommendations for monitoring therapeutic concentrations of tacrolimus in the blood
Selecting the doses should be based on clinical assessment of individual risk of rejection and tolerability, and the result of monitoring the therapeutic level of tacrolimus in the blood.
To select the optimal dose used several methods to determine the concentration of tacrolimus in whole blood. Comparison of the results of monitoring, published in the literature of monitoring results in a separate clinic should be implemented taking into account the method used for determining the concentration of tacrolimus blood. In current clinical practice, the concentration of tacrolimus in the blood predominantly controlled via immunoassay techniques.
The correlation between the minimum (FROM0, FROM24) concentration and systemic exposure (AUC0-24) tacrolimus in the blood when using both drugs, Advagraf® and Prograf®, the same.
In the post-transplant period, careful monitoring of minimum (FROM0, FROM24) tacrolimus concentrations in blood. The minimum concentration of the drug Advagraf® levels should be determined approximately 24 h after dosing, before taking the next dose. In the first two weeks after transplantation is recommended more frequent monitoring of the minimum concentration, then during maintenance therapy is conducted periodic monitoring. Therapeutic concentrations of tacrolimus in the blood should be carefully monitored after switching from drug Prograf® of Advagraf®, the correction of doses of drugs, in amending the regime of immunosuppressive therapy or concomitant use of drugs, which may cause a change in the concentration of tacrolimus in the blood. The frequency of monitoring the concentration of drug in the blood is determined by clinical need. As Advagraf® - A drug with low clearance, to achieve equilibrium concentration of tacrolimus in the blood after correcting the dose Advagraf® It may take several days.
According to clinical studies, in most cases treated successfully at a therapeutic concentration of tacrolimus in the blood of no more than 20 ng / ml. When interpreting the data on therapeutic concentration of tacrolimus in the blood must take into account the clinical condition of the patient.
According to available data, in the initial post-transplant patients after liver transplantation a therapeutic drug concentration in the blood is in the range 5-20 ng / ml, and after a kidney transplant or a heart - 10-20 ng / ml. During maintenance immunosuppressive therapy in patients after liver transplantation, kidney or heart drug concentration in blood is usually in the range 5-15 ng / ml.
Advagraf: side effects
In connection with the features of the underlying disease and more drugs, applied at the same time after transplantation, the adverse event profile of immunosuppressants is difficult to ascertain.
Many of the adverse reactions, represented below, reversible and / or reduced at lower doses. Within each frequency band adverse reactions are presented in order of decreasing seriousness. Adverse reactions, classified by organs and systems, are listed below in descending order of frequency detection: very frequent (≥ 1/10), frequent (of ≥ 1/100 to < 1/10), infrequent (of ≥ 1/1000 to 1/100), few (of ≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), unknown (to establish the frequency of which insufficient data).
Cardio-vascular system: frequent – ischemic coronary disorders, tachycardia, arterial hypertension; frequent – bleeding, thromboembolic and ischemic complications, the peripheral blood circulation, hypotension; infrequent – ventricular arrhythmias and cardiac arrest, heart failure, kardiomiopatii, ventricular hypertrophy, supraventricular arrhythmias, cardiopalmus, abnormal ECG, abnormal heart rhythm, Heart rate and pulse, infarct, deep vein thrombosis limb, shock; few – pericardial effusion; very rare – abnormal echocardiograms indicators.
From the hematopoietic system: frequent – anemia, leukopenia, thrombocytopenia, leukocytosis; infrequent – pancytopenia, neutropenia; few – tromboticheskaya trombotsitopenicheskaya purpura.
From the blood coagulation system: infrequent – coagulopathies, deviations in terms of coagulation, few – gipoprotrombinemii.
CNS: very frequent – tremor, headache, insomnia; frequent – epileptic seizures, disturbances of consciousness, paresthesia and dysesthesia, perifericheskie neuropathy, dizziness, violation of the letter, anxiety, confusion and disorientation, depression, dejection, emotional disorders, nightmares, hallucinations, mental disorders; infrequent – coma, bleeding in the central nervous system and cerebrovascular accident, paralysis and paresis, encephalopathy, articulation and speech disorders, amnesia, psychotic disorders; few – increased muscle tone; very rare – myasthenia.
On the part of the organ of vision: frequent – blurred vision, photophobia, eye diseases; infrequent – Cataract; few – blindness.
On the part of the organ of hearing: frequent – noise (ringing) in the ears; infrequent – hearing loss; few – sensorineural deafness; very rare – hearing loss .
The respiratory system: frequent – breathlessness, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequent – respiratory insufficiency, disorders of the respiratory tract, asthma; few – acute respiratory distress syndrome.
From the digestive system: very frequent – diarrhea, nausea; frequent – inflammatory diseases of the gastrointestinal tract, gastrointestinal ulceration and perforation, gastrointestinal bleeding, stomatitis and ulceration of the mucous membrane of the mouth, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, bloating and abdominal distension, loose stools, symptoms of disorders of the gastrointestinal tract; infrequent – paralytic ileus (paralytic ileus), peritonitis, Acute and chronic pancreatitis, increase the level of amylase in the blood, gastroesophageal reflux disease, violation of the evacuation function of the stomach; few – subileus, pancreatic pseudocyst.
Liver: frequent – elevated liver enzymes, abnormal liver function, cholestasis and jaundice, liver cell damage and hepatitis, kholangit; few – hepatic artery thrombosis, veno-occlusive disease of the liver; very rare – hepatic failure, bile duct stenosis.
From the urinary system: very frequent – impairment of renal function; frequent – renal failure, acute renal failure, oligurija, lower nephron syndrome, toksicheskaya nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequent – anurija, hemolytic uremic syndrome; very rare – nephropathy, hemorrhagic cystitis.
Dermatological reactions: frequent – itch, rash, alopecia, acne, hyperhidrosis; infrequent – dermatitis, photosensitivity; few – toxic epidermal necrolysis (Lyell's syndrome); very rare – Stevens-Johnson syndrome.
On the part of the musculoskeletal system: frequent – arthralgia, muscle cramps, pain in the extremities, backache; infrequent – articular disorders.
On the part of the endocrine system: very frequent – giperglikemiâ, diabetes; few – girsutizm.
Metabolism: very frequent – hyperkalemia; frequent – gipomagniemiya, gipofosfatemiя, kaliopenia, hypocalcemia, giponatriemiya, gipervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte abnormalities; infrequent – dehydration, hypoproteinemia, giperfosfatemiя, gipoglikemiâ.
Infections and infestations: during therapy with tacrolimus, as well as other immunosuppressants, increased risk of local and generalized infections (Viral, bacterial, fungal, protozoal). It may get worse during the earlier diagnoses of infectious diseases. Cases nephropathy, associated with BK virus, as well as progressive multifocal leukoencephalopathy, associated with JC-virus, observed on immunosuppressive therapy, including therapy with Advagraf®.
Injuries, poisoning, complications of procedures: frequent – Primary graft dysfunction.
Benign, malignant neoplasms and unidentified: Patients, receiving immunosuppressive therapy, have a higher risk of malignant tumors. When using tacrolimus noted appearance as benign, and malignant tumors, incl. Epstein-Barr virus – associated lymphoproliferative disorders and skin cancer.
General disorders: frequent – asthenia, fevers, swelling, pain and discomfort, increase the level of alkaline phosphatase in the blood, weight gain, disorders of perception of body temperature; infrequent – multiple organ failure, flu-like symptoms, perceptual disturbances ambient temperature, squeezing sensation in the chest, anxiety, deterioration of health, improvement in blood lactate levels, weight loss; few – thirst, disequilibrium (drop), feeling of tightness in the chest, difficulty of movement; very rare – increase in adipose tissue mass
On the part of the reproductive system: infrequent – dysmenorrhoea and uterine bleeding. The negative effect of tacrolimus on male fertility, results in a reduction in the number and motility of spermatozoa, found in rats.
Allergic reactions: patients, taking tacrolimus, experience allergic and anaphylactic reactions.
Advagraf: Contraindications
- Hypersensitivity to tacrolimus, other macrolides or to any of the excipients.
Pregnancy and lactation
The results of preclinical studies and research, conducted in humans, show, drug that can cross the placenta. There are reports of premature birth (< 37 weeks), as well as cases of hyperkalemia been resolved spontaneously in neonates (8 from 111 /7.2%/ Newborn). Unnecessarily. safety of tacrolimus in pregnant women has not been established sufficiently, The drug is taken during pregnancy only when there is no safer alternative and only in those cases, When the resulting benefits of treatment justifies the potential risk to the fetus. In order to detect potential adverse reactions of tacrolimus it is recommended to monitor the status of newborn, whose mothers received tacrolimus during pregnancy (in particular, note on renal function).
According to clinical experience, Tacrolimus passes into breast milk. So how to eliminate adverse effects of tacrolimus on the newborn is not possible, women, receiving Advagraf®, should refrain from breast-feeding.
Advagraf: Special instructions
Experience patients, non-white race, as well as patients at high immunological risk (ie. when re-transplantation, high titer of panel reactive antibodies [PRA]) limited. Clinical data on the drug Advagraf® in acute rejection, refractory to other immunosuppressive therapy in adult patients, no.
There is currently no clinical data on the drug Advagraf® to prevent graft rejection in heart transplant and childhood.
In the initial post-transplant period should be regular monitoring of the following options:: FROM, ECG, neurologic status and the status of, fasting blood glucose, the concentration of electrolytes (especially potassium), Indicators of liver and renal function, hematology, coagulogram, level proteinemii. If there is no clinically significant changes, a correction of immunosuppressive therapy.
In applying the drug Advagraf® should be avoided herbal preparations, containing St. John's wort (Hypericum perforatum), and other herbal remedies, which may cause a decrease (change) the concentration of tacrolimus in the blood and have an adverse impact on the clinical effect of the drug Advagraf®.
When diarrhea concentration of tacrolimus in the blood can vary considerably; the appearance of diarrhea requires careful monitoring of tacrolimus blood concentrations.
Avoid concurrent use of cyclosporin and tacrolimus, and use caution when treating patients with tacrolimus, who have previously received ciclosporin.
Cases of ventricular hypertrophy or hypertrophy of the heart walls, It reported as cardiomyopathies, rarely, but were observed in patients, taking Prograf®, and so there may be the treatment of drug Advagraf®. In most cases, myocardial hypertrophy was reversible and was observed at concentrations (FROM0) tacrolimus in the blood, than recommended. Other factors, increasing the risk of an adverse event, relate: JavaScript preceding heart disease, corticosteroids, arterial hypertension, renal and hepatic dysfunction, infection, gipervolemia, swelling. Patients, have a high risk and received intensive immunosuppressive therapy, before and after transplantation (through 3 and 9-12 months) necessary to conduct echocardiographic and ECG monitoring. If anomalies are detected, should consider lowering the dose of the drug Advagraf® or replacement drug to another immunosuppressant.
Tacrolimus may cause QT prolongation, in this type of heart rhythm disturbances “pirouette” (torsades ventricular tachycardia) not observed. In the treatment of patients diagnosed with congenital long QT syndrome or suspected such a state should be particularly careful.
Patients, treated with tacrolimus, may develop post-transplant lymphoproliferative disease (PTLZ), associated with Epstein-Barr virus. In an application of the drug to antilymphocytic antibodies increases the risk PTLZ. Also, there is evidence of an increased risk in patients with PTLZ identified capsid antigen Epstein-Barr virus. Therefore, before prescribing the drug Advagraf® in this group of patients should be conducted serological testing for the presence of capsid antigen of Epstein-Barr virus. In the course of treatment is recommended to be monitored closely in the Epstein-Barr virus by polymerase chain reaction (PCR). Positive PCR for Epstein-Barr virus may persist for months and of itself is not evidence of lymphoma or PTLZ.
Patients, receiving immunosuppressive therapy, including Advagraf®, increased risk of opportunistic infections (caused by bacteria, Mushrooms, viruses, protozoa). Among these infections are occurring nephropathy, associated with BK virus, and also associated with the JC-virus progressive multifocal leukoencephalopathy (PML). These infections are often associated with a profound suppression of the immune system and can lead to severe or fatal, that must be taken into account in the differential diagnosis in patients, with signs of impaired renal function or neurological symptoms on a background of immunosuppressive therapy.
Immunosuppressive therapy increases the risk of malignant neoplasms. It is recommended to limit sun exposure and UV exposure, wear appropriate clothing, use sunscreen with a high protection factor.
The risk of secondary cancer is unknown.
There have been reports of the occurrence of reversible posterior encephalopathy syndrome during therapy with tacrolimus. If the patient, receiving tacrolimus, symptoms, characteristic of the syndrome, reversible posterior encephalopathy (headache, mental disorders, seizures, and visual disturbances), necessary to carry out magnetic resonance imaging. Upon confirmation of the diagnosis is necessary to exercise adequate control of blood pressure and convulsions, and immediately stop the systemic administration of tacrolimus. In the case of the adoption of these measures, this condition is reversible in most patients.
Unnecessarily. sustained-release capsules contain lactose, Be particularly careful when administering the drug to patients with rare hereditary diseases, associated with galactose intolerance, lapp lactase deficiency (lactase deficiency, some people of the North) or malabsorption syndrome glucose / galactose.
Effects on ability to drive vehicles and management mechanisms
Tacrolimus may cause visual and neurological disorders, especially when combined preparation Advagraf® with alcohol.
Advagraf: overdose
Data on overdose are limited. Reported several episodes of accidental overdose patients, taking tacrolimus. Symptoms included tremor, Headache, nausea, vomiting, infection, krapivnicu, lethargic, increased content of urea nitrogen in the blood, serum creatinine and ALT.
Treatment: antidotes currently exists to tacrolimus. In case of overdose should take the standard measures and symptomatic treatment.
Considering the high molecular weight of tacrolimus, poor water solubility and pronounced binding to erythrocytes and plasma proteins, dialysis nyeeffyektivyen. For some patients with very high concentrations of tacrolimus in the blood to be effective hemofiltration or diafiltration. In the case of oral overdose can be effective gastric lavage and / or the use of adsorbents (eg, Activated Carbon), if these measures are taken shortly after administration.
Drug Interactions
Following oral administration, tacrolimus is metabolized in the intestinal cytochrome CYP3A4. Simultaneous administration of drugs or herbs with established or inhibitory effect on CYP3A4 inducer can correspondingly raise or lower the concentration of tacrolimus in the blood. Therefore, to maintain an adequate and constant exposure of tacrolimus is recommended to monitor the concentration of tacrolimus in the blood and, if necessary, adjust the dose of the drug Advagraf®.
Based on clinical experience has been established, that the concentration of tacrolimus in the blood can increase significantly following preparations: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (Erythromycin), HIV protease inhibitors (ritonavir). In appointing these drugs with tacrolimus may need to reduce doses of Advagraf®. Pharmacokinetic studies have shown, that increasing the concentration of tacrolimus in the blood is, primarily, consequence of increasing the oral bioavailability of the drug, induced inhibition of intestinal metabolism of tacrolimus. Inhibition of hepatic metabolism of tacrolimus plays a secondary role.
Less severe drug interactions observed with concomitant use of tacrolimus with clotrimazole, clarithromycin, dzhozamytsynom, nifedipine, nicardipine, diltiazemom, verapamil, danazolom, ethinylestradiol, omeprazole and nefazodone.
In in vitro studies have shown, that potential inhibitors of tacrolimus metabolism are the following substances: bromocriptine, kortizon, dapsone, ergotamin, gestodene, lidokain, mephenytoin, mikonazol, midazolam, nilvadipine, noretinodron, quinidine, Tamoxifen, (triacetyl)oleandomiцin.
It is also recommended to avoid grapefruit juice due to the possibility of increasing the level of tacrolimus in the blood. Lansoprazole and cyclosporine can potentially inhibit CYP3A4-mediated metabolism of tacrolimus and increase its concentration in blood.
Based on clinical experience has been established, that the concentration of tacrolimus in the blood can significantly reduce these preparations: rifampicin, phenytoin, tutsan (Hypericum perforatum). In appointing these drugs with tacrolimus may require increased doses of Advagraf®.
Clinically significant interactions have been observed with phenobarbital.
Corticosteroids in maintenance doses usually reduce the concentration of tacrolimus in the blood. High dose prednisolone or methylprednisolone, is used to treat acute rejection, may increase or decrease the level of tacrolimus in the blood.
Carbamazepine, metamizole and isoniazid may reduce the concentration of tacrolimus in the blood.
Tacrolimus inhibits the CYP3A4 isoenzyme and while taking may affect the drugs, metabolized by the CYP3A4 isoenzyme. T1/2 Cyclosporine while the use of tacrolimus increased. Also, there may be synergistic / additive nephrotoxic effects. For these reasons, the simultaneous reception of cyclosporin and tacrolimus is not recommended, and the appointment of tacrolimus in patients, who have taken cyclosporine, Care must be taken.
Tacrolimus increases the concentration of phenytoin in the blood.
Unnecessarily. tacrolimus may reduce the clearance of hormonal contraceptives, it is important to be careful when choosing a contraceptive.
The data on the interaction of tacrolimus with statins is limited. Clinical observations suggest that, that while admission to tacrolimus pharmacokinetics of statins does not change.
Experimental studies in animals have shown, tacrolimus that has the potential to reduce clearance and increase T1/2 pentobarbital and antipyrine.
The systemic exposure of tacrolimus may increase prokinetic agents (metoclopramide, cisapride), cimetidine, magnesium hydroxide and aluminum.
Concomitant use of tacrolimus with drugs, possessing nephrotoxicity- or neurotoxicity (eg, aminoglikozidy, gyrase inhibitors, vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir), may contribute to these effects.
As a result of the joint use of tacrolimus with amphotericin B and ibuprofen were increased nephrotoxicity.
Since tacrolimus may contribute to or exacerbate hyperkalemia, Avoid the use of high doses of potassium or potassium-sparing diuretics (amilorid, triamterene, spironolactone).
Immunosuppressive drugs can alter the body's response to vaccination. Vaccination during treatment with tacrolimus may be less effective. Avoid the use of live attenuated vaccines.
Tacrolimus is actively associated with plasma proteins. It should consider the possible competitive interaction of tacrolimus with drugs, having a high affinity to plasma proteins (NSAIDs, oral anticoagulants, oral hypoglycemics).
Tacrolimus nesovmestim with polivinilhloridom (PVC). Tubes, syringes and other equipment, used in the preparation of a suspension of the drug capsules Advagraf®, must not contain PVC.
Advagraf: terms of dispensing from pharmacies
The drug is released under the prescription.
Advagraf: terms and conditions of storage
The drug should be stored out of reach of children, in its original packaging at a temperature not exceeding 25 ° C. Shelf life – 3 year, After opening the aluminum package – 1 year.
