Composition, form of production and packaging
Capsules 1 caps.
tacrolimus 500 Ојg
10 pieces. - blisters aluminum bilateral (3) - packs cardboard.
10 pieces. - blisters aluminum bilateral (5) - packs cardboard.
10 pieces. - blisters aluminum bilateral (6) - packs cardboard.
10 pieces. - blisters aluminum bilateral (10) - packs cardboard.
Capsules 1 caps.
tacrolimus 1 mg
10 pieces. - blisters aluminum bilateral (3) - packs cardboard.
10 pieces. - blisters aluminum bilateral (5) - packs cardboard.
10 pieces. - blisters aluminum bilateral (6) - packs cardboard.
10 pieces. - blisters aluminum bilateral (10) - packs cardboard.
Capsules 1 caps.
tacrolimus 5 mg
10 pieces. - blisters aluminum bilateral (3) - packs cardboard.
10 pieces. - blisters aluminum bilateral (5) - packs cardboard.
10 pieces. - blisters aluminum bilateral (6) - packs cardboard.
10 pieces. - blisters aluminum bilateral (10) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Immunosuppressant. Tacrolimus binds to the cytosolic protein (FKBP12), which is responsible for intracellular cumulation of the drug. Complex FKVR12-tacrolimus specifically and competitively interacting with calcineurin inhibits it, which leads to calcium-dependent inhibition of T-cell signal transduction pathways and prevention of transcription of a discrete group of lymphokine genes.
Suppresses the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection, reduces T-cell activation, T-helper dependent B-cell proliferation, and the formation of lymphokines (such as interleukins-2 and 3 and gamma-interferon), expression of interleukin-2 receptor.
PHARMACOKINETICS
Suction
It is absorbed from the digestive tract. TCmax - 1-3 hours. In some patients, the drug is continuously absorbed for a long period. The average bioavailability is 20-25%.In most cases, after taking the drug inside (0.3 mg / kg / day) after liver transplantation, C ss is achieved within 3 days.
The speed and degree of absorption of tacrolimus is higher when taking the drug on an empty stomach. With the simultaneous use of the drug with food, a decrease in the rate and degree of absorption is noted, which is more pronounced after eating a meal with a moderate fat content. The influence of foods rich in carbohydrates is less pronounced.
Eating a meal with a moderate amount of fat reduces the speed and degree of absorption.
In patients with a liver transplant in a stable state, the bioavailability of tacrolimus decreased with ingestion after eating (34% of calories). In addition, there was a decrease in AUC (27%) and Cmax (50%) and TC max (173%) in whole blood.
In patients with a kidney transplant in a stable state, the effect of food intake on the bioavailability of the drug was less pronounced. There was a decrease in AUC (2-12%) and Cmax (15-38%) and an increase in TC max (38-80%) in whole blood.
Isolation of bile does not affect the absorption of tacrolimus.
A strong correlation between AUC and minimal concentrations of the drug in whole blood was found upon reaching the equilibrium state, so that control of tacrolimus concentration in the blood can serve to objectively evaluate its systemic effect.
Distribution and deduction
In the human body, the distribution of tacrolimus after iv administration of the drug is biphasic. The drug is largely associated with erythrocytes, so the distribution coefficient in whole blood plasma concentrations is approximately 20: 1. In the blood plasma tacrolimus binds well to proteins (> 98.8%), mainly with serum albumin and alpha1-glycoprotein.
Tacrolimus is widely distributed in the body. The equilibrium V d based on the concentration in the blood plasma is approximately 1300 liters (healthy volunteers), and in whole blood - 47.6 liters.
Tacrolimus is a drug with a low level of clearance. In healthy volunteers, the average overall clearance calculated from the concentration of the drug in whole blood was 2.25 l / h. In adult patients with a liver, kidney and heart transplant, the values ​​of this parameter were 4.1 l / h, 6.7 l / h and 3.9 l / h, respectively. In children with liver transplant, the total clearance value is approximately twice as high as in adult patients with a liver transplant. The higher clearance observed after transplantation is probably due to factors such as low hematocrit and hypoproteinemia, which leads to an increase in the free fraction of tacrolimus, or an increase in metabolism against a background of high doses of glucocorticosteroids.
T 1/2 of tacrolimus is long-lasting and changeable. In healthy volunteers, the mean T 1/2 of whole blood is approximately 43 hours. In adult patients and children with liver transplant, T 1/2 is on average 11.7 hours and 12.4 hours, respectively, compared to 15.6 hours in adult patients with transplant kidney.
Metabolism
Tacrolimus is actively metabolized in the liver, mainly with the involvement of hepatic microsomal cytochrome P450-3A4 (isoenzyme CYP3A4). In addition, the metabolism of tacrolimus occurs in the wall of the intestine. Several metabolites of the drug have been identified, among which only one has significant immunosuppressive activity in vitro equivalent to tacrolimus. Other metabolites have very weak immunosuppressive activity. In the systemic blood stream, only one inactive metabolite is detected in low concentrations.
Consequently, metabolites do not play a role in the formation of pharmacological activity of tacrolimus.
Excretion
After intravenous administration and ingestion of tacrolimus labeled with 14 C isotope, the majority of the radiolabeled drug is excreted through the intestine.Approximately 2% is excreted by the kidneys. Less than 1% of unchanged tacrolimus was found in urine and feces, therefore, tacrolimus is almost completely metabolized before excretion
from the body. The main way of elimination is bile.
INDICATIONS
- prevention of rejection of liver, kidney or heart allograft;
- Treatment of allograft rejection in the development of resistance to other immunosuppressive drugs.
DOSING MODE
The choice of tacrolimus dose should be based on a clinical evaluation of the rejection and tolerability response, in each patient individually, and also with monitoring of the drug concentration in the blood (the permissible ranges of drug concentrations in the blood are given below). In case of development of clinical signs of rejection, consideration should be given to changing immunosuppressive therapy.
In most cases, treatment can begin with the appointment of tacrolimus inside; If necessary, it is allowed to dissolve the contents of the capsule in water and inject it through a nasogastric tube.
Usually the drug is prescribed in combination with other immunosuppressive drugs in the postoperative period. The dose of tacrolimus may vary depending on the treatment regimen chosen.
The daily dose for ingestion is recommended. To divide, into two doses - in the morning and in the evening. The capsule should be used immediately after removal from the blister pack. The capsule must be swallowed with a liquid (preferably water).
Usually capsules are taken on an empty stomach or for 1 hour before or 2-3 hours after a meal, which allows achieving maximum absorption of the drug.
To suppress the rejection of graft rejection, immunosuppressive therapy should be carried out for a long time, so the duration of the drug is unlimited.
Recommended dosing regimens
Liver transplantation
Prophylaxis of graft rejection in adults
The recommended initial dose of tacrolimus is 010-0.2 mg / kg / day orally in two divided doses (morning and evening). The drug should be started approximately 12 hours after the operation is completed. If it is not possible to prescribe the medication internally due to the patient's severe condition after the operation, the drip administration of the drug at a dose of 0.01-0.05 mg / kg / day for 24 hours should be started.
Prophylaxis of transplant rejection in children
The recommended initial dose of tacrolimus is 0.3 mg / kg / day orally in two divided doses (morning and evening). If there is no possibility to prescribe the drug, inward due to the patient's severe condition after the operation, it is necessary to start iv drip administration of the drug at a dose of 0.05 mg / kg / day for 24 hours.
Correction of dose in the postoperative period in adults and children
In the postoperative period, the dose of the drug is usually lowered. In some cases, cancellation of concomitant immunosuppressive therapy, and management of the patient on monotherapy with Tacrolimus-Teva is allowed. Improvement of the patient's condition, after transplantation, may influence the pharmacokinetics of tacrolimus, which necessitates correction of the dose of the drug.
Treatment of rejection in adults and children
To treat graft rejection, higher doses of Tacrolimus-Teva in combination with GCS and short courses of mono- polylon antibodies are necessary. If signs of toxicity appear, you may need to reduce the dose of Tacrolimus-Teva.
Kidney Transplantation
Prophylaxis of graft rejection in adults
The recommended initial dose of tacrolimus is 0.2-0.3 mg / kg / day in two divided doses (morning and evening). The drug should be started within 24 hours after the operation is completed. If there is no possibility to prescribe the drug inside due to the patient's severe condition after the operation, it is necessary to start intravenous administration of the drug at a dose of 0.05
-0.1 mg / kg / day for 24 hours.
Prophylaxis of transplant rejection in children
The recommended initial dose of tacrolimus is 0.30 mg / kg / day in two divided doses (morning and evening). If it is not possible to prescribe the medication internally due to the patient's severe condition after the operation, the drip administration of the drug at a dose of 0.075-0.1 mg / kg / day for 24 hours should be started.
Correction of dose in the postoperative period in adults and children
In the postoperative period, the dose of Tacrolimus-Teva is usually reduced. In some cases, cancellation of concomitant immunosuppressive therapy and management of the patient on monotherapy with Tacrolimus-teva is allowed. Improvement of the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus,
which entails the need to correct the dose of the drug.
To achieve a similar concentration of the drug in the blood, children usually require doses in terms of body weight 1.5-2 times higher than for adults.
Treatment of rejection in adults and children
For treatment of graft rejection, a dose increase of Tacrolimus-Teva is administered, combined with the addition of glucocorticosteroid therapy and short courses of mono- or polyclonal antibodies. In case of signs of toxicity, the dose of the drug should be reduced. When switching to Tacrolimus-Teva, treatment starts with the dose recommended for initial immunosuppression.
Recommendations for the transfer of patients with cyclosporine on tacrolimus are described in the section Adjusting the dose of the drug in special clinical cases.
Heart transplantation
Prophylaxis of graft rejection in adults
Tacrolimus-Teva may be administered against a background of mono / polyclonal antibodies (which allows delaying therapy with Tacrolimus-Teva) or in a clinically stable patient without the introduction of mono / polyclonal antibodies. After the introduction of mono / polyclonal antibodies, the recommended dose of the drug is 0.075. mg / kg / day orally in two divided doses (morning and evening). The first dose of the drug should be prescribed within 5 days after the operation is completed, as soon as the patient's condition is stabilized. If it is not possible to prescribe the drug inside, because of the patient's severe condition after the operation, it is possible to drip into the drip for 0.01 to 02.02 mg / kg / day for 24 hours.
As an alternative regimen for patients without symptoms of liver dysfunction, kidney tachrolimus may be administered orally within 12 hours after transplantation. In this case, the initial dose of tacrolimus is 2-4 mg / day in combination with mycophenolate mofetil and glucocorticosteroids, or in combination with sirolimus and glucocorticosteroids.
Prophylaxis of transplant rejection in children
After heart transplantation in children, Tacrolimus-Teva is used both in combination with and in the absence of antibody inducers.
Without the appointment of antibody inducers, the recommended initial dose of tacrolimus for intravenous drip infusion is 0.03-0.05 mg / kg / day for 24 hours, which allows the tacrolimus concentration in the blood to reach 15-25 ng / ml. If the patient's clinical condition allows him to take medications internally, it is recommended to transfer the patient to taking tacrolimus in capsules. The initial dose of the drug for oral administration is 0.3 mg / kg / day and can be administered 8-12 hours after completion of IV infusion of tacrolimus.
After the induction of antibodies, the recommended dose of Tacrolimus-Teva is 0.10-0.3 mg / kg / day orally in two divided doses (morning and evening).
Correction of dose in the postoperative period in adults and children
In the postoperative period, the dose of Tacrolimus-Teva is usually reduced. Improvement of the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus, which entails the need for correction of the dose of the drug.
Treatment of rejection in adults and children
For the treatment of graft rejection, an increase in the dose of Tacrolimus-Teva is made in combination with an additional appointment of glucocorticosteroid therapy and short courses of mono- or polyclonal
antibodies.
In adult patients, the initial dose is 0.15 mg / kg / day in the Tahrolimus-Teva preparation in two divided doses (morning and evening).
In children, when switching to Tacrolimus-Richter, the initial dose is 0.20-0.30 mg / kg / day in two divided doses (morning and evening).
Recommendations for the transfer of patients with cyclosporine on tacrolimus are described in the section "Correction of the dose of the drug in special clinical cases."
Treatment of rejection, other transplants
Recommended doses for lung, pancreatic and intestinal transplantation are based on very limited prospective clinical data. In lung transplantation, the initial dose of Tacrolimus-Teva was 0.10-0.15 mg / kg / day inwards, 0.2 mg / kg / day for pancreas transplantation and 0.3 mg / kg / day for intestinal transplantation.
Correction of the dose of the drug in special clinical cases
Patients with hepatic impairment
Patients with severe impairment of liver function may need to reduce the dose of the drug in order to maintain the concentration of the drug in the blood in the recommended range.
Patients with impaired renal function
Since the pharmacokinetics of tacrolimus does not depend on the function of the kidneys, correction of the dose in such cases is not required. However, given the presence of nephrotoxic action in tacrolimus, it is recommended to carefully monitor the kidney function (including the concentration of serum creatinine, creatinine clearance and diuresis).
Elderly
At present, there are no data on the need to correct the dose of the drug in the elderly.
Transfer of patients with cyclosporine therapy
Care should be taken when transferring patients from cyclosporine to Tacrolimus-Teva. Admission tacrolimus can begin after the determination of the concentration of cyclosporine in the blood and clinical assessment of the patient's condition. In case of an increased concentration of cyclosporine in the blood, taking Tacrolimus-Teva should be postponed. In practice, treatment with tacrolimus begins 12-24 hours after the abolition of cyclosporine. Therapy should begin with the initial oral dose recommended for primary immunosuppression in a specific allograft
(both in adult patients and in children). After transferring the patient to tacrolimus, the concentration of cyclosporine in the blood should be monitored, since cyclosporine clearance may be impaired.
Recommendations for maintaining the required concentration of the drug in whole blood
The choice of dose should be based on. clinical evaluation of rejection and tolerability in each patient individually.
In the postoperative period, it is necessary to monitor the concentration of tacrolimus in the blood. When taking the drug inside the analysis to determine the concentration of tacrolimus, it is necessary to obtain blood samples 12 hours after taking the drug, just before taking the next dose. The frequency of monitoring the concentration of the drug in the blood depends on the clinical situation. Since Tacrolimus-Teva is a drug with a low level of clearance, correction of the dosing regimen may take several days, when changes in drug concentrations in the blood will become apparent. In the early posttransplant period, drug concentrations in the blood should be monitored approximately twice a week. In addition, the concentration of tacrolimus in the blood should be monitored after adjusting the dose of the drug, changing the regime of immunosuppressive therapy, or after a combined dose with drugs that can affect the concentration of tacrolimus in the blood.
Clinical studies suggest that most patients can be treated successfully, if the concentration of tacrolimus is maintained below 20 u / ml. In assessing the results of the analysis it is important to
take into account the clinical condition of the patient. In clinical practice in the early posttransplant period, the concentration of drug in whole blood ranged from 5 to 20 ng / ml in patients after liver transplantation and from 10 to 20 ng / ml in patients after transplantation of kidneys and heart. Subsequently, during the course of maintenance therapy the drug concentration in blood is usually 5-15 ng / ml after any of said operations
(liver transplantation, kidney and heart).
SIDE EFFECT
Many of the following side reactions are reversible and / or decreasing with a decrease in the dose. In applying the drug inside the incidence of adverse events lower than on / in the introduction. Adverse reactions listed in descending order of frequency of occurrence: very often (> 1/10); common (> 1/100, <1/10); uncommon (> 1/1000, <1/100); rare (> 1/10 000, <1/1000); very rare (<1/10 000, including isolated cases).
Cardio-vascular system:very often - arterial hypertension; often - ischemic heart disease, tachycardia, thromboembolic ischemic symptoms, bleeding, peripheral vascular disorders, reduced vascular tone; infrequently - disorders of heart rhythm and conduction, cardiac arrest, cardiac failure, cardiomyopathy, hypertrophy of the ventricular myocardium, heart, abnormalities in ECG parameters, heart deficiency, myocardial infarction, deep vein thrombosis limb shock; rarely - pericardial effusion; very seldom - abnormalities by echocardiography.
From hemopoiesis system:often - anemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell pathology; infrequently - coagulopathy, abnormal blood coagulation system, pancytopenia, neutropenia; rarely - thrombocytopenic purpura, hypoprothrombinemia.
From the digestive system:very often - diarrhea, nausea; often - inflammatory gastrointestinal diseases, gastrointestinal ulceration and perforation, gastrointestinal bleeding, stomatitis, ulceration of the oral mucosa, ascites, vomiting, abdominal pain, indigestion, feeling of abdominal discomfort, constipation, flatulence, bloating, diarrhea ; infrequently - intestinal obstruction, peritonitis, acute and chronic pancreatitis, blood amylase increased activity, gastroesophageal reflux disease, impaired evacuation function of the stomach; rarely - subileus, pseudocyst of the pancreas.
On the part of the hepatobiliary system: frequently - violation of liver enzymes, cholestasis and jaundice, impaired
integrity hepatocytes and hepatitis, cholangitis; rarely - thrombosis of the hepatic artery, hepatic vein thrombosis; very rare - hepatic failure, bile duct stenosis.
Infections and infestations: in patients receiving tacrolimus, as well as in the treatment of other immunosuppressive drugs, increased risk of infections (viral, bacterial, fungal or protozoal etiology). It is also possible worsening of previously diagnosed infectious diseases, generalization or localization of the infectious process.
Benign, malignant and non-classified growths:patients receiving immunosuppressive drugs, are at increased risk of developing malignancies. Against the background of tacrolimus reported the development of benign and malignant tumors, including the development of Epstein-Barr virus - associated (EBV) lymphoproliferative disorders and skin cancer.
Allergic reactions: in patients treated with tacrolimus have been marked allergic and anaphylactic reactions.
From endocrine system: rarely - hirsutism.
Metabolic disorders and nutrition:very often - hyperglycemia, diabetes mellitus, hyperkalaemia; often - hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, giperuremiya, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and other disorders of water and electrolyte balance; infrequently - dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.
Psychiatric disorders: very often - insomnia; often - agitation, confusion and disorientation, depression, mood disorders, nightmares, hallucinations, mental disorders; infrequently - psychopathy.
CNS:very often - tremor, headache; often - epileptic seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, dizziness, writing disorders, disorders of the nervous system; infrequently - coma, bleeding in the brain, stroke, paralysis and paresis, encephalopathy, speech disorders, amnesia; seldom - hypertension; very rarely - myasthenia gravis.
From a sight organ: often - blurred vision, photophobia, eye diseases; infrequently - cataracts; rarely - blindness.
On the part of the organ of hearing and balance: often - ringing in the ears; infrequently - hearing loss; rarely - sensorineural deafness; very rarely - hearing impairment.
On the part of the respiratory system:often - shortness of breath, diffuse parenchymal lung disease, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequently - respiratory failure, disorders of the respiratory tract, bronchial asthma; rarely - acute respiratory distress syndrome.
Skin and subcutaneous tissue: often - itching, rash, alopecia, acne, increased sweating; infrequently - dermatitis, photosensitivity; rarely - toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome.
On the part of the musculoskeletal system and connective tissue disorders: often - arthralgia, cramps, pain in extremity, back pain; rare - diseases of the joints.
On the part of the kidney and urinary tract:very often - renal dysfunction; often - kidney failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the urinary bladder, and urethra; infrequently - anuria, haemolytic uraemic syndrome; very rarely - nephropathy, hemorrhagic cystitis.
On the part of the reproductive system: rarely - dysmenorrhea, and uterine bleeding.
General disorders and reactions at the injection site:often - fatigue, fever, swelling, pain and discomfort, increased alkaline phosphatase, weight gain, impaired temperature sensitivity; infrequently - multiorgan failure, flu-like state, temperature variations, feeling of pressure behind the sternum, fear, anxiety, discomfort, increased activity of lactate dehydrogenase (LDH), blood, weight loss; rarely - thirst, fall restraint during breathing, decrease of motor activity, ulcers; very rarely - the hypertrophy of adipose tissue.
Injury, poisoning and complications of medical procedures: often - primary graft dysfunction.
CONTRAINDICATIONS
- Hypersensitivity to tacrolimus or other macrolides;
- hypersensitivity to any drug.
PREGNANCY AND LACTATION
Results of pre-clinical research and studies conducted on humans have shown that the drug can cross the placenta. Safety of application of tacrolimus in pregnant women has not been established, so it should not be given to pregnant women except in cases where the resulting benefits of treatment to the mother
justifies the potential risk to the fetus. In applying the drug in utero newborn status should be monitored for possible adverse effects of tacrolimus (especially nephrotoxicity). There is a risk of preterm delivery (<37 weeks), the development of hyperkalemia in the newborn, which, however, spontaneously corrected.
These clinical studies have shown that tacrolimus is excreted in breast milk. If necessary, the appointment during lactation should stop breastfeeding because you can not eliminate the undesirable effects of the drug on the child's body.
APPLICATION FOR FUNCTIONS OF THE LIVER
Since the pharmacokinetics of tacrolimus is independent of renal function, the dose correction in such cases is not required. However, considering the presence of tacrolimus nephrotoxicity, should carefully monitor renal function (including the concentration of serum creatinine, creatinine clearance and urine output).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with severe hepatic impairment may require dose reduction, in order to maintain the blood concentration of the drug in the recommended range.
APPLICATION IN ELDERLY PATIENTS
Currently no data about the need to correct the dose in the elderly.
SPECIAL INSTRUCTIONS
.In the early postoperative period is necessary to monitor the following indicators: blood pressure, ECG; Ophthalmic and neurological status, blood glucose, fasting electrolytes (in particular potassium), liver and kidney function parameters CBC, coagulation parameters and determination of the blood plasma protein. In the event of clinically significant changes should consider "changing the regime, receiving immunosuppressive drugs.
Avoid co-administration of the drug Tacrolimus Teva with vegetable preparations, in particular preparations of St. John's wort (Hypericum perforatum), since there is a high risk of cross-reaction, which may lead to a decrease in the concentration of tacrolimus in the blood and reduce the effectiveness of the drug.
Since the concentration of tacrolimus in the blood can vary considerably with the development of diarrhea, in this case a careful monitoring of tacrolimus concentrations.
Avoid co-administration of cyclosporin and tacrolimus, and caution should be exercised when assigning tacrolimus patients who previously received cyclosporine.
There are few reports about the development of ventricular hypertrophy and ventricular septal recorded as cardiomyopathy. In most cases, these effects were reversible and occurred primarily in children with tacrolimus blood concentrations considerably higher than the recommended level.
Other risk factors include the following: the presence of diseases of the cardiovascular system in the history of GCS, hypertension, renal or hepatic insufficiency, infectious diseases, hypervolemia and swelling. Thus, the risk group includes children and patients receiving long-term immunosuppressive therapy in high doses. For such patients should be carefully monitored; regularly heart ultrasound, ECG, both before and after transplantation. In the case of development and change detection should consider lowering the dose of the drug Tacrolimus-Teva or to move to another immunosuppressive drug.
Tacrolimus-Teva is able to lengthen the interval QT, but has a weak potential in the development of torsades ventricular tachycardia (torsade de rointes). When administering the drug to patients with congenital QT syndrome elongate slot caution.
Patients taking tarolimus, noted the development of lymphoproliferative disorders associated with Epstein-Barr virus (EBV). Patients taking the drug Tacrolimus-Teva should not be given anti-lymphocyte preparations. In young children (under two years), EBV-VCA-negative children observed increased risk of developing lymphoproliferative disorders. Therefore, this group of patients prior to administration of the drug Tacrolimus-Teva should be serodiagnosis to EBV-VCA. During treatment, it is recommended to perform PCR EBV diagnosis. A positive polymerase chain reaction (PCR) can be stored for several months and by itself does not indicate the presence of lymphoproliferative disease or lymphoma.
As is the case with other immunosuppressive drugs because of the high risk of skin cancer, the patient should limit contact with sources of UV radiation and sunlight: It is recommended to wear long-sleeved clothing, sunglasses and hats.
As is the case with other immunosuppressive drugs the risk of secondary cancer is not defined.
In patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption drug should be used with caution (lactose contained in the dosage form of the drug).
Impact on the ability to drive vehicles and manage mechanisms
Tacrolimus may cause visual and neurological disorders, which are enhanced when coadministered with alcohol.
OVERDOSE
These tacrolimus overdose is very limited. There are only a few reports of accidental overdose, at the same time notes the following symptoms : tremor, headache, nausea and vomiting, infectious complications, urticaria, lethargy, increased blood urea nitrogen and creatinine, and increased ALT.
Specific antidote to the drug Tacrolimus-Teva does not exist. In case of overdose appointed general supportive and symptomatic therapy. Given the high molecular weight, poor solubility in water and form strong bonds with red blood cells and plasma proteins, it can be assumed that tacrolimus is not subjected to dialysis. Some patients with very high concentration of the drug in-plasma, hemofiltration has reduced its toxic concentration. In the case of intoxication after taking the drug inside is necessary to perform a gastric lavage and / or assign adsorbents (activated carbon) as soon as possible after ingestion.
DRUG INTERACTION
The metabolic interaction
metabolism occurs in the liver tacrolimus involving isoenzyme CYP3A4. In addition, there is evidence of the existence, metabolism in the intestinal wall, with the participation of isoenzyme CYP3A4. Interactions with drugs or herbal preparations that inhibit or induce the CYP3A4 isozyme may interfere with the metabolism of tacrolimus, which leads to an increase or decrease in blood concentration. Therefore, when assigning tacrolimus with drugs that are metabolized by CYP3A4 isoenzyme dependent pathways, it is recommended to control the concentration of tacrolimus in the blood and adjust the dose to maintain the desired clinical effect of the drug.
Metabolism Inhibitors
The following substances was increased concentration of tacrolimus in the blood.
Expressed interaction was observed with antifungal drugs: ketoconazole, fluconazole, itraconazole and voriconazole; macrolide antibiotics: erythromycin; or HIV protease inhibitor (ritonavir). Combined assignment of these drugs may require dose reduction of tacrolimus in almost all patients.
Less pronounced interaction was observed with the following preparations: clotrimazole, clarithromycin, josamycin; nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.
In in vitro conditions following preparations showed a pronounced inhibitory effect on the metabolism of tacrolimus: bromocriptine, cortisone, dapzon, ergotamine, gestodene, lidocaine mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, kvinidin tamoxifen, troleandomycin.
Grapefruit juice increases the concentration of tacrolimus in the blood, so use it in conjunction with the reception of tacrolimus should not be.
Inductors metabolism
The following substances reduced the concentration of tacrolimus in cr
