Tacrolimus - instructions for use, dose, side effects, contraindications

Immunodepressant group of macrolides, inhibitor of calcineurin.Linking to the cytosolic protein (FKBP12), responsible for intracellular cumulation of the drug, forms the complex FKBP12-tacrolimus, which specifically and competitively interacts with calcineurin, inhibiting it. This leads to calcium-dependent blocking of T-cell signaling pathways and prevention of transcription of a discrete group of lymphokine genes. Suppresses the formation of cytotoxic lymphocytes that play a key role in graft rejection, reduces T cell activation and T helper-dependent proliferation of B cells, and the formation of lymphokines (such as interleukins-2 and -3, interferon gamma), interleukin-2 receptor expression. Inhibits the transcription of genes encoding interleukins-4 and -5, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor, which take part in the initial stages of T-lymphocyte activation. Under the influence of tacrolimus, inhibition of the release of inflammatory mediators from mast cells, basophils and eosinophils occurs.

Pharmacokinetics:

Absorbed mainly from the upper gastrointestinal tract. Bioavailability is on average 20-25%.Eating lowers the speed and degree of absorption, especially in the case of high levels of fat in it. The influence of foods rich in carbohydrates is less pronounced. Bile secretion does not affect absorption.

C_max is achieved in 1-3 hours. In some patients, the drug is continuously absorbed for a long period of time, reaching a relative level of the absorption profile.

There is a pronounced correlation between AUC and C_min in the blood upon reaching the equilibrium state, in connection with this, monitoring the minimum levels of the drug in whole blood can be an adequate assessment of the systemic effect of the drug.

Absorption of tacrolimus in the systemic blood stream with topical application is minimal. Systemic absorption depends on the area of the lesion and decreases with the disappearance of clinical manifestations of atopic dermatitis. Cumulation of the drug with prolonged external application (up to 1 year) in children and adults was not noted.

The distribution after intravenous administration of the drug is biphasic. In the systemic circulation is largely associated with erythrocytes. The ratio of concentrations in whole blood and plasma is 20: 1.The connection with proteins is 98.8% (mainly with serum albumin and alpha-1-acid glycoprotein). Widely distributed in the body. The equilibrium volume of distribution based on plasma concentrations is about 1300 liters (healthy volunteers), on the basis of whole blood - an average of 47.6 liters.

The total clearance (for concentrations in whole blood) in healthy volunteers averaged 2.25 l / h; in adult patients with a liver and kidney transplant - 4.1 and 6.7 l / h, respectively. In children with a liver transplant, the total clearance is 2 times higher than in adult patients with a liver transplant.

T_1/2 at systemic introduction it is prolonged and changeable. In healthy volunteers, T_1/2 from whole blood for about 43 hours, in adult patients and children with liver transplant - 11,7 and 12,4 hours, respectively, in adults with kidney transplant - 15,6 hours.

With multiple external application of tacrolimus in the form of ointment T_1/2 is 75 hours in adults and 65 hours in children.

Tacrolimus is largely metabolized in the liver with the participation of the enzyme cytochrome P-450 CYP3A4. Metabolism tacrolimus intensively flows in the intestinal wall. Identified 8 metabolites of tacrolimus, one of which exhibits significant immunosuppressive activity, close to the activity of tacrolimus.In the systemic circulation, only one of the metabolites of tacrolimus in low concentration was detected, i.e. The pharmacological activity of tacrolimus is practically independent of metabolites.

In the skin tacrolimus not metabolized.

After oral or intravenous injection, it is mostly excreted with feces, 2% is excreted in the urine. Less than 1% of unchanged tacrolimus is found in urine and feces, i.e. it is almost completely metabolized before elimination. The main way of elimination is bile.

Indications:

Systemic application: prevention and treatment of rejection of liver, kidney and heart allograft, incl. resistant to standard regimens of immunosuppressive therapy.

External application: treatment of atopic dermatitis (moderate severity and severe forms) in case of insufficient response of patients to traditional methods of treatment or contraindications to such.

ICD-10

XXI.Z80-Z99.Z94.9 Presence of transplanted organ and tissue, unspecified

XII.L20-L30.L20.8 Other atopic dermatitis

Contraindications:

For systemic use: hypersensitivity to tacrolimus and other macrolides,as well as to the auxiliary substances of preparations (for intravenous administration - to polyoxyethylated hydrogenated castor oil / HCO-60 /, for oral - to lactose),

For external use: genetic defects of the epidermal barrier, such as the Netherton syndrome, lamellar ichthyosis, cutaneous manifestations of the "graft versus host" reaction, generalized erythroderma (due to the risk of a progressive increase in systemic absorption of tacrolimus); children's age up to 2 years and adolescence up to 16 years (depending on the concentration of the ointment used).

Pregnancy and lactation:

Tacrolimus is contraindicated in pregnancy. Can penetrate the placenta. Prescribe should not be given to pregnant women, unless the benefits of treatment justify the potential risk to the fetus. Tacrolimus excreted in breast milk, if necessary, the appointment of the drug during lactation should stop breastfeeding.

Action category for the fetus by FDA - FROM

Dosing and Administration:

Systemic application (inand intravenously)

The dose is selected individually, depending on the results of monitoring the concentration of the drug in the blood. The daily oral dose is divided into 2 doses (morning and evening).Capsules are taken on an empty stomach or 1 hour before or 2-3 hours after eating, if necessary, the contents of the capsules can be dissolved in water and injected through a nasogastric tube.

Prevention of graft rejection: adults -: orally 0.1-0.2-0.3 mg / kg / day 12 hours after the completion of the operation, if oral administration is not possible - in / in the drip (!) - 0,01-0,05 mg / kg / day for 24 hours; children - oral 0.3 mg / kg / day, if oral medication is not possible - intravenously (!) 0.05 mg / kg / day for 24 hours.

Supportive therapy in adults and children: the dose is usually reduced; in some cases tacrolimus can be used as a basic monotherapy (cancellation of concomitant immunosuppressive drugs). Improving the patient's condition after transplantation can alter the pharmacokinetics of tacrolimus, which may require dose adjustment. Children usually require doses 1.5-2 times higher than adults.

Treatment of rejection in adults and children: higher doses of tacrolimus should be used in combination with GCS and short courses of mono- and polyclonal antibodies. In case of signs of toxicity, a dose reduction of tacrolimus may be required.

Correction of the dose of the drug in special clinical cases. Patients with severe impairment of liver function may need to reduce the dose of the drug. Patients with impaired renal function are not required to adjust the dose, but careful monitoring of their functions is recommended. When translated from therapy with cyclosporine on tacrolimus Care should be taken and start it after determining the concentration of cyclosporine in the blood and the clinical state of the patient. The use of the drug should be postponed if there is an increased concentration of cyclosporine. In practice, tacrolimus pass 12-24 hours after the removal of cyclosporine. Therapy begins with the initial oral dose recommended for primary immunosuppression in a specific allograft (in adults and children).

External application

Adults and teens over 16 years of age - ointment 0.1% on the affected surface 2 times / day until the symptoms disappear completely. As the application rate is improved, the application frequency is reduced or transferred to the use of 0.03% ointment.

Children (2 years and older) and adolescents under 16 years of age - ointment 0,03% 2 times / day. Duration of treatment should not exceed 3 weeks. With the improvement, the frequency of application is reduced to 1 time / day, the treatment is continued until the lesions are completely cleared.

When the first signs of exacerbation of atopic dermatitis appear, treatment should be resumed. To prevent exacerbations and increase the duration of remission in patients with frequent (more than 4 times / year) exacerbations of the disease in the history of supportive therapy - applying ointment 2 times / week is recommended.

Side effects:

Many of the following adverse reactions are reversible and / or reduced with a decrease in the dose of tacrolimus.

Systemic application

In connection with the large number of drugs used simultaneously after transplantation, the profile of undesirable reactions of immunosuppressants is difficult to establish accurately. When administered orally, the incidence of side effects is lower than with the / in the introduction.

From the side of the cardiovascular system: very often - arterial hypertension; often - violations of the coronary circulation, tachycardia, thromboembolic and ischemic complications, violation of peripheral circulation, arterial hypotension ;; infrequently - ventricular arrhythmias, heart failure, hypertrophic cardiomyopathy, myocardial infarction, deep vein thrombosis, arrhythmias, supraventricular arrhythmias,abnormal ECG, palpitation, cardiac arrest; rarely - pericardial effusion; very rarely - a violation of the indicators of the echocardiogram.

On the part of the hematopoiesis system: often - anemia, leukopenia, thrombocytopenia, hemorrhage, leukocytosis, a decrease or increase in the level of hemoglobin and / or hematocrit; infrequently - coagulopathy, suppression of hemopoiesis, incl. pancytopenia, thrombotic microangiopathy; rarely thrombotic thrombocytopenic purpura, hypoprothrombinemia.

From the side of the central nervous system: very often - a tremor, a headache; often epileptoid seizures, convulsive syndrome of various origins, dysesthesia and paresthesia, impaired consciousness, peripheral neuropathy, dizziness, ataxia; infrequently - encephalopathy, increased intracranial pressure, strokes, amnesia, speech disorders, paralysis, coma; rarely - hypertension; very rarely - myasthenia gravis.

From the side of the psyche: very often insomnia; often - anxiety, confusion and disorientation, depression, depressed mood, emotional disorders, nightmarish dreams, hallucinations; infrequently - psychotic disorders.

From the sense organs: often - blurred vision, photophobia, eye diseases, noise (ringing) in the ears; infrequently - cataract, hearing loss; rarely blindness of vision impairment, cataract, neurosensory deafness; very rarely - blindness, deafness.

From the digestive system: very often - diarrhea, nausea, vomiting; often - inflammatory diseases of the digestive tract, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, increased activity of "liver" enzymes, gastrointestinal and abdominal pain, constipation, flatulence, anorexia, dyspepsia , dysfunction of the biliary tract and gallbladder, jaundice; infrequently - intestinal obstruction, gastroesophageal reflux disease, hepatotoxicity, pancreatitis; rarely - liver failure.

From the respiratory system: often - violation of breathing (including shortness of breath), pleural effusion; infrequently - atelectasis of the lungs, asthma; rarely acute respiratory distress syndrome.

From the side of urinary function: very often - a violation of kidney function (including hypercreatininaemia); often - damage to kidney tissue, kidney failure,oliguria, toxic nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequently - anuria, proteinuria, very rarely - nephropathy, hemorrhagic cystitis.

From the endocrine system and metabolism: very often - hyperglycemia, hyperkalemia; often hypomagnesemia, hypophosphatemia, hypokalemia, hyperuricemia, hypocalcemia, metabolic acidosis, hyponatremia, hypovolemia, dehydration, hyperlipidemia, hypercholesterolemia; infrequently - hypoproteinuria, hyperphosphatemia, increased amylase, hypoglycemia, rarely - hirsutism, very rarely - an increase in the mass of adipose tissue.

From the side of the musculoskeletal system: often - convulsions; infrequently - myasthenia gravis, arthritis.

From the skin: often - itching, alopecia, rash, sweating, acne, photosensitivity; rarely - Lyell's syndrome; very rarely - Stevens-Johnson syndrome.

Infections and infestations: against the background of tacrolimus therapy, as well as other immunosuppressants, the risk of local and generalized infectious diseases (viral, bacterial, fungal, protozoal) increases. Possible worsening of the course of previously diagnosed infectious diseases.

Neoplasms: risk of developing benign and malignant neoplasms, incl. associated with the Epstein-Barr virus, lymphoproliferative diseases and skin cancer.

Other: very often - localized pain (including arthralgia); often - fever, peripheral edema, asthenia, impaired urination, weight gain; infrequently - multi-organ failure, influenza-like syndrome, edema of the genitals and vaginitis in women.

External application

The most frequent symptoms are skin irritation (burning sensation and itching, redness, pain, paresthesia and rash) at the site of application. Often there is intolerance to alcohol (redness of the face or symptoms of skin irritation after drinking alcohol).

Overdose:

Symptoms: tremor, headache, nausea, vomiting, infection, urticaria, lethargy, increased blood urea nitrogen concentration and hypercreatininaemia, increased ALT activity. There is no specific antidote. Treatment: symptomatic; after oral administration - gastric lavage and / or intake of adsorbents (Activated carbon). Due to the high molecular weight, poor solubility in water and a high bond with erythrocytes and plasma proteins, it is assumed that tacrolimus Do not undergo dialysis.In some patients (with a very high concentration of the drug in the blood plasma), hemofiltration and diafiltration made it possible to reduce the toxic concentration. The clinical experience of overdose management is limited.

When topical application of cases of overdose was not noted.

Interaction:

Simultaneous intake of substances that inhibit or induce CYP3A4 can affect the metabolism of tacrolimus and, accordingly, reduce or increase the concentration of tacrolimus in the blood plasma.

Inhibitors of metabolism, increasing the concentration tacrolimus in the blood (the appointment of these drugs with tacrolimus often requires a reduction in its dose): antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir). Potential inhibitors of tacrolimus metabolism are bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, miconazole, midazolam, norethisterone, tamoxifen. It is also recommended to avoid grapefruit juice in connection with the possibility of increasing the concentration of tacrolimus in the blood.

Inductors of metabolism, reducing the concentration of tacrolimus in the blood (the appointment of these drugs with tacrolimus may require an increase in its dose): rifampicin, phenytoin, preparations containing St. John's wort.

The concentration of tacrolimus in the blood also decreases phenobarbital, carbamazepine, metamizol sodium, isoniazid. corticosteroids (in maintenance doses). Prednisolone or methylprednisolone in high doses, used to treat acute rejection, can both increase and decrease the concentration of tacrolimus in the blood.

Effect of tacrolimus on the pharmacokinetics of other drugs

It can affect the metabolism of drugs metabolized by CYP3A4 (including cortisone, testosterone).

Increases T_1/2 cyclosporine, synergistic / additive nephrotoxic effects may be observed. Therefore, simultaneous administration of cyclosporine and tacrolimus is not recommended, and in the appointment of tacrolimus to patients who have previously taken ciclosporin, care must be taken.

Increases the concentration of phenytoin in the blood plasma.

It is able to reduce the clearance of hormonal contraceptives, so it is important to be careful when choosing contraceptives.

It is possible to increase the systemic exposure of tacrolimus when used simultaneously with prokinetic agents (metoclopramide, cisapride), cimetidine, magnesium hydroxide and aluminum hydroxide.

Due to the high degree of tacrolimus plasma protein binding might its interaction with others. PM having high affinity to blood proteins (including NSAIDs, oral hypoglycemic agents and anticoagulants for oral use).

Potentially unfavorable interaction with other drugs

Simultaneous treatment with tacrolimus PM providers neuro- and nephrotoxicity action (including aminoglycosides, gyrase inhibitors, vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir), may contribute to these effects.

Increased risk of hyperkalemia while the use of drugs potassium and potassium-sparing diuretics (including amiloride, triamterene, spironolactone).

Changes the reaction of the body to vaccination: during treatment with tacrolimus, it may be less effective. The use of live attenuated vaccines should be avoided.

It is necessary to avoid the joint use of the reconstituted concentrate for infusions with other drugs that change the pH of the solution, in an alkaline medium tacrolimus is unstable.

Pharmaceutical incompatibility

Tacrolimus is incompatible with PVC.Tubes, syringes, nasogastric probes and other devices used to prepare and administer the solution or contents of the capsules must not contain polyvinyl chloride.

With external application tacrolimus It is not metabolized in the skin, which excludes the risk of its drug interactions. Interaction with inhibitors of CYP3A4 (erythromycin, itraconazole, ketoconazole, etc.) with simultaneous application with ointment is unlikely, but it can not be completely excluded in patients with extensive lesions and / or erythroderma.

Special instructions:

Due to the high risk of side effects, including anaphylaxis and impaired renal function, tacrolimus parenteral dosage forms are prescribed only if oral administration is not possible.

In the initial post-transplant period, regular monitoring of blood pressure, ECG, neurological status and vision, fasting blood glucose level, electrolyte concentration (especially potassium), hepatic and renal function, hematological parameters, proteinemia level, coagulogram should be monitored.In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary. Correction of the dosing regimen may take several days until the changes in the concentration of the drug in the blood become obvious.

The patient should be kept on one of the medicinal forms of tacrolimus with the appropriate dosing regimen; the change in dosage form or dosage regimen should only be carried out under the supervision of a transplant specialist.

When using tacrolimus preparations, the appointment of herbal remedies that can cause a decrease (change) in the concentration of tacrolimus in the blood should be avoided and adversely affect its clinical effect.

In diarrhea, significant changes in the concentration of tacrolimus in the blood are possible (careful monitoring of its concentration is necessary).

Simultaneous use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating tacrolimus patients who previously received ciclosporin.

In patients receiving immunosuppressants, the risk of opportunistic infections caused by bacteria, fungi, viruses, protozoa is increased.

Due to the potential risk of developing malignant skin diseases during treatment, exposure to sunlight and UV radiation should be limited, protecting the skin with clothing and using creams with a high protective factor.

During the treatment period, it is recommended to refrain from engaging in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions (including driving).

Instructions

Tacrolimus (Tacrolimusum)