Tacrolimus (When ATH L04AD02)
When ATH:
L04AD02
Pharmacological action
Tacrolimus binds to cytosolic protein (FKBP12), responsible for the intracellular accumulation of the drug. FKVR12-tacrolimus complex 'specific and competitive interacts with calcineurin inhibits its, which leads to a calcium-dependent inhibition of T-cell signal transduction pathways and prevent transcription of a discrete group of lymphokine genes. Suppresses the formation of cytotoxic lymphocytes, that, primarily, are responsible for graft rejection, reduces T-cell activation, dependent T-helper cell proliferation, as well as the formation of lymphokines (such as interleukin-2, and 3 and gamma-interferon), expression of the IL-2 receptor.
Pharmacokinetics
It absorbed primarily from the upper GI. Ingestion of moderate-fat reduces the rate and extent of absorption, reduces AUC by 27% и Cmax на 50%, increases in the TSmax 173%. Bile does not affect the absorption. TCmax - 1-3. In some patients, the drug is absorbed continuously over a long period, reaching a relatively flat absorption profile. TCSS - 3 days after oral administration 0,3 mg / kg / day in patients with liver transplant. There is a strong correlation between the AUC and Cmin in the blood when the CSS. The distribution after the on / in the preparation is biphasic. Substantially binds to erythrocytes. The ratio of distribution in whole blood plasma concentration - 20:1. Contact proteins - 98,8% (mainly serum albumin and alpha-1-acid glycoprotein). Widely distributed in the body. The volume of distribution in the plasma - 1300 l, in whole blood - 47,6 l. Total clearance (at concentrations in whole blood) - Average 2,25 l /; adult patients with kidney and liver transplants - 4,1 l / h 6,7 l / hr, respectively. Children with liver transplant in total clearance 2 times higher, than in adult liver transplant patients. To a large extent metabolized in the liver by CYP3A4 to form 8 metabolites, one of which has a significant immunosuppressive activity. T1 / 2 of whole blood - about 43 no; in adult and pediatric patients with liver transplant - 11,7 and h 12,4 h, respectively, in adult patients with kidney transplant - 15,6 no. After the in / and oral administration is mainly excreted in the feces, 2% excreted in the urine. Less 1% excreted unchanged.
Testimony
Prevention and treatment of liver allograft rejection, kidney and heart, incl. resistant to standard immunosuppressive therapy regimens.
Contraindications
Hypersensitivity (incl. macrolide and polyoxyethylated hydrogenated castor oil (HCO-60)).
Dosage regimen
Inside and in /. Dose picked individually, depending on the results of control of drug concentration in the blood.
Inside: the daily dose is divided into 2 admission (in the morning and in the evening). The capsules should be taken immediately after removal from the blister package, Fasting or 1 hours before or 2-3 hours after ingestion, swallowed whole, with some liquid (preferably water) or if necessary the contents of capsules may be dissolved in water and administered through a nasogastric tube.
It is not recommended to enter the jet! Use only clear and colorless solutions. B / drip (5 mg / ml diluted 5% or dextrose 0,9% NaCl solution). The concentration of the infusion solution should vary within 0,004-0,1 mg / ml. The total volume of the infusion 24 h - 20-500 ml.
Roasted transplant
Primary immunosuppression in adults: po - 0.1-0.2 mg / kg / day. Use of the drug should be initiated through 12 hours after the operation. If the patient is not able to receive the drug inside, in / infusion - 0.01-0.05 mg / kg / day for 24 no. Primary immunosuppression in children: os - 0,3 mg / kg / day. If the patient is not able to receive the drug inside, in / infusion - 0,05 mg / kg / day for 24 no.
Supportive therapy in adults and children: dose typically reduce; in some cases, tacrolimus may be used alone as a base (cancellation related immunosuppressive drugs). Improving the condition of the patient after transplantation may change the pharmacokinetics of tacrolimus, which may require correction dose. Children are usually required dose is 1.5-2 times higher doses for adults.
Treatment of rejection reactions in adults and children: requires the use of higher doses of tacrolimus in combination with corticosteroids and short courses of mono / polyclonal antibodies. If signs of toxicity, It may require dose reduction of tacrolimus.
Kidney transplantation
Primary immunosuppression in adults: patients, which is not carried out basic therapy (aimed at stimulating the production of antibodies) os - 0,3 mg / kg / day. Drug therapy should start approximately 24 hours after the operation.
Patients, receiving basic therapy inside - 0,2 mg / kg / day. If the patient is not able to receive the drug inside, / drip - 0.05-0.1 mg / kg / day for 24 no.
Primary immunosuppression in children: before surgery - inside 0,15 mg / kg. After surgery - / drip 0,075-0,1 mg / kg / day for 24 h with the transition to oral 0,3 mg / kg / day.
Supportive therapy in adults and children: dose typically reduce; in some cases, tacrolimus may be used alone as a base (cancellation related immunosuppressive drugs). Improving the condition of the patient after transplantation may change the pharmacokinetics of tacrolimus, which may require correction dose. Dose picked individually, in accordance with the results of the clinical assessment of rejection and tolerability. If clinical signs of rejection are evident, you need to consider changing the mode of immunosuppressive therapy.
Treatment of rejection reactions in adults and children: requires the use of higher doses of tacrolimus in combination with corticosteroids and short courses of mono / polyclonal antibodies. If signs of toxicity, It may require dose reduction of tacrolimus.
The response of the heart transplant rejection
Initial therapy of rejection: os - 0,3 mg / kg / day. If the clinical condition of the patient does not allow him to take the drug inside, in / infusion - 0,05 mg / kg / day for 24 no.
Patients with severe hepatic impairment may require dose reduction; CRF is not required if dose adjustment, However, due to the presence of tacrolimus nephrotoxicity should carefully monitor renal function (incl. creatinine concentration in the serum, KK and diuresis).
Translation from cyclosporin therapy: treatment should be started after the determination of the concentration of cyclosporine in the blood plasma and clinical condition of the patient. Use of the drug should be delayed in the presence of elevated concentrations of cyclosporine. In practice, treatment is initiated 12-24 hours after the discontinuation of ciclosporin. Therapy begins with the initial oral dose of, recommended for primary immunosuppression in particular allograft (in adults and children).
Side effect
Often (more 1/10); often (more 1/100 less 1/10); infrequently (more 1/1000 less 1/100); rarely (more 1/10000 less 1/1000); rarely (less 1/10000, incl. isolated cases).
From the CCC: very often - increased blood pressure, frequently - blood pressure reduction, tachycardia, Arrhythmia, conduction disorders, thromboembolism, išemiâ, angina, vascular disease; not often - ECG changes, infarct, SN, shock, myocardial hypertrophy, cardiac arrest.
From the digestive system: very often - diarrhea, nausea, vomiting; often - dysfunction of the gastrointestinal tract (incl. dyspepsia), increased activity of "liver" enzymes, abdominal pain, constipation, weight change, appetite disorders, inflammation and ulcers of the gastrointestinal mucosa, jaundice, dysfunction of the biliary tract and gall bladder; rarely - ascites, ileus, gepatotoksichnostь, pancreatitis; rarely - liver failure.
From the side of hematopoiesis: often - anemia, leukopenia, thrombocytopenia, gemorragija, leukocytosis, blood coagulation disorders; rarely - inhibition of hematopoiesis, incl. pancytopenia, thrombotic microangiopathy.
Urinary function: very often - renal dysfunction (incl. giperkreatininemiя); often - tissue damage kidneys, renal failure; not private - proteinuria.
Metabolism: very often - hyperglycemia, hyperkalemia, giperglikemiâ; often - hypomagnesemia, hyperlipidemia, gipofosfatemiя, kaliopenia, hyperuricemia, hypocalcemia, Acidosis, giponatriemiya, gipovolemiя, degidratatsiya; not often - gipoproteinuriya, giperfosfatemiя, increase in amylase, gipoglikemiâ.
On the part of the musculoskeletal system: often - seizures; rarely - myasthenia gravis, arthritis.
From the nervous system and sensory organs: very often - tremor, headache, insomnia; often - dysesthesia (incl. paraesthesia), visual impairment, confusion, depression, dizziness, excitation, neuropathy, convulsions, ataxia, psychosis, anxiety, nervousness, sleep disturbance, disturbance of consciousness, emotional lability, hallucinations, hearing loss, aphronia, encephalopathy; rarely - increased intracranial pressure, eye diseases, amnesia, Cataract, speech disorders, paralysis, coma, deafness; very rarely - blindness.
The respiratory system: often - respiratory failure (incl. breathlessness), pleural effusion; rarely - pulmonary atelectasis, bronchospasm.
For the skin: often - itching, alopecia, rash, Sweating, acne, photosensitivity; not often - hirsutism; rarely - Lyell's syndrome; very rarely - Stevens-Johnson syndrome.
Other: very often - localized pain (incl. arthralgia); often - fever, peripheral edema, asthenia, violation of urination; not often - swelling of the genitals, and vaginitis in women.
Neoplasms: the development of benign and malignant tumors, incl. associated with the Epstein-Barr virus, lymphoproliferative disorders and skin cancer.
Allergic and anaphylactic reactions
Development of virus, bacterial, fungal and protozoan diseases; worsening of previously diagnosed infections.
In rare cases, there was the development of ventricular hypertrophy or hypertrophy of the interventricular septum of the heart, registered, as cardiomyopathy, primarily, children. Risk factors include pre-existing heart disease, the use of GCS, arterial hypertension, renal failure or liver, infection, gipergidratatsiya, swelling.
At random I / A or perivascular administration can occur irritation at the injection site.
For oral application the incidence of side effects below, than on / in.
Overdose. Symptoms: tremor, headache, nausea, vomiting, infection, hives, lethargy, increasing the concentration of blood urea nitrogen and hypercreatininemia, increased ALT.
Treatment: symptomatic; after oral administration - gastric lavage and / or reception of adsorbents (Activated carbon). No specific antidote. Due to the high molecular weight, poor solubility in water and high bond to erythrocytes and plasma proteins, expected, that dialysis is not effective. For some patients (with a very high concentration of drug in blood plasma) diafiltration and hemofiltration have proved effective, reducing toxic concentrations of the drug. Clinical experience is limited to the treatment of overdose.
Cautions
Recommendations for achieving the desired concentration of the drug in whole blood: in the early postoperative period should be monitored Cmin tacrolimus whole blood. When administered orally for determining Cmin must receive blood samples via 12 hours after receiving tacrolimus, directly before applying the next dose. The frequency of monitoring depends on the Cmin clinical need. Because tacrolimus has a low clearance, correction dosing regimen may take several days before the date, When changing the concentration of the drug in the blood will be apparent. Cmin should be monitored 2 twice a week during the early post-transplant period and then periodically during maintenance therapy. Also check after changing the dose Cmin, immunosuppressive regime or after a joint application with drugs, that can affect the concentration of tacrolimus in whole blood. The results of the analysis of clinical studies suggest, that successful treatment is achieved at lower Cmin 20 ng / ml.
In clinical practice, during the early post-transplant period Cmin whole blood is 5-20 ng / ml in liver transplant recipients and 10-20 ng / ml - in renal transplant patients. Hence, during maintenance therapy drug concentration in the blood should be 5-15 ng / ml in liver transplant recipients and kidneys.
Noted the development associated with the Epstein-Barr virus (EBV) lymphoproliferative diseases, that can be caused by excessive immunosuppression before the application of this preparation. When transferring to tacrolimus therapy is contraindicated in concomitant therapy antilymphocytic. In EBV-ceponegativnyh children under 2 years observed an increased risk of developing lymphoproliferative disorders (before treatment is necessary serological determination of EBV).
It crosses the placenta and is excreted in breast milk. Safety in pregnant women has not been established, therefore, should not be given the drug during pregnancy, except, when the intended benefits to the mother outweighs the potential risk to the fetus. During treatment, it is recommended to cancel breastfeeding.
In the initial post-transplant period necessary to control blood pressure, ECG, neurological and ophthalmic status, glucose concentration in blood glucose, proteins in the blood plasma, electrolytes (especially K ), liver and renal function, complete blood count, indicators of blood coagulation.
Because of the potential risk of malignant skin diseases in the period of treatment should limit exposure to sunlight and UV radiation, protecting the skin clothing and use creams with high protection factor.
Concentrate for solution for I / O administration contains polyoxyethylene hydrogenated castor oil, which, can cause anaphylactic reactions. The risk of anaphylaxis could be reduced by introducing the concentrate reconstituted with a low speed or prior administration of antihistamine drugs.
Unused concentrate on / in the open ampoule or unused reconstituted solution should be immediately disposed of to prevent it from bacterial contamination.
Tacrolimus nesovmestim with polivinilhloridom (PVC plastic is absorbed) - Tubes, syringes, nasogastric tubes, etc.. devices, used for the preparation and administration of the concentrate for infusion, or the contents of the capsules, probe should not contain polyvinyl chloride.
During treatment should refrain from activities potentially hazardous activities, require high concentration and speed of psychomotor reactions (incl. driving).
Drug Interactions
Simultaneous administration of substances, ингибирующих или индуцирующих CYP3A4, It may affect the metabolism of tacrolimus, and, accordingly, reduce or increase the concentration of tacrolimus in the blood plasma.
It may affect the metabolism of drugs, метаболизирующихся CYP3A4 (incl. kortizon, Testosterone).
Due to the high degree of protein binding of tacrolimus is possible interaction with other. Drugs with a high affinity to proteins of blood (incl. NSAIDs, oral anticoagulants and hypoglycemic agents for oral use).
Simultaneous treatment of neuro- and nefrotiksicheskih PM (incl. aminoglikozidy, gyrase inhibitors, vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir) It increases the risk of neural- and nephrotoxicity.
The risk of hyperkalemia while the use of drugs K and potassium-sparing diuretics (incl. amilorid, triamterene, spironolactone).
Avoid administration of live attenuated vaccines during therapy with tacrolimus (may decrease the effectiveness of vaccines).
Increase the concentration of tacrolimus in the blood plasma (may require correction of the dose): ketoconazole, fluconazole, itraconazole, clotrimazole, voriconazole, nifedipine, nikardipin, Erythromycin, clarithromycin, dzhozamitsin, HIV protease inhibitors, danazol, ethinylestradiol, omeprazole, BMKK (incl. diltiazem), nefazodon, grapefruit juice.
Reduce the concentration of tacrolimus in the blood plasma (may require correction of the dose): rifampicin, phenytoin, phenobarbital, St. John's wort.
Tacrolimus increases the concentration of phenytoin in blood plasma.
Methylprednisolone may increase or reduce the concentration of tacrolimus.
Амфотерицин B, ibuprofen increase the risk of nephrotoxicity of tacrolimus.
Increases T1 / 2 ciclosporin, at the same time may increase the toxic effect. Not recommended simultaneous appointment of cyclosporine and tacrolimus in patients, previously treated with cyclosporine. It is recommended to be careful when transferring patients from cyclosporine to tacrolimus therapy (necessary to monitor the concentration of cyclosporin).
Inhibits the metabolism of tacrolimus: bromocriptine, kortizon, dapsone, ergotamin, gestodene, lidokain, mephenytoin, mikonazol, midazolam, nilvadipine, poretidron, quinidine, Tamoxifen, oleandomiцin, verapamil.
Induce the metabolism of tacrolimus: Carbamazepine, metamizol, Isoniazid.
It may affect the metabolism of oral contraceptives (necessary to use alternative methods of contraception).
Avoid joint use of reconstituted concentrate for infusion with others. PM, altering the solution pH (incl. ganciclovir and acyclovir), tk. tacrolimus in alkaline medium not stable.
