PROHRAF

Active material: Tacrolimus
When ATH: L04AD02
CCF: Immunosuppressive drugs
ICD-10 codes (testimony): Z94
When CSF: 14.02
Manufacturer: ASTELLAS PHARMA EUROPE B.V. (Netherlands)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Capsules hard gelatin, size №5, housing and lid, opaque capsules, light yellow with red overprint “0,5 mg” – and on the lid “[f]607” – on the body; contents of capsules – white powder.

Excipients: hydroxypropyl, sodium croscarmellose, lactose, magnesium stearate.

Capsule: Titanium dioxide, iron oxide yellow, Purified water, gelatin.

10 PC. – blisters (5) – bags of aluminum foil (1), containing 1 g silica – packs cardboard.

Capsules hard gelatin, size №5, housing and lid, opaque capsules, white with red overprint “1 mg” – and on the lid “[f]617” – on the body; contents of capsules – white powder.

Excipients: hydroxypropyl, sodium croscarmellose, lactose, magnesium stearate.

Capsule: Titanium dioxide, Purified water, gelatin.

10 PC. – blisters (5) – bags of aluminum foil (1), containing 1 g silica – packs cardboard.

Capsules hard gelatin, size №4, housing and lid, opaque capsules, grayish-red color with white overprint “5 mg” – and on the lid “[f]657” – on the body; contents of capsules – white powder.

Excipients: hydroxypropyl, sodium croscarmellose, lactose, magnesium stearate.

Capsule: Titanium dioxide, iron oxide red, Purified water, gelatin.

10 PC. – blisters (5) – bags of aluminum foil (1), containing 1 g silica – packs cardboard.

Concentrate for solution for i / v administration as a clear, colorless solution.

Excipients: polyoxyethylene hydrogenated castor oil (HCO-60) – 200 mg, Anhydrous alcohol – 638 mg.

1 ml – ampoules of glass containers 2 ml (10) – packings Valium plastic (1) – packs cardboard.

Pharmacological action

Immunosuppressant. At the molecular level, the effects of tacrolimus are mediated by binding to a cytosolic protein (FKBP 12), who is responsible for the intracellular accumulation of the drug. Complex 12 FKVR tacrolimus specifically and competitively binds to calcineurin and inhibits its, which leads to a calcium-dependent inhibition of T-cell signal transduction pathways, preventing, thus, transcription of a discrete group of lymphokine genes.

Suppresses the formation of cytotoxic lymphocytes, which are responsible for transplant rejection, reduces T-cell activation, B cell proliferation, zavisimuyu T-helperov, as well as the formation of lymphokines (such as interleukin-2, -3 and γ-interferon), expression of the IL-2 receptor.

Pharmacokinetics

Absorption

After oral administration, tacrolimus is absorbed from the gastrointestinal tract; predominantly – in the upper.

C_max tacrolimus in the blood is approximately 1-3 no. In some patients, the drug is absorbed continuously over a long period, reaching a relatively flat absorption profile. Average absorbance values ​​are presented in Table.

After oral administration at a dose rate of 0.30 mg / kg / day for most patients with liver transplant equilibrium state is established within 3 days.

Postprandial moderate-fat in liver transplant patients at steady state bioavailability decreased while taking the drug, and also noted a decrease in AUC (27%), C_max (50%) and an increase in T_max (173%) whole blood. With the simultaneous use of the drug with food reduced the rate and extent of absorption. Bile does not affect the absorption.

There is a strong correlation between the AUC and the value of C_ss^min in whole blood upon reaching equilibrium, concerning monitoring of C_min in whole blood can be used to adequately assess the systemic exposure of the drug.

Distribution

The distribution of tacrolimus after / in the administration is biphasic.

In the systemic circulation largely tacrolimus binds to erythrocytes. The ratio of the concentration values ​​in whole blood and plasma concentration of approximately 20:1. The blood plasma drug largely (>98.8%) It binds to proteins, primarily, serum albumin and α₁-acid glycoprotein.

Tacrolimus is widely distributed in the body. In Равновесный_d (based on the plasma concentration) is approximately 1300 l (healthy volunteers). The corresponding figure based on whole blood averaged 47.6 l.

Metabolism

When using in vitro models revealed 8 metabolites, among which only one metabolite has significant immunosuppressive activity.

Tacrolimus is largely metabolized by CYP3A4 isoenzyme.

Deduction

Tacrolimus is a drug with low clearance. In healthy volunteers, the mean value of the total clearance, as measured by the concentration of drug in whole blood, made 2.25 l /. In adult patients with kidney and liver transplant this value amounted to 4.1 l / h 6.7 l / hr, respectively. Children with liver transplant value of the total clearance of approximately 2 times higher, than in adult liver transplant patients.

T_1/2 Tacrolimus continuous and erratic. In healthy volunteers, the mean value of T_1/2 of whole blood is approximately 43 no. Adult and pediatric liver transplant T_1/2 averages 11.7 and h 12.4 h, respectively, compared with 15.6 h adult kidney transplant patients.

Write mainly in the bile. After the on / in the introduction and oral tacrolimus, -labeled ¹⁴FROM, most radioactively labeled drug is excreted in the feces; about 2% – urine; with the unchanged output of less than 1%, which indicates, that tacrolimus is almost completely metabolized in the body.

Testimony

- Prevention and treatment of liver allograft rejection, kidney and heart, incl. resistant to standard immunosuppressive therapy regimens.

Dosage regimen

The preparation can be applied both orally, and / in.

If required, contents of capsules may be dissolved in water and administered through a nasogastric tube.

The dosage regimen of the preparation should be adjusted according to the individual needs of the patient, taking into account the results of monitoring of drug levels in the blood of the patient.

At oral administration it is recommended to divide the daily oral dose of the drug in the two stages (eg, in the morning and in the evening). The capsules should be taken immediately after removal from the blister package, with some liquid (preferably water). To achieve maximum absorption of the capsules should be taken on an empty stomach (fasting) or at least 1 hours prior to or 2-3 h postprandial. There was no significant effect of food on the absorption of the drug in patients with kidney transplant.

At on / in Concentrate in / infusion should only be used after diluting it with an appropriate solvent. The concentrate should not be administered undiluted: it should be diluted 5% dextrose or saline solution in glass, polyethylene or polypropylene vials. Do not use vials and infusion systems, soderzhashtie polyvinylchloride. Use only clear and colorless solutions.

Not recommended bolus drug.

The concentration of the final solution for infusion should be varied within 0.004-0.100 mg / ml; and total solution infuziionnogo, input for 24 no, should vary 20-500 ml.

Unused concentrate for infusion into the open ampoule or unused reconstituted solution should immediately throw to, to avoid contamination (contamination).

Roasted transplant

To of primary immunosuppression in Adult oral therapy should be started at a dose rate of 0.10-0.20 mg / kg / day, dividing this dose into two doses (eg, in the morning and in the evening). Use of the drug should begin in about 12 hours after the operation.

If the patient is not able to receive the drug inside, I / therapy should start with a dose rate of 0.01-0.05 mg / kg / day in the form of I / 24-hour infusion.

To of primary immunosuppression in children initial dose of oral therapy is 0.30 mg / kg / day 2 admission (eg, in the morning and in the evening). If the clinical condition of the patient does not allow him to take oral medication, should start in / therapy dose 0.05 mg / kg / day in the form of I / 24-hour infusion.

At maintenance therapy in Adults and children dose Prograf^® usually reduced. In some cases, you can cancel the other drugs concomitant immunosuppressive therapy, leaving Prograf^® as monotherapy base. Improving the condition of the patient after transplantation may change the pharmacokinetics of tacrolimus and require correction dose.

To achieve similar drug levels in the blood of children are usually required dose (based on the weight of the body) in 1.5-2 times higher, than the dose for adults.

To Treatment of rejection in Adults and children you need to use the drug Prograf^® at higher doses combined with additional therapy Valium and short courses introducing mono / polyclonal antibodies. If signs of toxicity may require dose reduction of Prograf^®.

Kidney transplantation

To of primary immunosuppression in Adult initial dose of oral therapy is 0.30 mg / kg / day for 2 admission (eg, in the morning and in the evening). Drug therapy should start within approximately 24 hours after the operation.

Patients, receiving induction therapy with antibodies, it is recommended to start with the oral administration of the drug dose 0.20 mg / kg / day, razdelennoy of 2 admission (eg, in the morning and in the evening).

If the patient is not able to receive the drug inside, I / therapy should start with a dose 0.05-0.10 mg / kg / day, introducing a drug in / 24-hour infusion.

To of primary immunosuppression in children before surgery drug inside prescribe a dose 0.15 mg / kg / day. After the operation should be carried on / in a dose therapy with 0.075-0.100 mg / kg / day by infusion for 24 no, until the patient can not move to take oral medication. After this, the drug therapy administered orally at an initial dose 0.30 mg / kg / day, dividing by 2 admission.

At maintenance therapy in Adults and children dose Prograf^® usually reduced. In some cases, you can cancel the concomitant immunosuppressive drugs, leaving Prograf^® as monotherapy base. Improving the condition of the patient after transplantation may change the pharmacokinetics of tacrolimus and require correction dose.

The principle of the dosing of the drug must be based on the results of clinical assessment of rejection and tolerability in each patient individually. If clinical signs of rejection are evident, you need to consider changing the mode of immunosuppressive therapy.

To achieve similar drug levels in the blood of children are usually required dose (based on the weight of the body) in 1.5-2 times higher, than for adults.

To treatment of rejection reactions adults and children held high doses of Prograf^®, additional therapy was administered corticosteroids and short courses of introduction of mono / polyclonal antibodies. If signs of toxicity may require dose reduction of Prograf^®.

Heart transplant

At conducting initial therapy of rejection dose for oral administration is 0.30 mg / kg / day, razdelennaya of 2 admission (eg, in the morning and in the evening). If the clinical condition of the patient does not allow him to take oral medication, should start in / therapy dose 0.05 mg / kg / day in a 24-hour infusion.

Adjusting the dose to special clinical situations

Patients with severe hepatic insufficiency dose reduction may be required in order, to maintain a minimum level of the drug within the recommended range.

Patients with renal insufficiency It does not require correction dose, tk. Tacrolimus pharmacokinetic parameters do not change depending on renal function. However, due to the presence of tacrolimus nephrotoxicity should carefully monitor renal function (incl. creatinine concentration in the serum, creatinine clearance and urine output).

Currently, no data on the need to adjust the dose of the drug in the elderly.

At transferring the patient with cyclosporin therapy Caution should be taken into account and, that the concomitant use of the drug cyclosporine and Prograf^® It may increase the half-life of cyclosporin and increase toxic effects. Treatment with Prograf^® should begin after the assessment of concentrations of cyclosporine in the blood of the patient and the patient's clinical status. Use of the drug should be delayed in the presence of elevated levels of cyclosporine in the blood of the patient. Practically this means, that treatment with Prograf^® begins 12-24 h after discontinuation of cyclosporine. Therapy should start with a dose of oral, recommended for primary immunosuppression with the type of allograft (in adults, and children).

After the transfer of the patient should continue to monitor levels of cyclosporine in the blood of the patient in connection with the possibility of violations of the clearance of cyclosporine.

Recommendations for achieving the required level of drug concentration in whole blood

In the early postoperative period should monitor the levels of tacrolimus in the minimum whole blood. When administered orally to a certain minimum level of tacrolimus in the blood must receive blood samples via 12 h after dosing, directly before applying the next dose. Frequency control of drug level in the blood should depend on the clinical need. Unnecessarily. Prohraf^® It is a drug with low clearance, correction dosing regimen may take several days before the date, when changes in the blood levels of the drug will become apparent. Minimum levels of drug in the blood should be controlled approximately 2 twice a week during the early post-transplant period and then periodically during maintenance therapy. It is also necessary to control the minimum levels of tacrolimus in the blood after the dose changes, change the immunosuppressive therapy, after a joint use with drugs, that can affect the concentration of tacrolimus in whole blood.

The results of the analysis of clinical studies suggest, it is possible to successfully treat the majority of patients, if the minimum levels of tacrolimus in the blood is maintained below 20 ng / ml.

In clinical practice, during the early post-transplant period, minimum levels of drug in whole blood usually fluctuated 5-20 ng / ml in liver transplant recipients, and 10-20 ng / ml in patients with kidney transplant. Hence, during maintenance therapy drug concentration in the blood should be 5-15 ng / ml as in liver transplant recipients, and kidney transplant.

Side effect

In describing the side effects, the following criteria for evaluating the frequency of occurrence: Often (> 1/10); often (> 1/100, < 1/10); sometimes (>1/1000, <1/100); rarely (> 1/10 000, < 1/1000); rarely (< 1/10 000, incl. in a few cases).

Cardio-vascular system: Often – arterial hypertension; often - hypotension, tachycardia, arrhythmias and conduction disturbances, thromboembolism, ischemic events, angina, vascular disease; sometimes – ECG changes, infarct, heart failure, shock, myocardial hypertrophy, cardiac arrest.

From the digestive system: Often – diarrhea, nausea and / or vomiting; often – gastrointestinal dysfunction (incl. dyspepsia), changes in liver enzymes, abdominal pain, constipation, changes in body weight and appetite, inflammation and ulcers in the gastrointestinal tract, jaundice, diseases of the biliary tract and gall bladder; sometimes – ascites, ileus (ileus), liver tissue damage, pancreatitis; rarely – hepatic failure.

From the hematopoietic system: often – anemia, leukopenia, thrombocytopenia, gemorragija, leukocytosis, clotting; sometimes - a violation of hematopoiesis (incl. pancytopenia), thrombotic microangiopathy.

From the urinary system: Often – impairment of renal function (eg, increase in serum creatinine); often – kidney tissue damage, renal failure; sometimes – proteinuria.

Metabolism: Often – giperglikemiâ, hyperkalemia, diabetes; often – gipomagniemiya, hyperlipidemia, gipofosfatemiя, kaliopenia, hyperuricemia, hypocalcemia, Acidosis, giponatriemiya, gipovolemiя, other violations of water-electrolyte balance, degidratatsiya; sometimes – gipoproteinuriya, giperfosfatemiя, increased activity of amylase, gipoglikemiâ.

On the part of the musculoskeletal system: often - seizures; sometimes – myasthenia, arthropathy.

From the central and peripheral nervous system: Often – tremor, headache, insomnia; often - sensory disturbances (eg, paresthesia), visual impairment, confusion, depression, dizziness, excitation, Neuropathy, convulsions, dystaxia, psychosis, anxiety, nervousness, sleep disturbance, disturbance of consciousness, emotional lability, hallucinations, hearing loss, aphronia, encephalopathy; sometimes – gipertonus, eye diseases, amnesia, Cataract, speech disorders, paralysis, coma, deafness; rarely – blindness.

The respiratory system: often - respiratory disorders (eg, breathlessness), pleural effusion; sometimes – atelectasis, bronchospasm.

Dermatological reactions: often – itch, alopecia, rash, Sweating, acne, photosensitivity; sometimes - hirsutism; rarely – Lyell's syndrome; rarely – syndrome Stevens-Jones.

Allergic reactions: It was marked by a variety of allergic and anaphylactic reactions.

Other: Often – localized pain (eg, arthralgia); often - fever, peripheral edema, asthenia, violation of urination; sometimes – swelling of the external genitalia and other disorders of the reproductive organs in women.

Neoplasms: Patients, receiving immunosuppressive therapy, are at increased risk of developing malignant tumors. When using tacrolimus noted the development of both benign, and malignant tumors, incl. development of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders and skin cancer. Patients, which translated into therapy with Prograf^®, this complication can be caused by excessive immunosuppression prior to use of the drug. Patients, which translated into therapy with Prograf^®, It prohibited the use of concomitant therapy antilymphocytic. In very young children EBV-ceponegativnyh (aged 2 years) marked by an increased risk of developing lymphoproliferative disorders (in this group of patients before the drug Prograf^® serological definition of EBV necessary).

Infection: patients, receiving tacrolimus (As with other immunosuppressive), increased risk of infectious diseases (Viral, bacterial, fungal, protozoal) and possible 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. In most cases these symptoms are reversible and developed mainly in children, in which the minimum concentration of tacrolimus in the blood is much higher than the recommended maximum levels. Other factors, which increase the risk of these clinical conditions, It was pre-existing heart disease, the use of GCS, arterial hypertension, kidney or liver dysfunction, infection, excess body fluids and swelling.

Many of the undesirable side-effects are reversible and / or reduced at lower doses. For oral application the incidence of adverse drug reactions below, than on / in.

Contraindications

- Established hypersensitivity to tacrolimus or other macrolides;

- Established hypersensitivity to polyoxyethylated hydrogenated castor oil (HCO-60) or structurally related components.

Pregnancy and lactation

Prohraf^® should not be administered during pregnancy, tk. safety have not been established, except, When the resulting benefits of treatment justifies the potential risk to the fetus. The results of preclinical studies and clinical trials show, drug that can cross the placenta.

If necessary, the appointment during lactation should stop breastfeeding, tk. we can not exclude an undesirable impact on the child. The results of preclinical studies and clinical trials show, that tacrolimus is excreted in breast milk.

Cautions

Noted, that grapefruit juice increases the level of tacrolimus in the blood due to inhibition of CYP3A4 activity.

Overdose

Clinical experience is limited to the treatment of overdose. Several cases of accidental drug overdose, It has been observed following symptoms: tremor, headache, nausea, vomiting, infection, hives, lethargy, increases in blood urea nitrogen and elevated serum creatinine concentrations and ALT.

Treatment: No specific antidote. Spend standard event and, if necessary, symptomatic therapy. Due to the high molecular weight, poor water solubility and binding to erythrocytes and plasma proteins is largely expected, that an overdose of tacrolimus dialysis will not be effective. For some patients with very high levels of the drug in the blood plasma and hemofiltration diafiltration have been effective, reducing toxic concentrations of tacrolimus. In cases of intoxication after oral administration of the drug can help gastric lavage and / or reception of adsorbents (such as activated charcoal).

Drug Interactions

Pharmacokinetic interactions

Tacrolimus largely metabolized CYP3A4. Concomitant use of drugs or herbal medicines, that inhibit or induce the CYP3A4, It may affect the metabolism of tacrolimus and, thus, reduce or increase tacrolimus levels in the blood.

Tacrolimus has a significant effect on the pharmacokinetics of both drugs used, CYP3A4 metabolized via (eg, kortizon, Testosterone).

Tacrolimus binds to a large extent to plasma proteins. It should take into account possible interactions with other drugs, which exhibit high affinity to proteins of the blood (eg, NSAIDs, oral anticoagulants, or oral antidiabetic drugs).

Pharmacodynamic interactions

The concomitant use of tacrolimus with drugs, possessing nephrotoxic or neurotoxic effects, can increase toxicity (eg, aminoglikozidy, gyrase inhibitors (ДНК-топоизомераза II), vancomycin, co-trimoxazole, NSAIDs, acyclovir or ganciclovir).

The use of tacrolimus may cause hyperkalemia or enhance pre-existing hyperkalaemia, so you should avoid taking potassium-containing medications or use of potassium-sparing diuretics (eg, amilorid, triamterene, or spironolactone).

When vaccination during treatment with tacrolimus should be considered a possible reduction in the effectiveness of vaccines, and to avoid the introduction of live attenuated vaccines.

Clinically significant interactions

Following interaction with drugs tacrolimus concomitant therapy were observed for clinical use. The main mechanism of interaction is known. Preparations, marked with an asterisk (*), require changes in dosage of tacrolimus in nearly all patients. Other drugs, following, may require adjustment of the dose in some cases.

The following drugs inhibit CYP3A4: ketoconazole *, fluconazole *, itraconazole *, clotrimazole, voriconazole *; nifedipine, nikardipin, Erythromycin *, clarithromycin, dzhozamitsin; HIV protease inhibitors, danazol, ethinylestradiol, omeprazole, Calcium channel blockers (diltiazem), nefazodon. It has been shown, they increase tacrolimus levels in the blood.

The following drugs induce CYP3A4: rifampicin * (rifampin), phenytoin *, phenobarbital, St. John's wort. It has been shown, they lower blood levels of tacrolimus.

Tacrolimus increased the level of phenytoin in the blood.

Noted, that it increases methylprednisolone, and lowers the levels of tacrolimus in the blood plasma.

There is an increasing nephrotoxicity of amphotericin B after administration, ibuprofen together with tacrolimus.

Displaying, that the half-life of cyclosporine increased while the use of tacrolimus, besides possible additive effects and the development of synergies (this combination is not recommended).

Potential interactions

Based on in vitro studies, the following materials can be considered as potential inhibitors of cytochrome P450 metabolism of tacrolimus and A3: bromocriptine, kortizon, dapsone, ergotamin, gestodene, lidokain, mephenytoin, mikonazol, midazolam, nilvadipine, poretidron, quinidine, Tamoxifen, (triacetyl)oleandomycin and verapamil.

Carbamazepine, metamizole and isoniazid are potent inducers of cytochrome P450 isoenzymes A3.

Unnecessarily. Tacrolimus may affect the metabolism of estrogen, in hormonal contraceptives (inhibition of tacrolimus metabolism, mediated by the cytochrome P450 A3), special attention should be given to contraception.

Pharmaceutical interaction

In an alkaline environment tacrolimus not stable. Avoid joint use of reconstituted concentrate for infusion (5 mg / ml) with other drugs, which substantially basified solution (eg, ganciclovir and acyclovir).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The capsules should be stored in a dry place in its original packaging at a temperature not exceeding 25 ° C. Shelf life of capsules 500 g, 1 mg 5 mg – 3 year. Shelf life after opening the primary packaging (brazed aluminum package) – 1 year.

Concentrate for solution for / in the introduction should be stored in a dark place at a temperature no higher than 25 ° C. After dilution the solution should be stored in glass, polyethylene or polypropylene cup at a temperature of from 2 ° to 8 ° C. 24 no. Shelf life – 2 year.

The drug should not be used after the time indicated on the package.