Protopic ointment for external use of 0,1% 30 g
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Active ingredients
Tacrolimus
Release form
Ointment
Composition
Tacrolimus (in the form of monohydrate) 30 mg. Adjuvants: white soft paraffin - 77.47 mg, liquid paraffin - 11 mg, propylene carbonate - 5 mg, white beeswax - 3.5 mg, solid paraffin - 3 mg.
Pharmacological effect
Immunosuppressant. At the molecular level, the effects and intracellular cumulation of tacrolimus are due to binding to the cytosolic protein (FKBP 12). The FKBP 12 complex — tacrolimus specifically and competitively inhibits calcineurin, providing calcium-dependent blocking of T-cell signaling pathways and preventing the transcription of a discrete series of lymphokine genes. Tacrolimus is a highly active immunosuppressant. In in vitro and in vivo experiments, tacrolimus clearly reduced the formation of cytotoxic lymphocytes, which play a key role in the graft rejection reaction. Tacrolimus inhibits the formation of lymphokines (interleukin-2, interleukin-3, γ-interferon), T-cell activation, expression of the interleukin-2 receptor, as well as T-helper-dependent B-cell proliferation.
Pharmacokinetics
Tacrolimus absorption is variable (absorption variability in adult patients - 6-43%). The bioavailability of tacrolimus averages 20-25%. Bioavailability, as well as the rate and extent of absorption of tacrolimus, while taking it with food, are reduced. The nature of biliary excretion does not affect the absorption of the drug. The distribution of tacrolimus in the human body after the on / in the introduction has a two-phase character. In the systemic circulation, tacrolimus binds well to red blood cells. The ratio of tacrolimus concentrations in whole blood and plasma is about 20: 1. A significant proportion of tacrolimus plasma (> 98.8%) is associated with plasma proteins (serum albumin, α1-acid glycoprotein) state. Tacrolimus is widely distributed in the body. Vd in the equilibrium state, taking into account concentrations in plasma is about 1300 l (in healthy people). The same indicator, calculated on whole blood, is on average 47.6 l. Tacrolimus has a low clearance. In healthy people, the average total clearance calculated by concentration in whole blood is 2.25 l / h. In adult patients after liver, kidney and heart transplantation, clearance values were 4.1 l / h, 6.7 l / h and 3.9 l / h, respectively. Low hematocrit and hypoproteinemia increase the unbound fraction of tacrolimus, accelerating clearance of tacrolimus.Corticosteroids used in transplantation can also increase the intensity of metabolism and accelerate the clearance of tacrolimus. T1 / 2 tacrolimus is long and variable. In healthy people, the average T1 / 2 in whole blood is about 43 hours. Tacrolimus is actively metabolized in the liver, mainly with the participation of the CYP3A4 isoenzyme. Tacrolimus metabolism intensively proceeds in the intestinal wall. Identified several metabolites of tacrolimus. In in vitro experiments it was shown that only one of the metabolites has immunosuppressive activity close to that of tacrolimus. Other metabolites differed weak immunosuppressive activity or its absence. Only one of the low concentrations of tacrolimus metabolites was detected in the systemic circulation. Thus, the pharmacological activity of tacrolimus is almost independent of the metabolites. After iv administration and oral administration of 14C-labeled tacrolimus, the majority of the radioactivity was detected in the feces. Approximately 2% of radioactivity was recorded in the urine. In the urine and feces about 1% was determined unchanged.
Indications
For systemic use: prevention and treatment of allograft rejection of the liver, kidney in adult patients. Treatment of allograft rejection resistant to standard modes of immunosuppressive therapy in adult patients. For external use: treatment of atopic dermatitis (moderate and severe forms) in case of insufficient response of patients to traditional methods of treatment or the presence of contraindications to such.
Contraindications
For systemic and external use: pregnancy; lactation period (breastfeeding); hypersensitivity to tacrolimus. For external use: genetic defects of the epidermal barrier, such as Netherton syndrome; lamellar ichthyosis; skin manifestations of graft versus host reaction; generalized erythroderma (due to the risk of a progressive increase in systemic absorption of tacrolimus); children and adolescents up to 16 years (depending on the dosage form used).
Use during pregnancy and lactation
Contraindicated use during pregnancy and lactation (breastfeeding).
Dosage and administration
The dose and frequency of use is determined individually, depending on the evidence, the clinical situation and the dosage form used.
Side effects
Since the cardiovascular system: very often - myocardial ischemia, tachycardia, hypertension, bleeding, thromboembolic and ischemic complications, impaired peripheral circulation, hypotension; infrequently - ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmias, heart palpitations, abnormal ECG, heart rhythm disturbances, heart rate and pulse, heart attack, deep vein thrombosis of extremities, shock; rarely, pericardial effusion; very rarely - violations of the echocardiogram. From the side of the hemopoietic system: often - anemia, leukopenia, thrombocytopenia, leukocytosis; infrequently - pancytopenia, neutropenia; rarely - thrombotic thrombocytopenic purpura. From the blood coagulation system: infrequently - coagulopathy, deviations in coagulogram indices, rarely - hypoprothrombinemia. From the side of the CNS: very often - tremor, headache, insomnia; frequent - epileptoid seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, dizziness, impaired writing, anxiety, confusion and disorientation, depression, depressed mood, emotional disorders, nightmares, hallucinations, mental disorders; infrequently - coma, hemorrhages in the central nervous system and disorders of cerebral circulation, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia, psychotic disorders; rarely, increased muscle tone; very rarely - myasthenia. For the organ of vision: often - blurred vision, photophobia, eye diseases; infrequently - cataract; rarely - blindness. On the part of the organ of hearing: often - noise (ringing) in the ears; infrequently - hearing loss; rarely - neurosensory deafness; very rarely - hearing impairment. Respiratory system disorders: often - shortness of breath, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequently - respiratory failure, disorders of the respiratory tract, asthma; rarely, acute respiratory distress syndrome. From the digestive system: very often diarrhea, nausea; often - inflammatory diseases of the digestive tract, gastrointestinal ulcers and perforation, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting,gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, feelings of bloating and distention in the abdomen, loose stools, symptoms of gastrointestinal disorders; infrequently - paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased amylase level in the blood, gastroesophageal reflux disease, impaired evacuation function of the stomach; rarely, subileus, pancreatic pseudocysts. From the liver: often - increased levels of liver enzymes, abnormal liver function, cholestasis and jaundice, liver cell damage and hepatitis, cholangitis; rarely - hepatic artery thrombosis, obliterating endoflebitis of the hepatic veins; very rarely - liver failure, stenosis of the bile ducts. From the urinary system: very often - impaired renal function; often - renal failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequently - anuria, hemolytic uremic syndrome; very rarely - nephropathy, hemorrhagic cystitis. Dermatological reactions: often - itching, rash, alopecia, acne, hyperhidrosis; infrequently - dermatitis, photosensitivity; rarely, toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome. From the musculoskeletal system: often - arthralgia, muscle cramps, pain in the limbs, back pain; infrequently - joint disorders. From the endocrine system: very often - hyperglycemia, diabetes mellitus; rarely - hirsutism. Metabolism: very often - hyperkalemia; often - hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, loss of appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; infrequently - dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia. Infections and invasions: during therapy with tacrolimus, like other immunosuppressants, the risk of local and generalized infectious diseases (viral, bacterial, fungal, protozoal) increases. The course of previously diagnosed infectious diseases may worsen; cases of nephropathy,associated with VK virus, as well as progressive multifocal leukoencephalopathy. Injuries, poisoning, complications of procedures: often primary graft dysfunction. Benign, malignant and unidentified tumors: patients receiving immunosuppressive therapy have a higher risk of malignant tumors. When using tacrolimus, both benign and malignant neoplasms, including Epstein-Barr virus-associated lymphoproliferative diseases and skin cancer. On the reproductive system: infrequently - dysmenorrhea and uterine bleeding. The negative effect of tacrolimus on male fertility, expressed in reducing the number and motility of spermatozoa, was found in rats. Allergic reactions: allergic and anaphylactic reactions were observed in patients taking tacrolimus. On the whole body: often asthenia, feverish conditions, swelling, pain and discomfort, increased levels of alkaline phosphatase in the blood, weight gain, impaired perception of body temperature; infrequently - multiple organ failure, flu-like syndrome, impaired perception of ambient temperature, feeling of pressure in the chest, anxiety, worsening of well-being, increased LDH activity in the blood, weight loss; seldom - thirst, loss of balance (falling), feeling of stiffness in the chest, difficulty in moving; very rarely - an increase in the mass of adipose tissue.
Interaction with other drugs
After oral administration, tacrolimus is metabolized in the intestinal cytochrome CYP3A4 system. Simultaneous administration of drugs or medicinal herbs with an established inhibitory or inducing effect on CYP3A4 can accordingly increase or decrease blood tacrolimus concentrations. Based on clinical experience, it was found that the following drugs can significantly increase the blood tacrolimus concentration: , voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir) (this combination may require a reduction in doses s tacrolimus). Pharmacokinetic studies have shown that an increase in the concentration of tacrolimus in the blood is primarily a consequence of an increase in the bioavailability of tacrolimus when ingested, caused by inhibition of the intestinal metabolism of tacrolimus.Suppression of hepatic metabolism of tacrolimus plays a secondary rol.Menee expressed drug interactions observed with simultaneous application of tacrolimus with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinyl estradiol, omeprazole nefazodonom.V and in vitro studies have shown that potential inhibitors tacrolimus metabolism are the following substances: bromocriptine, cortisone, dapsone, ergotamine, gestoden, lidocaine, mephenytoin, miconase l, midazolam, nilvadipine, noretinodron, quinidine, tamoxifen, (triacetyl) oleandomycin. It is recommended to avoid using grapefruit juice due to the possibility of increasing tacrolimus in the blood. Based on clinical experience, it was found that the following drugs can significantly reduce the concentration of tacrolimus in the blood: rifampicin, phenytoin, and St. John's wort (Hypericum perforatum). Clinically significant in borrowing was observed with phenobarbital. Maintenance doses of corticosteroids usually reduce the concentration of tacrolimus in the blood. High doses of prednisolone or methylprednisolone, used to treat acute rejection, can increase or decrease the concentration of tacrolimus in the blood. Carbamazepine, metamizole and isoniazid can reduce the concentration of tacrolimus in the blood. Tacrolimus inhibits the isoenzyme CYP3A4 and, while taking it, can have an effect on the blood. . T1 / 2 cyclosporine with simultaneous use with tacrolimus increases. Synergistic / additive nephrotoxic effects may also occur. For these reasons, concurrent use of cyclosporine and tacrolimus is not recommended, and caution must be exercised when prescribing tacrolimus to patients who have previously taken cyclosporine. Tacrolimus increases the concentration of phenytoin in the blood. Tacrolimus can reduce the clearance of hormonal contraceptives. reduce clearance and increase T1 / 2 phenobarbital and antipyrine. The bioavailability of tacrolimus can increase prokinetic agents (labels lopramid, cisapride), cimetidine, magnesium hydroxide and aluminum. Simultaneous use of tacrolimus with drugs that have nephro or neurotoxicity (for example, aminoglycosides,Girase inhibitors, vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir) can enhance these effects. As a result of the combined use of tacrolimus with amphotericin B and ibuprofen, increased nephrotoxicity was observed. Tacrolimus can promote the development or enhance hyperkalemia (concurrent use of potassium should be observed) potassium-sparing diuretics in high doses). Immunosuppressants can change the body's response to vaccination. Vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided. Tacrolimus is actively associated with plasma proteins. It is necessary to take into account the possible competitive interaction of tacrolimus with drugs with high affinity for plasma proteins (NSAIDs, oral anticoagulants, oral hypoglycemic agents).
special instructions
In the initial post-transplantation period, the following parameters should be regularly monitored: blood pressure, ECG, neurological status and state of vision, fasting blood glucose level, electrolyte concentration (especially potassium), indicators of hepatic and renal function, hematological parameters, coagulogram, level of proteinemia. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary. During the period of use of tacrolimus, the use of herbal preparations containing St. John's wort (Hypericum perforatum), as well as other herbal remedies that can cause a decrease (change) in the concentration of tacrolimus in the blood and have an adverse effect on the clinical effect of tacrolimus. In diarrhea, the concentration of tacrolimus in the blood can vary significantly; when diarrhea appears, careful monitoring of tacrolimus concentrations in the blood is necessary. Simultaneous use of cyclosporine and tacrolimus should be avoided, and caution should be exercised in treating tacrolimus patients who have previously received cyclosporine. When using tacrolimus, cases of cardiomyopathy - ventricular hypertrophy or hypertrophy of the septum of the heart are described. In most cases, myocardial hypertrophy was reversible and was observed at tacrolimus concentrations in the blood that exceed the recommended ones.Other risk factors are: the presence of previous heart disease, the use of corticosteroids, arterial hypertension, renal and hepatic dysfunction, infections, hypervolemia, edema. Patients who are at high risk and receive intensive immunosuppressive therapy, before and after transplantation (after 3 and 9-12 months), should undergo echocardiographic and ECG monitoring. If anomalies are detected, consideration should be given to reducing the dose of tacrolimus or replacing it with another immunosuppressant. Tacrolimus can cause a prolongation of the QT interval. When treating patients with a diagnosed congenital long QT interval syndrome or suspicion of such a condition, special care should be taken. Patients receiving tacrolimus may develop post-transplant lymphoproliferative diseases (PTHL) associated with Epstein-Barr virus. With simultaneous use of the drug with anti-lymphocytic antibodies, the risk of PTLZ increases. There is also evidence of an increase in the risk of PTLZ in patients with the Epstein-Barr virus capsid antigen. Therefore, before using tacrolimus in this group of patients, a serological study should be conducted for the presence of the Epstein-Barr capsid antigen. In the course of treatment, it is recommended to conduct thorough monitoring of the Epstein-Barr virus using the polymerase chain reaction (PCR). Positive PCR for Epstein-Barr virus can persist for months and is not in itself evidence of PTHD or lymphoma. Patients receiving immunosuppressants have an increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). Among these infections, nephropathy associated with the BK virus, as well as progressive multifocal leukoencephalopathy (PML) associated with the JC virus is noted. Such infections are often associated with deep suppression of the immune system and can lead to severe or fatal outcomes, which must be taken into account when carrying out a differential diagnosis in patients with signs of impaired renal function or neurological symptoms during immunosuppressive therapy. Immunosuppressive therapy increases the risk of malignant tumors.It is recommended to limit insolation and ultraviolet radiation, wear appropriate clothing, use sunscreen with a high protection factor. There are reports of the occurrence of reversible posterior encephalopathy syndrome during tacrolimus therapy. If a patient taking tacrolimus develops symptoms characteristic of reversible posterior encephalopathy (headache, mental disorders, convulsions, and visual impairment), then magnetic resonance imaging is necessary. When confirming the diagnosis, one should monitor blood pressure, the occurrence of seizures, and also immediately stop systemic administration of tacrolimus. If these measures are taken, this condition is completely reversible in most patients. Use in pediatrics When used topically, tacrolimus should be used in dosage forms that are appropriate for the child’s age. . During the treatment period, patients should refrain from driving vehicles and working with machinery.