PROTOPIC OINTMENT 0.03% 10G

Indications and usage

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 severity and severe forms) in case of insufficient response of patients to traditional methods of treatment or the presence of contraindications to such.

Adverse Effects

Cardiovascular: very often - myocardial ischemia, tachycardia, arterial hypertension, bleeding, thromboembolic and ischemic complications, impaired peripheral circulation, hypotension; infrequently - ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmias, rapid heartbeat, abnormal ECG, heart rhythm disturbances, heart rate and pulse, heart attack, deep venous thrombosis of extremities, shock; rarely, pericardial effusion; very rarely - violations of the echocardiogram.

Hemic and lymphatic: 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 central nervous system: 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.

On the part of the organ of vision: often - blurred vision, photophobia, eye diseases; infrequently - cataract; rarely - blindness.

From the organ of hearing: often - noise (ringing) in the ears; infrequently - hearing loss; rarely - neurosensory deafness; very rarely - hearing impairment.

Respiratory: 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.

Gastrointestinal: very often - diarrhea, nausea; often - inflammatory diseases of the digestive tract, gastrointestinal ulcers and perforations, Gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, feelings of bloating and abdominal distention, 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.

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.

On the part of 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: with tacrolimus therapy, as well as 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 the BK virus, as well as progressive multifocal leukoencephalopathy.

Injuries, poisoning, complications of procedures: often primary graft dysfunction.

Benign, malignant and unidentified neoplasms: patients receiving immunosuppressive therapy have a higher risk of malignant tumors. When using tacrolimus, both benign and malignant neoplasms, includingEpstein-Barr virus-associated lymphoproliferative diseases and skin cancer.

From the reproductive system: infrequently - dysmenorrhea and uterine bleeding. The negative effect of tacrolimus on male fertility, expressed in a decrease in the number and motility of spermatozoa, was found in rats.

Allergic reactions: Allergic and Anaphylactic reactions were observed in patients taking tacrolimus.

On the part of the body as a whole: often - asthenia, fever, 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.

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 disease; 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).

Pregnancy and Breastfeeding

Contraindicated use during pregnancy and lactation (breastfeeding).

Special notes

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 tacrolimus, the use of herbal preparations containing St. John's wort (Hypericum perforatum), as well as other herbal remedies, which can cause a decrease (change) in the concentration of tacrolimus in the blood and adversely affect the clinical effect of tacrolimus, should be avoided.

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.

The simultaneous use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating patients with tacrolimus who have previously received cyclosporine.

When using tacrolimus, cases of cardiomyopathy are described - ventricular hypertrophy or hypertrophy of the heart walls. 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 may cause 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 treated with 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 profound 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 in the background of immunosuppressive therapy.

Immunosuppressive therapy increases the risk of malignant neoplasms. 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 with 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 you confirm the diagnosis should be monitored blood pressure, the occurrence of seizures,and immediately stop systemic administration of tacrolimus. If these measures are taken, this condition is completely reversible in most patients.

Use in pediatrics

When applied topically, tacrolimus should be used in dosage forms that are appropriate for the age of the child.

Influence on ability to drive motor transport and control mechanisms

Tacrolimus can cause visual and neurological disorders, especially when combined with alcohol. During the treatment period, patients should refrain from driving vehicles and working with machinery.

After oral administration, tacrolimus is metabolized in the intestinal cytochrome CYP3A4 system. The simultaneous administration of drugs or medicinal herbs with an established inhibitory or inducing effect on CYP3A4 can increase or decrease the concentration of tacrolimus in the blood, respectively.

Based on clinical experience, it was found that the following drugs can significantly increase the concentration of tacrolimus in the blood: antifungal agents (ketoconazole, Fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir) (this combination may require dose reduction tacrolimus). Pharmacokinetic studies have shown that an increase in the concentration of tacrolimus in the blood is primarily due to an increase in the bioavailability of tacrolimus when taken orally,caused by inhibition of intestinal metabolism of tacrolimus. Suppression of hepatic metabolism of tacrolimus plays a secondary role.

A less pronounced drug interaction was observed with simultaneous use of tacrolimus with Clotrimazole, Clarithromycin, josamycin, Nifedipine, nicardipine, diltiazem, Verapamil, danazol, ethinyl estradiol, Omeprazole and nefazodone.

In vitro studies have shown that the following substances are potential inhibitors of tacrolimus metabolism: Bromocriptine, Cortisone, dapsone, ergotamine, gestoden, Lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, noretinodron, quinidine, Tamoxifen, (triacetsetil), (triacetseceleta);

It is recommended to avoid the use of grapefruit juice due to the possibility of increasing the level of tacrolimus in the blood.

Lansoprazole and cyclosporin can potentially inhibit CYP3A4-mediated tacrolimus metabolism and increase its concentration in the blood.

Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly reduce the following drugs: rifampicin, phenytoin, and St. John's wort (Hypericum perforatum).

Clinically significant interactions have been 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 CYP3A4 isoenzyme and, when taken simultaneously, may affect the drugs metabolized by the CYP3A4 isoenzyme. T1/2 cyclosporine with simultaneous use with tacrolimus increases. Synergistic / additive nephrotoxic effects may also occur. For these reasons, the simultaneous use of cyclosporine and tacrolimus is not recommended, and when prescribing tacrolimus to patients who have previously taken cyclosporine, care must be taken.

Tacrolimus increases the concentration of phenytoin in the blood.

Tacrolimus can reduce the clearance of hormonal contraceptives.

Experimental studies in animals have shown that tacrolimus has the potential to reduce clearance and increase T1/2 phenobarbital and antipyrine.

The bioavailability of tacrolimus can increase prokinetic agents (metoclopramide, cisapride), cimetidine, Magnesium hydroxide and aluminum.

The simultaneous use of tacrolimus with drugs that have nephro- or neurotoxicity (for example, aminoglycosides, gyrase inhibitors, Vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir) can enhance these effects.

As a result of the joint use of tacrolimus with amphotericin B and Ibuprofen, an increase in nephrotoxicity was observed.

Tacrolimus may contribute to the development or enhance hyperkalemia (the simultaneous use of potassium or potassium-sparing diuretics in high doses should be avoided).

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).