Takrolimus retard-Teva (Capsules) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Pharmaceutical Works, Private Limited Company (Hungary)

ATC Code

L04AD02 (Tacrolimus)

Active Substance

Tacrolimus (Rec.INN registered by WHO)

Dosage Forms

	Tacrolimus retard-Teva	Prolonged-release capsules 0.5 mg: 30, 50, 60 or 100 pcs.
		Prolonged-release capsules 1 mg: 30, 50, 60 or 100 pcs.
		Prolonged-release capsules 5 mg: 30, 50, 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release capsules hard gelatin size 5 with opaque light yellow cap and light orange body; “TR” printed in black ink on the cap, “0.5 mg” printed in black ink on the body.

Excipients: ethylcellulose, hypromellose, lactose monohydrate 450 M, lactose monohydrate 100 M, magnesium stearate, gelatin, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), printing ink (shellac, anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, iron oxide black, sodium hydroxide, purified water).

10 pcs. – blisters (3, 5, 6 or 10) – bag (1) – cardboard packs with leaflet.

Prolonged-release capsules hard gelatin size 4 with opaque white cap and light orange body; “TR” printed in black ink on the cap, “1 mg” printed in black ink on the body.

Excipients: ethylcellulose, hypromellose, lactose monohydrate 450 M, lactose monohydrate 100 M, magnesium stearate, gelatin, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), printing ink (shellac, anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, iron oxide black, sodium hydroxide, purified water).

10 pcs. – blisters (3, 5, 6 or 10) – bag (1) – cardboard packs with leaflet.

Prolonged-release capsules hard gelatin size 0 with opaque grey-red cap and light orange body; “TR” printed in black ink on the cap, “5 mg” printed in black ink on the body.

Excipients: ethylcellulose, hypromellose, lactose monohydrate 450 M, lactose monohydrate 100 M, magnesium stearate, gelatin, titanium dioxide (E171), ponceau 4R (E124), iron oxide yellow (E172), iron oxide red (E172), iron oxide black (E172), printing ink (shellac, anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, iron oxide black, sodium hydroxide, purified water).

10 pcs. – blisters (3, 5, 6 or 10) – bag (1) – cardboard packs with leaflet.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, calcineurin inhibitors

Pharmacological Action

Immunosuppressant. At the molecular level, the effects and intracellular accumulation of tacrolimus are due to binding to a cytosolic protein (FKBP 12). The FKBP 12 – Tacrolimus complex specifically and competitively inhibits calcineurin, providing calcium-dependent blockade of T-cell signal transduction pathways and preventing the transcription of a discrete set of lymphokine genes.

In in vitro and in vivo experiments, Tacrolimus markedly reduced the formation of cytotoxic lymphocytes, which play a key role in transplant rejection. Tacrolimus suppresses the formation of lymphokines (interleukin-2, interleukin-3, γ-interferon), T-cell activation, interleukin-2 receptor expression, and T-helper-dependent B-cell proliferation.

Pharmacokinetics

The absorption of tacrolimus is variable (variability of absorption in adult patients is 6-43%). The bioavailability of tacrolimus averages 20-25%. Bioavailability, as well as the rate and extent of tacrolimus absorption, are reduced when taken concomitantly with food. The nature of bile secretion does not affect the absorption of the drug. The distribution of tacrolimus in the human body after IV administration is biphasic. In the systemic circulation, Tacrolimus is well bound to erythrocytes. The ratio of tacrolimus concentrations in whole blood and plasma is about 20:1. A significant proportion of plasma tacrolimus (> 98.8%) is bound to plasma proteins (serum albumin, α₁-acid glycoprotein).

Tacrolimus is widely distributed in the body. The V_d at steady state based on plasma concentrations is about 1300 L (in healthy individuals). The same parameter calculated from whole blood averages 47.6 L.

Tacrolimus has low clearance. In healthy individuals, the mean total clearance calculated from whole blood concentrations 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 contribute to an increase in the unbound fraction of tacrolimus, accelerating tacrolimus clearance. Corticosteroids used in transplantation may also increase the intensity of metabolism and accelerate tacrolimus clearance.

The T_1/2 of tacrolimus is long and variable. In healthy individuals, the mean T_1/2 in whole blood is approximately 43 h.

Tacrolimus is actively metabolized in the liver, mainly by the CYP3A4 isoenzyme. Tacrolimus metabolism occurs intensively in the intestinal wall. Several metabolites of tacrolimus have been identified. The pharmacological activity of tacrolimus is practically independent of metabolites.

Indications

Prevention and treatment of allograft rejection of the liver, kidney in adult patients. Treatment of allograft rejection resistant to standard immunosuppressive therapy regimens in adult patients.

ICD codes

Dosage Regimen

Determine the initial dose based on the transplanted organ and patient’s clinical status.

Administer the capsules once daily in the morning, consistently either with or without food.

Swallow the capsules whole; do not crush, chew, or divide them.

Initiate therapy approximately 12 hours after IV tacrolimus infusion is discontinued.

For liver transplantation, the recommended initial oral dose is 0.10-0.15 mg/kg/day.

For kidney transplantation, the recommended initial oral dose is 0.15-0.20 mg/kg/day.

Adjust subsequent doses based on frequent therapeutic drug monitoring of tacrolimus whole blood trough concentrations.

Maintain close clinical monitoring for signs of toxicity or organ rejection during the dosage titration period.

Adhere strictly to the concomitant immunosuppressive therapy regimen, typically including corticosteroids.

Manage adverse reactions primarily through dosage reduction; discontinue therapy if severe toxicity occurs.

Exercise caution when switching from other immunosuppressants, particularly cyclosporine; allow for a washout period.

Consider dose adjustments in patients with hepatic impairment or when initiating/discontinuing interacting drugs.

Monitor tacrolimus blood levels more frequently during episodes of diarrhea due to potential for significant concentration changes.

Adverse Reactions

Cardiovascular system very common – myocardial ischemia, tachycardia, arterial hypertension, bleeding, thromboembolic and ischemic complications, peripheral circulation disorders, arterial hypotension; uncommon – ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG parameters, cardiac rhythm, heart rate and pulse disorders, myocardial infarction, deep vein thrombosis of the extremities, shock; rare – pericardial effusion; very rare – echocardiogram abnormalities.

Hematopoietic system common – anemia, leukopenia, thrombocytopenia, leukocytosis; uncommon – pancytopenia, neutropenia; rare – thrombotic thrombocytopenic purpura.

Blood coagulation system uncommon – coagulopathies, abnormalities in coagulation parameters, rare – hypoprothrombinemia.

Nervous system very common – tremor, headache, insomnia; common – epileptiform seizures, consciousness disorders, paresthesia and dysesthesia, peripheral neuropathies, dizziness, writing impairment, anxiety, confusion and disorientation, depression, depressed mood, emotional disorders, nightmares, hallucinations, mental disorders; uncommon – coma, CNS hemorrhages and cerebrovascular disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia, psychotic disorders; rare – increased muscle tone; very rare – myasthenia.

Organ of vision: common – blurred vision, photophobia, eye diseases; uncommon – cataract; rare – blindness.

Organ of hearing: common – tinnitus; uncommon – hearing loss; rare – sensorineural deafness; very rare – hearing disorders.

Respiratory system common – dyspnea, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; uncommon – respiratory failure, airway disorders, asthma; rare – acute respiratory distress syndrome.

Digestive system very common – diarrhea, nausea; common – inflammatory gastrointestinal diseases, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and oral mucosa ulceration, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, abdominal bloating and distension sensations, loose stools, gastrointestinal symptoms; uncommon – paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased blood amylase levels, gastroesophageal reflux disease, impaired gastric emptying; rare – subileus, pancreatic pseudocysts.

Liver: common – increased liver enzyme levels, liver function disorders, cholestasis and jaundice, liver cell damage and hepatitis, cholangitis; rare – hepatic artery thrombosis, obliterating endophlebitis of hepatic veins; very rare – liver failure, bile duct stenosis.

Urinary system: very common – renal function impairment; common – renal failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, bladder and urethra disorders; uncommon – anuria, hemolytic uremic syndrome; very rare – nephropathy, hemorrhagic cystitis.

Dermatological reactions: common – pruritus, rash, alopecia, acne, hyperhidrosis; uncommon – dermatitis, photosensitivity; rare – toxic epidermal necrolysis (Lyell’s syndrome); very rare – Stevens-Johnson syndrome.

Musculoskeletal system: common – arthralgia, muscle cramps, limb pain, back pain; uncommon – joint disorders.

Endocrine system very common – hyperglycemia, diabetes mellitus; rare – hirsutism.

Metabolism very common – hyperkalemia; common – hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; uncommon – dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.

Infections and infestations: during therapy with tacrolimus, as with 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 BK virus-associated nephropathy, as well as progressive multifocal leukoencephalopathy.

Injuries, poisonings, procedural complications: common – primary graft dysfunction.

Benign, malignant and unspecified neoplasms: patients receiving immunosuppressive therapy have a higher risk of malignant tumors. With the use of tacrolimus, the occurrence of both benign and malignant neoplasms has been noted, including Epstein-Barr virus-associated lymphoproliferative diseases and skin cancer.

Reproductive system uncommon – dysmenorrhea and uterine bleeding. A negative effect of tacrolimus on male fertility, expressed in a decrease in the number and motility of spermatozoa, has been established in rats.

Allergic reactions: allergic and anaphylactic reactions have been observed in patients taking Tacrolimus.

General disorders: common – asthenia, febrile conditions, edema, pain and discomfort, increased blood alkaline phosphatase levels, weight gain, body temperature perception disorders; uncommon – multiorgan failure, flu-like syndrome, ambient temperature perception disorders, chest tightness sensation, feeling of anxiety, malaise, increased blood LDH activity, weight loss; rare – thirst, loss of balance (falls), chest stiffness sensation, movement difficulties; very rare – increase in adipose tissue mass.

Contraindications

Pregnancy; lactation (breastfeeding) period; hypersensitivity to tacrolimus.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Special Precautions

In the initial post-transplantation period, regular monitoring of the following parameters should be carried out: blood pressure, ECG, neurological status and vision condition, fasting blood glucose level, electrolyte concentrations (especially potassium), liver and kidney function parameters, hematological parameters, coagulogram, proteinemia level. If clinically significant changes are present, correction of immunosuppressive therapy is necessary.

During the use of tacrolimus, the prescription of herbal preparations containing St. John’s wort (Hypericum perforatum), as well as other herbal remedies that may 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 may change significantly; if diarrhea occurs, careful monitoring of tacrolimus blood concentrations is necessary.

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

Effect on ability to drive vehicles and operate machinery

Tacrolimus may cause visual and neurological disorders, especially in combination with alcohol. During treatment, patients should refrain from driving vehicles and operating machinery.

Drug Interactions

After oral administration, Tacrolimus undergoes metabolism in the intestinal cytochrome CYP3A4 system. Concomitant administration of drugs or herbal medicines with established inhibitory or inducing effects on CYP3A4 may respectively increase or decrease tacrolimus blood concentrations.

Based on clinical experience, it has been established that the following drugs can significantly increase tacrolimus blood concentrations: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir) (with this combination, a dose reduction of tacrolimus may be required). Pharmacokinetic studies have shown that the increase in tacrolimus blood concentration is primarily a consequence of increased oral bioavailability of tacrolimus 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 the 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, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin.

It is recommended to avoid consumption of grapefruit juice due to the possibility of increasing tacrolimus blood levels.

Lansoprazole and cyclosporine may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and increase its blood concentration.

Based on clinical experience, it has been established that the following drugs can significantly decrease tacrolimus blood concentrations: rifampicin, phenytoin, St. John’s wort (Hypericum perforatum).

Clinically significant interaction was observed with phenobarbital.

Corticosteroids in maintenance doses usually decrease tacrolimus blood concentrations. High doses of prednisolone or methylprednisolone used to treat acute rejection may increase or decrease tacrolimus blood concentrations.

Carbamazepine, metamizole and isoniazid can decrease tacrolimus blood concentrations.

Tacrolimus inhibits the CYP3A4 isoenzyme and upon concomitant administration may affect drugs metabolized by the CYP3A4 isoenzyme. The T_1/2 of cyclosporine increases when used concomitantly with tacrolimus. Synergistic/additive nephrotoxic effects may also be observed. For these reasons, concomitant administration of cyclosporine and tacrolimus is not recommended, and caution should be exercised when prescribing tacrolimus to patients who have previously taken cyclosporine.

Tacrolimus increases phenytoin blood concentrations.

Tacrolimus may decrease the clearance of hormonal contraceptives.

Experimental animal studies have shown that Tacrolimus may potentially decrease the clearance and increase the T_1/2 of phenobarbital and antipyrine.

Prokinetic agents (metoclopramide, cisapride), cimetidine, magnesium and aluminum hydroxide may increase the bioavailability of tacrolimus.

Concomitant use of tacrolimus with drugs possessing nephro- or neurotoxicity (e.g., aminoglycosides, gyrase inhibitors, vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir) may contribute to an enhancement of these effects.

Enhanced nephrotoxicity was observed as a result of concomitant use of tacrolimus with amphotericin B and ibuprofen.

Tacrolimus may promote the development of or enhance hyperkalemia (concurrent use of potassium or high doses of potassium-sparing diuretics should be avoided).

Immunosuppressants may alter 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 actively binds to plasma proteins. Possible competitive interaction of tacrolimus with drugs that have a high affinity for plasma proteins (NSAIDs, oral anticoagulants, oral hypoglycemic agents) should be taken into account.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.