What Are the Most Common Tacrolimus Side Effects?

Tacrolimus capsules are intended to prevent graft rejection after liver or kidney transplantation. Graft rejection after liver or kidney transplantation cannot be controlled with other immunosuppressive drugs.

Drug Name: Tacrolimus capsules

Drug type: Prescription drugs, work injury drugs
Use classification: Other immunosuppressants

Tacrolimus capsule warnings

Due to immunosuppression, there is an increased risk of lymphoma and other malignancies, especially skin cancer; increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections. This product should be prescribed by a physician with experience in immunosuppressive therapy and organ transplant patient management. Patients taking this product should be followed up by a medical institution equipped with adequate laboratory equipment and medical staff. The physician responsible for maintenance treatment should have all the information needed for follow-up.

Tacrolimus capsule ingredients

The main ingredient of this product is tacrolimus. 26aR]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26a-hexa-decane-5,19-dihydroxy-3- [2 -(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -14,16-dimethoxy-4,10,12,18-tetramethyl-8- (2-propenyl) -15,19-epoxy-3H-pyrido [2,1-c] [1,4] oxaazaheterocosadiene-1,7,20,21 (4H, 23H) -tetraone , Monohydrate. Chemical Structure:

Molecular formula: C ₄₄ H ₆₉ NO ₁₂ · H ₂ O
Molecular weight: 822.03

Tacrolimus capsule properties

0.5mg: light yellow hard capsule, the content is white powder.
1mg: white hard capsule, the content is white powder.
5mg: Gray-red hard capsule, the content is white powder.

Indications for tacrolimus capsules

Prevent graft rejection after liver or kidney transplantation. Graft rejection after liver or kidney transplantation cannot be controlled with other immunosuppressive drugs.

Tacrolimus capsule specifications

0.5mg; 1mg; 5mg.

Dosage and dosage of tacrolimus capsules

The treatment of this product requires close monitoring under conditions equipped with adequate laboratory equipment and personnel. Only physicians experienced in immunosuppressive therapy and transplant patient management can prescribe this product and change the immunosuppressive treatment regimen.
It is not safe to switch between tacrolimus capsules and tacrolimus extended-release capsules accidentally, accidentally or under supervision. This may lead to graft rejection or increased adverse reactions. Including insufficient or excessive immunosuppression due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be treated with a single dosage form of tacrolimus and a corresponding daily dosing regimen. Changing the dosage form or adjusting the dosage can only be performed under the close supervision of a transplant specialist. After any dosage change, the therapeutic agent needs to be monitored and the dose adjusted to ensure consistent systemic exposure of tacrolimus.
The following recommended starting doses are for general guidance only. The dose of proxetil is mainly based on clinical evaluation of rejection and tolerance in individual patients supplemented by blood drug concentration monitoring (see recommended target whole blood trough concentration below). If the clinical symptoms of rejection are obvious, consideration should be given to changing the immunosuppressive treatment regimen.
Proxetil can be administered intravenously or orally. It is usually administered orally, and the capsule contents are suspended in water if necessary, and administered by nasal feeding. (Some transplant research institutions report nasal feeding.)
In the early postoperative period, proxox is usually used in combination with other immunosuppressants, and the dosage varies depending on the immunosuppressive regimen chosen.
Dosing is recommended twice daily (eg morning and evening). Capsules should be taken with a liquid immediately after removal from the blister (preferably with water). Never swallow a desiccant.
It is recommended to take capsules on an empty stomach or 1 hour before or 2 to 3 hours after a meal. To maximize drug absorption.
Tacrolimus is not compatible with PVC. Catheters, syringes, and other equipment used in the preparation and administration of the contents of this product must not contain PVC.
The time limit for administration is to inhibit graft rejection, and patients need to take immunosuppressants for a long time, so the period of oral administration of this product cannot be set.
Dosage recommendationsThe recommended starting dose for adult patients receiving oral this product after surgery:
For patients with liver transplantation, the initial oral dose should be 0.1 to 0.2 mg / kg daily based on body weight, divided into two oral doses, and medication should be started 6 hours after surgery.
For kidney transplant patients, the initial oral dose should be 0.15-0.3 mg / kg daily based on body weight, divided into two oral doses, and medication should be started within 24 hours after surgery.
The dose adjustment after transplantation usually reduces the dose of this product after transplantation. In some cases, combined immunosuppressive therapy can be discontinued and treated with proxetil alone. Improvements in the patient's condition after transplantation may alter the pharmacokinetics of tacrolimus and may require further dose adjustments.
Treatment of rejection Increasing the dose of this product, supplementation with steroid hormone therapy, and intervention with short-term monoclonal or polyclonal antibodies can all be used to control rejection. If signs of poisoning (such as obvious adverse reactions at first sight), you may need to reduce the dose of this product.
Switching from other therapies to procloft should be started at the recommended postoperative oral starting dose.
Patients are converted from cyclosporine to commercial products, and the interval between the first administration of this product does not exceed 24 hours. If the plasma concentration of cyclosporine is too high, the administration time should be further delayed.
Dose Adjustment for Specific Populations. Patients with liver injury may need to reduce the dose to maintain liver whole blood trough concentrations within the recommended target range for patients with severe liver injury.
In patients with renal impairment, the pharmacokinetics of tacrolimus are not affected by renal function, so no dose adjustment is required. However, due to the potential renal toxicity of tacrolimus, close monitoring of renal function (including continuous blood creatinine concentration, creatinine clearance calculation, and urine volume monitoring) is recommended.
Pediatric Patients: See "Pediatric Medication".
Elderly patients: see "Medications for the elderly".
The recommended target whole blood trough concentration is based on a clinical assessment of rejection and tolerance in each patient. Tacrolimus is a drug with a narrow therapeutic window. The therapeutic dose and the toxic dose are quite close, and there are large differences between individuals and individuals. Therefore, the whole blood valley concentration of tacrolimus should be monitored after transplantation.
There are currently several immunoassay methods used to determine the whole blood concentration of tacrolimus including semi-automated microparticle enzyme immunoassay (MEIA) to optimize drug administration. When comparing clinically measured individual concentrations with those published in the literature, care should be taken and consideration should be given to the chosen measurement method. In current clinical practice, whole blood concentrations are monitored using immunoassays.
For oral administration, the trough concentration should be measured about 12 hours after administration, that is, before the next administration. The frequency of whole blood valley concentration monitoring depends on clinical needs. Since Puleco is a low-clearance drug, adjust the dose and maintain it for several days until the blood concentration reaches a steady state before the next adjustment.
Liver transplant patients: The ideal monitoring time in clinical practice is the second or third day after starting the medicine, the first 1 to 2 weeks after transplantation, the average monitoring is 3 times a week, and then gradually reduced, the 3 to 4 weeks Twice a week, once a week from 5 to 6 weeks, and once every 2 weeks from 7 to 12 weeks. Periodic maintenance should be monitored.
Renal transplant patients: During the first 1 to 2 weeks after transplantation, the average is monitored once or twice a week, and then gradually reduced, once a week at 3 to 4 weeks and once every 2 weeks at 5 to 12 weeks. Periodic maintenance should be monitored.
In special cases, such as changes in liver function, side effects, and the use of drugs that change the pharmacokinetics of tacrolimus, the frequency of monitoring must be increased. The tacrolimus whole blood trough concentration should be monitored after dose adjustment, immunosuppressive regimen changes, or with other drugs that may change the tacrolimus whole blood trough concentration.
Analysis of clinical studies shows that the whole blood trough concentration of tacrolimus is maintained below 20ng / ml, and the clinical condition of most patients is controllable. Therefore, the clinical condition of the patient should be considered when explaining the whole blood valley concentration.
Patients with liver transplantation: The target whole blood trough concentration is 10-15 ng / ml within 1 month after operation, 7-11 ng / ml after 2 to 3 months, and 5.0-8.0 ng / ml after 3 months and maintained.
Renal transplant patients: The target whole blood trough concentration within 6 months is 6 to 15 ng / ml, 2 to 3 months is 8 to 15 ng / ml, and 4 to 6 months is 7 to 12 ng / ml. Six After 5 months, it was 5-10 ng / ml and maintained.

Adverse effects of tacrolimus capsules

Due to the patient's underlying disease and multiple medications taken at the same time, adverse reactions associated with immunosuppressive drugs are often difficult to establish.
The following adverse drug reactions are reversible or can be reduced or disappeared after reducing the dose. Compared with intravenous administration, the incidence of adverse reactions was lower in oral administration. The following adverse drug reactions are listed according to the frequency of occurrence: extremely common (1 / 10); common (1 / 100; <1/10); rare (1 / 1,000; <1/100); rare ( 1 / 10,000; <1 / 1,000); very rare (<1 / 10,000); unknown (cannot be estimated from available data).
Cardiac abnormalities, common ischemic coronary artery disease, tachycardia are rare: ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, palpitations, abnormal electrocardiogram, abnormal heart rate and pulse are rare : Pericardial effusion is very rare: Abnormal echocardiography Blood and lymphatic system abnormalities are common: Anemia, leukopenia, thrombocytopenia, leukocytosis, abnormal red blood cell analysis are rare: coagulopathy, abnormal coagulation factor analysis, whole blood cell reduction, neutrophil Rare reduction: thrombotic thrombocytopenic purpura, hypothrombinemia nervous system abnormalities are very common: tremors, headaches common: seizures, disturbances of consciousness, paresthesia and dullness, peripheral neuropathy, dizziness, writing disorders, nervous system disorders Rare: coma, central nervous system bleeding and cerebrovascular accidents, paralysis and local paralysis, encephalopathy, abnormal speech function, forgetfulness are rare: hypertonic muscles are very rare: muscle weakness, eye abnormalities are common: blurred vision, photophobia, and eye discomfort are rare: Cataracts Rare: Blind Ears and Lost Common: Tinnitus is rare: Hearing retardation is rare: Neurological deafness is very rare: Hearing impaired breathing, chest and mediastinal abnormalities are common: dyspnea, abnormal lung parenchyma, pleural effusion, pharyngitis, cough, nasal congestion and inflammation Rare: breathing Failure, respiratory diseases, asthma rare: Acute respiratory distress syndrome gastrointestinal abnormalities are extremely common: diarrhea, nausea common: gastrointestinal inflammation, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulcers, ascites, vomiting , Gastrointestinal and abdominal pain, indigestion signs and symptoms, constipation, flatulence, flatulence, constipation, gastrointestinal signs and symptoms are rare: paralytic intestinal obstruction, peritonitis, acute and chronic pancreatitis, blood amylase High, gastroesophageal reflux, abnormal gastric emptying are rare: intestinal obstruction, pancreatic pseudocysts, kidney and urinary abnormalities are very common: kidney damage is common: renal failure, acute renal failure, oliguria, tubular necrosis, toxic nephropathy, Abnormal urinary system, bladder and urethral symptoms are rare: anuria, hemolytic uremic syndrome are very rare: nephropathy, hemorrhagic cystitis, skin and subcutaneous Woven abnormal common: pruritus, rash, hair loss, acne, sweating uncommon: dermatitis, photosensitive rare: toxic epidermal necrolysis (Lyell's syndrome)
Very rare: skeletal muscle and connective tissue abnormalities in Sj-Jones syndrome are common: joint pain, muscle spasms, limb pain, back pain are rare: joint disorders endocrine abnormalities are rare: hirsutism metabolism and nutrition abnormalities are very common: hyperglycemia, diabetes, high Common hyperkalemia: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, fluid retention, hyperuricemia, loss of appetite, anorexia, metabolic acidosis, high Lipidemia, hypercholesterolemia, hypertriglyceridemia, other electrolyte abnormalities are rare: dehydration, hypoalbuminemia, hyperphosphatemia, hypoglycemia infections and infections, as with other powerful immunosuppressants, take Tacrolimus patients have an increased risk of infection (virus, bacteria, fungi and protozoa). Existing infections may worsen, and systemic or local infections may occur. Patients receiving immunosuppressants, including this product, have reported kidney disease associated with BK virus and progressive multifocal leukoencephalopathy (PML) associated with JC virus.
Injuries, poisoning, and operational complications are common: Medication errors have been observed with primary graft dysfunction, including switching between this product and tacrolimus extended-release capsules by accident, unintentional, or unsupervised administration. Related cases of transplant rejection have been reported in some cases (existing data cannot estimate their frequency).
Benign, malignant, and unspecified tumors (including cysts and polyps)
Patients receiving immunosuppressive therapy have an increased risk of developing malignancies. Benign and malignant tumors have been reported including EBV-associated lymphoid tissue hyperplasia and skin malignancies. May be related to tacrolimus treatment.
Vascular abnormalities are very common: hypertension is common: bleeding, thrombosis and ischemia, peripheral vascular abnormalities, vascular hypotension are rare: infarction, deep venous thrombosis of the limb, general shock and abnormalities at the site of administration are common: weakness, fever, edema, Pain and discomfort, elevated blood alkaline phosphatase, weight gain, and temperature sensory disorders are rare: multiple organ failure, flu-like illness, temperature intolerance, chest pressure, tension, paresthesia, elevated blood lactate dehydrogenase Weight loss is rare: thirst, falls, chest urgency, decreased activity, ulcers are very rare: increased adipose tissue, abnormal immune system, allergies and allergic-like reactions were observed in patients treated with tacrolimus.
Hepatobiliary abnormalities are common: liver enzymes and liver dysfunction, cholestasis and jaundice, hepatocyte damage and hepatitis, cholangitis rare: hepatic artery thrombosis, venous occlusive liver disease are very rare: liver failure, biliary stricture reproductive system and breast abnormalities are rare: dysmenorrhea Mental disorders and uterine bleeding are extremely common: Insomnia is common: anxiety, confusion and disorientation, depression, depressed mood, emotional instability and disorders, nightmares, hallucinations, and mental disorders are rare: mental disorders.

Tacrolimus contraindications

Those who are allergic to tacrolimus or other macrolides, and allergic to any excipients of this product.

Precautions for tacrolimus capsules

This product should be prescribed by a physician with experience in immunosuppressive therapy and organ transplant patient management. Patients taking this product should be followed up by a medical institution equipped with adequate laboratory equipment and medical staff. The physician responsible for maintenance treatment should have all the information needed for follow-up.
The following parameters should be routinely monitored early after transplantation: blood pressure, electrocardiogram, nerve and vision status, fasting blood glucose, electrolytes (especially potassium), liver and kidney function tests, hematological parameters, coagulation value, and plasma protein determination. If clinically relevant changes occur to the above parameters, consideration should be given to adjusting the immunosuppressive treatment regimen.
Medication errors have been observed, including switching to tacrolimus capsules or tacrolimus extended-release capsules due to inadvertent, inadvertent, or unsupervised use. This can lead to serious adverse events, including graft rejection or other side effects caused by insufficient or excessive tacrolimus exposure. Patients should maintain a single dosage form of tacrolimus and a corresponding daily dosing schedule. Changing the dosage form or adjusting the dosage regimen can only be performed under the close supervision of a transplant specialist.
While taking this product, avoid taking herbal preparations containing St. John's wort or other herbal preparations at the same time. The risk of interaction may lead to a decrease in the blood concentration of this product and a reduction in clinical efficacy.
The blood concentration of tacrolimus may change significantly during diarrhea, and it is recommended that the blood concentration of tacrolimus be closely monitored during the onset of diarrhea.
Co-administration of tacrolimus with cyclosporine should be avoided, and caution should be exercised when tacrolimus is administered to patients previously treated with cyclosporine.
Because this product contains lactose. Particular attention should be paid to patients with rare genetic diseases such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
Tacrolimus may cause vision and nervous system disorders, and this effect may be exacerbated if taken with alcohol.
Lymphomas and other malignancies Patients who use immunosuppressants, including plelocox, have an increased risk of lymphomas and other malignancies, especially skin cancer. The risk appears to be related to the intensity and duration of the immunosuppression, regardless of the type of drug used.
Patients with an increased risk of skin cancer should usually wear protective clothing and use sunscreen with a high protection factor to limit sunlight and UV exposure.
Post-transplant lymphoproliferative disease (PTLD) has been reported in organ transplant recipients receiving immunosuppressive therapy. Most PTLD events are related to Epstein Barr virus (EBV) infection. EBV seronegative individuals appear to be at the highest risk for PTLD, and this population includes many young children.
Patients with severe infections who use immunosuppressive drugs, including plelocox, have an increased risk of bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections can cause serious results, including death. Due to the danger of excessive suppression of the immune system and increased susceptibility to infection, caution should be exercised in combination with immunosuppressive agents.
Polyoma virus infections Patients who use immunosuppressive agents, including proctor, have an increased risk of opportunistic infections, including polyoma virus infections. Polyoma infections in transplant patients can have serious consequences, sometimes leading to death. Such infections include polyoma virus-associated kidney disease (PVAN), mostly caused by BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML), which has been seen in patients who have used tacrolimus .
PVAN can cause serious consequences, including worsening renal function and loss of kidney grafts. Patient monitoring can help identify patients at risk for PVAN.
Cases of PML have been reported in patients treated with Proxe. PML is sometimes fatal, often with hemiplegia, indifference, confusion, cognitive deficits, and dyskinesias. Risk factors for PML include immunosuppressive therapy and immune impairment. For immunosuppressed patients, doctors should consider PML when making differential diagnosis of patients who report neurological symptoms, and should consult a neurologist clinically.
For patients showing signs of PVAN or PML. Consideration should be given to reducing immunosuppression. Physicians should also consider reducing the risk of immunosuppression for a functioning allograft.
Patients with cytomegalovirus (CMV) infection who use immunosuppressants, including plelocox, have an increased risk of developing CMV viremia and CMV disease. CMV serology-negative transplant recipients who received grafts from CMV-seropositive donors at the time of transplantation were at the highest risk of developing CMV disease. Existing treatments that limit CMV disease should be routinely provided. Patient monitoring can help identify patients at risk for CMV disease. For patients with CMV viremia and / or CMV disease, consideration should be given to reducing the amount of immunosuppressive drugs.
Clinical trials of kidney, liver and heart transplantation for newly diagnosed diabetic patients after transplantation have shown that proxetil can cause new-onset diabetes. Some patients with recurrent diabetes after transplantation are reversible. Black and Hispanic kidney transplant patients have an increased risk. Blood glucose levels should be closely monitored in patients taking Proxox.
Renal Toxicity Like other calcineurin inhibitors, Proxe can cause acute or chronic nephrotoxicity, especially at high doses. Acute nephrotoxicity is most often associated with vasoconstriction of the arteriolar arteries, and is characterized by elevated serum creatinine, hyperkalemia, and / or decreased urine output. This toxicity is generally reversible. Chronic calcineurin inhibitor nephrotoxicity is often accompanied by an increase in serum creatinine, a shortened kidney graft lifespan, and characteristic histological changes can be seen on renal biopsy; changes in chronic calcineurin inhibitor nephrotoxicity are generally progressive. Patients with impaired renal function should be closely monitored, as reductions in proxetil may be required. For patients who do not respond to dose adjustments and have persistently elevated serum creatinine, consideration should be given to switching to another immunosuppressive therapy.
According to reported adverse reaction terminology related to decreased renal function, approximately 52% of kidney transplant patients reported renal toxicity, and approximately 40% and 36% of liver transplant patients reported renal failure in randomized trials in the United States and Europe, respectively. Toxicity, renal toxicity was reported in 59% of heart transplant patients in a randomized European trial.
Due to potential additive or synergistic renal function impairment, caution should be exercised in combination with Proxox with drugs that may cause renal impairment. These drugs include, but are not limited to, glycosaminoglycans, ganciclovir, amphoteric toxin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritona Wei, indinavir). Likewise, caution should be exercised when used with CYP3A4 inhibitors, such as antifungals (e.g. ketoconazole), calcium channel blockers (e.g. diltiazem, verapamil) and macrolide antibiotics (e.g. : Clarithromycin, erythromycin, aceandromycin), these drugs can inhibit the metabolism of tacrolimus and increase the whole blood concentration of tacrolimus [see Drug Interactions].
Neurotoxicity Proxox can cause a wide range of neurotoxicity, especially when used at high doses. The most severe neurotoxicities include reversible posterior encephalopathy syndrome (PRES), delirium, and coma. PRES has been reported in patients treated with tacrolimus. Symptoms indicative of PRES include headache, altered mental state, seizures, visual impairment, and hypertension. Diagnosis can be confirmed by radiological examination. If PRES is suspected or confirmed, blood pressure control should be maintained and an immediate reduction in the dose of immunosuppressive drugs is recommended. This syndrome is characterized by reduced doses of immunosuppressive drugs or immediate recovery of symptoms after discontinuation.
In the absence of PRES, coma and delirium always occur at high plasma concentrations of tacrolimus. Seizures can be seen in adult and pediatric patients treated with Proxe.
Severe neurotoxicity includes tremor, paresthesia, and headache. Other changes include motor function, mental state, and sensory function. Tremors and headaches may occur at high levels of tacrolimus, and dose adjustment may be effective.
Hyperkalemia has been reported to cause hyperkalemia using tacrolimus. Blood potassium levels should be monitored. In the treatment with proclofen, other drugs (potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists) that cause hyperkalemia should be carefully considered before using.
Hypertension Hypertension is a common adverse reaction to the treatment with Procovir, and antihypertensive treatment may be required. Although commonly used antihypertensive drugs can control blood pressure, antihypertensive drugs (potassium-preserving diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists) related to hyperkalemia are being used. Think carefully before you go. Calcium channel blockers may increase the blood concentration of tacrolimus, so the dose of this product should be reduced [see Drug Interactions].
Allergic reactions to Proxox injections A small number of patients (0.6%) experienced allergic reactions when using injections containing castor oil derivatives (including Proxox). The exact cause of such reactions is unclear. Prolecote injection is for patients who cannot take Prolecole capsules orally.
Patients who use Procote injection should be continuously observed at least during the first 30 minutes after starting the infusion and frequently thereafter. If allergic symptoms or signs occur, the infusion should be stopped. An adrenaline solution and an oxygen source should be available by the bed.
Combination with sirolimus has not established the safety and effectiveness of concurrent use of procloc and sirolimus in patients with renal transplantation.
The simultaneous use of sirolimus and proxecole in studies of new-onset liver transplant patients has shown excessive mortality, transplantation failure, and hepatic arterial thrombosis (HAT), which is not recommended.
In a U.S. trial, patients with heart transplants who used sirolimus (2 mg / day) and proxetil concurrently developed renal impairment, wound healing complications, and an increased risk of diabetes after insulin-dependent transplantation. This is not recommended Kind of usage.
Combination with strong cytochrome P450 3A (CYP3A) strong inhibitors and inducers When whole blood trough concentrations are not closely monitored, it is not recommended to use strong cytochrome P450 3A (CYP3A) strong inhibitors (e.g., ritonavir, ketoconazole , Itraconazole, voriconazole, clarithromycin) and potent inducers (eg, rifampicin, rifabutin) [see Drug Interactions].
Myocardial hypertrophy has been reported in infants, children, and adults, especially in patients with high tacrolimus trough concentrations. Myocardial hypertrophy has generally been demonstrated by echocardiography to demonstrate a concentric increase in the thickness of the posterior wall and the septum of the left ventricle. Most cases of this condition recover after reducing the dose or discontinuing treatment. Echocardiography should be considered in patients with renal failure or clinically manifest ventricular dysfunction when treated with Proxe. If a diagnosis of myocardial hypertrophy is made, consideration should be given to reducing proxetil or stopping the drug.
Immunizations should not use live vaccines while receiving tacrolimus, including (but not limited to): intranasal influenza vaccine, measles, mumps, rubella, oral polio vaccine, BCG, yellow fever Disease, chicken pox and typhoid vaccine.
Patients with simple erythrocyte aplasia have received reports of pure erythrocyte aplastic disorder (PRCA) in patients receiving tacrolimus. The mechanism by which tacrolimus causes PRCA remains unclear. All patients reported possible risk factors for PRCA: such as parvovirus B19 infection, underlying diseases, and combination of PRCA-related drugs. If diagnosed with PRCA, plelocorazole should be discontinued.

Tacrolimus capsules for pregnant and lactating women

Clinical data indicate that tacrolimus can pass through the placenta. Limited data from pregnant patients undergoing organ transplantation have shown that this product does not increase the risk of adverse pregnancy events and outcomes compared to other immunosuppressive drugs. So far, there are other relevant epidemiological data. Pregnant women due to treatment needs, if there is no other safer therapy and only if the potential benefits of the mother outweigh the potential risks to the fetus, this product can be used. If there is drug exposure in the womb, it is recommended to monitor the potential adverse effects of tacrolimus on the newborn (especially on the kidneys). Newborns may be at risk for preterm birth (<37 weeks) and hyperkalemia, but hyperkalemia can return to normal on its own.
In experiments in rats and rabbits, tacrolimus caused embryonic toxicity at maternal toxic doses. Tacrolimus can affect the reproductive capacity of male rats.
Clinical data show that tacrolimus is secreted into milk. Because the adverse effects on newborns cannot be ruled out. Women who take this product should not breastfeed.

Tacrolimus capsules for children

For pediatric patients, it is usually necessary to use 1.5 to 2 times the recommended adult dose to achieve the same blood concentration as an adult (except for those with impaired liver and renal function). Pediatric patients have less experience with starting oral therapies. For children with liver and kidney transplantation, the dose is 0.3 mg / kg per day based on body weight. If oral administration is not possible, intravenous drip should be given continuously for 24 hours.
In the maintenance treatment stage of liver and kidney transplantation, this product must be continuously used to maintain the graft function. Recommendations should be based on individual patient differences. During maintenance treatment, the dosage of this product gradually decreased. The dose adjustment is mainly based on the clinical treatment effect on rejection and the patient's tolerance.

Tacrolimus capsules for the elderly

There is no evidence that dose adjustments are needed in elderly patients.

Tacrolimus capsule drug interactions

Metabolic Interactions Tacrolimus is metabolized by the liver CYP3A4 enzyme. There is also evidence of gastrointestinal metabolism by the CYP3A4 enzyme in the intestinal wall. Combination with other drugs or herbs known to inhibit or induce CYP3A4 enzyme may affect the metabolism of tacrolimus, thereby increasing or decreasing the blood concentration of tacrolimus. Therefore, it is recommended to monitor the blood concentration of tacrolimus and adjust the dose of tacrolimus to maintain similar tacrolimus exposure when combined with drugs that can potentially alter CYP3A4 enzyme metabolism.
Metabolic inhibitors have clinically shown that the following drugs can increase the blood concentration of tacrolimus:
Strong interactions with antifungal drugs such as ketoconazole, fluconazole, itraconazole and voriconazole, macrolide erythromycin, or HIV protease inhibitors (such as ritonavir). When combined with these drugs, almost all patients need to reduce the dose of tacrolimus.
Weaker with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinyl estradiol, omeprazole and nafazodone interaction.
In vitro experiments have shown that the following drugs are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodone, lidocaine, mefentoin, miconazole, milfazole Darzolam, Nilvadipine, Norethindrone, Quinidine, Tamoxifen, Amygdalin.
Grapefruit juice can increase the blood concentration of tacrolimus and should be avoided at the same time.
Lansoprazole and cyclosporine can potentially inhibit tacrolimus metabolism mediated by CYP3A4 and increase its whole blood concentration.
Metabolism inducers have clinically shown that the following drugs can reduce the blood concentration of tacrolimus:
Stronger interactions with rifampicin, phenytoin or St. John's wort, almost all patients may need to increase the dose of tacrolimus. Clinically significant interaction with phenobarbital. Maintenance doses of hormones have been shown to reduce tacrolimus plasma levels.
High-dose prednisolone or methylprednisolone for the treatment of acute rejection can potentially increase or decrease the blood concentration of tacrolimus.
Carbamazepine, analgin, and isoniazid can potentially reduce tacrolimus concentrations.
Effects of Tacrolimus on Metabolism of Other Drugs Tacrolimus is a known inhibitor of the CYP3A4 enzyme. Therefore, tacrolimus may affect the metabolism of such drugs when combined with drugs known to be metabolized by CYP3A4.
When tacrolimus is combined with cyclosporine, the half-life of cyclosporine can be prolonged, and synergistic / cumulative renal toxicity may occur. Therefore, it is not recommended to use tacrolimus in combination with cyclosporine. Attention should be paid to tacrolimus in patients previously treated with cyclosporine.
Tacrolimus can increase the blood concentration of phenytoin.
Tacrolimus can reduce the clearance of hormonal contraceptives, leading to increased hormone exposure, so special care should be taken when choosing contraceptives.
Limited understanding of the interaction between tacrolimus and statins. Available data indicate that when statins are used in combination with tacrolimus, their pharmacokinetics remain essentially unchanged.
Animal experiments show that tacrolimus may reduce the clearance of phenobarbital and antipyrine and extend its half-life.
Other clinically adverse effects Interaction of tacrolimus with drugs known to be nephrotoxic or neurotoxic can increase these toxic effects (e.g., aminoglycosides, gyrase inhibitors, vancomycin, compound Neonomine, a non-steroidal anti-inflammatory drug, ganciclovir or acyclovir).
Amphotericin B and ibuprofen in combination with tacrolimus enhance renal toxicity.
Tacrolimus treatment may cause hyperkalemia or exacerbate preexisting hyperkalemia. Therefore, avoid high potassium intake or use potassium-sparing diuretics (e.g., amiloride, amphotericin, Body Shutong).
Immunosuppressants can affect vaccine response, and vaccination may not be effective during tacrolimus treatment. Therefore, the use of live attenuated vaccines should be avoided.
Effects on protein binding Tacrolimus is highly bound to plasma proteins. Therefore, its possible interaction with other drugs with high plasma protein binding rate (such as non-steroidal anti-inflammatory drugs, oral anticoagulants or oral hypoglycemic agents) should be considered.

Tacrolimus capsules overdose

Experience with overdose is limited. Several occasional overdose events have been reported with symptoms including tremor, headache, nausea, vomiting, infection, rubella, lethargy, elevated blood urea nitrogen and elevated serum creatinine concentration, and elevated alanine aminotransferase.
There is no specific antidote for this product. If overdose occurs, general supportive and symptomatic treatment should be taken.
Due to its large molecular weight, poor water solubility, and extensive binding to red blood cells and plasma proteins, tacrolimus cannot be removed by dialysis. For individuals with extremely high plasma concentrations, hemofiltration or diafiltration can effectively reduce toxic concentrations. For oral poisoning, gastric lavage and the use of adsorbents (such as activated carbon) within a short period of time after taking the drug may be helpful.

Clinical trial of tacrolimus capsules

1. Kidney Transplantation of Proxox / Azathioprine (AZA)
A randomized, careful, non-blind, prospective trial assessing the immunosuppressive effects of proxatil combined with azathioprine and hormones on renal transplant patients after surgery. The trial enrolled 412 kidney transplant patients at 19 clinical research centers in the United States. After stable renal function, that is, serum creatinine 4 mg / dl (median is 4 days after transplantation, range 1 to 14 days), study treatment was started. Patients younger than 6 years were not selected for this trial.
205 patients were randomly entered into the immunosuppressive treatment group mainly based on Proxox, and 207 patients were randomly entered into the immunosuppressive treatment group mainly based on cyclosporine. All patients received prophylactic induction therapy including anti-lymphocyte antibody preparations, hormones, and azathioprine. The overall one-year survival rates for patients and grafts were 96.1% and 89.6%, respectively.
Data from the combination of Proxox with azathionein in this trial showed that in the first three months of the trial, the trough concentration of 80% of patients was maintained at 7-20 ng / ml, and 5-15 ng / ml within 1 year.
Cyclamate / mycophenolate (MMF)
The immunosuppressive effect of proxetil combined with MMF and hormones and induction therapy was studied. In a randomized, open, multi-center trial (Study 1), 1589 renal transplant patients received proctopox (group C, n = 401), sirolimus (group D, n = 399), or both One of the cyclosporine (CsA) regimens (group A, n = 390 and group B, n = 399) in combination with MMF and hormones: all patients except one group of patients in the cyclosporine group received Induction therapy with daclizumab. The trial was conducted outside the United States, and 93% of the trial population was Caucasian. In the trial, the 12-month mortality rate was similar in patients receiving Proxetil / MMF, cyclosporine / MMF, or sirolimus / MMF, at 3%; 3% and 2%; 3%, respectively. Compared to any of the other three groups, patients in the Procloplast group had higher creatinine clearance (eCLcr) (Table 1), as estimated by the Cockcroft-Gault formula, and had fewer ineffective cases. Ineffectiveness was confirmed by biopsy Acute rejection (BPAR), graft loss, death, and / or loss of follow-up (Table 2). Compared with patients who were randomized to receive cyclosporine / MMF, patients who were randomized to receive proxetil / MMF were more likely to develop diarrhea and diabetes after transplantation, and their chances of infection were similar.

a) All deaths / graft loss (numbers of patients n in groups A, B, C, and D are 41, 27, 23, and 42) and patients whose last creatinine value was recorded before the 3rd month visit (A, The number of patients n in groups B, C, and D is 10, 9, 7, and 9, respectively. The glomerular filtration rate (GFR) is recorded as 10 ml / min. For other subjects with a missing creatinine value at 12 months, The last observed creatinine value from month 3 (the number of patients n in groups A, B, C, and D was 11, 12, 15, and 19, respectively) was replaced. If data is missing, weight data is entered to calculate the estimated GFR value.
b) Use Bonferroni correction to adjust multiple (6) pairwise comparisons. Table 2. Incidence of BPAR, graft loss, death, or lost follow-up at 12th month (Study 1)

a) Use Bonferroni correction to adjust multiple (6) pairwise comparisons. The target tacrolimus valley concentration (Ctrough, Tac) specified by the protocol was 3-7 ng / ml; however, Ctrough was observed in the 12-month test, and the median Tac value was about 7 ng / ml (Table 3). About 80% of patients maintain tacrolimus whole blood concentration within the range of 4-11 ng / ml within one year after transplantation.

a) 10th to 90th percentile: Ctrough, Tac (Excluding Ctrough, the lowest 10% and highest 10% of Tac.
The protocol stipulates that the target cyclosporine valley concentration (Ctrough, CsA) of group B is 50-100 ng / ml; the median value of Ctrough and CsA observed in the 12-month test is about 100 ng / ml. The plan stipulates that the target Ctrough, csA of group A is 150-300 ng / ml in the first 3 months, and 100-200 ng / ml from 4 to 12 months; the median value of Ctrough, CsA observed in the first 3 months It was 225ng / ml, and it was 140ng / ml from the 4th month to the 12th month.
The starting dose of MMF for all study groups was 1 g twice a day; by the 12th month, 63% of patients in the tacrolimus treatment group had their MMF dose reduced to less than 2 g per day (Table 4); Approximately 50% of the MMF dose reduction is due to adverse reactions.12(AB)49%45%MMF2g40%MMF

a)MMF2gMMFMMF
(2)424(N=212)(N=212)MMF(1)12/MMF/MMFBPAR12/MMF(4%)/MMF(5)

a)Fishcr95%2(Ctrough,Tac)3716ng/ml515ng/ml3Ctrough,Tac10ng/ml4128ng/ml(6)80%13616ng/ml412512ng/ml

a)1090CtroughTacCtroughTac10%10%
(CtroughCsA)3)125400ng/ml100300ng/ml3CtroughCsA280ng/ml412190ng/ml
MMF112/MMF/MMF62%47%MMF2(7)/MMF/MMF63%55%MMF12(AB)49%45%MMF2g40%MMF

a) Percentage of patients for each time-averaged MMF dose range in different treatment stages. The time-averaged MMF dose of 2 g / day means that the MMF dose did not decrease in these patients during the treatment period.
2. Liver transplantation In two prospective, randomized, non-blind, multi-center trials, the safety and effectiveness of immunosuppressive therapies based on plelocoxine after orthotopic liver transplantation were evaluated. The positive control group used a cyclosporine-based immunosuppressive regimen (CsA / AZA). The immunosuppressive regimens of both trials combined adrenocortical hormones. These trials compared patient and graft survival at 12 months after transplantation.
In a trial conducted in the United States, a total of 529 patients were enrolled in 12 clinical research centers; before surgery, 263 patients were randomly enrolled into the prosox-based immunosuppressive regimen group and 266 patients were enrolled in the CsA / AZA group. Ten of the 12 clinical research centers used the same CsA / AZA protocol, and the other 2 centers used different control protocols. This test excluded patients with renal insufficiency, fulminant liver failure, stage IV encephalopathy, and cancer. Pediatric patients (less than 12 years old) can be enrolled. In the second trial, 8 clinical research centers randomly enrolled 545 patients; before surgery, 270 patients were randomly enrolled in the proscopol-based immunosuppressive regimen group, and 275 patients were enrolled in the CsA / AZA regimen group. In this trial, the positive control group at each center used the local standard CsA / AZA protocol. This trial excludes pediatric patients, but allows patients with renal insufficiency, fulminant liver failure stage IV encephalopathy, and cancers other than primary liver metastases.
In both trials, the one-year patient survival rate and graft survival rate were similar between the treatment group proxetil and the CsA / AZA treatment group. The overall one-year patient survival rate (CsA / AZA and proxetin-based treatment group) was 88% in the US trial and 78% in the European trial. The overall one-year graft survival rate (combined with CsA / AZA and proxox-based treatment groups) was 81% in the US trial and 73% in the European trial. In both trials, the median time to switch from intravenous to oral Proxer was 2 days.
Although there is a lack of a direct correlation between tacrolimus concentration and drug efficacy, clinical trial data from patients with liver transplantation show that the incidence of adverse reactions increases with increasing blood valley concentrations. When the whole blood trough concentration is maintained at 5-20 ng / ml, the condition of most patients is stable. The long-term trough concentration of patients after transplantation is usually maintained at the lower limit of the target range.
Data from clinical trials in the United States show that the median value of whole blood valley concentration measured regularly from 2 weeks to 1 year after transplantation ranges from 9.8 ng / ml to 19.4 ng / ml.

Tacrolimus capsule pharmacology and toxicology

Pharmacological classification: Calcineurin inhibitor.
Mechanism of action and pharmacodynamics At the molecular level, the role of tacrolimus is mediated through its binding to cytosolic protein (FKBP12), which acts to cause tacrolimus to aggregate in cells. FKBP12-tacrolimus complex specifically and competitively binds to calcineurin and inhibits calcineurin, leading to inhibition of calcium-dependent signaling pathways in T cells, thereby blocking a range of lymphokine genes Transcription.
In vitro and in vivo experiments have proved that tacrolimus is a powerful immunosuppressant. In particular, tacrolimus can inhibit the formation of cytotoxic lymphocytes, which is the main factor causing graft rejection. Tacrolimus inhibits the activation of T cells and the proliferation of T helper-dependent B cells and inhibits the formation of lymphokines (such as interleukin-2, interleukin-3, and gamma-interferon) and the expression of interleukin-2 receptors.
Preclinical safety data Toxicity studies in rats and baboons have shown that the kidneys and pancreas are the organs to be affected. Other studies in rats have shown that tacrolimus is toxic to the nervous system and eyes. Reversible cardiotoxicity occurred after intravenous administration of tacrolimus in rabbits.
In reproductive toxicity experiments in rats and rabbits, embryo toxicity was observed at doses in which the mother had a significant toxic reaction. In rats, reproductive functions including delivery are impaired after toxic doses are administered to female rats, and the weight, survival, and developmental capacity of pups at birth are reduced. The effects of tacrolimus on fertility in male rats are reduced sperm count and decreased sperm motility.
Mutagenic in vivo and in vitro related tests have shown that this product has any potential mutagenicity.
Carcinogenicity In one-year chronic toxicity studies (rats and baboons) and long-term carcinogenicity studies (18 months in mice, 24 months in rats, maximum tolerated daily dose of 2.5-5 mg / kg) Does not show any direct tumorigenic potential. According to medication experience, the use of immunosuppressants may cause malignant tumors such as lymphoma and skin cancer, but it rarely occurs in patients using this product.

Pharmacokinetics of tacrolimus capsules

Absorption studies have shown that tacrolimus is absorbed throughout the gastrointestinal tract in men. The tacrolimus blood concentration reached a peak about 1 to 3 hours after the oral administration of this product. In some patients, the absorption of tacrolimus lasts longer and therefore presents a relatively flat absorption curve. The average oral bioavailability of tacrolimus ranges from 20 to 25%.
Oral liver transplant patients (0.30mg / kg / day) after oral administration, most patients reach steady state concentration within 3 days.
In healthy subjects, Proctor 0.5mg, 1mg, and 5mg capsules are bioequivalent when administered at the same dose.
The rate and extent of tacrolimus absorption are greatest on an empty stomach. Diet can reduce the rate and extent of tacrolimus absorption, and this effect is most pronounced after eating high-fat foods. Foods high in carbohydrates have less of an effect.
In stable liver transplant patients, the bioavailability of oral administration of this product decreases after eating medium-fat foods (34% calories), AUC and Cmax of whole blood are reduced by 27% and 50%, respectively, and tmax is prolonged by 173%.
Stable kidney transplant patients take this product immediately after eating a standard continental breakfast. The effect on oral bioavailability is not obvious. The AUC of whole blood decreases by 2-12%, the Cmax decreases by 15-38%, and the tmax increases by 38-80%. .
Bile does not affect the absorption of this product.
At steady state, the area under the drug time curve (AUC) has a good correlation with the whole blood valley concentration. Therefore monitoring whole blood trough concentrations is a good predictor of systemic exposure.
Distribution and elimination of male subjects was biphasic after intravenous infusion of tacrolimus. In the systemic circulation, tacrolimus is highly bound to red blood cells. The whole blood / plasma concentration distribution ratio is approximately 20: 1. In plasma, tacrolimus is highly bound to plasma proteins (> 98.8%), mainly to serum albumin and -1-acid glycoprotein.
Tacrolimus is widely distributed in the body. Calculated based on the plasma concentration, the steady-state volume of tacrolimus distribution was approximately 1300 L (healthy subjects). Calculated by whole blood concentration, it is 47.6L.
Tacrolimus is a low clearance drug. Estimated by whole blood concentration, the average total body clearance (TBC) of healthy subjects was 2.25 L / h. In adult liver, kidney, and heart transplant patients, the average total body elimination rates were 4.1 L / h, 6.7 L / h, and 3.9 L / h, respectively. The total elimination rate of children with liver transplantation is about twice that of adults with liver transplantation. Increased free tacrolimus due to low hematocrit and low protein levels, or increased hormone-induced metabolism, are all reasons for higher clearance of tacrolimus after transplantation.
Tacrolimus has a long half-life and large individual differences. The average half-life of whole blood in healthy subjects is about 43 hours. The average half-life of adult and pediatric liver transplant patients was 11.7 hours and 12.4 hours, respectively, and that of adult kidney transplant patients was 15.6 hours. The shorter half-life observed in transplant patients is due to increased clearance.
Metabolism and biotransformation Tacrolimus is generally metabolized in the liver, and the main metabolic enzyme is P450-3A4. Tacrolimus is also metabolized in the intestinal wall. There are several identified metabolites of tacrolimus, only one of which has shown similar immunosuppressive activity in vitro to tacrolimus. Other metabolites have little or no immunosuppressive activity. Only one inactive metabolite is present at low concentrations in the systemic circulation. Therefore, metabolites have no effect on the pharmacological activity of tacrolimus.
Most of the radioactivity was excreted in the feces after intravenous and oral administration of 14C-labeled tacrolimus. About 2% of the radioactivity is excreted in the urine. Less than 1% of the tacrolimus prototype is detected in urine and feces, suggesting that tacrolimus is almost completely metabolized before elimination: bile is the main elimination route.

Tacrolimus capsule storage

0.5mg: This product should be kept in complete packaging and stored below 25 . 1mg, 5mg: This product should be kept in complete packaging and stored at room temperature (15-30 ° C).

Tacrolimus capsules

Aluminum-plastic packaging 0.5mg: 50 capsules / box 1mg, 5mg: 50 capsules / box; 100 capsules / box

Tacrolimus capsule expiration date

The complete package is valid for 36 months. After opening the aluminum foil bag, it should be used up within 12 months.

Tacrolimus capsules perform the standard

0.5mg: JX20010230 1mg, 5mg: JX200L0481 ^[1]