This product should be prescribed by a physician experienced in immunosuppressive therapy and management of organ transplant patients. Patients taking this product should be followed by a healthcare facility with adequate laboratory equipment and medical staff. The physician responsible for maintenance therapy should have all the information necessary for follow-up. The following parameters should be routinely monitored in the early post-transplant period: blood pressure, electrocardiogram, neurological and visual status, fasting blood glucose, electrolytes (especially potassium), liver and renal function tests, haematological parameters, coagulation values, and plasma protein measurements. Adjustment of the immunosuppressive regimen should be considered if clinically relevant changes occur in the above parameters. Medication errors have been observed, including inadvertent, unintentional, or unsupervised switching of application of tacrolimus capsules or tacrolimus extended-release capsules. This may result in serious adverse events, including graft rejection or other side effects due to under- or over-exposure to tacrolimus. Patients should maintain a single dose form of tacrolimus and the corresponding daily dosing regimen. Changes in dosage form or adjustments to the dosage regimen should be made only under the close supervision of a transplant specialist. The concomitant administration of herbal preparations containing Sanguisorba or other herbal preparations should be avoided during the administration of this product; the risk of interactions may lead to a decrease in the blood concentration of the product and a reduction in its clinical efficacy. Blood concentrations of tacrolimus may be significantly altered during diarrhea and it is recommended that tacrolimus blood concentrations should be closely monitored during episodes of diarrhea. Coadministration of tacrolimus and cyclosporine should be avoided, and caution should be exercised when administering tacrolimus to patients previously treated with cyclosporine. Because this product contains lactose. Special attention should be paid to patients with rare genetic disorders such as galactose intolerance, lactase deficiency or glucose-galactose absorption disorders. Tacrolimus may cause visual and neurological disturbances, which may be exacerbated if this product is taken with alcohol. Lymphoma and Other MalignanciesPatients using immunosuppressive agents (including Procopaxil) have an increased risk of developing lymphoma and other malignancies, particularly skin cancer. The risk appears to be related to the intensity and duration of immunosuppression rather than to the type of drug used. Patients at increased risk for skin cancer should normally wear protective clothing and use sunscreen with a high protection factor to limit sunlight and UV exposure. Post-transplant lymphoproliferative disorders (PTLD) have been reported in organ transplant recipients receiving immunosuppressive therapy.The majority of PTLD events have been associated with Epstein Barr virus (EBV) infection.Individuals who are seronegative for EBV appear to be at the highest risk for PTLD, and this population includes many young children. Serious InfectionsPatients using immunosuppressive drugs (including Procopaxil) are at increased risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections can lead to serious outcomes, including death. Combination immunosuppressive therapy should be used with caution due to the risk of excessive immune system suppression, which increases susceptibility to infection. Polyomavirus InfectionsPatients using immunosuppressive agents (including Procopaxil) are at increased risk for opportunistic infections, including polyomavirus infections. Polyomavirus infections in transplant patients can have serious consequences, sometimes resulting in death. Such infections include polyomavirus-associated nephropathy (PVAN), which is mostly caused by BK virus infection, and JC virus-associated progressive multifocal leukoencephalomalacia (PML), which has been seen in patients on tacrolimus.PVAN can lead to serious consequences, including deterioration of renal function and loss of the kidney graft. Monitoring of patients can help identify those at risk for PVAN. Cases of PML have been reported in patients treated with Procopaxil.PML is sometimes fatal and often presents with mild hemiparesis, apathy, confusion, cognitive deficits, and movement disorders.Risk factors for PML include treatment with immunosuppressive drugs and impaired immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis of patients reporting neurologic symptoms and should consult with a neurologist in the clinical setting. For patients who show signs of PVAN or PML. Reduced immunosuppression should be considered. Physicians should also consider the risk of reduced immunosuppression for functioning allografts. Patients with cytomegalovirus (CMV) infections who use immunosuppressive agents (including Procodone) are at increased risk for CMV viremia and CMV disease. The risk of CMV disease is highest among CMV seronegative transplant recipients receiving grafts from CMV seropositive donors at the time of transplantation. Available treatments to limit CMV disease should be routinely offered. Patient monitoring can help identify patients at risk for CMV disease. Lower amounts of immunosuppressive medications should be considered for patients with CMV viremia and/or CMV disease. Post-Transplant New-Onset Diabetes Clinical trials of renal, hepatic, and cardiac transplants have shown that Procopaxil can cause new-onset diabetes. Post-transplant new-onset diabetes is reversible in some patients. Black and Hispanic kidney transplant patients are at increased risk. Blood glucose concentrations should be closely monitored in patients on Procopaxil. Nephrotoxicity As with other calmodulin phosphatase inhibitors, Procopaxil can cause acute or chronic nephrotoxicity, especially at high doses. Acute nephrotoxicity is usually associated with vasoconstriction of the small entering arteries and is characterized by elevated serum creatinine, hyperkalemia, and/or decreased urine output, and is generally reversible. Chronic calcineurin inhibitor nephrotoxicity is often accompanied by elevated serum creatinine, shortened renal graft life, and characteristic histologic changes seen on renal biopsy; changes in chronic calcineurin inhibitor nephrotoxicity are generally progressive. Patients with renal impairment should be monitored closely, as dose reductions of Procoprazole may be required. In patients who do not respond to dose adjustments and have persistent elevations in serum creatinine, consideration should be given to switching to another immunosuppressive therapy. Based on the terminology of reported adverse reactions related to reduced renal function, nephrotoxicity was reported in approximately 52% of renal transplant patients, in approximately 40% and 36% of liver transplant patients in U.S. and European randomized trials, respectively, and in 59% of heart transplant patients in a European randomized trial. Because of the potential for additive or synergistic renal impairment, caution should be exercised when combining Procopaxil with drugs that may cause renal impairment. These drugs include, but are not limited to: aminoglycans, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, 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, vinpocetine), which may inhibit the metabolism of tacrolimus and increase the whole blood concentration of tacrolimus See Drug Interactions. NeurotoxicityProcodone can cause a wide range of neurotoxicity, especially at high doses. The most severe neurotoxicity includes posterior reversible encephalopathy syndrome (PRES), delirium, and coma. PRES has been reported in patients treated with tacrolimus.Symptoms indicative of PRES include headache, altered mental status, seizures, visual disturbances, and hypertension. The diagnosis can be confirmed by radiologic examination. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate dose reduction of immunosuppressive medications is recommended. This syndrome is characterized by an immediate return of symptoms after reducing the dose of immunosuppressive drugs or discontinuing them. In the absence of PRES, coma and delirium invariably occur with high tacrolimus plasma concentrations. Seizures have been seen in adult and pediatric patients treated with Procodone. Neurotoxicity of secondary severity includes tremor, abnormal sensation, headache, and other changes in motor function, mental status, and sensory function. Tremor and headache occur at high whole blood concentrations of tacrolimus, and dose adjustments may be effective. Hyperkalemia has been reported with tacrolimus. Blood potassium levels should be monitored. Careful consideration should be given prior to the use of other medications (potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists) associated with causing hyperkalemia during treatment with Procopaxil. Hypertension Hypertension is a common adverse effect of treatment with Procodone and may require antihypertensive therapy. Although commonly used antihypertensive medications are capable of controlling blood pressure, careful consideration should be given before using antihypertensive medications (potassium-preserving diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists) that have been associated with causing hyperkalemia. Calcium channel blockers may increase tacrolimus blood levels and therefore the dose of this product should be reduced see Drug Interactions. Allergic Reactions to Procodone Injection A small number of patients (0.6%) have experienced allergic reactions when using injections containing castor oil derivatives, including Procodone. The exact cause of such reactions is not known. Procopaxil Injection is intended for use only in patients who cannot take Procopaxil capsules by mouth. Patients on Procodone Injection should be observed continuously for at least the first 30 minutes after initiation of the infusion and frequently thereafter. If signs or symptoms of hypersensitivity occur, the infusion should be discontinued. An aqueous epinephrine solution and an oxygen source should be available at the bedside. Combination with Sirolimus The safety and efficacy of concomitant use of Procopaxel with sirolimus in renal transplant patients have not been established. Excessive mortality, graft failure, and hepatic artery thrombosis (HAT) have occurred with concomitant use of sirolimus and Procopaxil in studies of patients with new liver transplants, and this use is not recommended. Increased risk of renal impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus with concomitant use of sirolimus (2 mg/day) and Procopaxil in heart transplant patients in a U.S. trial; this use is not recommended. Combination with strong inhibitors and inducers of cytochrome P450 3A (CYP3A) See Drug Interactions with strong inhibitors of cytochrome P450 3A (CYP3A) (e.g., ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampicin, rifabutin) when whole-blood glutamate concentration is not closely monitored. Cardiac hypertrophy has been reported to occur in infants, children, and adults, particularly in patients with high tacrolimus trough concentrations, and is generally manifested by echocardiographic evidence of concentric increases in the thickness of the posterior wall of the left ventricle and the interventricular septum. The majority of cases in which this occurred recovered after dose reduction or discontinuation of therapy. Echocardiographic evaluation should be considered in patients who develop renal failure or clinically manifest ventricular dysfunction while on treatment with Procodone. If cardiac hypertrophy is diagnosed, dose reduction or discontinuation of Procopaxil should be considered. Immunizations Live vaccines should not be used during treatment with tacrolimus, including (but not limited to): intranasal influenza vaccine, measles, mumps, rubella, oral polio vaccine, bacillus Calmette-Guérin (BCG), yellow fever, varicella, and TY21a typhoid vaccine. Pure Red Cell Aplasia Several cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. The mechanism by which tacrolimus causes PRCA remains unclear. Possible risk factors for PRCA have been reported in all patients: e.g., microvirus B19 infection, underlying disease, and association with medications associated with PRCA. If PRCA is diagnosed, Procopaxil should be discontinued.