Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under- or over-exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see Dosage & Administration and Adverse Reactions).
During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.
When substances with a potential for interaction (see Interactions) - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) - are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.
Herbal preparations containing St. John's wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Prograf due to the risk of interactions that lead to decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus (see Interactions).
The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see Dosage & Administration and Interactions).
High potassium intake or potassium-sparing diuretics should be avoided (see Interactions).
Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see Interactions).
Vaccination: Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.
Gastrointestinal disorders: Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur.
Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.
Cardiac disorders: Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies have been observed on rare occasions. Most cases have been reversible, occurring primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients, particularly young children and those receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g., initially at three months and then at 9- 12 months). If abnormalities develop, dose reduction of Prograf therapy, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see Interactions).
Lymphoproliferative disorders and malignancies: Patients treated with Prograf have been reported to develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (see Adverse Reactions). Patients switched to Prograf therapy should not receive anti-lymphocyte treatment concomitantly. Very young (< 2 years old), EBV-VCA-negative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Prograf. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.
As with other immunosuppressive agents, owing to the potential risk of malignant, skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see Adverse Reactions).
Posterior reversible encephalopathy syndrome (PRES): Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g., MRI) should be performed. If PRES is diagnosed, adequate blood pressure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
Infections including opportunistic infections: Patient treated with immunosuppressants, including Prograf are at increased risk of infections (bacterial, fungal, viral and protozoal) such as BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). Patients are also at an increased risk of infections with viral hepatitis (for example, hepatitis B and C reactivation and de novo infection, as well as hepatitis E, which may become chronic). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in patients with deteriorating hepatic or renal function or neurological symptoms.
Prevention and management should be in accordance with appropriate clinical guidance.
Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.
Excipients: As Prograf contains lactose, special care should be taken in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. The printing ink used to mark Prograf capsules 0.5 mg and 1mg contains soya lecithin. In patients who are hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the benefit of using Prograf.
Prograf 5 mg/ml concentrate for solution for infusion contains polyoxyethylene hydrogenated castor oil, which has been reported to cause anaphylactoid reactions. Caution is therefore necessary in patients who have previously received preparations containing polyoxyethylene castor oil derivative either by intravenous injection or infusion, and in patients with an allergenic predisposition, The risk of anaphylaxis may be reduced by slow infusion of reconstituted Prograf 5 mg/ml concentrate for solution for infusion or by the prior administration of an antihistamine.
The ethanol content (638 mg per ml) of Prograf 5 mg/ml concentrate for solution for infusion should be taken into account.
If administered accidentally either arterially or perivasally, the reconstituted Prograf 5 mg/ml concentrate for solution for infusion may cause irritation at the injection site.
Warnings and precautions for patients with Lupus nephritis: The safety of this product in children has not been established in lupus nephritis (no clinical experiences).
Patients with lupus nephritis also need special attention because the renal disorder may become aggravated as the lupus nephritis progresses.
Since patients with lupus nephritis are more likely to suffer from hyperlipidaemia, hypertension, or the like which is considered to be a risk factor for the development of the coronary artery disease associated with systemic lupus erythematosus, the underlying disease, patients being treated with this product should also receive appropriate therapy for these risk factors of the coronary diseases.
In patients with lupus nephritis, creatinine clearance decreased after 28 weeks of treatment.
There are only a few results from clinical trials in patients with lupus nephritis lasting longer than 28 weeks, and therefore the long-term safety of this product has not been established.
Effects on Ability to Drive and Use Machines: Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if Prograf is administered in association with alcohol.