Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Teva B.V., Swensweg 5, 2031GA Haarlem, Netherlands
Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.
Hypersensitivity to other macrolides.
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse reactions, including graft rejection, or other adverse reactions 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 sections 4.2 and 4.8).
Tacforius is not recommended for use in children below 18 years due to limited data on safety and/or efficacy.
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients clinical data are not yet available for the prolonged-release formulation of tacrolimus.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for the prolonged-release formulation of tacrolimus.
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 section 4.5) - 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 tacrolimus due to the risk of interactions that lead to either a decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in blood concentrations of tacrolimus and risk of tacrolimus toxicity (see section 4.5).
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 sections 4.2 and 4.5).
High potassium intake or potassium-sparing diuretics should be avoided (see section 4.5).
Certain combinations of tacrolimus with substances known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see section 4.5).
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 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.
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed in patients treated with immediate release tacrolimus on rare occasions and may also occur with prolonged-release tacrolimus. Most cases have been reversible, occurring 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, highrisk patients receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9-12 months). If abnormalities develop, dose reduction of Tacforius, 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 section 4.5).
Patients treated with tacrolimus have been reported to develop Epstein-Barr-Virus (EBV)-associated lymphoproliferative disorders (see section 4.8). A combination of immunosuppressives such as antilymphocytic antibodies (e.g. basiliximab, daclizumab) given concomitantly increases the risk of EBV associated lymphoproliferative disorders. EBV-Viral Capsid Antigen (VCA)-negative patients 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 Tacforius. 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 potent immunosuppressive compounds, the risk of secondary cancer is unknown (see section 4.8).
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.
Patients treated with immunosuppressants, including tacrolimus are at increased risk for infections including opportunistic 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 the differential diagnosis in immunosuppressed patients with deteriorating hepatic or renal function or neurological symptoms. Prevention and management should be in accordance with appropriate clinical guidance.
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 and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
Eye disorders, sometimes progressing to loss of vision, have been reported in patients treated with tacrolimus. Some cases have reported resolution on switching to alternative immunosuppression. Patients should be advised to report changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, and in such cases, prompt evaluation is recommended with referral to an ophthalmologist as appropriate.
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.
There is limited experience in non-Caucasian patients and patients at elevated immunological risk (e.g. retransplantation, evidence of panel reactive antibodies, PRA).
Dose reduction may be necessary in patients with severe liver impairment (see section 4.2).
Tacforius capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Tacforius 5 mg capsules contain ponceau 4R. This may cause allergic reactions.
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
It is strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG), renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).
Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole, voriconazole and isavuconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), or the CMV antiviral letermovir, the pharmacokinetic enhancer cobicistat, and the tyrosine kinase inhibitors nilotinib and imatinib. Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients. Pharmacokinetics studies have indicated that the increase in blood levels is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole, nefazodone and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera.
In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin. Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided. Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.
Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics).
Other potential interactions that may increase systemic exposure of tacrolimus include prokinetic agents (such as metoclopramide and cisapride), cimetidine and magnesium-aluminium-hydroxide.
Clinically the following substances have been shown to decrease tacrolimus blood levels: Strong interactions have been observed with rifampicin, phenytoin, St. John’s Wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels.
High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels. Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.
Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products. The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.4).
Tacrolimus has been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.
Limited knowledge of interactions between tacrolimus and statins is available. Clinical data suggest that the pharmacokinetics of statins are largely unaltered by the co-administration of tacrolimus. Animal data have shown that tacrolimus could potentially decrease the clearance and increase the halflife of pentobarbital and antipyrine.
Mycophenolic acid. Caution should be exercised when switching combination therapy from ciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Active substances which interfere with mycophenolic acid’s enterohepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa.
Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase these effects (e.g., aminoglycosides, gyrase inhibitors, vancomycin, cotrimoxazole, NSAIDs, ganciclovir or aciclovir). Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene, or spironolactone) should be avoided (see section 4.4).
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 (see section 4.4).
Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse reactions on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. To date, no other relevant epidemiological data are available.
Tacrolimus treatment can be considered in pregnant women, when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse reactions of tacrolimus is recommended (in particular effects on the kidneys). There is a risk for premature delivery (<37 week) (incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the newborns had normal birth weight for their gestational age) as well as for hyperkalaemia in the newborn (incidence 8 of 111 neonates, i.e. 7.2%) which, however normalises spontaneously.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3).
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Tacforius.
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).
Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol.
No studies on the effects of tacrolimus on the ability to drive and use machines have been performed.
The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.
The most commonly reported adverse reactions (occurring in >10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.
The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of preexisting infections may be aggravated. Both generalised and localised infections can occur. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including tacrolimus prolonged-release capsules.
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.
common: anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis
uncommon: coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses abnormal
rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia, thrombotic microangiopathy
not known: pure red cell aplasia, agranulocytosis, haemolytic anaemia
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).
rare: hirsutism
very common: diabetes mellitus, hyperglycaemic conditions, hyperkalaemia
common: metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, hypophosphataemia
uncommon: dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
very common: insomnia
common: confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon: psychotic disorder
very common: headache, tremor
common: nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired
uncommon: encephalopathy, central nervous system haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia
rare: hypertonia
very rare: myasthenia
common: eye disorders, vision blurred, photophobia
uncommon: cataract
rare: blindness
not known: optic neuropathy
common: tinnitus
uncommon: hypoacusis
rare: deafness neurosensory
very rare: hearing impaired
common: ischaemic coronary artery disorders, tachycardia
uncommon: heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ventricular hypertrophy, palpitations
rare: pericardial effusion
very rare: Torsades de Pointes
very common: hypertension
common: thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders
uncommon: venous thrombosis deep limb, shock, infarction
common: parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations
uncommon: respiratory failures, respiratory tract disorders, asthma
rare: acute respiratory distress syndrome
very common: diarrhoea, nausea
common: gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal pains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages, gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools
uncommon: acute and chronic pancreatitis, ileus paralytic, gastrooesophageal reflux disease, impaired gastric emptying
rare: pancreatic pseudocyst, subileus
common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
rare: veno-occlusive liver disease, hepatitic artery thrombosis
very rare: hepatic failure
common: rash, pruritus, alopecias, acne, sweating increased
uncommon: dermatitis, photosensitivity
rare: toxic epidermal necrolysis (Lyell’s syndrome)
very rare: Stevens Johnson syndrome
common: arthralgia, back pain, muscle spasms, pain in extremity
uncommon: joint disorders
rare: mobility decreased
very common: renal impairment
common: renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms
uncommon: haemolytic uraemic syndrome, anuria
very rare: nephropathy, cystitis haemorrhagic
uncommon: dysmenorrhoea and uterine bleeding
common: febrile disorders, pain and discomfort, asthenic conditions, oedema, body temperature, perception disturbed
uncommon: influenza like illness, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance
rare: fall, ulcer, chest tightness, thirst
very rare: fat tissue increased
not known: febrile neutropenia
very common: liver function tests abnormal
common: blood alkaline phosphatase increased, weight increased
uncommon: amylase increased, ECG investigations abnormal, heart rate and pulse investigations abnormal, weight decreased, blood lactate dehydrogenase increased
very rare: echocardiogram abnormal, electrocardiogram QT prolonged
common: primary graft dysfunction
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).
Pain in extremity has been described in a number of published case reports as part of CalcineurinInhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used to prepare a suspension of Tacforius capsule contents must not contain PVC.
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