Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Astellas Pharma Ltd., 2000 Hillswood Drive, Chertsey, Surrey, KT16 0RS, United Kingdom
Hypersensitivity to tacrolimus or other macrolides.
Hypersensitivity to any of the excipients listed in section 6.1 – in particular polyoxyethylene hydrogenated castor oil or structurally related compounds.
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 Prograf 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 drugs 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 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 section 4.5).
Patients treated with Prograf have been reported to develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (see section 4.8). Patients switched to Prograf therapy should not receive anti-lymphocyte treatment concomitantly. Very young (<2 years), 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 section 4.8).
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.
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.
Patients treated with immunosuppressants, including Prograf 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.
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.
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.
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 derivatives 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. Patients should be closely observed during the first 30 minutes of infusion for possible anaphylactoid reaction.
The ethanol content (638 mg per ml) of Prograf 5 mg/ml concentrate for solution for infusion should be taken into account.
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
It is therefore 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 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 isavuconalzole, 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.
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, norethisterone, quinidine, tamoxifen, troleandomycin.
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 medicinal products 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 the prokinetic agent metoclopramide, 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 or 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. Available data suggests 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 half-life of pentobarbital and phenazone.
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. Drugs 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, sulfamethoxazole+trimethoprim, 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 is able to cross the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse effects 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. Due to the need of treatment, tacrolimus 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 effects of tacrolimus is recommended (in particular the effects on the kidneys). There is a risk for premature delivery (<37 week) as well as for hyperkalaemia in the newborn, which, however, normalizes 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 into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Prograf.
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).
Not relevant.
The adverse drug reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medications.
Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
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 pre-existing 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 Prograf.
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, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal
uncommon: coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia
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 under Excipients).
rare: hirsutism
very common: hyperglycaemic conditions, diabetes mellitus, hyperkalaemia
common: hypomagnesaemia, hypophosphataemia, hypokalaemia, hypocalcaemia, hyponatraemia, fluid overload, hyperuricaemia, appetite decreased, metabolic acidoses, hyperlipidaemia, hypercholesterolaemia, hypertriglyceridaemia, other electrolyte abnormalities
uncommon: dehydration, hypoproteinaemia, hyperphosphataemia, hypoglycaemia
very common: insomnia
common: anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmare, hallucination, mental disorders
uncommon: psychotic disorder
very common: tremor, headache
common: seizures, disturbances in consciousness, paraesthesias and dysaesthesias, peripheral neuropathies, dizziness, writing impaired, nervous system disorders
uncommon: coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and language abnormalities, amnesia
rare: hypertonia
very rare: myasthenia
common: vision blurred, photophobia, eye disorders
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: ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations
rare: pericardial effusion
very rare: Torsades de Pointes
very common: hypertension
common: haemorrhage, thrombembolic and ischaemic events, peripheral vascular disorders, vascular hypotensive disorders
uncommon: infarction, venous thrombosis deep limb, shock
common: dyspnoea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammations
uncommon: respiratory failures, respiratory tract disorders, asthma
rare: acute respiratory distress syndrome
very common: diarrhoea, nausea
common: gastrointestinal inflammatory conditions, gastrointestinal ulceration and perforation, gastrointestinal haemorrhages, stomatitis and ulceration, ascites, vomiting, gastrointestinal and abdominal pains, dyspeptic signs and symptoms, constipation, flatulence, bloating and distension, loose stools, gastrointestinal signs and symptoms
uncommon: ileus paralytic, acute and chronic pancreatitis, gastrooesophageal reflux disease, impaired gastric emptying
rare: subileus, pancreatic pseudocyst
common: cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis
rare: hepatitic artery thrombosis, venoocclusive liver disease
very rare: hepatic failure, bile duct stenosis
common: pruritus, rash, alopecias, acne, sweating increased
uncommon: dermatitis, photosensitivity
rare: toxic epidermal necrolysis (Lyell’s syndrome)
very rare: Stevens Johnson syndrome
common: arthralgia, muscle spasms, pain in extremity, back pain
uncommon: joint disorders
rare: mobility decreased
very common: renal impairment
common: renal failure, renal failure acute, oliguria, renal tubular necrosis, nephropathy toxic, urinary abnormalities, bladder and urethral symptoms
uncommon: anuria, haemolytic uraemic syndrome
very rare: nephropathy, cystitis haemorrhagic
uncommon: dysmenorrhoea and uterine bleeding
common: asthenic conditions, febrile disorders, oedema, pain and discomfort, body temperature perception disturbed
uncommon: multi-organ failure, influenza like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal
rare: thirst, fall, chest tightness, ulcer
very rare: fat tissue increased
not known: febrile neutropenia
common: hepatic enzymes and function abnormalities, 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
Pain in extremity has been described in a number of published case reports as part of Calcineurin-Inhibitor 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
When diluting, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Tacrolimus is absorbed by PVC plastics. Tubing, syringes and any other equipment used to prepare and administer Prograf 5 mg/ml concentrate for solution for infusion should not contain PVC.
Tacrolimus is unstable under alkaline conditions. Combination of the reconstituted Prograf 5 mg/ml concentrate for solution for infusion with other pharmaceutical products that produce a marked alkaline solution (e.g. aciclovir and ganciclovir) should be avoided.
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