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Advagraf is a brand name for Tacrolimus. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Prophylaxis of transplant rejection in adult kidney or liver allograft recipients. Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.
Verbatim from this product's EMA label. Tap a section to expand.
Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoring by adequately qualified and equipped personnel. This medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.
Different oral formulations of tacrolimus should not be substituted without clinical supervision. Inadvertent, unintentional or unsupervised switching between different oral formulations of tacrolimus with different release characteristics is unsafe.
This can lead to graft rejection or increased incidence of adverse reactions, including under- or over-immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. 8). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.
Posology The recommended initial doses presented below are intended to act solely as a guideline. Advagraf is routinely administered in conjunction with other immunosuppressive agents in the initial post- operative period. The dose may vary depending upon the immunosuppressive regimen chosen.
Advagraf dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below under “Therapeutic drug monitoring”). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.
In de novo kidney and liver transplant patients AUC0-24 of tacrolimus for Advagraf on Day 1 was 30% and 50% lower respectively, when compared with that for the immediate release capsules (Prograf) at equivalent doses. By Day 4, systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients with both formulations.
Careful and frequent monitoring of tacrolimus trough levels is recommended in the first two weeks post-transplant with Advagraf to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Advagraf dose regimen may take several days before steady state is achieved.
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. Infections and infestations 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 CMV infection, 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 Advagraf.
Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders, skin malignancies and Kaposi’s sarcoma have been reported in association with tacrolimus treatment.
4). Endocrine disorders rare: hirsutism Metabolism and nutrition disorders 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 16 Psychiatric disorders very common: insomnia common: confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare uncommon: psychotic disorder Nervous system disorders 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 not known: posterior reversible encephalopathy syndrome (PRES) Eye disorders common: eye disorders, vision blurred, photophobia uncommon: cataract rare: blindness not known: optic neuropathy Ear and labyrinth disorders common: tinnitus uncommon: hypoacusis rare: deafness neurosensory very rare: hearing impaired Cardiac disorders 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 Vascular disorders very common: hypertension common: thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders uncommon: venous thrombosis deep limb, shock, infarction Respiratory, thoracic and mediastinal disorders 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 Gastrointestinal disorders 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 17 rare: pancreatic pseudocyst, subileus Hepatobiliary disorders common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice rare: venoocclusive liver disease, hepatic artery thrombosis very rare: hepatic failure Skin and subcutaneous tissue disorders common: rash, pruritus, alopecias, acne, sweating increased uncommon: dermatitis, photosensitivity rare: toxic epidermal necrolysis (Lyell’s syndrome) very rare: Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders common: arthralgia, back pain, muscle spasms, pain in extremity uncommon: joint disorders rare: mobility decreased Renal and urinary disorders 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 Reproductive system and breast disorders uncommon: dysmenorrhoea and uterine bleeding General disorders and […]
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.
8). Advagraf 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 Advagraf.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for Advagraf. 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. 5). CYP3A4 inhibitors Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which could lead to serious adverse reactions, including nephrotoxicity, neurotoxicity and QT prolongation.
It is recommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin) 7 with tacrolimus should be avoided.
If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of co-administration, under the supervision of a transplant specialist, to adjust the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure.
1. Hypersensitivity to other macrolides.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given. 30 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant 4 changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.
20 mg/kg/day administered once daily in the morning. Administration should commence approximately 12-18 hours after the completion of surgery. Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to Advagraf monotherapy.
Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments. Conversion of Prograf-treated patients to Advagraf Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis.
Advagraf should be administered in the morning. In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1 (mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC0-24) for Advagraf was approximately 10% lower than that for Prograf.
The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) for Advagraf is similar to that of Prograf. When converting from Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks after conversion.
Following conversion, tacrolimus trough levels should be monitored and if necessary dose adjustments made to maintain similar systemic exposure. Dose adjustments should be made to ensure that similar systemic exposure is maintained.
5). The combined administration of ciclosporin and tacrolimus is not recommended. Advagraf therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels.
In practice, tacrolimus-based therapy has been initiated 12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.
Treatment of allograft rejection Increased doses of tacrolimus, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. 8), the dose of Advagraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation For conversion from other […]
Renal function, ECG including the QT interval, and the clinical condition of the patient should also be closely monitored. Dose adjustment needs to be based upon the individual situation of each patient. 5). Similarly, discontinuation of CYP3A4 inhibitors may affect the rate of metabolism of tacrolimus, thereby leading to subtherapeutic blood levels of tacrolimus, and therefore requires close monitoring and supervision of a transplant specialist.
CYP3A4 inducers Concomitant use with CYP3A4 inducers may decrease tacrolimus blood levels, potentially increasing the risk of transplant rejection. It is recommended that concomitant use of strong CYP3A4 inducers (such as rifampicin, phenytoin, carbamazepine) with tacrolimus should be avoided.
If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of co- administration, under the supervision of a transplant specialist, to adjust the tacrolimus dose if appropriate, in order to maintain similar tacrolimus exposure.
5). Similarly, discontinuation of CYP3A4 inducers may affect the rate of metabolism of tacrolimus, thereby leading to supratherapeutic blood levels of tacrolimus, and therefore requires close monitoring and supervision of a transplant specialist.
P-glycoprotein Caution should be observed when co-administering tacrolimus with drugs that inhibit P-glycoprotein, as an increase in tacrolimus levels may occur. Tacrolimus whole blood levels and the clinical condition of the patient should be monitored closely.
5). Herbal preparations Herbal preparations containing St. 5). 5). 5). 5). 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.
Nephrotoxicity Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairment without active intervention may progress to chronic renal impairment. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced.
5). Concurrent use of tacrolimus with drugs known to have 8 nephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus trough blood level and renal function should be monitored […]