DAILIPORT

Dailiport is a once-a-day oral formulation of tacrolimus. Dailiport 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 formulation of tacrolimus with different release characteristics is unsafe.

This can lead to graft rejection or increased incidence of adverse reactions, including under- or overimmunosuppression, 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. Dailiport 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.

Dailiport 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 tacrolimus prolonged-release on Day 1 was 30% and 50% lower respectively, when compared with that for tacrolimus immediate-release 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 Dailiport to ensure adequate drug exposure in the immediate post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Dailiport 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 tacrolimus.

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). Undesirable effects System organ class Frequency Adverse reaction Common Anaemia, Thrombocytopenia, Leukopenia, Red blood cell analyses abnormal, Leukocytosis Blood and lymphatic system disorders Uncommon Coagulopathies, Pancytopenia, Neutropenia Coagulation and bleeding analyses, abnormal Thrombotic microangiopathy Rare Thrombotic thrombocytopenic purpura Hypoprothrombinaemia, Not known Pure red cell aplasia, Agranulocytosis, haemolytic anaemia, febrile neutropenia 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 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 Not Known Myasthenia Posterior reversible encephalopathy syndrome (PRES) Eye disorders Common Eye disorders, Vision blurred, Photophobia Uncommon Cataract Rare Unknown Blindness 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, Periphera vascular disorders Uncommon Venous thrombosis deep limb, shock, infarction Respiratory, thoracic and mediastinal disorders Common Parenchymal lung disorders, Dyspnoea, Pleura 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, Gastrointestina 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 Hepatobiliary disorders Common Bile duct disorders, Hepatocellular damage and hepatitis, Cholestasis and jaundice Rare Venoocclusive liver disease, Hepatitic 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 urethra symptoms Uncommon Haemolytic uraemic syndrome, Anuria Very rare Nephropathy, Cystitis haemorrhagic Reproductive system and breast disorders Uncommon Dysmenorrhoea and uterine bleeding General disorders and administration site conditions […]

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). Dailiport 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 tacrolimus prolonged-release.

For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for tacrolimus prolonged-release. 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) 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.