CAPEXION

Capexion therapy requires careful monitoring by adequately qualified and equipped personnel. The medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.

Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, 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. General considerations The recommended initial dosages presented below are intended to act solely as a guideline.

Tacrolimus dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below for recommended target whole blood through concentrations If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

Tacrolimus can be administered intravenously or orally. In general, dosing may commence orally, if necessary, by administering the capsule contents suspended in water, via nasogastric tubing. Tacrolimus is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period.

The Capexion dose may vary depending upon the immunosuppressive regimen chosen. g. morning and evening). Capsules should be taken immediately following removal from the blister. The capsules should be swallowed with fluid (preferably water).

2). Patients should be advised not to swallow the desiccant. Duration of dosing To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given. g. morning and evening).

Administration should commence approximately 12 hours after the completion of surgery. 05 mg/kg/day should be initiated as a continuous 24-hour infusion. g. morning and evening). 05 mg/kg/day should be administered as a continuous 24- hour infusion.

Dose adjustment during post-transplant period in adults and children Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to tacrolimus monotherapy.

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).

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 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 and skin malignancies have been reported in association with tacrolimus treatment.

4).

Endocrine disorders Rare:

Hirsutism Metabolism and nutrition disorders 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 Psychiatric disorders Very common: Insomnia Common: Anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmare, hallucination, mental disorders, Uncommon: Psychotic disorder Nervous system disorders Very common: Headache, tremor 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 Eye disorders Common: Vision blurred, photophobia, eye disorders Uncommon: Cataract Rare: Blindness Ear and labyrinth disorders Common: Tinnitus Uncommon: Hypoacusis Rare: Deafness neurosensory Very rare: Hearing impaired Cardiac disorders 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 Vascular disorders Very common: Hypertension Common: Haemorrhage, thromboembolic and ischaemic events, peripheral vascular disorders, vascular hypotensive disorders Uncommon: Infarction, venous thrombosis deep limb, shock Respiratory, thoracic and mediastinal disorders 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 Gastrointestinal disorders 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, gastro oesophageal reflux disease, impaired gastric emptying Rare: Subileus, pancreatic pseudocyst Hepatobiliary disorders Common: Cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis Rare: Hepatic artery thrombosis, venoocclusive liver disease Very rare: Hepatic failure, bile duct stenosis Skin and subcutaneous tissue disorders Common: Pruritus, rash, 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, muscle cramps, pain in limb, back pain, Uncommon: Joint disorders Rare: Mobility decreased Renal and urinary disorders 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 Reproductive system and breast disorders Uncommon: Dysmenorrhoea and uterine bleeding General disorders and administration site conditions 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, […]

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 overexposure to tacrolimus.

8). 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) - 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. 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.

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.

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