Medicinal Products

ADOPORT 5 mg

Generic drug of the therapeutic class: Immunology
Active ingredients: Tacrolimus
laboratory: Sandoz

capsule
Box of 50
All forms

Indication

Prevention of graft rejection in liver, kidney or heart transplant patients.

Treatment of allograft rejection resistant to treatment with other immunosuppressive drugs.

Dosage ADOPORT 5 mg Capsule Box of 50

Treatment with ADOPORT requires close supervision by medical staff with the necessary skills and equipment. Only physicians familiar with immunosuppressive drugs and experienced in the management of transplant patients are able to prescribe this drug and initiate changes in immunosuppressive therapy.

Medication errors, including inadvertent, unintentional or no-control substitution between ADOPORT-containing immediate-release and sustained-release formulations, have been observed. This may lead to graft rejection or an increase in the frequency of adverse events, including sub-immunosuppression or over-immunosuppression, due to clinically significant differences in systemic exposure to ADOPORT. Patients should be maintained under one formulation containing ADOPORT with the corresponding daily dosing regimen; the formulation or dosage schedule should be changed only under the close supervision of a transplant specialist (see sections Warnings and precautions for use and Adverse reactions ). Following conversion to any other formulation, therapeutic drug monitoring should be performed and dose adjustments initiated to maintain systemic exposure to ADOPORT.

Overview

The initial dosing recommendations presented below are for illustrative purposes only. The dosage of ADOPORT should be based primarily on the clinical evaluation of the signs of rejection and tolerance for each patient, aided by the monitoring of blood levels (see below for recommendations for whole blood target residuals). In the event of clinical signs of rejection, a modification of the immunosuppressive protocol should be considered.

ADOPORT can be administered intravenously or orally. In general, treatment can be started orally; if necessary, the contents of the capsule can be mixed with water and administered by nasogastric tube.

ADOPORT is generally administered in combination with other immunosuppressive agents in the initial postoperative period. The dose of ADOPORT may vary depending on the chosen immunosuppressive protocol.

Administration mode

It is recommended to administer the daily oral dose in two divided doses (eg morning and evening). Capsules should be taken immediately after removal from the blister pack. Patients should be warned not to swallow the desiccant. The capsules should be swallowed with a liquid (preferably water).

Capsules should generally be taken on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal to allow maximum absorption (see section 5.2 Pharmacokinetic Properties ).

Duration of treatment

Immunosuppression must be maintained to avoid rejection of the graft; therefore, no limitation of the duration of the oral treatment can be given.

Dosing recommendations - Liver transplantation

Prevention of graft rejection - Adults

Oral ADOPORT treatment will start at 0.10-0.20 mg / kg / day in two separate doses (eg morning and evening). Treatment should begin approximately 12 hours after transplantation.

If the patient's clinical condition does not permit oral dosing, the drug should be administered intravenously at a dose of 0.01-0.05 mg / kg / day as a continuous 24-hour infusion.

Prevention of graft rejection - Children

An initial oral dose of 0.30 mg / kg / day will be administered in two divided doses (eg morning and evening). If the clinical condition of the patient does not permit oral administration, an initial intravenous dose of 0.05 mg / kg / day will be administered as a 24-hour continuous infusion.

Dose adjustment during the post-transplant period in adults and children

In general, the dosage of ADOPORT is reduced during the post-transplant period. It is possible in some cases to stop other concomitant immunosuppressive treatments and to use ADOPORT as monotherapy. Improving the patient's condition after transplantation may alter the pharmacokinetics of ADOPORT and may require subsequent dose adjustments.

Treatment of rejection - Adults and children

Increasing ADOPORT dosage, supplemental corticosteroid administration and the introduction of short courses of monoclonal or polyclonal antibodies were used to treat rejection episodes. If signs of toxicity appear (for example, in the case of marked adverse effects - see section 4.8 ), it may be necessary to reduce the dose of ADOPORT.

If ADOPORT is used, treatment should start at the recommended initial oral dose for primary immunosuppression.

For further information on ADOPORT's substitution of ciclosporin, see "Dose Adjustments in Special Patient Populations" below.

Dosage Recommendations - Renal Transplantation

Prevention of graft rejection - Adults

Oral ADOPORT treatment will start at 0.20-0.30 mg / kg / day in two divided doses (eg morning and evening). Treatment should begin 24 hours after transplantation.

If the patient's clinical condition does not permit oral dosing, the drug should be administered intravenously at a dose of 0.05-0.10 mg / kg / day as a continuous 24-hour infusion.

Prevention of graft rejection - Children

An initial oral dose of 0.30 mg / kg / day will be administered in two divided doses (eg morning and evening). If the clinical condition of the patient does not permit oral administration, an initial intravenous dose of 0.075-0.100 mg / kg / day will be administered as a 24-hour continuous infusion.

Dose adjustment during the post-transplant period in adults and children

In general, the dosage of ADOPORT is reduced during the post-transplant period. It is possible in certain cases to stop other concomitant immunosuppressive treatments and thus to use a dual therapy protocol based on ADOPORT. Improving the patient's condition after transplantation may alter the pharmacokinetics of ADOPORT and may require subsequent dose adjustments.

Treatment of rejection - Adults and children

Increasing ADOPORT dosage, supplemental corticosteroid administration and the introduction of short courses of monoclonal or polyclonal antibodies were used to treat rejection episodes. If signs of toxicity appear (for example, in the case of marked adverse effects - see section 4.8 ), it may be necessary to reduce the dose of ADOPORT.

If ADOPORT is used, treatment should start at the recommended initial oral dose for primary immunosuppression.

For more information on ADOPORT's substitution of ciclosporin, see "Dosage Adjustments in Special Patient Populations" below.

Dosage Recommendations - Cardiac Transplantation

Prevention of graft rejection - Adults

ADOPORT can be used either in combination with induction therapy with antibodies (allowing delayed administration of ADOPORT) or without induction therapy with antibodies in clinically stable patients.

Following induction therapy with antibodies, treatment with oral ADOPORT will start at a dose of 0.075 mg / kg / day administered in two divided doses (eg morning and evening). Treatment should begin within 5 days of transplantation as soon as the patient's condition is stabilized. If the patient's clinical condition does not permit oral dosing, the drug should be administered intravenously at a dose of 0.01 to 0.02 mg / kg / day as a continuous 24-hour infusion.

Another therapeutic strategy was published in which oral ADOPORT was administered within 12 hours of transplantation. This approach was reserved for patients with no organ dysfunction (eg renal failure). In this case, an initial oral dose of ADOPORT of 2 to 4 mg daily was administered in combination with mycophenolate mofetil and corticosteroids, or in combination with sirolimus and corticosteroids.

Prevention of graft rejection - Children

ADOPORT has been used with and without antibody induction in cardiac transplanted children.

In patients who have not received anti-body induction therapy, if ADOPORT is initially administered intravenously, the recommended starting dose is 0.03-0.05 mg / kg / day as a continuous 24-hour infusion. in order to reach blood concentrations of ADOPORT between 15-25 ng / ml. The transition to oral therapy should begin as soon as the clinical condition of the patient permits. The first dose of oral therapy should be 0.30 mg / kg / day starting 8 to 12 hours after discontinuation of intravenous therapy.

After induction therapy with antibodies, if ADOPORT is initially administered orally, the recommended starting dose is 0.10-0.30 mg / kg / day administered in two divided doses (eg morning and evening ).

Dose adjustment during the post-transplant period in adults and children

In general, the dosage of ADOPORT is reduced during the post-transplant period. Improving the patient's condition after transplantation may alter the pharmacokinetics of ADOPORT and may require subsequent dose adjustments.

Treatment of rejection - Adults and children

Increasing ADOPORT dosage, supplemental corticosteroid administration and the introduction of short courses of monoclonal or polyclonal antibodies were used to treat rejection episodes.

In adults, if ADOPORT is used, an initial oral dose of 0.15 mg / kg / day will be administered in two divided doses (eg morning and evening).

In children, when ADOPORT is used, an initial oral dose of 0.20-0.30 mg / kg / day will be administered in two divided doses (eg morning and evening).

For more information on ADOPORT's substitution of ciclosporin, see "Dosage Adjustments in Special Patient Populations" below.

Dosing recommendations - Treatment of rejection, other allografts

The recommended dosages for pulmonary, pancreatic or intestinal transplantation are based on limited data from prospective clinical studies. ADOPORT was used at initial oral doses of 0.10-0.15 mg / kg / day in lung transplantation, 0.2 mg / kg / day in pancreatic transplant and 0.3 mg / kg / day in intestinal transplantation. .

Dosage Adjustments in Special Patient Populations

Hepatic insufficiency

Dose reduction may be necessary in patients with severe hepatic impairment to maintain blood residue levels within the recommended range.

Renal insufficiency

As the pharmacokinetics of ADOPORT are not affected by renal function, no dose adjustment should be necessary. However, because of the nephrotoxic potential of ADOPORT, it is recommended to closely monitor renal function (including serum creatinine, creatinine clearance, and urinary flow monitoring).

children

In general, the doses required in children are 1.5 to 2 times higher than in adults to obtain similar blood levels.

Elderly patients

Currently available data do not show the need to adjust dosage in elderly patients.

Substitution of ciclosporin

Increased surveillance is recommended when switching from a ciclosporin-based protocol to an ADOPORT-based protocol (see Warnings and Precautions and Interactions with other medicinal products and other forms of interactions ). Treatment with ADOPORT should be initiated taking into account ciclosporin blood levels and the clinical status of the patient. Administration of ADOPORT should be delayed in case of high blood concentrations of ciclosporin. In practice, treatment with ADOPORT should be initiated 12-24 hours after stopping ciclosporin. The monitoring of ciclosporin blood concentrations should continue after the substitution as the clearance of ciclosporin may be modified.

Recommendations on target residual concentrations in whole blood

The dosage should be based primarily on the clinical evaluation of the signs of rejection and tolerance for each patient.

In order to assist with dosage optimization, several immunoanalytical techniques are available to determine ADOPORT concentrations in whole blood and among them, the semi-automated Microparticle Immunoassay Method (MEIA). The comparison of the concentrations described in the literature with the individual values ​​observed in clinical practice should be evaluated with caution and taking into account the dosing method used. Currently, in clinical practice, monitoring of whole blood concentrations is performed by immunoassay methods.

Residual whole blood concentrations of ADOPORT should be monitored post-transplantation. If administered orally, blood levels should be determined approximately 12 hours after the last dose and just before the next dose. The periodicity of concentration monitoring should be based on clinical status. Given the low clearance of ADOPORT, changes in blood levels may not appear until several days later in case of dose adjustment. Residual blood levels of ADOPORT should be monitored approximately twice weekly during the immediate post-transplant period and then regularly during maintenance therapy. Residual blood levels should also be monitored after any dose adjustment, following changes in the immunosuppressive protocol or after concomitant administration of substances that may affect whole blood ADOPORT concentrations (see section 4.5). other forms of interaction ).

Analysis of clinical studies suggests that when residual blood levels of ADOPORT are kept below 20 ng / ml, the majority of patients can be treated effectively. It is necessary to consider the clinical condition of the patient when interpreting product concentrations in whole blood.

In clinical practice, residual whole blood concentrations are generally between 5-20 ng / ml in liver transplant recipients and 10-20 ng / ml in renal and cardiac transplant patients in the immediate post-transplant period. During maintenance therapy, blood levels generally range from 5-15 ng / ml in liver, kidney and heart transplant recipients.

Against indications

· Hypersensitivity to tacrolimus or other macrolides.

· Hypersensitivity to any of the excipients listed under Composition .

Adoport side effects

The profile of adverse events associated with immunosuppressive therapy is often difficult to establish because of the underlying pathology and the concomitant use of many other drugs.

Most of the side effects listed below are reversible and / or respond to a reduction in dosage. Oral administration appears to be associated with a lower incidence of adverse events than intravenous administration. Adverse effects are listed below in descending order of frequency of occurrence: very common (≥1 / 10); frequent (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10 000, <1/1000); very rare (<1 / 10, 000), not known (can not be estimated based on available data).

Infections and infestations

As with other potent immunosuppressants, patients receiving tacrolimus frequently have an increased risk of infections (viral, bacterial, fungal, protozoal). The evolution of pre-existing infectious diseases can be aggravated. Generalized or localized infections can develop.

Cases of BK virus nephropathy and JC virus progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with immunosuppressants, including tacrolimus.

Benign, malignant and unspecified tumors (including cysts and polyps)

Patients receiving immunosuppressive therapy have an increased risk of developing malignant tumors. Both benign and malignant tumors, including EBV-associated lymphoproliferative syndromes and skin cancers, have been reported in connection with tacrolimus therapy.

Blood and lymphatic system disorders

Frequent: anemia, leukopenia, thrombocytopenia, leukocytosis, erythrocyte abnormalities.

Uncommon: coagulopathies, bleeding and bleeding time abnormalities, pancytopenia, neutropenia.

Rare: idiopathic thrombocytopenic purpura, hypoprothrombinemia.

Not known: erythroblastopenia, agranulocytosis, hemolytic anemia.

Immune system disorders

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Warnings and Precautions ).

Endocrine disorders

Rare: hirsutism.

Metabolism and nutrition disorders

Very common: hyperglycemia, diabetes mellitus, hyperkalemia.

Frequent: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, fluid overload, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, other electrolyte abnormalities.

Uncommon: dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.

Psychiatric disorders

Very common: insomnia.

Frequent: signs of anxiety, confusion and disorientation, depression, depressed mood, mood disorders, nightmares, hallucinations, mental disorders.

Uncommon: psychotic disorders.

Nervous system disorders

Very common: tremors, headache.

Frequent: convulsions, disturbances of consciousness, paresthesia and dysesthesia, peripheral neuropathies, vertigo, impaired writing, disorders of the nervous system.

Uncommon: coma, central nervous system hemorrhages and strokes, paralysis and paresis, encephalopathy, speech and language disorders, amnesia.

Rare: hypertonia.

Very rare: myasthenia.

Eye disorders

Frequent: blurred vision, photophobia, eye disorders.

Uncommon: cataract.

Rare: blindness.

Affections of the ear and labyrinth

Frequent: Tinnitus

Uncommon: hearing loss.

Rare: sensorineural deafness.

Very rare: hearing disorders.

Heart conditions

Frequent: ischemic coronary artery disease, tachycardia.

Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, ECG abnormalities, abnormal pulse and heart rate.

Rare: pericardial effusions.

Very rare: abnormalities of the echocardiogram.

Vascular disorders

Very common: hypertension.

Frequent: haemorrhage, thromboembolic and ischemic events, peripheral vascular disease, hypotensive vascular disorders.

Uncommon: infarction, deep vein thrombosis of a limb, collapse.

Respiratory, thoracic and mediastinal disorders

Frequent: dyspnea, pulmonary parenchymal diseases, pleural effusion, pharyngitis, cough, congestion and nasal inflammation.

Uncommon: Respiratory failure, Respiratory tract disease, Asthma.

Rare: acute respiratory distress syndrome.

Gastrointestinal disorders

Very common: diarrhea, nausea.

Gastrointestinal inflammation, ulceration and perforation of the gastrointestinal tract, gastrointestinal bleeding, stomatitis and ulceration, ascites, vomiting, gastrointestinal and abdominal pain, dyspeptic signs and symptoms, constipation, flatulence, meteorism and bloating, loose stools, gastrointestinal signs and symptoms.

Uncommon: paralytic ileus, peritonitis, acute and chronic pancreatitis, hyperamylasemia, gastroesophageal reflux, gastric emptying.

Rare: subtle, pancreatic pseudocyst.

Hepatobiliary disorders

Frequent: abnormal liver enzymes and function, cholestasis and jaundice, hepatocellular lesions and hepatitis, cholangitis.

Rare: thrombosis of the hepatic artery, hepatic veno-occlusive disease.

Very rare: hepatic insufficiency, stenosis of the bile ducts.

Skin and subcutaneous tissue disorders

Frequent: pruritus, rash, alopecia, acne, sweating.

Uncommon: dermatitis, photosensitivity.

Rare: Bullous erythroderma with epidermolysis (Lyell's syndrome).

Very rare: Stevens-Johnson syndrome.

Musculoskeletal and systemic disorders

Frequent: arthralgia, muscle cramps, pain in the limbs, back pain.

Uncommon: joint disorders

Renal and urinary disorders

Very common: abnormalities of renal function.

Frequent: renal failure, acute renal failure, oliguria, renal tubular necrosis, toxic nephropathy, urinary disorders, bladder and urethral symptoms.

Uncommon: anuria, haemolytic uremic syndrome.

Very rare: nephropathy, haemorrhagic cystitis.

Disorders of reproductive organs and breast

Uncommon: dysmenorrhea and uterine bleeding.

General disorders and administration site conditions

Frequent: asthenia, fever, edema, pain and discomfort, increased alkaline blood phosphatase, weight gain, impaired perception of body temperature.

Uncommon: multi-organ failure, flu-like condition, intolerance to hot and cold, feeling of chest tightness, feeling of nervousness, feeling of not being in a normal state, increased blood lactate dehydrogenase, weight loss.

Rare: thirst, falls, chest tightness, decreased mobility, ulcers.

Very rare: increase in adipose tissue.

Injury, poisoning and procedural complications

Common: primary graft dysfunction.

Medication errors, including inadvertent, unintentional or no-control substitution between tacrolimus-containing sustained-release formulations, have been observed. Following these errors, a number of cases of rejection of the transplanted organ have been reported (the frequency can not be estimated from the available data).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Healthcare professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers - Website: www.ansm.sante.fr

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