TACROLIMUS - GENERIC DRUG - PACKAGE LEAFLET - LEAFLETS

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Tacrolimus - Generic Drug - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Tacrolimus

Tacrolimus Accord Healthcare 0.5 mg hard capsules
Tacrolimus Accord Healthcare 1 mg hard capsules
Tacrolimus Accord Healthcare 5 mg hard capsules

Why is Tacrolimus used - Generic drug? What is it for?

Tacrolimus belongs to a group of medicines called immunosuppressants. After an organ transplant (e.g. liver, kidney or heart), your body's defense system will try to reject the new organ. Tacrolimus is used to prevent rejection of recently transplanted organs.

Tacrolimus may also be prescribed to treat transplant organ rejection. If you are taking medicines to prevent rejection and these are not effective enough, your doctor may change your treatment by starting tacrolimus therapy.

Tacrolimus is often used in combination with other medicines that also suppress the immune system.

Contraindications When Tacrolimus should not be used - Generic drug

Do not take Tacrolimus Accord Healthcare:

if you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 6)
if you are allergic to macrolide antibiotics, eg. erythromycin, clarithromycin, iosamycin.

Precautions for use What you need to know before taking Tacrolimus - Generic drug

Talk to your doctor or pharmacist before taking Tacrolimus Accord Healthcare:

You will need to take tacrolimus every day until you need immunosuppression to prevent rejection of your transplanted organ. Keep in regular contact with your doctor.
During the period of treatment with Tacrolimus Accord Healthcare, your doctor may decide to periodically carry out a series of tests (including blood, urine, heart function, vision and neurological tests). These tests are normal and necessary to ensure that your doctor can determine the most appropriate dose of tacrolimus for you.
Do not take herbal remedies, eg. St. John's wort (Hypericum perforatum) or other herbal medicine, as these can affect the action of tacrolimus and therefore the dose you should take. If in doubt, contact your doctor before taking any herbal medicine.
If you have liver problems or have ever had a disease which may have affected your liver, please tell your doctor as this may affect the dose of Tacrolimus Accord Healthcare you receive.
If you have had diarrhea for more than a day, please tell your doctor, as the dose of Tacrolimus Accord Healthcare you receive may need to be adjusted.
While taking Tacrolimus Accord Healthcare, limit your exposure to sunlight and ultraviolet light while taking Tacrolimus Accord Healthcare by wearing protective clothing that completely covers your body and applying a sunscreen with a high protection factor. It must do this because of the possible risk of skin cancer changes during immunosuppressive therapy.
If you need to have a vaccination, tell your doctor in advance. Your doctor will advise you on the best solution.

Interactions Which drugs or foods can modify the effect of Tacrolimus - Generic drug

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Tacrolimus should not be taken with cyclosporine.

The levels of tacrolimus in the blood can be affected by taking other medicines, and the levels of other medicines in the blood can be affected by taking tacrolimus. Consequently, the tacrolimus dose may need to be increased or decreased. In particular, you should tell your doctor if you take or have recently taken medicines containing active ingredients, such as:

antifungal medicines and antibiotics (especially those called macrolide antibiotics) to treat infections, such as ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole, erythromycin, clarithromycin, iosamycin and rifampicin
HIV protease inhibitors, eg ritonavir
omeprazole or lansoprazole, for the treatment of stomach ulcers
hormone treatments with ethinylestradiol (such as the contraceptive pill) or danazol
medicines used to treat high blood pressure, such as nifedipine, nicardipine, diltiazem and verapamil
medicines known as 'statins' for the treatment of high cholesterol and triglyceride levels
anti-epileptic medicines, phenobarbital and phenytoin
the corticosteroids prednisolone and methylprednisolone
the antidepressant nefadozone
St. John's wort (Hypericum perforatum) or other herbal medicines (see Warnings and precautions)
anti-emetic medicines, used to treat nausea and vomiting (e.g. metoclopramide)
cisapride or magnesium-aluminum hydroxide antacid, used to treat heartburn.

Tell your doctor in advance if you are taking this medicine, if you need to have any vaccinations.

Tell your doctor if you are taking (or are taking) ibuprofen, amphotericin B or antiviral drugs (such as aciclovir). These medicines can aggravate kidney and nervous system disorders when taken with Tacrolimus Accord Healthcare.

While taking Tacrolimuns Accord Healthcare, you should tell your doctor if you use potassium supplements or potassium-sparing diuretics (some diuretics such as amiloride, triamterene or spironolactone), certain pain relievers (called NSAIDs, such as ibuprofen), anticoagulants or medicines oral for the treatment of diabetes.

Taking Tacrolimus Accord Healthcare with food and drink:

You should generally take Tacrolimus Accord Healthcare on an empty stomach either at least 1 hour before or 2-3 hours after a meal. You should not consume grapefruit or grapefruit juice while taking Tacrolimus Accord Healthcare.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility:

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Tacrolimus is excreted in breast milk. You should therefore not breast-feed while taking Tacrolimus Accord Healthcare.

Driving and using machines:

Do not drive or use tools or machines if you feel dizzy or sleepy, or have difficulty seeing clearly after taking Tacrolimus Accord Healthcare. These effects are most noticeable when Tacrolimus Accord Healthcare is taken at the same time as alcoholic beverages.

Tacrolimus Accord Healthcare contains lactose

Tacrolimus Accord Healthcare 0.5 / 1/5 mg capsules contain 0.050 / 0.048 / 0.098 g of lactose, respectively. When taken at the recommended doses, each dose provides 0.050 / 0.048 / 0.098g of lactose, respectively. If you have been told by your doctor that you have "intolerance to some sugars, consult your doctor before taking this medicine. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Dose, Method and Time of Administration How to use Tacrolimus - Generic drug: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

The starting dose of Tacrolimus Accord Healthcare to prevent rejection of the transplanted organ will be decided by your doctor and will be based on your body weight. The first dose immediately after the transplant operation will usually be between 0.075 and 0.30 mg per kg of body weight per day, depending on the transplanted organ.

Your dose will depend on your general condition and if you are taking other immunosuppressive drugs. Your doctor will have regular blood tests to determine the correct dose and occasionally to adjust it. Your doctor will usually reduce the dose of Tacrolimus Accord Healthcare when your condition has stabilized. Your doctor will tell you exactly how many tacrolimus hard capsules to take and how often.

Tacrolimus Accord Healthcare capsules are taken orally twice a day, usually in the morning and evening. You should generally take Tacrolimus Accord Healthcare on an empty stomach either at least 1 hour before or 2-3 hours after a meal. The hard capsules should be swallowed whole with a glass of water.

Take the capsule immediately after removal from the blister. Avoid grapefruit juice while taking tacrolimus.

If you forget to take Tacrolimus Accord Healthcare

Do not take a double dose to make up for a forgotten dose.

If you have forgotten to take your tacrolimus capsules, wait until it is time for your next dose and then continue as usual.

If you stop taking Tacrolimus Accord Healthcare

Stopping treatment with Tacrolimus Accord Healthcare may increase the risk of organ rejection. Do not stop treatment unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken an overdose of Tacrolimus - Generic drug

If you have accidentally taken too many capsules, contact your doctor immediately or contact the emergency department of the nearest hospital.

Side Effects What are the side effects of Tacrolimus - Generic drug

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Immunosuppressants, including tacrolimus, reduce defense mechanisms to prevent the body from rejecting the transplanted organ. As a result, your body will not be able to fight off infections as it normally does. So if you take tacrolimus it could be. be prone to more infections than usual, such as skin, oral, gastric, intestinal, lung and urinary infections.

Serious effects, including allergic and anaphylactic reactions, have been reported. Benign and malignant tumors have been reported following tacrolimus therapy due to immunosuppression.

Possible side effects are listed in frequency groups, using the following categories:

very common: affects more than 1 in 10 patients
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 in 10,000 patients
not known: frequency cannot be estimated from the available data

Very common

increased blood sugar
diabetes mellitus
increased potassium in the blood
difficulty in falling asleep
tremor
headache
increase in blood pressure
diarrhea
nausea
kidney problems

common

decrease in the number of blood cells (platelets, red or white blood cells) increase in the number of white blood cells, changes in the number of red blood cells
decrease in magnesium, phosphate, potassium, calcium or sodium in the blood, fluid overload, increase in uric acid or lipids in the blood, decreased appetite, increased acidity of the blood, other changes in blood salts
symptoms of anxiety, confusion and disorientation, mood changes, depression, nightmares, hallucinations, mental disorders
seizures, disturbances of consciousness, tingling and numbness (sometimes with pain) in the hands and feet, dizziness, impaired ability to write, nervous system disorders
blurred vision, increased sensitivity to light, eye diseases
ringing in the ears
reduced blood flow in the vessels of the heart, rapid heartbeat
bleeding, partial or total blockage of blood vessels, decrease in blood pressure
shortness of breath, changes in lung tissue, collection of fluid around the lung, inflammation of the pharynx, cough, flu-like symptoms
inflammation or ulcers causing abdominal pain or diarrhea, bleeding in the stomach, inflammation or ulcers in the mouth, collection of fluid in the abdomen, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, loose stools, stomach problems
changes in enzyme levels and liver function, yellowing of the skin due to liver problems, liver tissue damage and inflammation of the liver
itching, rash, hair loss, acne, increased sweating
pain in the joints, limbs or back, muscle cramps
insufficient kidney function, reduced urine production, impaired or painful urination
general weakness, fever, collection of fluids in the body, pain and discomfort, increase in the enzyme alkaline phosphatase in the blood, weight gain, sensation of altered temperature
insufficient function of the transplanted organ

Uncommon

changes in blood clotting, reduction in all blood cell counts
dehydration, decreased protein or sugar in the blood, increased phosphate in the blood
coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and speech disorders, memory problems
opacity of the lens
hearing disorders
irregular heartbeat, stopped heartbeat, decreased heart performance, heart muscle disorder, enlarged heart ventricles (lower chambers), rapid heartbeat, abnormal ECG, abnormal heart rate and pulse
blood clot in a vein in a limb, shock
difficulty in breathing, respiratory disorders, asthma
bowel paralysis, increased blood level of the enzyme amylase, backflow of stomach contents into the throat, delayed stomach emptying
dermatitis, burning sensation in sunlight
joint disorders
inability to urinate, painful menstruation and abnormal menstrual bleeding
failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on the chest, feeling restless or nervous, increased blood lactate dehydrogenase enzyme, weight loss
haemolytic-uremic syndrome which is characterized by acute renal failure (low urine production / or failure to produce urine), microangiopathic haemolytic anemia (reduced number of red blood cells with extreme tiredness) and low platelet counts with abnormal bleeding or bruising and signs of infection. It can be fatal.

Rare

small bleeding in the skin due to blood clots
increased muscle stiffness
collection of fluid around the heart
blindness
deafness (impaired hearing)
acute shortness of breath
formation of cysts in the pancreas
problems with blood flow in the liver
increased hair growth
severe disease with blistering of the skin, mouth, eyes and genitals
thirst
feeling of constriction in the chest
reduced mobility
ulcer
thrombotic thrombocytopenic purpura which is characterized by fever and bruising under the skin that may present as small red dots, with or without extreme unexplained tiredness, confusion, yellowing of the skin or eyes (jaundice), with symptoms of low urine production (or absence of of urine production). It can be fatal.

Very rare

muscle weakness
abnormal echocardiogram
liver failure
narrowing of the biliary vessels
painful urination with blood in the urine
increased fatty tissue or Stevens-Johnson Syndrome which initially manifests as target reddish spots or circular patches often with central blisters on the trunk. The rash may progress to extensive blistering of the skin or peeling. Additional signs to look for include ulcers in the mouth, throat, nose, genitals and conjunctivitis (red or swollen eyes). Rashes are often accompanied by symptoms flu-like It can be fatal.

Not known

pure red cell aplasia causing a very serious reduction in red blood cell numbers accompanied by fatigue
agranulocytosis which causes severe reduction in the number of white blood cells, accompanied by mouth ulcers, fever and infection (s)
haemolytic anemia which causes reduction in the number of red blood cells due to abnormal breakdown accompanied by fatigue.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton (and on the blister after EXP). The expiry date refers to the last day of that month.

Store below 25 ° C. Store in the original package to protect from moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Tacrolimus Accord Healthcare contains:

The active ingredient is tacrolimus.
- For 0.5 mg: each capsule contains 0.5 mg of tacrolimus (as tacrolimus monohydrate).
- For 1 mg: each capsule contains 1 mg of tacrolimus (as tacrolimus monohydrate).
- For 5 mg: each capsule contains 5 mg of tacrolimus (as tracrolimus monohydrate).
The other ingredients are: lactose monohydrate, croscarmellose sodium (E 468), hypromellose (E 464), magnesium stearate (E 470b)

Composition of the capsule shell for Tacrolimus 0.5 mg: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), sodium lauryl sulfate

Composition of the capsule shell for Tacrolimus Accord Healthcare 1 mg: gelatin, titanium dioxide (E 171), sodium lauryl sulfate

Composition of the capsule shell for Tacrolimus Accord Healthcare 5 mg: gelatin, titanium dioxide (E 171), red iron oxide (E 172), sodium lauryl sulfate

Hard capsule shell printing ink: shellac, propylene glycol, potassium hydroxide, black iron oxide (E172)

What Tacrolimus Accord Healthcare looks like and contents of the pack:

Tacrolimus Accord Healthcare 0.5 mg: Light yellow / light yellow hard gelatin capsules, approximately 11.40 mm, size "5", imprinted with "TCR" on the top of the capsule and "0.5" on the body of the capsule. , containing white to off-white granular powder.

Tacrolimus Accord Healthcare 1 mg: White / white hard gelatin capsules, approximately 11.40 mm, size "5", imprinted with "TCR" on the top of the capsule and "1" on the body of the capsule, containing granular powder white to off-white.

Tacrolimus Accord Healthcare 5 mg: Pink / pink hard gelatin capsules, approximately 14.30 mm, size "4", imprinted with "TCR" on the top of the capsule and "5" on the body of the capsule, containing granular powder white to off-white.

Tacrolimus Accord Healthcare is available in blister packs of:

Tacrolimus Accord Healthcare 0.5 mg hard capsules
- Packs of 20, 30, 50, 60 and 100 hard capsules.
Tacrolimus Accord Healthcare 1 mg hard capsules
- Packs of 20, 30, 50, 60, 90 and 100 hard capsules.
Tacrolimus Accord Healthcare 5 mg hard capsules:
- Packs of 30, 50, 60 and 100 hard capsules.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information on Tacrolimus - Generic drug can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

TACROLIMUS ACCORD HEALTHCARE - HARD CAPSULES

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

For 0.5 mg

Each capsule contains 0.5 mg of tacrolimus.

Excipients: 50.14 mg of lactose monohydrate

For 1 mg:

Each capsule contains 1 mg of tacrolimus.

Excipients: 48.68 mg of lactose monohydrate

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM -

Hard capsules.

For 0.5 mg

Light yellow / light yellow hard gelatin capsules, approximately 11.40 mm, size "5", imprinted with "TCR" on the top of the capsule and "0.5" on the body of the capsule, containing white to off-white granular powder .

For 1 mg

White / white hard gelatin capsules, approximately 11.40 mm, size "5", imprinted with "TCR" on the top of the capsule and "1" on the body of the capsule, containing white to off-white granular powder.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Prophylaxis of transplant rejection in patients receiving allogeneic liver, kidney or heart transplantation.

Treatment of allogeneic transplant rejection resistant to treatment with other immunosuppressive medicinal products.

04.2 Posology and method of administration -

Tacrolimus Accord Healthcare therapy requires careful monitoring by suitably qualified and equipped personnel. Prescribing of the drug as well as changes in immunosuppressive therapy should only be performed by physicians experienced in immunosuppressive therapy and in the management of transplant patients.

Unintentional, unintentional or unsupervised interchange between immediate-release and sustained-release formulations of tacrolimus is dangerous. This may lead to transplant rejection or an increased incidence of undesirable effects, including poor or excessive immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; Changes in formulation or regimen should only be made under the careful supervision of a transplant specialist (see sections 4.4 and 4.8). After transfer to any alternative formulation, therapeutic drug monitoring should be performed and adjustments made to ensure that systemic exposure to tacrolimus is maintained.

General consideration

The recommended starting doses presented below should serve as a guideline only. The dose of Tacrolimus Accord Healthcare should be based primarily on individual patient clinical rejection and tolerability assessments with the aid of blood level monitoring (see below for recommended minimum blood concentrations). If clinical signs of rejection are evident. , a change in the immunosuppressive regimen should be considered.

Tacrolimus Accord Healthcare can be administered intravenously or orally. It is usually possible to start with oral administration; if necessary, by administering the contents of the capsule suspended in water, by means of a nasogastric tube.

In the early postoperative period, Tacrolimus Accord Healthcare is normally administered in combination with other immunosuppressive drugs in the early postoperative period. The dose of Tacrolimus Accord Healthcare may vary according to the immunosuppressive regimen chosen.

Method of administration

It is recommended that the oral daily dose be administered in two divided doses (e.g. morning and evening). The hard capsules should be taken immediately after removal from the blister. The hard capsules should be swallowed with a liquid (preferably water).

To achieve maximum absorption, the hard capsules should generally be taken on an empty stomach either at least 1 hour before or 2-3 hours after a meal (see section 5.2).

Duration of treatment

To suppress transplant rejection, it is necessary to maintain the immunosuppressed state; consequently, it is not possible to establish a limit for the duration of oral therapy.

Recommended doses - Liver transplant

Prophylaxis of transplant rejection - adults

Oral therapy with tacrolimus should begin with 0.10-0.20 mg / kg / day administered in two divided doses (e.g. morning and evening). Administration should commence approximately 12 hours after completion of surgery.

If the patient's clinical condition does not allow oral administration, intravenous administration of 0.01-0.05 mg / kg / day should be initiated by continuous infusion for 24 hours.

Prophylaxis of transplant rejection - children

An initial oral dose of 0.30 mg / kg / day should be administered in two divided doses (e.g. morning and evening). If the patient's clinical condition does not allow oral administration, administer an intravenous dose of 0.05 mg / kg / day by continuous infusion for 24 hours.

Dosage adjustments during the post-transplant period in adults and children

Doses of Tacrolimus Accord Healthcare are usually reduced in the post-transplant period. In some cases, concomitant immunosuppressive therapy can be withdrawn until Tacrolimus Accord Healthcare monotherapy. Clinical improvement of the patient in the post-transplant period may modify the pharmacokinetics of tacrolimus with the need for further dose adjustments.

Anti-rejection therapy - adults and children

Increased doses of Tacrolimus Accord Healthcare, combination of supplemental corticosteroid therapies, and introduction of short courses of monoclonal / polyclonal antibodies have been used to manage rejection episodes. e.g. pronounced adverse reactions - see section 4.8) dose reduction of Tacrolimus Accord Healthcare is likely required.

For conversion to Tacrolimus Accord Healthcare, therapy should begin with a recommended starting oral dose for primary immunosuppression.

For information on conversion from cyclosporine to tacrolimus, see below under "Dosage adjustments in specific patient populations".

Recommended doses - Kidney transplant

Prophylaxis of transplant rejection - adults

Oral therapy with tacrolimus should begin with 0.20-0.30 mg / kg / day administered in two divided doses (e.g. morning and evening). Administration should commence within 24 hours of completing surgery.

If the clinical condition of the patient does not allow oral administration, therapy should be initiated by continuous intravenous infusion for 24 hours with doses of 0.05-0.10 mg / kg / day.

Prophylaxis of transplant rejection - children

An initial oral dose of 0.30 mg / kg / day should be administered in two divided doses (e.g. morning and evening). If the patient's clinical condition does not allow for oral administration, an initial intravenous dose of 0.075-0.100 mg / kg / day should be administered as a continuous infusion for 24 hours.

Dosage adjustments during the post-transplant period in adults and children

Generally, doses of Tacrolimus Accord Healthcare are reduced in the post-transplant period. In some cases, concomitant immunosuppressive therapy can be withdrawn until dual therapy with Tacrolimus Accord Healthcare. Clinical improvement of the patient in the post-transplant period may modify the pharmacokinetics of tacrolimus with the need for further dose adjustments.

Anti-rejection therapy - adults and children

Increased doses of Tacrolimus Accord Healthcare, adjunctive corticosteroid therapy, and introduction of short courses of monoclonal / polyclonal antibodies were used to manage rejection episodes. If signs of toxicity are observed (e.g. pronounced adverse reactions - see section 4.8) dose reduction of Tacrolimus Accord Healthcare is likely required.

For conversion to Tacrolimus Accord Healthcare, therapy should begin with the recommended starting oral dose for primary immunosuppression.

For information on conversion from cyclosporine to tacrolimus, see the section "Dosage adjustments in specific patient populations" below.

Recommended doses - Heart transplant

Prophylaxis of transplant rejection - adults

Tacrolimus Accord Healthcare can be used with induction with an antibody (which allows delayed initiation of Tacrolimus Accord Healthcare therapy) or alternatively in clinically stable patients without induction with an antibody.

After induction with an antibody, oral therapy with Tacrolimus Accord Healthcare should commence at 0.075 mg / kg / day administered in two divided doses (eg morning and evening). Administration should commence within 5 days after completion of the procedure. surgery, as soon as the patient's clinical condition has stabilized. If the patient's clinical condition does not allow oral administration, initiate therapy by continuous intravenous infusion for 24 hours with doses of 0.01-0.02 mg / kg / day.

An alternative strategy was published in which oral tacrolimus was administered within 12 hours of transplantation. This therapeutic approach was reserved for patients without organ dysfunction (eg renal dysfunction). In that case, an initial oral dose of tacrolimus of 2-4 mg per day was used in combination with mycophenolate mofetil and corticosteroids or in association with sirolimus and corticosteroids.

Prophylaxis of transplant rejection - children

Tacrolimus Accord Healthcare has been used with or without antibody induction in pediatric heart transplant patients.

In patients without antibody induction, if tacrolimus therapy is initiated intravenously, the recommended starting dose is 0.03-0.05 mg / kg / day by continuous intravenous infusion for 24 hours with the aim of achieving concentration. tacrolimus blood content of 15-25 ng / ml. Patients should be converted to oral therapy as soon as clinical conditions permit. The first dose of oral therapy should be 0.30 mg / kg / day, starting 8-12 hours after discontinuation of intravenous therapy.

Following antibody induction, if Tacrolimus Accord Healthcare therapy is initiated orally, the recommended starting dose is 0.10-0.30 mg / kg / day given in two divided doses (e.g. morning and evening. ).

Dosage adjustments during the post-transplant period in adults and children

Doses of Tacrolimus Accord Healthcare are usually reduced in the post-transplant period. Clinical improvements in the patient in the post-transplant period may modify the pharmacokinetics of tacrolimus with the need for further dose adjustments.

Anti-rejection therapy - adults and children

In adult patients transferred to Tacrolimus Accord Healthcare therapy, an initial oral dose of 0.15 mg / kg / day should be administered in two divided doses (e.g. morning and evening).

In pediatric patients transferred to Tacrolimus Accord Healthcare therapy, an initial oral dose of 0.20-0.30 mg / kg / day should be administered in two divided doses (e.g. morning and evening).

For information on transferring from cyclosporine to Tacrolimus Accord Healthcare, see "Dosage adjustments in specific patient populations" below.

Recommended doses - Anti-rejection therapy, other allografts

The recommended doses for lung, pancreas and bowel transplantation are based on limited prospective clinical experience. In lung transplant patients, Tacrolimus Accord Healthcare has been used at an initial oral dose of 0.10-0.15 mg / kg / day, in pancreatic transplant patients at an initial oral dose of 0.2 mg / kg / day and in bowel transplant patients at an initial oral dose of 0.3 mg / kg / day.

Dosage adjustments in specific patient populations

Race

Compared to Caucasians, black patients may require higher doses of tacrolimus to achieve similar trough levels.

Sex

There is no evidence that male and female patients require different doses to achieve similar trough levels.

Patients with hepatic impairment

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

Patients with renal impairment

Since the pharmacokinetics of tacrolimus are not affected by renal function, no dosage adjustment is necessary. However, due to the nephrotoxic potential of tacrolimus, careful monitoring of renal function is recommended (including periodic assessments of serum creatinine, calculation of creatinine clearance and monitoring of diuresis).

Pediatric patients

Typically, pediatric patients require doses 1½ - 2 times higher than those in adults to achieve similar blood levels.

Elderly patients

No data are currently available to suggest the need for dose adjustments in elderly patients.

Transfer from cyclosporine

Caution should be exercised when converting patients on ciclosporin to tacrolimus therapy (see sections 4.4 and 4.5). Tacrolimus Accord Healthcare therapy should be initiated after consideration of the blood concentrations of ciclosporin and the clinical condition of the patient. In the presence of elevated blood levels of ciclosporin, administration should be delayed. In practice, Tacrolimus Accord Healthcare therapy was initiated 12-24 hours after discontinuation of cyclosporine. Control of cyclosporine blood levels should continue even after transfer to the new therapy, as cyclosporine clearance may be affected.

Recommendations on minimum blood concentrations

Administration should primarily be based on clinical evaluation of rejection and tolerability in each individual patient.

To aid in optimizing posology, various immunoassays are available to determine tacrolimus levels in whole blood, including a semi-automated microparticle enzyme immunoassay (MEIA). The comparison of individual concentrations in clinical practice with the concentrations published in the literature must be done with care and knowledge of the methods used. Currently in clinical practice, whole blood levels are determined using immunoassay methods.

Tacrolimus blood trough levels should be monitored in the post-transplant period. When administered orally, trough levels should be assessed approximately 12 hours after administration, just prior to the next administration. The frequency of blood level monitoring should be based on clinical need. Since Tacrolimus Accord Healthcare is a low-clearance drug, it may take several days for dose adjustments to be evident in blood levels. Tacrolimus trough blood levels should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Tacrolimus blood trough levels should also be monitored after any dose adjustments, after changes in the immunosuppressive regimen or after concomitant administration of substances that may affect blood concentrations of tacrolimus (see section 4.5).

Analysis of clinical studies suggests that most patients can be successfully treated if blood trough levels of tacrolimus are kept below 20 ng / mL. The patient's clinical condition should be considered when interpreting blood levels.

In clinical practice, in the immediate post-transplant period, minimum blood levels are generally in the range between 5 and 20 ng / ml in liver transplant patients and between 10 and 20 ng / ml in kidney and kidney transplant patients. heart. Subsequently, during maintenance therapy, blood concentrations were generally in the range of 5 to 15 ng / mL in liver, heart and kidney transplant patients.

04.3 Contraindications -

Hypersensitivity to the active substance, to other macrolides or to any of the excipients listed in section 6.1.

04.4 Special warnings and appropriate precautions for use -

Monitoring during the post-transplant period

During the initial post-transplant period, regular monitoring of the following parameters should be carried out: blood pressure, ECG, neurological and ophthalmological control, fasting blood glucose, electrolytes (especially potassium), liver and kidney function tests, haematological parameters, parameters coagulation and plasma protein determinations. If clinically significant changes are observed, appropriate modifications of the immunosuppressive regimen should be considered.

Drug administration errors

Drug administration errors have been observed, including inadvertent, unintentional, or unsupervised switch between the immediate-release and prolonged-release formulations of tacrolimus. This has led to serious adverse events, including organ transplant rejection or other undesirable effects that may be a consequence of too little or too much exposure to tacrolimus. Patients should be kept on one formulation of tacrolimus with the corresponding regimen. daily dosage; changes in formulation or regimen should only be made under close supervision of a transplant specialist (see sections 4.2 and 4.8).

Herbal preparations

The intake of phytotherapeutic preparations containing St. John's wort (Hypericum perforatum) or other herbal preparations should be avoided while taking Tacrolimus Accord Healthcare due to the risk of interactions resulting in decreased blood concentrations of tacrolimus and decreased clinical efficacy of tacrolimus (see section 4.5).

Diarrhea

Since blood levels of tacrolimus can vary significantly during episodes of diarrhea, additional monitoring of tacrolimus concentrations during these episodes is recommended.

Cyclosporine

Combination administration of ciclosporin and tacrolimus should be avoided and particular caution should be exercised when tacrolimus is administered to patients previously on ciclosporin therapy (see sections 4.2 and 4.5).

Cardiac pathologies

In rare cases, ventricular hypertrophy or septal hypertrophy has been observed, reported as cardiomyopathies. In most cases they have been shown to be reversible, occurring mainly in children with blood trough concentrations of tacrolimus much higher than the maximum recommended levels. Other factors believed to increase the risk of these clinical conditions included pre-existing heart disease, use of corticosteroids, hypertension, renal or hepatic dysfunction, infections, volume overload and edema. Consequently, high-risk patients, particularly young children and those receiving "substantial immunosuppression, should be monitored with instrumental tests such as echocardiography, or ECG before and after transplantation (eg, initially after three months and then after 9-12 months). In the event of abnormalities occurring, a reduction in the dose of Tacrolimus Accord Healthcare or a transfer to another immunosuppressive drug should be considered. Tacrolimus may prolong the QT interval, but substantial evidence is currently lacking that can cause torsade de pointes. Caution is advised in patients diagnosed with or suspected of congenital QT interval prolongation syndrome.

Epstein-Barr virus (EBV) associated lymphoproliferative disorders

Patients treated with Tacrolimus Accord Healthcare have been reported to have developed lymphoproliferative diseases associated with Epstein-Barr virus (EBV) infection. Patients transferred to Tacrolimus Accord Healthcare therapy should not receive concomitant anti-lymphocyte treatment. An increased risk of developing lymphoproliferative disease in very young children has been reported (PCR. Positive EBV-PCR may persist for months and is not in itself indicative of lymphoproliferative disease or lymphoma.

Posterior reversible encephalopathy syndrome (PRES)

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms of PRES, such as headache, altered mental status, seizures and visual disturbances, radiological investigation (e.g. MRI) should be done. If PRES is diagnosed, appropriate monitoring of blood pressure and seizures and immediate discontinuation of systemic tacrolimus is recommended. Most patients recover completely after taking appropriate measures.

Specific red cell aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients had risk factors for PRCA such as parvovirus B19 infections, underlying disease, or concomitant therapies typically associated with PRCA.

Risk of opportunistic infections

Patients treated with immunosuppressive drugs, including tacrolimus, are at increased risk of opportunistic infections (bacterial, fungal, viral or protozoal). These diseases include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopy (PML). These infections are often related to a high total immunosuppressive burden and can cause serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with worsening renal function or neurological symptoms.

Photosensitivity

As with other immunosuppressive drugs, given the potential for malignant skin changes, exposure to sunlight and ultraviolet rays should be limited by wearing protective clothing and applying a sunscreen with a high protection factor.

Other

As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see section 4.8).

Allergic and anaphylactoid reactions have been observed in patients taking tacrolimus (see section 4.8).

As Tacrolimus Accord Healthcare contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This drug contains less than 1 mmol sodium (23 mg) per dose, meaning it is "essentially sodium-free".

04.5 Interactions with other medicinal products and other forms of interaction -

Metabolic interactions

Systemically available tacrolimus is metabolised via hepatic CYP3A4 in the liver. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. The concomitant use of medicinal products or herbal remedies that inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and therefore increase or decrease its blood levels. It is therefore advisable to monitor the blood levels of tacrolimus when concomitantly used substances capable of altering metabolism of CYP3A, and to adjust the tacrolimus dose as appropriate to maintain constant tacrolimus exposure (see sections 4.2 and 4.4).

Inhibitors of metabolism

In clinical practice, the following substances have been shown to increase the blood levels of tacrolimus:

Strong interactions have been observed with antifungal drugs such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (eg ritonavir). Concomitant use of these substances may require reduction of tacrolimus doses. in almost all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, iosamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.

In vitro, the following substances have been shown to be potential inhibitors of the metabolism of tacrolimus: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

Grapefruit juice intake has been reported to cause an increase in the blood level of tacrolimus and should therefore be avoided.

Lansoprazole and cyclosporine have the potential to inhibit CYP3A4 mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.

Inducers of metabolism

In clinical practice, the following substances have been shown to decrease the blood levels of tacrolimus:

Strong interactions have been observed with rifampicin, phenytoin and with St. John's wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been reported with phenobarbital. Corticosteroids at maintenance doses have been shown to reduce blood levels of tacrolimus.

High doses of prednisolone or methylprednisolone, given to treat acute rejection, have the potential to increase and decrease blood levels of tacrolimus.

Carbamazepine, metamizole and isoniazid have the potential to reduce tacrolimus concentrations.

Effect of tacrolimus on the metabolism of other medicinal products

Tacrolimus is a known inhibitor of CYP3A4, so concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may interfere with the metabolism of these medicinal products.

The half-life of cyclosporine is prolonged when co-administered with tacrolimus. In addition, synergistic / additive nephrotoxic effects may occur. For these reasons, concomitant administration of cyclosporine and tacrolimus is not recommended and care should be taken when administering tacrolimus in patients who have previously received cyclosporine (see sections 4.2 and 4.4).

Tacrolimus has been shown to increase the blood level of phenytoin.

Since tacrolimus may reduce the clearance of steroid-based contraceptives resulting in increased hormone exposure, special care should be taken when deciding on contraceptive measures.

Limited data are available on the interactions between tacrolimus and statins. Available data suggest that the pharmacokinetics of statins are largely unchanged by concomitant administration of tacrolimus.

Data from animal studies showed that tacrolimus could potentially reduce the clearance and increase the half-life of pentobarbital and phenazone.

Other interactions that have caused clinically harmful effects

Concomitant use of tacrolimus with medicinal products known for their nephrotoxic or neurotoxic effects may enhance these effects (eg aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, non-steroidal anti-inflammatory drugs (NSAIDs), ganciclovir or aciclovir).

Increased nephrotoxicity was observed following administration of amphotericin B and ibuprofen concomitantly with tacrolimus.

Since treatment with tacrolimus may be associated with the onset of hyperkalaemia or with the increase of pre-existing hyperkalaemia, it is necessary to avoid the intake of potassium in high doses, or potassium-sparing diuretics (eg. Amiloride, triamterene or spironolactone).

Immunosuppressants may affect the response to vaccinations and vaccination during tacrolimus therapy may be less effective. The use of live attenuated vaccines should be avoided.

Protein binding considerations

Tacrolimus is extensively bound to plasma proteins. Possible interactions with other medicinal products known for their high affinity for plasma proteins (eg non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants or oral antidiabetic drugs) should be considered.

04.6 Pregnancy and breastfeeding -

Human data demonstrate that tacrolimus is able to cross the placenta. The limited data available in organ transplant patients demonstrate that there is no evidence of an increased risk of adverse course and outcome effects. of pregnancy during treatment with tacrolimus, compared to 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 for treatment, tacrolimus may be considered in pregnant women when there is no safer alternative and when the perceived benefits justify the potential risk to the fetus. In case of in utero exposure, monitoring is recommended. of the newborn to check for potential adverse effects of tacrolimus (especially kidney effects) There is a risk of premature birth (

In rats and rabbits, tacrolimus causes embryonic toxicity at doses that have demonstrated maternal toxicity (see section 5.3).

Feeding time

Male data show that tacrolimus is excreted in breast milk. Since harmful effects on the newborn cannot be excluded, women taking Tacrolimus Accord Healthcare should not breastfeed.

Fertility

A negative effect of tacrolimus on male fertility was observed in rats and manifested as decreased sperm count and motility (see section 5.3).

04.7 Effects on ability to drive and use machines -

Tacrolimus can cause visual and neurological disturbances. These disorders may be accentuated if Tacrolimus Accord Healthcare is administered in combination with alcohol.

04.8 Undesirable effects -

The adverse reaction profile associated with the use of immunosuppressants is often difficult to establish due to the underlying disease and the concomitant use of many other medicinal products.

Many of the adverse reactions listed below are reversible and / or respond to dose reduction. Oral administration is associated with a lower incidence of adverse reactions than intravenous use. Adverse reactions are listed below in order of decreasing frequency of occurrence: very common (≥1 / 10); common (≥1 / 100 a

The following adverse reactions have been reported in post-marketing experience:

Infections and infestations As is well known for other potent immunosuppressive drugs, patients treated with tacrolimus are often at an increased risk of infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections can be aggravated. Infections can occur both in a generalized and in a localized form. Cases of BK virus associated nephropathy as well as cases of JC virus associated progressive multifocal leukoencephalopy (PML) have been reported in patients treated with immunosuppressants, including tacrolimus. Neoplasms benign, malignant and unspecified (including cysts and polyps) Patients treated with immunosuppressants have an increased risk of developing malignant tumors. Benign and malignant neoplasms, including lymphoproliferative disorders associated with EBV infections and malignant skin neoplasms, have been reported in association with tacrolimus treatment. Disorders of the blood and lymphatic system Common: anemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analysis abnormalities Uncommon: coagulopathy, abnormalities in coagulation and bleeding analyzes, pancytopenia, neutropenia Rare: thrombotic thrombocytopenic purpura, hypoprothrombinemia Not known: specific red cell aplasia, agranulocytosis, haemolytic anemia Disorders of the immune system Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4). Endocrine pathologies Rare: hirsutism Metabolism and nutrition disorders Very common: hyperglycemic conditions, diabetes mellitus, hyperkalemia Common: hypomagnesaemia, hypophosphataemia, hypokalaemia, hypocalcaemia, hyponatremia, fluid overload, hyperuricaemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidaemia, hypercholesterolemia, hypertriglyceridaemia, other electrolyte disturbances Uncommon: dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia Psychiatric disorders Very common: insomnia Common: symptoms of anxiety, confusion and disorientation, depression, depressed mood, mood alterations and disturbances, nightmares, hallucinations, mental disorders Uncommon: psychotic disorder Nervous system disorders Very common: tremor, headache Common: seizures, changes in consciousness, paraesthesia and dysesthesia, peripheral neuropathies, dizziness, inability to write, nervous system disorders Uncommon: coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and language changes, amnesia Rare: hypertonia Very rare: myasthenia Eye disorders Common: blurred vision, photophobia, eye disorders Uncommon: cataract Rare: blindness Ear and labyrinth disorders Common: tinnitus Uncommon: hearing loss Rare: sensorineural deafness Very rare: impaired hearing Cardiac pathologies Common: coronary ischemic disorders, tachycardia Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG tests, abnormal heart rate and pulse tests Rare: pericardial effusion Very rare: altered echocardiogram Vascular pathologies Very common: hypertension Common: haemorrhages, thromboembolic and ischemic events, peripheral vascular disorders, hypotensive vascular disorders Uncommon: heart attack, deep vein thrombosis of the limb, shock Respiratory, thoracic and mediastinal disorders Common: dyspnoea, lung parenchyma disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammation Uncommon: respiratory failure, respiratory tract disorders, asthma Rare: acute respiratory distress syndrome Gastrointestinal disorders Very common: diarrhea, nausea Common: conditions of inflammation of the gastrointestinal tract, ulceration and perforation of the gastrointestinal tract, gastrointestinal bleeding, stomatitis and ulcer, ascites, vomiting, gastrointestinal and abdominal pain, signs and symptoms of dyspepsia, constipation, flatulence, bloating and distention, soft stools, signs and symptoms gastrointestinal Uncommon: paralytic ileus, peritonitis, acute and chronic pancreatitis, increased blood amylase, gastroesophageal reflux, impaired gastric emptying Rare: subileus, pancreatic pseudocysts Pathologies hepatobiliary Common: changes in enzymes and liver function, cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis Rare: thrombosis of the hepatic artery, hepatic veno-occlusive pathology Very rare: liver failure, stenosis of the bile duct Skin and subcutaneous tissue disorders Common: itching, rash, alopecia, acne, increased sweating Uncommon: dermatitis, photosensitivity Rare: toxic epidermal necrolysis (Lyell's syndrome) Very rare: Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders Common: arthralgia, muscle cramps, pains in limbs, back pain Rare: joint disorders Renal and urinary disorders Very common: kidney damage Common: renal failure, acute renal failure, oliguria, tubulo-renal necrosis, toxic nephropathy, urinary changes, bladder and urethral symptoms Uncommon: anuria, hemolytic uremic syndrome Very rare: nephropathy, hemorrhagic cystitis Diseases of the reproductive system and breast Uncommon: dysmenorrhea and uterine bleeding General disorders and administration site conditions Common: asthenic conditions, blood alkaline phosphatase increased, febrile disorders, edema, pain and discomfort, alkaline phosphatase increased, weight gain, altered perception of body temperature Uncommon: multi-organ failure, flu-like illness, temperature intolerance, chest tightness, feeling jittery, feeling abnormal, blood lactate dehydrogenase increased, weight loss Rare: thirst, lipothymia, chest tightness, reduced mobility, ulcer Very rare: increase in adipose tissue Injury, poisoning and procedural complications Common: Primary graft dysfunction Therapy errors including inadvertent, unintentional or unsupervised exchange of immediate-release or prolonged-release formulations of tacrolimus have been observed. A number of associated transplant rejection cases have been reported (frequency cannot be estimated from the available data).

04.9 Overdose -

Experience with overdose is limited. Several cases of accidental overdose have been reported with symptoms including: tremor, headache, nausea and vomiting, infections, hives, lethargy, increased blood nitrogen levels and alanine aminotransferase levels.

There are no specific antidotes for tacrolimus. In the event of an overdose, supportive measures and symptomatic treatment should be employed.

Due to its high molecular weight, poor water solubility, and high erythrocyte and plasma protein binding, tacrolimus is not expected to be dialyzable. In individual patients with very high plasma levels, haemofiltration and haemodiafiltration have been found to be effective in reducing toxic concentrations. In cases of intoxication following oral administration, gastric lavage and / or the use of adsorbents (such as activated carbon) may be useful if taken immediately after ingestion.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02

Mechanism of action and pharmacodynamic effects

At the molecular level, the effects of tacrolimus are mediated by binding to a cytoplasmic protein (FKBP12) which is responsible for the intracellular accumulation of the drug. The FKBP12-tacrolimus complex binds specifically and competitively to calcineurin and causes its inhibition, with consequent calcium-dependent inhibition of the signal transduction mechanism to T cells, thus preventing the transcription of a discrete group of lymphokine genes.

Tacrolimus is a very potent immunosuppressant whose activity has been demonstrated in both experiments in vitro that in vivo.

In particular, tacrolimus inhibits the production of cytotoxic lymphocytes, which are mainly responsible for transplant rejection. Tacrolimus suppresses T-cell activation and T-helper-dependent B cell proliferation, as well as lymphokine production (such as interleukin-2, interleukin-3, and γ-interferon) and interleukin-receptor expression. 2.

Results from published data in other primary organ transplants

Tacrolimus is considered an established treatment as a primary immunosuppressant after pancreas, lung and intestinal transplantation. In published prospective studies, tacrolimus has been studied as a primary immunosuppressant in approximately 175 patients after lung transplantation, 475 patients after pancreatic transplantation and 630 patients after bowel transplantation. Overall, the safety profile of tacrolimus in these published studies was found to be similar to that reported in the larger studies where tacrolimus was studied as a primary treatment in liver, kidney and heart transplantation. The efficacy results of the largest studies in each indication are summarized below.

Lung transplant

The interim analysis of a recent multicenter study evaluated 110 patients randomly assigned 1: 1 to tacrolimus or cyclosporine treatment groups. Tacrolimus was initially administered by continuous intravenous infusion at a dose ranging from 0.01 to 0. 03 mg / kg / day while oral tacrolimus was administered at a dose ranging from 0.05 to 0.3 mg / kg / day. In the first year of treatment after transplantation, a lower incidence of rejection episodes was observed. acute in patients treated with tacrolimus compared to those treated with cyclosporine (11.5% versus 22.6%) and a "lower incidence of chronic rejection, bronchiolitis obliterans syndrome (2.86% versus 8.57%). The one-year patient survival rate was 80.8% in the tacrolimus group and 83% in the cyclosporine group (Treede et al., 3rdICI San Diego, US, 2004; Abstract 22).

In another randomized study, 66 patients with tacrolimus and 67 patients with cyclosporine were treated. Tacrolimus was administered initially as a continuous intravenous infusion at a dose of 0.025 mg / kg / day while oral therapy was administered at a dose of 0.15 mg / kg / day with subsequent dose adjustments down to trough blood levels. 10-20 ng / ml. Patient survival at 1 year was 83% in the tacrolimus group and 71% in the cyclosporine group; 2-year survival rates were 76% and 66%, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus group (0.85 episodes) than in the cyclosporine group (1.09 episodes). Obliterative bronchiolitis occurred in 21.7% of patients in the tacrolimus group compared with 38.0% of patients in the cyclosporine group (p = 0.025). Significantly more patients treated with cyclosporine (n = 13) required a change of therapy to tacrolimus compared to patients treated with tacrolimus who required a change of therapy to cyclosporine (n = 2) (p = 0.02 ) (Keenan et al., Ann Thoracic Surg 1995; 60: 580).

In another two-center study, 26 patients were randomized to tacrolimus treatment compared with 24 patients randomized to the cyclosporine group. Tacrolimus was initially administered by continuous intravenous infusion at an initial dose of 0.05 mg / kg / day while oral therapy was administered at a dose between 0.1 and 0.3 mg / kg / day with subsequent adjustments. of the dose down to trough blood levels between 12 and 15 ng / mL. 1-year survival rates were 73.1% in the tacrolimus group compared to 79.2% in the cyclosporine group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7% vs 45.8%) and 1 year after lung transplantation (50% vs 33.3%) (Treede et al., J Heart Lung Transplant 2001; 20: 511).

The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically lower with tacrolimus in all three studies and one of the studies showed a significantly lower incidence of obliterative bronchiolitis syndrome with tacrolimus.

Pancreas transplant

A multicenter study involved 205 patients undergoing simultaneous kidney and pancreas transplantation, randomly assigned to treatment with tacrolimus (n = 103) or cyclosporine (n = 102). The initial oral dose of tacrolimus according to the protocol was 0.2 mg / kg / day with subsequent dose adjustments to trough blood levels between 8 and 15 ng / mL by Day 5 and between 5 and 10 ng / mL after 6 months. 1-year pancreatic survival was significantly longer with tacrolimus: 91.3% versus 74.5% with cyclosporine (p

Intestine transplant

Published clinical experience, derived from a single center, on the use of tacrolimus for primary treatment following bowel transplantation demonstrated that the actuarial survival rate of 155 patients (65 bowel only, 75 liver and intestine, and 25 multivisceral) undergoing tacrolimus and prednisone therapy was 75% at 1 year, 54% at 5 years, and 42% at 10 years. In the early years, the initial oral dose of tacrolimus was 0.3 mg / kg / day. Outcomes continuously improved as clinical experience increased over the course of 11 years.A series of innovations, such as early detection techniques for Epstein-Barr (EBV) and CMV infections, bone marrow growth factors, the addition of interleukin-2 antagonist daclizumab, initial doses lower tacrolimus with minimum target levels between 10 and 15 ng / ml, and more recently allogeneic transplant irradiation were considered factors that contributed to improving outcomes in this indication over time. (Abu-Elmagd et al., Ann Surg 2001; 234: 404).

05.2 "Pharmacokinetic properties -

Absorption

In humans, tacrolimus has been shown to be absorbed via the gastrointestinal tract. Following oral administration of Tacrolimus Accord Healthcare, maximum blood concentrations (Cmax) of tacrolimus are achieved in approximately 1 to 3 hours. In some patients it appears. that tacrolimus continues to be absorbed for an extended period of time, showing a relatively flat absorption profile. The mean oral bioavailability of tacrolimus is in the range of 20% -25%.

After oral administration (0.30 mg / kg / day) to liver transplant patients, steady-state concentrations of tacrolimus are achieved within 3 days in most patients.

In healthy subjects, tacrolimus 0.5 mg, 1 mg and 5 mg capsules have been shown to be bioequivalent when administered at equivalent dosages.

The rate and extent of absorption of tacrolimus are increased under fasting conditions. The presence of food decreases both the rate and extent of absorption of tacrolimus, and the effect is more pronounced after a high-fat meal. The effect from a high-carbohydrate meal is less pronounced.

In stable liver transplant patients, the oral bioavailability of tacrolimus was reduced when administered after a moderate fat (34% calorie) meal. Reductions in AUC (27%) and Cmax (50%), and increases in tmax (173%) were observed in whole blood.

In a study of stable kidney transplant patients who were given tacrolimus immediately following a standard continental breakfast, the effect on oral bioavailability was less pronounced. Reductions in AUC (from 2 to 12%) and Cmax (15 to 38%), and increased tmax (38 to 80%) in whole blood.

Bile flow does not affect the absorption of tacrolimus.

There is a strong correlation between AUC and steady-state trough levels. Monitoring of blood trough levels therefore provides a reliable estimate of systemic exposure.

Distribution and disposal

In humans, the distribution of tacrolimus after intravenous infusion can be described as biphasic.

In the systemic circulation, tacrolimus binds tightly to erythrocytes, resulting in an approximate 20: 1 distribution ratio of whole blood / plasma concentrations. In plasma, tacrolimus is highly bound (> 98.8%) to plasma proteins, primarily serum albumin and alpha-1 acid glycoprotein.

Tacrolimus is widely distributed in the body. The steady-state volume of distribution, based on plasma concentrations, is approximately 1300 l (healthy subjects). Corresponding data based on internal blood averaged 47.6 L.

Tacrolimus is a low-clearance substance. In healthy subjects, the mean total body clearance (TB) as assessed on whole blood concentrations was 2.25 L / h. In adult liver, kidney and heart transplant patients, values of 4.1 l / h, 6.7 l / h and 3.9 l / h respectively were observed. In liver transplantation, pediatric patients who received liver transplantation had approximately twice that of adult patients total clearance (TB). Factors such as low hematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism are considered to be responsible for the higher clearance rates observed after transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours. In adult and pediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant patients. The increase in clearance rates contributes to a shorter half-life observed in transplant patients.

Metabolism and biotransformation

Tacrolimus is extensively metabolised in the liver, mainly by cytochrome P450-3A4. Tacrolimus is also significantly metabolised in the intestinal wall. Several metabolites have been identified. Only one of these proved in vitro to have "immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no" immunosuppressive activity. In the systemic circulation only one of the inactive metabolites is present in the systemic circulation at low concentrations. The metabolites therefore do not contribute to the pharmacological activity of tacrolimus.

Excretion

Following intravenous and oral administration of 14C-labeled tacrolimus, most of the radioactivity was eliminated in the faeces. About 2% of the radioactivity was excreted in the urine. Less than 1% of tacrolimus is excreted unchanged in the urine and faeces, indicating its almost complete metabolism prior to elimination, with bile being the major route of elimination.

05.3 Preclinical safety data -

The kidneys and pancreas were the primary organs involved in toxicity studies conducted in the rat and baboon. In rats, tacrolimus caused toxic effects on the nervous system and eyes. Reversible cardiotoxic effects were observed in rabbits after intravenous administration of tacrolimus.

Embryonic toxicity was observed in rats and rabbits, limited to doses causing significant maternal toxicity. In rats, female reproductive function, including birth, was impaired at toxic doses and the offspring showed reduced birth weight, as well as viability and growth.

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Contents of hard capsules

Lactose monohydrate

Croscarmellose sodium (E 468)

Hypromellose (E 464)

Magnesium stearate (E 470b)

Capsule shell

Jelly

Titanium dioxide (E 171)

Yellow iron oxide (E 172) (only for 0.5 mg)

Sodium lauryl sulfate

Hard capsule shell printing ink: shellac, propylene glycol, potassium hydroxide, black iron oxide (E172).

06.2 Incompatibility "-

Tacrolimus is not compatible with PVC. Probes, syringes and other instruments used to prepare or administer a suspension of the contents of Tacrolimus Accord Healthcare must not contain PVC.