Consumer medicine information

Tacrolimus APOTEX Capsules

Tacrolimus

BRAND INFORMATION

Brand name

Tacrolimus APOTEX

Active ingredient

Tacrolimus

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tacrolimus APOTEX Capsules.

What is in this leaflet

This leaflet answers some common questions about TACROLIMUS APOTEX Capsules. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TACROLIMUS APOTEX against the benefits this medicine is expected to have for you.

If you have any concerns about using TACROLIMUS APOTEX ask your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What TACROLIMUS APOTEX is used for

You have been given a new transplanted liver or kidney, lung or heart from another person because your own was no longer healthy. Your body recognises that this new organ is different from your other organs and will try to reject it by attacking it in the same way that it would attack germs that enter your body. This could make you become ill again. TACROLIMUS APOTEX stops this attack; it is very important to take TACROLIMUS APOTEX given to you by your doctor regularly so that your new liver, kidney, lung or heart will not be attacked or rejected.

If you have been taking other medicines for this purpose, but are still feeling unwell, your doctor may change your treatment and begin giving you TACROLIMUS APOTEX.

TACROLIMUS APOTEX contains the active ingredient tacrolimus, which is an immunosuppressive agent.

Your doctor may have prescribed TACROLIMUS APOTEX for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you use TACROLIMUS APOTEX

When you must not use it

Do not use TACROLIMUS APOTEX if you have an allergy to:

  • Any medicine containing tacrolimus or other macrolides (these are antibiotics of the erythromycin family – trade names are Eryc, EES, Klacid, Zithromax, Rulide and Biaxsig)
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not use TACROLIMUS APOTEX if the packaging is torn or shows signs of tampering. Do not use TACROLIMUS APOTEX beyond the expiry date printed on the pack.

Before you start to use it

You must tell your doctor if

  • you are pregnant or planning to become pregnant
  • you are using oral contraceptives
  • you are breast feeding
  • you are receiving cyclosporin immunosuppressive therapy.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given TACROLIMUS APOTEX.

Your doctor will advise you whether or not to take TACROLIMUS APOTEX or if you need to adjust the dose or adapt your treatment.

Taking other medicines:

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and TACROLIMUS APOTEX may interfere with each other.

TACROLIMUS APOTEXTACROLIMUS APOTEXAmong these medicines is the herbal preparation St John’s Wort (Hypericum perforatum) which is capable of decreasing tacrolimus blood levels.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

Effects on driving and operating machinery

  • TACROLIMUS APOTEX may cause visual or nervous disturbances. If affected, do not drive or operate machinery.

Effects of food and alcohol

  • Food reduces the absorption of TACROLIMUS APOTEX so the capsules should be taken at least 1 hour before a meal.

Using TACROLIMUS APOTEX

How much to take:

You can only get TACROLIMUS APOTEX from your doctor. Your dose will be calculated according to your weight, age, and medical condition. As your health and the function of your new liver or kidney, lung or heart can be affected by how much medicine you take, it is normal that your doctor collects samples of blood and urine at regular intervals. This is in order to test whether your medicine requires adjustment.

TACROLIMUS APOTEX should be taken in two doses (e.g. morning and evening). Take the capsule from the blister pack and swallow it whole with plenty of water. Do not use grapefruit juice as it contains substances that interfere with the action of TACROLIMUS APOTEX.

How to take it:

  • TACROLIMUS APOTEX capsules should be taken at least 1 hour before a meal.
  • You must never change the dose yourself even if you are feeling better. It is very important that you keep taking this medicine so that your body will not reject your new liver kidney, lung or heart.
  • If you accidentally take a larger dose than recommended, tell your doctor immediately.
  • If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

If you forget to take it

  • If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.
  • Do not take a double dose to make up for the dose you missed.

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you have taken too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Poisons Information Centre telephone numbers:

While you are taking TACROLIMUS APOTEX

Things you must do

  • Always follow your doctor’s instructions carefully
  • Tell your doctor if you become pregnant while taking TACROLIMUS APOTEX
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking TACROLIMUS APOTEX.
  • TACROLIMUS APOTEX suppress your immune system by lowering your body's immune defence system. This increases your risk of skin cancer and other cancers while taking TACROLIMUS APOTEX. You should always protect yourself from the sun, wear sunscreen, a hat and protective clothing.

Things you must not do

  • Do not take TACROLIMUS APOTEX to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following and they worry you:

  • tiredness, lack of energy
  • stomach upset, including nausea (feeling sick), vomiting, loss of appetite, diarrhoea, stomach cramps
  • tremor (shaking)
  • headache
  • feeling depressed (sad)
  • sleeping difficulties
  • blurred vision or sensitive to light
  • muscle cramps, tenderness or weakness

Tell your doctor immediately if you notice any of the following as you may need urgent medical care:

  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing
  • fever
  • diabetes / increased blood sugar
  • swelling, numbness or tingling (pins and needles) in your hands and feet
  • constant "flu-like" symptoms such as chills, sore throat, aching joints, swollen glands, or any other signs of infection
  • unusual bleeding or bruising
  • high blood pressure
  • palpitations, abnormal heart rhythms, chest pain
  • new lumps or moles, or changes to existing moles, anywhere on the body
  • swelling of the eyelids, hands or feet due to excess fluid
  • a change in the amount of urine passed or in the number of times you urinate, pain on urinating, or other kidney problems.
  • yellowing of the skin and/or eyes (jaundice) often accompanied by generally feeling unwell (for example, tiredness, lack of energy, loss of appetite, nausea and vomiting, pain in the abdomen)
  • symptoms of anaemia, such as shortness of breath, tiredness or dizziness
  • seizures (fits)
  • buzzing or ringing in the ears, difficulty hearing

Other side effects not listed above may also occur in some people.

Tell your doctor if you notice any other effects.

After using TACROLIMUS APOTEX

Storage

Use all the capsules within 12 months of opening the aluminium wrapper.

Keep TACROLIMUS APOTEX Capsules in the blisters until it is time to take them.

Keep TACROLIMUS APOTEX Capsules in a cool dry place where the temperature is below 25 degrees C.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Do not store TACROLIMUS APOTEX, or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking TACROLIMUS APOTEX Capsules, or your medicine has passed its expiry date, ask your pharmacist what to do with any medicine which may be left over.

Product Description

What it looks like

TACROLIMUS APOTEX

  • TACROLIMUS APOTEX capsules 0.5 mg are yellow, packed in blister sheets of ten capsules and sealed in an aluminium wrapper (Pack size 100 capsules).
  • TACROLIMUS APOTEX 1 mg capsules are white, packed in blister sheets of ten capsules and sealed in an aluminium wrapper (Pack size 100 capsules).
  • TACROLIMUS APOTEX 5 mg capsules are greyish-red, packed in blister sheets of ten capsules and sealed in an aluminium wrapper (Pack size 50 capsules).

Ingredients

TACROLIMUS APOTEX Capsules contains:

  • Hypromellose
  • croscarmellose sodium
  • lactose
  • magnesium stearate
  • gelatin
  • water
  • sodium lauryl sulfate
  • titanium dioxide
  • colorants: iron oxide yellow for 0.5 mg capsules and iron oxide red for 5 mg capsules
  • printing ink: 0.5 mg and 1 mg capsules contains shellac and iron oxide red, 5 mg capsule contain shellac, potassium hydroxide and titanium dioxide.

Sponsor

Pharmacor Pty Ltd.
Suite 803, Level 8,
Tower A, The Zenith,
821 Pacific Highway,
Chatswood, NSW 2067,
Australia

Australian Registration numbers:

0.5 mg capsules:
ARTG No. 209273 blister pack

1 mg capsules:
ARTG No. 209275 blister pack

5 mg capsules:
ARTG No. 209269 blister pack

This leaflet was last updated in October 2020

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Tacrolimus APOTEX

Active ingredient

Tacrolimus

Schedule

S4

 

Notes

Distributed by Apotex Pty Ltd

1 Name of Medicine

Tacrolimus (as monohydrate).

2 Qualitative and Quantitative Composition

Each capsule contains 0.5 mg, 1 mg or 5 mg tacrolimus.

Excipients with known effect.

Lactose, gelatin (contains sulfites).
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tacrolimus APOTEX capsules 0.5 mg.

White to off white powder filled in size '5' yellow cap/yellow coloured body HGC printed with "0.5 mg" on cap and "Tacro" on body with red ink.

Tacrolimus APOTEX capsules 1 mg.

White to off white powder filled in size '5' white cap/white coloured body HGC printed with "1 mg" on cap and "Tacro" on body with red ink.

Tacrolimus APOTEX capsules 5 mg.

White to off white powder filled in size '4' greyish red cap/ greyish red coloured body HGC printed with "5 mg" on cap and "Tacro" on body with white ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Indicated for use as an adjunct to liver, kidney, lung or heart allograft transplantation in adults and children.

4.2 Dose and Method of Administration

Dosage.

The dosage recommendations given below for oral and intravenous administration (intravenous dosage form can be available from other brand/s) should act as a guideline. Tacrolimus doses should be adjusted according to individual patient requirements.
If allograft rejection or adverse events occur, alteration in the immunosuppressive regimen should be considered.

Method of administration.

It is recommended that the oral daily dose of Tacrolimus APOTEX be administered as two divided doses, in the morning and in the evening.
Tacrolimus APOTEX capsules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximum absorption (see Section 5.2 Pharmacokinetic Properties, Absorption).
Tacrolimus APOTEX capsules should be taken immediately following removal from the blister. The capsules should be swallowed with fluid (preferably water).
Oral administration of Tacrolimus APOTEX should commence as soon as practicable. In some transplantation patients, therapy has commenced orally by administering the Tacrolimus APOTEX capsule contents suspended in water via an intranasal gastric tube.

Instructions for use and handling.

Based on immunosuppressive effects of tacrolimus, inhalation or direct contact with skin or mucous membranes of injection solutions or powder contained in tacrolimus products should be avoided during preparation. If such contact occurs, wash the skin and eyes.

Liver transplantation.

Oral tacrolimus therapy should commence at 0.10-0.20 mg/kg/day administered as two divided doses for Tacrolimus APOTEX. Administration should start approximately 6 hours after the completion of liver transplant surgery. If the clinical condition of the patient does not allow for oral dosing then intravenous tacrolimus therapy should be initiated as a continuous 24 hour infusion, at 0.01 to 0.05 mg/kg/day.

Kidney transplantation.

Oral tacrolimus therapy should commence at 0.15-0.30 mg/kg/day administered as two divided doses for Tacrolimus APOTEX. Administration should start within 24 hours of kidney transplant surgery. If the clinical condition of the patient does not allow for oral dosing then intravenous tacrolimus therapy should be initiated as a continuous 24 hour infusion, at 0.04 to 0.06 mg/kg/day.

Lung transplantation.

Oral tacrolimus therapy should commence at 0.10-0.30 mg/kg/day administered as two divided doses for Tacrolimus APOTEX. Administration should start within 24 hours of lung transplant surgery. If the clinical condition of the patient does not allow for oral dosing then intravenous tacrolimus therapy should be initiated as a continuous 24 hour infusion, at 0.01-0.05 mg/kg/day.

Heart transplantation.

Oral tacrolimus therapy should commence at 0.075 mg/kg/day administered as two divided doses for Tacrolimus APOTEX. Administration should start within 24 hours of heart transplant surgery. If the clinical condition of the patient does not allow for oral dosing then intravenous tacrolimus therapy should be initiated as a continuous 24 hour infusion, at 0.01-1.2 mg/kg/day.

Further information for all indications follows.

Children.

Higher mg/kg doses may be required in children compared with adults to achieve the same tacrolimus blood concentration. It is recommended that the initial intravenous dose if needed should be 0.05-0.06 mg/kg/day. Initial oral doses should be 0.15-0.30 mg/kg/day as two divided doses.

Therapy dose levels for kidney, liver, lung or heart allograft rejection resistant to existing immunosuppressive regimens.

In patients experiencing rejection episodes, which are unresponsive to conventional immunosuppressive therapy, Tacrolimus APOTEX treatment should begin with the initial dose recommended for primary immunosuppression in that particular allograft.

Conversion.

Conversion from ciclosporin to Tacrolimus APOTEX.

Care should be taken when converting patients from ciclosporin based to tacrolimus based therapy (see Section 4.4 Special Warnings and Precautions for Use, Conversion between agents; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Tacrolimus based therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus based therapy has been initiated 12-24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.

Conversion between tacrolimus formulations.

Differences between oral formulations of tacrolimus can lead to important differences in systemic exposure to tacrolimus. Inadvertent or unsupervised switching between formulations is unsafe and could lead to graft rejection or increased incidence of side effects. Therefore it is appropriate to prescribe and dispense tacrolimus by trade name, taking care to specify appropriate daily dosing (e.g. Tacrolimus APOTEX twice daily). Patients must only be switched from one tacrolimus formulation to another under the close supervision of a transplant specialist.

Dose adjustments in special populations.

Elderly.

Experience in the elderly is limited. There is no evidence presently available to suggest that doses should be altered in elderly patients.

Patients with renal impairment.

No dose adjustment is required. However, careful monitoring of renal function is recommended.

Patients with liver impairment.

Tacrolimus is extensively metabolised by the liver. In patients with liver impairment dose reduction is recommended.
Tacrolimus is normally administered together with other immunosuppressive drugs. In isolated cases, successful maintenance therapy with tacrolimus alone has been described. Tacrolimus should not be given concurrently with ciclosporin.

Race.

In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels.

Gender.

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

Monitoring advice.

Monitoring of tacrolimus whole blood trough concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood trough concentration monitoring is not a replacement for renal or liver function monitoring and tissue biopsies.
Various assays have been used to measure blood or plasma concentrations of tacrolimus. Comparison of the concentrations in published literature to patient concentrations should be made with care and knowledge of the assay methods employed.
Trough blood concentrations should be measured at 12 hours after a Tacrolimus APOTEX dose. The majority of patients (adults and children) can be successfully managed if the trough blood concentrations are maintained within the following range.

Liver transplant.

5-20 nanogram/mL for the first 3 months, 5-15 nanogram/mL thereafter.

Kidney transplant.

10-20 nanogram/mL for the first 3 months, 5-15 nanogram/mL thereafter.

Heart transplant.

10-20 nanogram/mL for the first 3 months, 5-15 nanogram/mL thereafter.

Lung transplant.

10-20 nanogram/mL for the first month, then 5-15 nanogram/mL thereafter.
During the first months post-transplant, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, visual status, blood glucose levels, electrolytes (particularly potassium), creatinine, BUN, urinary output, haematology parameters, coagulation values, and liver and renal function tests. If clinically relevant changes are seen, adjustment of the immunosuppressive regimen should be considered.
Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of Tacrolimus APOTEX. This should be considered when deciding upon a maintenance regimen.

4.3 Contraindications

Tacrolimus is contraindicated in patients hypersensitive to tacrolimus or other macrolides, or to other ingredients of the capsules.

4.4 Special Warnings and Precautions for Use

Tacrolimus therapy requires careful monitoring in hospital units equipped and staffed with adequate laboratory and supportive medical resources. The drug should only be prescribed, and changes in immunosuppressive therapy should be initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Post-transplant diabetes mellitus (PTDM).

Post-transplant insulin dependent diabetes mellitus (PTDM: use of insulin for 30 or more consecutive days, with < 5 day gap, by patients without a prior history of insulin or noninsulin dependent diabetes mellitus), was reported in 20% (30/151) and 6% (17/281) of tacrolimus treated kidney transplant patients in the U.S. and European randomised trials respectively. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these patients at one year and in 50% at two years post-transplant. Black and Hispanic patients were found to be at increased risk of development of PTDM in the U.S. trial. The risk/benefit ratio should be carefully considered before using tacrolimus in kidney transplant patients with a pretransplant diabetic condition.
In liver transplantation PTDM was reported in 18% (42/239) and 11% (26/239) of tacrolimus treated patients and was reversible in 45% and 31% of these patients at one year post-transplant in the U.S. and European randomised trials respectively.
Insulin dependent post-transplant diabetes mellitus was reported in 13% (10/75) and 22% (29/132) of tacrolimus treated heart transplant patients receiving mycophenolate mofetil or azathioprine and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomised studies, respectively.

Neurotoxicity.

Neurological and CNS disorders have been reported with tacrolimus therapy. Symptoms include tremor, headache, changes in motor function, sensory function or mental status, insomnia, seizures, coma and delirium. Patients experiencing such events should be carefully monitored. In cases of severe or worsening neurological disorder, adjustment of the immunosuppressive regimen should be considered.

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 indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

Pure red cell aplasia (PRCA).

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

Nephrotoxicity.

Tacrolimus can cause renal impairment characterised by increases in serum creatinine as a result of a reduced glomerular filtration rate, particularly when used in high doses. These changes have been observed to be dose dependent and improvements have been associated with reduced dosing. The mechanism leading to these changes is not fully understood. Use of tacrolimus with sirolimus in heart transplantation patients in a US study was associated with increased risk of renal function impairment, and is not recommended. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced.
Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, tacrolimus should not be used simultaneously with ciclosporin. Tacrolimus or ciclosporin should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus or ciclosporin concentrations, dosing with the other drug usually should be further delayed.

Hyperkalaemia.

Mild to severe hyperkalaemia was reported in patients treated with tacrolimus, especially in patients with renal impairment. Patients may require treatment, and should avoid high dietary potassium intake. Serum potassium levels should be monitored and potassium sparing diuretics should not be used during tacrolimus therapy.

Vaccinations.

As with other immunosuppressants, response to 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, although all cases were considered a complication of transplant surgery or accompanied by infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments including surgery should be considered immediately after a suspect symptom occurs.

Potential interactions.

When substances with a potential for interaction (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole 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.
Early and frequent continued monitoring of tacrolimus blood levels within the first few days of coadministration, as well as monitoring for renal function, for QT prolongation with ECG, and for other side effects is strongly recommended when co-administered with CYP3A4 inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Malignancies.

As with other potent immunosuppressive compounds, patients treated with tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. In patients switched to tacrolimus, this may be attributable to over immunosuppression before commencing therapy with this agent. Very young (< 2 years), EBV seronegative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV serology should be ascertained before starting treatment with tacrolimus. During treatment, careful monitoring is recommended.

Infections.

Like other immunosuppressants, tacrolimus predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections. Oversuppression of the immune system can also increase susceptibility to opportunistic infections, sepsis and fatal infections. Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

Hypertension.

Hypertension is a common adverse effect of tacrolimus therapy. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium sparing diuretics should be avoided. While calcium channel blocking agents can be effective in treating tacrolimus associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction.

Myocardial hypertrophy.

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies have been observed in a few cases in association with administration of tacrolimus. Most of these have been reversible, occurring primarily in patients having tacrolimus blood trough levels higher than the recommended level. Mean tacrolimus whole blood trough concentrations during the period prior to diagnosis of myocardial hypertrophy in 20 patients with pre and post-treatment echocardiograms ranged from 10.6 to 53.3 nanogram/mL in infants (N = 10, age 0.4 to 2 years), 4.0 to 45.7 nanogram/mL in children (N = 7, age 2 to 15 years) and 10.9 to 24.3 nanogram/mL in adults (N = 3, age 37 to 45 years). Other factors observed to increase the risk of these clinical conditions are, for example, previously existing heart diseases, corticosteroid usage, hypertension, renal or hepatic dysfunction, and fluid overload. Accordingly, high risk patients should be monitored, e.g. with echocardiography or ECG. If abnormalities develop, dose reduction of tacrolimus therapy, or change of treatment to other immunosuppressive agent should be considered.

QT interval prolongation.

Tacrolimus may prolong the QT interval and may cause torsades de pointes. Caution should be exercised in patients with known risk factors for QT prolongation (including, but not limited to, congenital or acquired QT prolongation, concomitant medications known to prolong the QT interval or known to increase tacrolimus exposure).

Conversion between agents.

Conversion between tacrolimus formulations.

Various formulations of tacrolimus are available. Medication errors have resulted in incorrect dosing or unsupervised switching between tacrolimus formulations. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under exposure or over exposure to tacrolimus. Therefore it is appropriate to prescribe and dispense tacrolimus by trade name, taking care to specify appropriate daily dosing (e.g. Tacrolimus APOTEX twice daily). It should be emphasised that patients, once titrated to an effective dose of a particular formulation of tacrolimus, should not be changed to another formulation of tacrolimus without blood trough level monitoring, clinical assessment and retitration (see Section 4.2 Dose and Method of Administration, Conversion).

Conversion with ciclosporin.

Tacrolimus should not be administered concurrently with ciclosporin as the half-life of the latter may be increased. Synergistic/additive nephrotoxic effects can also occur. Care should be taken when administering tacrolimus to patients who have previously received ciclosporin and when converting patients from ciclosporin to tacrolimus based therapy. It is recommended that ciclosporin blood levels are monitored prior to the administration of tacrolimus. The most appropriate time to initiate tacrolimus therapy should be based upon information on ciclosporin blood levels and the clinical condition of the patient. Dosing may be delayed in the presence of elevated ciclosporin levels. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin may be affected. A 24 hour interval between stopping ciclosporin and starting tacrolimus has been commonly used.
Patients switched to tacrolimus rescue therapy should not be given antilymphocyte treatment concomitantly.

Use in hepatic impairment.

Tacrolimus is extensively metabolised by the liver. In patients with liver impairment dose reduction is recommended.

Use in renal impairment.

Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced.

Use in the elderly.

Experience in the elderly is limited. There is no evidence presently available to suggest that doses should be altered in elderly patients. (See Section 4.2 Dose and Method of Administration, Dose adjustments in special populations.)

Paediatric use.

Higher mg/kg doses may be required in children compared with adults to achieve the same tacrolimus blood concentration. It is recommended that the initial oral doses should be 0.15-0.30 mg/kg/day as two divided doses. (See Section 4.2 Dose and Method of Administration.)

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Metabolic interactions.

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of drugs or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. Significant tacrolimus dose reductions and prolongation of dosing interval may be required in order to maintain similar tacrolimus exposure when co-administered with strong CYP3A4 inhibitors, particularly telaprevir. Rapid increase in tacrolimus level may occur when co-administered with CYP3A4 inhibitors. Cases have been reported in which a sharp rise in tacrolimus levels occurred very rapidly, as early as within 1-3 days after co administration with a strong CYP3A4 inhibitor, clarithromycin, despite immediate reduction of tacrolimus dose. Therefore early, within the first few days of co-administration, and frequent continued monitoring of tacrolimus blood levels, as well as monitoring for renal function, for QT prolongation with ECG, and for other side effects is strongly recommended.

Inhibitors of metabolism.

Clinically the following substances have been shown to increase tacrolimus blood levels.
Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir), or the CMV antiviral letermovir and amiodarone. Concomitant use of these drugs may require decreased tacrolimus doses in nearly all patients.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.
The herbal remedy Schisandra sphenanthera extract inhibits CYP3A4 and may increase the blood levels of tacrolimus.
In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethindrone, quinidine, tamoxifen, (triacetyl) oleandomycin.
Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.
Lansoprazole and ciclosporin may potentially inhibit CYP3A4 mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.

Inducers of metabolism.

Clinically the following substances have been shown to decrease tacrolimus blood levels.
Strong interactions have been observed with rifampicin, phenytoin or St John's wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels.
High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels.
Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.

Effect of tacrolimus on the metabolism of other drugs.

Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with drugs known to be metabolised by CYP3A4 may affect the metabolism of such drugs.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin.
Tacrolimus have been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.
Limited knowledge of interactions between tacrolimus and statins is available. Available data suggests that the pharmacokinetics of statins are largely unaltered by the coadministration of tacrolimus.
Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and antipyrine.
Other potential interactions that may increase systemic exposure of tacrolimus: prokinetic agents such as metoclopramide and cisapride; cimetidine; magnesium aluminum hydroxide.

Other interactions which have led to clinically detrimental effects.

Concurrent use of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase these effects (e.g. aminoglycosides, gyrase inhibitors, vancomycin, cotrimoxazole, NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium sparing diuretics (e.g. amiloride, triamterene or spironolactone) should be avoided.
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.

Protein binding considerations.

Tacrolimus is extensively bound to plasma proteins. Possible interactions with other drugs known to have high affinity for plasma proteins should be considered (e.g. NSAIDs, oral anticoagulants or oral antidiabetics).

Other considerations.

Combination therapy with mycophenolic acid (MPA) products.

Caution should be exercised when switching combination therapy from ciclosporin to tacrolimus and vice versa. Exposure to MPA is higher with tacrolimus co-administration than with ciclosporin coadministration because ciclosporin interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Therapeutic drug monitoring of MPA is recommended.

Impact of direct-acting antiviral (DAA) therapy.

The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy and safety.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Tacrolimus subcutaneously administered to male rats at doses of 2 or 3 mg/kg/day resulted in a dose-related decrease in sperm count.
(Category C)
In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to the dams.
Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction which were indicated by a higher rate of postimplantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.
Human data show that tacrolimus is able to cross the placenta.
There are no adequate and well controlled studies in pregnant women. There is data from a voluntary pregnancy exposure registry (Transplantation Pregnancy Registry International (TPRI)) that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus.
Safety data from postmarketing surveillance and the TPRI suggest infants of organ transplant recipients using immunosuppressive medications including tacrolimus have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress.
The use of tacrolimus during pregnancy has been associated with neonatal hyperkalaemia and renal dysfunction.
Tacrolimus use may also be associated with hyperglycemia or diabetes in pregnancy in the absence of pre-existing diabetes or gestational. Monitor maternal blood glucose levels regularly.
Tacrolimus may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure.
Females and males of reproductive potential should consider the use of appropriate contraception prior to starting treatment with tacrolimus.
Tacrolimus should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
 Tacrolimus is excreted into breast milk. It is therefore recommended that mothers should not breastfeed while receiving tacrolimus.

4.7 Effects on Ability to Drive and Use Machines

Tacrolimus may cause visual and neurological disturbances. Patients treated with tacrolimus who are affected by such disorders should not drive a car or operate dangerous machinery.

4.8 Adverse Effects (Undesirable Effects)

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.
The most commonly reported adverse drug reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.
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, including isolated reports).

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.

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.

Blood and lymphatic system disorders.

Common: anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal.
Uncommon: coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia.
Rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia.

Immune system disorders.

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see Section 4.4 Special Warnings and Precautions for Use).

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, anorexia, metabolic acidosis, 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: tremor, headache.
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, ECG investigations abnormal, heart rate and pulse investigations abnormal, QT prolongation, torsades de pointes.
Rare: pericardial effusion.
Very rare: echocardiogram abnormal.

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, peritonitis, acute and chronic pancreatitis, blood amylase increased, gastroesophageal reflux disease, impaired gastric emptying.
Rare: subileus, pancreatic pseudocyst.

Hepatobiliary disorders.

Very common: liver function test abnormal.
Common: bile duct disorders, cholestasis and jaundice, hepatocellular damage and hepatitis.
Rare: hepatitic artery thrombosis, veno-occlusive liver disease.
Very rare: hepatic failure.

Skin and subcutaneous 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.

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, blood alkaline phosphatase increased, weight increased, body temperature perception disturbed.
Uncommon: multi-organ failure, influenza-like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal, blood lactate dehydrogenase increased, weight decreased.
Rare: thirst, fall, chest tightness, mobility decreased, ulcer.
Very rare: fat tissue increased.

Injury, poisoning and procedural complications.

Common: primary graft dysfunction.
* In isolated cases, pain in limb has been reported as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS), which typically presents bilaterally and symmetrical, severe, ascending pain in the lower extremities.

Postmarketing experience.

The following adverse events have been reported in association with tacrolimus use during worldwide postmarketing experience:

Blood and lymphatic system disorders.

Unknown frequency: agranulocytosis, haemolytic anaemia, pure red cell aplasia, febrile neutropenia.

Eye disorders.

Unknown frequency: optic neuropathy.

Nervous system disorders.

Unknown frequency: posterior reversible encephalopathy syndrome (PRES).

Musculoskeletal and connective tissue disorders.

Unknown frequency: calcineurin-inhibitor induced pain syndrome (CIPS)*.
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate or prolonged release tacrolimus formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Experience of overdosage is limited.
Early clinical experience (when initial induction doses were 2-3 times greater than those currently recommended) suggested that symptoms of overdosage may include glucose intolerance, renal, neurological and cardiac disorders, hyperkalaemia and hypertension. Over immunosuppression may increase risk of severe infections.
Liver function clearly influences all pre and postoperative pharmacokinetic variables. Patients with failing liver grafts or those switched from other immunosuppressive therapy to Tacrolimus APOTEX should be monitored carefully to avoid overdosage.
No specific antidote to tacrolimus therapy is available. If overdosage occurs, general supportive measures and symptomatic treatment should be conducted.
Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that Tacrolimus APOTEX will not be dialysable. Data on haemoperfusion are not available. Activated charcoal may reduce absorption of the drug if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tacrolimus is a macrolide lactone with potent in vitro and in vivo immunosuppressive activity. Studies suggest that tacrolimus inhibits the formation of cytotoxic lymphocytes which are regarded as being primarily responsible for graft rejection. Tacrolimus suppresses T cell activation and T helper cell dependent B cell proliferation, as well as the formation of lymphokines such as interleukins-2 and -3 and gamma-interferon and the expression of the interleukin-2 receptor. At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP), which is responsible for the intracellular accumulation of the compound. A complex of tacrolimus-FKBP-12, calcium, calmodulin and calcineurin is formed and the phosphatase activity of calcineurin inhibited.
Studies in animals and man have shown that tacrolimus is able to prevent and treat graft rejection following transplantation of the liver, kidney, and other solid organs.

Clinical trials.

Liver.

The efficacy and safety of a tacrolimus based immunosuppressive regimen following orthotopic liver transplantation was assessed in two prospective, randomised, nonblinded multicentre trials. The active control groups were treated with a ciclosporin based regimen. In a European trial, patients received a tacrolimus-steroid based regimen (n = 264) or a ciclosporin-azathioprine-steroid (with or without antilymphocyte globulin) based regimen (n = 265).
Equivalent graft survival (77.5 vs 72.69%) and patient survival (82.9 vs 77.5%) was seen. Significant reductions were seen in the tacrolimus treated patients for incidence of acute rejection (40.5 vs 49.8%), refractory acute rejection (0.8 vs 5.3%) and chronic rejection (1.5 vs 5.3%). In American trial patients received a tacrolimus-steroid regimen (n = 263) or a ciclosporin (mainly triple therapy) based regimen (n = 266). Equivalent graft survival (82 vs 79%) and patient survival (88 vs 88%) rates were observed. Tacrolimus was associated with significant reductions in the incidence of acute rejection (68 vs 76%), steroid resistant rejection (19 vs 36%) and refractory rejection (3 vs 15%).

Kidney.

Two randomised, multicentre nonblinded comparative trials were performed in cadaveric kidney transplantation. In an American trial patients received a tacrolimus based (n = 205) or ciclosporin based (n = 207) regimen. All patients also received maintenance azathioprine and corticosteroids and an induction course of an antilymphocyte antibody preparation. Equivalent graft survival (91.2 vs 87.9%) and patient survival (95.6 vs 96.6%) was seen for the tacrolimus and ciclosporin treated patients respectively. A significantly reduced one year incidence rate of biopsy confirmed acute rejection (30.7 vs 46.4%), moderate to severe acute rejection (10.7 vs 26.6%) and use of antilymphocyte antibody preparation for treatment of rejection (10.7 vs 25.1%) was seen in the tacrolimus treated patients.
A European trial compared triple drug based immunosuppression with tacrolimus or ciclosporin centred regimens, with 303 and 145 patients randomised to the tacrolimus and ciclosporin arms respectively. Equivalent one year graft survival (82.5 vs 86.2%) and one year patient survival (93.0 vs 96.5%) rates were observed, but with significantly reduced one year acute rejection rate (32.3 vs 54.5%), rate of corticosteroid sensitive rejections (24.4 vs 42.1%) and rate of corticosteroid resistant rejections (10.2 vs 20.7%).

Heart.

Two open label, randomised, comparative studies evaluated the safety and efficacy of tacrolimus based and ciclosporin based immunosuppression in primary orthotopic heart transplantation. In a phase 3 study conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids and azathioprine in combination with tacrolimus or ciclosporin modified for 18 months. In a 3 arm study conducted in the US, 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or ciclosporin modified plus MMF for 1 year.
In the European phase 3 study, patient/ graft survival at 18 months post-transplant was similar between treatment arms, 91.7% in the tacrolimus group and 89.2% in the ciclosporin group. In the US study, patient and graft survival at 12 months was similar with 93.5% survival in the tacrolimus plus MMF group and 86.1% survival in the ciclosporin modified plus MMF group. In the European study, the ciclosporin trough concentrations were above the predefined target range (i.e. 100-200 nanogram/mL) at day 122 and beyond in 32-68% of the patients in the ciclosporin treatment arm, whereas the tacrolimus trough concentrations were within the predefined target range (i.e. 5-15 nanogram/mL) in 74-86% of the patients in the tacrolimus treatment arm.
The US study contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full dose tacrolimus; however, this regimen was associated with increased risk of wound healing complications, renal function impairment, and insulin dependent post-transplant diabetes mellitus, and is not recommended in de novo heart transplant patients (see Section 4.4 Special Warnings and Precautions for Use).

Lung.

In a prospective, 2 centre, open label randomised trial, 74 lung transplant patients (aged 20-66 years old) were randomised to tacrolimus based (n = 37) and ciclosporin based (n = 37) immunosuppression. The drugs were given in combination with mycophenolate mofetil and corticosteroids. Tacrolimus was started immediately after transplantation as continuous intravenous infusion at a dose of 0.015 mg/kg/day and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments to target trough levels of 12 to 15 nanogram/mL in the first month and 9 to 12 nanogram/mL thereafter. The 6 months and 1 year patient survival data was similar in both groups (89% vs 84% and 82% vs 71%, ciclosporin vs tacrolimus respectively). Freedom from acute rejection was comparable at 1 year, 35% in the ciclosporin group and 46% in the tacrolimus group.
Another prospective, randomised, open label study included 66 patients on tacrolimus versus 67 patients on ciclosporin, aged 20 to 66 years old. The drugs were given in combination with azathioprine and corticosteroids. Tacrolimus was started 6 to 8 hours after transplantation as continuous intravenous infusion at a dose of 0.025 mg/kg/day and oral tacrolimus was administered at a dose of 0.15 mg/kg/day with subsequent dose adjustments to target trough levels of 10 to 20 nanogram/mL. The 1 year patient survival was 83% in the tacrolimus group and 71% in the ciclosporin group, the 2 year survival rates were 76% and 66%, respectively. The differences between groups were not statistically significant. Freedom from acute rejection after at least 37 weeks follow-up was also comparable (14% in the tacrolimus group and 11.5% in the ciclosporin group).
A number of published, open, uncontrolled studies have examined the use of tacrolimus in lung transplant patients who have developed refractory acute rejection or bronchiolitis obliterans syndrome while receiving ciclosporin based immunosuppressive regimens. In these studies, conversion from ciclosporin to tacrolimus has been associated with improved clinical outcomes such as reduced frequency of further acute rejection episodes and stabilisation or improvement in declining FEV1 values.

5.2 Pharmacokinetic Properties

Absorption.

In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed.
Following oral administration of tacrolimus peak concentrations (Cmax) of tacrolimus in blood are achieved in approximately 1-3 hours. Prolonged release formulation of tacrolimus resulted in an extended oral absorption profile with an average time to Cmax of approximately 2 hours. In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding 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 were achieved within 3 days in the majority of patients.
In healthy subjects, tacrolimus 0.5 mg, tacrolimus 1 mg and tacrolimus 5 mg capsules have been shown to be bioequivalent, when administered as equivalent dose.
The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced after a high fat meal. The effect of a high carbohydrate meal is less pronounced.
In stable liver transplant patients, the oral bioavailability of tacrolimus was reduced when it was administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and Cmax (50%), and an increase in tmax (173%) in whole blood were evident.
In a study of stable renal transplant patients who were administered tacrolimus immediately after a standard continental breakfast the effect on oral bioavailability was less pronounced. Decreases in AUC (2 to 12%) and Cmax (15 to 38%), and an increase in tmax (38 to 80%) in whole blood were evident.
Bile flow does not influence the absorption of tacrolimus.
A strong correlation exists between AUC and whole blood trough levels at steady-state for tacrolimus. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.

Distribution.

In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly 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 protein, mainly to serum albumin and α-1-acid glycoprotein.
Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1300 L (healthy subjects). Corresponding data based on whole blood averaged 47.6 L.
Tacrolimus is a low clearance substance. In healthy subjects, the average total body clearance (TBC) estimated from 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, have been observed. Paediatric liver transplant recipients have a TBC approximately twice that of adult liver transplant patients. Factors such as low haematocrit 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 following 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 paediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased clearance rates contribute to the shorter half-life observed in transplant recipients.

Metabolism.

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to pharmacological activity of tacrolimus.

Excretion.

Following intravenous and oral administration of 14C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.

Pharmacokinetics in special populations.

The pharmacokinetics of tacrolimus in special populations have not been studied in detail. See Section 4.2 Dose and Method of Administration for dose adjustments in special populations.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxicity was seen in a series of assays for gene mutations and clastogenicity. Tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes but high concentrations of tacrolimus have been reported to increase the frequency of sister chromatid exchanges in human lymphocytes in vitro.

Carcinogenicity.

Tacrolimus did not show any tumourigenic effects in long-term carcinogenicity studies using the mouse and rat. The maximum dose tested in the rat resulted in a blood exposure less than, and a plasma exposure 1.4 times the exposure achieved after the maximum recommended clinical dose, 0.3 mg/kg, based on AUC. In mice the maximum dose was 0.8 times the recommended clinical dose based on body surface area.
Patients receiving long-term immunosuppressive therapy are at an increased risk of developing lymphomas and other malignancies (see Section 4.4 Special Warnings and Precautions for Use, Malignancies).

6 Pharmaceutical Particulars

6.1 List of Excipients

Hypromellose, croscarmellose sodium, lactose, magnesium stearate, gelatin, water, sodium lauryl sulfate, titanium dioxide, colorants: iron oxide yellow for 0.5 mg capsules and iron oxide red for 5 mg capsules), printing ink: 0.5 mg and 1 mg capsules contains shellac and iron oxide red, 5 mg capsule contain shellac, potassium hydroxide and titanium dioxide).

6.2 Incompatibilities

Tacrolimus is incompatible with PVC plastics. Tubing, syringes, and other equipment used to administer tacrolimus should not contain PVC.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. After opening the aluminium wrapper, Tacrolimus APOTEX capsules are stable for 12 months when stored at room temperature. The blister strips should be kept in a dry place and the capsules should be left in the blister until required for use.

6.5 Nature and Contents of Container

Tacrolimus APOTEX capsules are supplied as blister strips each containing 10 capsules packed within a protective aluminium wrapper.

Tacrolimus APOTEX capsules 0.5 mg (AUST R 209273).

Cartons of 100 capsules PVC/PVDC/Al.

Tacrolimus APOTEX capsules 1 mg (AUST R 209275).

Cartons of 100 capsules PVC/PVDC/Al.

Tacrolimus APOTEX capsules 5 mg (AUST R 209269).

Cartons of 50 capsules PVC/PVDC/Al.
APOTEX is a registered trade mark of Apotex Inc.
Not all strengths may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Tacrolimus appears as white to off white powder, soluble in acetone, chloroform and ethyl acetate, insoluble in water. Tacrolimus is obtained by fermentation as a single enantiomer but exists in tautomeric equilibration in aqueous solution.

Chemical structure.


[3S [3R* [E(1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]- 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4- hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8- (2-propenyl)-15,19-epoxy-3H-pyrido [2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)- tetrone, monohydrate.
Molecular Formula: C44H69NO12.H2O.
Molecular Weight: 822.03.

CAS number.

104987-11-3 (anhydrous).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes