Tacrolimus Capsules IP 1mg (TACROTAJ) Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Tacrolimus Capsules IP 0.5mg (Tacrotaj) Taj Pharma
Tacrolimus Capsules IP 1mg (Tacrotaj) Taj Pharma
Tacrolimus Capsules IP 2mg (Tacrotaj) Taj Pharma
Tacrolimus Capsules IP 5mg (Tacrotaj) Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
   a) Each hard gelatin capsule contains:
   Tacrolimus IP equivalent to Anhydrous Tacrolimus                 0.5mg
   Excipients                                         q.s.
   Approved colours used in capsule shells
   
   b) Each hard gelatin capsule contains:
   Tacrolimus IP equivalent to Anhydrous Tacrolimus                   1mg
   Excipients                                        q.s.
   Approved colours used in capsule shells

   c) Each hard gelatin capsule contains:
   Tacrolimus IP equivalent to Anhydrous Tacrolimus                   2mg
   Excipients                                        q.s.
   Approved colours used in capsule shells

   d) Each hard gelatin capsule contains:
   Tacrolimus IP equivalent to Anhydrous Tacrolimus                   5mg
   Excipients                                        q.s. Approved colours used in capsule shells

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prophylaxis of transplant rejection in liver, kidney or heart allograft recipients.

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

4.2 Posology and method of administration

Tacrotaj therapy requires careful monitoring by adequately qualified and equipped personnel.

The medicinal product should only be prescribed, and changes in immunosuppressive therapy initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients.

Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including under- or over-immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

General considerations

The recommended initial dosages presented       below are intended to act solely as a guideline. Tacrolimus dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below for recommended target whole blood through concentrations If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

Tacrolimus can be administered intravenously or orally. In general, dosing may commence orally, if necessary, by administering the capsule          contents suspended in water, via nasogastric     tubing.

Tacrolimus is routinely administered in  conjunction with other immunosuppressive       agents in the initial post-operative period. The Tacrotaj dose may vary depending upon 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). Capsules should be taken immediately following removal from the blister. The capsules should be swallowed with fluid     (preferably water).

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 maximal absorption (see section 5.2).

Patients should be advised not to swallow the desiccant.

Duration of dosing

To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given.

Dosage recommendations – Liver transplantation

Prophylaxis of transplant rejection – adults

Oral tacrolimus therapy should commence at 0.10 – 0.20mg/kg/day administered as two divided doses (e.g. morning and evening). Administration should commence approximately 12 hours after the completion of surgery.

If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of tacrolimus 0.01 – 0.05mg/kg/day should be initiated as a continuous 24-hour infusion.

Prophylaxis of transplant rejection – children

An initial oral dose of 0.30mg/kg/day should be administered in two divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of tacrolimus 0.05mg/kg/day should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and children

Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to tacrolimus monotherapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Rejection therapy – adults and children

Increased tacrolimus doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity are noted (e.g. pronounced adverse reactions – see section 4.8) the dose of tacrolimus need to be reduced.

For conversion to tacrolimus, treatment should begin with the initial oral dose recommended for primary immunosuppression.

For information on conversion from ciclosporin to Tacrotaj, see below under “Dose adjustments in special populations”.

Dosage recommendations – Kidney transplantation

Prophylaxis of transplant rejection – adults

Oral tacrolimus therapy should commence at 0.20 – 0.30 mg/kg/day administered as two divided doses (e.g. morning and evening). Administration should commence within 24 hours after the completion of surgery.

If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of tacrolimus 0.05 – 0.10 mg/kg/day should be initiated as a continuous 24-hour infusion.

Prophylaxis of transplant rejection – children

An initial oral dose of 0.30mg/kg/day should be administered in two divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of tacrolimus 0.075 – 0.100mg/kg/day should be administered as a continuous 24-hour infusion.

Dose adjustment during post-transplant period in adults and children

Tacrolimus doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw concomitant immunosuppressive therapy, leading to tacrolimus-based dual-therapy. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Rejection therapy – adults and children

Increased tacrolimus doses, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity are noted (e.g. pronounced adverse reactions – see section 4.8) the dose of tacrolimus may need to be reduced.

For conversion to tacrolimus, treatment should begin with the initial oral dose recommended for primary immunosuppression.

For information on conversion from ciclosporin to Tacrotaj, see below under “Dose adjustments in special populations”.

Dosage recommendations – Heart transplantation

Prophylaxis of transplant rejection – adults

Tacrolimus can be used with antibody induction (allowing for delayed start of tacrolimus therapy) or alternatively in clinically stable patients without antibody induction.

Following antibody induction, oral tacrolimus therapy should commence at a dose of 0.075mg/kg/day administered as two divided doses (e.g. morning and evening). Administration should commence within 5 days after the completion of surgery as soon as the patient’s clinical condition is stabilised. If the dose cannot be administered orally as a result of the clinical condition of the patient, intravenous therapy of tacrolimus 0.01 to 0.02mg/kg/day should be initiated as a continuous 24-hour infusion.

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

Prophylaxis of transplant rejection – children

Tacrolimus has been used with or without antibody induction in paediatric heart transplantation. In patients without antibody induction, if tacrolimus therapy is initiated intravenously, the recommended starting dose is 0.03 – 0.05 mg/kg/day as a continuous 24-hour infusion targeted to achieve tacrolimus whole blood concentrations of 15 – 25 ng/ml. Patients should be converted to oral therapy as soon as clinically practicable. The first dose of oral therapy should be 0.30 mg/kg/day starting 8 to 12 hours after discontinuing intravenous therapy.

Following antibody induction, if tacrolimus therapy is initiated orally, the recommended starting dose is 0.10 – 0.30 mg/kg/day administered as two divided doses (e.g. morning and evening).

Dose adjustment during post-transplant period in adults and children

Tacrolimus doses are usually reduced in the post-transplant period. Post-transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments.

Rejection therapy – adults and children

Increased tacrolimus doses, supplemental          corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. In adult patients converted to tacrolimus, an initial oral dose of 0.15 mg/kg/day should be administered in two divided doses (e.g. morning and evening).

In paediatric patients converted to tacrolimus, an initial oral dose of 0.20 – 0.30mg/kg/day should be administered in two divided doses (e.g. morning and evening).

For information on conversion from ciclosporin to Tacrotaj, see below under “Dose adjustments in special populations”.

Dosage recommendations – Rejection therapy, other allografts

The dose recommendations for lung, pancreas and intestinal transplantation are based on limited prospective clinical trial data. In lung-transplanted patients tacrolimus has been used at an initial oral dose of 0.10 – 0.15mg/kg/day, in pancreas-transplanted patients at an initial oral dose of 0.2mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3mg/kg/day.

Dosage adjustments in special populations

Patients with liver impairment

Dose reduction may be necessary in patients with severe liver impairment in order to maintain the tacrolimus blood trough levels within the recommended target range.

Patients with kidney impairment

As the pharmacokinetics of tacrolimus are unaffected by renal function, no dose adjustment is required. However, owing to the nephrotoxic potential of tacrolimus careful monitoring of renal function is recommended (including serial serum creatinine concentrations, calculation of creatinine clearance and monitoring of urine output).

Paediatric patients

In general, paediatric patients require doses 1½ – 2 times higher than the adult doses to achieve similar blood levels.

Elderly patients

There is no evidence currently available to indicate that dosing should be adjusted in elderly patients.

Conversion from ciclosporin

Care should be taken when converting patients from ciclosporin-based to tacrolimus based therapy (see sections 4.4 and 4.5). Tacrolimus 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 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.

Target whole blood through concentration recommendations

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient.

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood including a semi-automated microparticle enzyme immunoassay (MEIA). Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods.

Blood trough levels of tacrolimus should be       monitored during the post-transplantation period. When dosed orally, blood trough levels should be drawn approximately 12 hours post-dosing, just prior to the next dose. The frequency of blood   level monitoring should be based on clinical     needs. As Tacrotaj is a medicinal product with low clearance, adjustments to the dosage regimen may take several days before changes in blood levels are apparent. Blood trough levels should be monitored approximately twice weekly during the early post-transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be monitored following dose adjustment, changes in the       immunosuppressive regimen, or following co-administration of substances which may alter tacrolimus whole blood concentrations     (see section 4.5).

Clinical study analysis suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels.

In clinical practice, whole blood trough levels have generally been in the range 5 – 20 ng/ml in liver transplant recipients and 10 – 20 ng/ml in kidney and heart transplant patients in the early post-transplant period. Subsequently, during maintenance therapy, blood concentrations have generally been in the range of 5 – 15 ng/ml in liver, kidney and heart transplant recipients.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under- or overexposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8).

During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.

Substances with potential for interaction

When substances with a potential for interaction (see section 4.5) – particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) – are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Herbal preparations containing St. John’s wort (Hypericum perforatum) or other herbal preparations should be avoided when taking Tacrotaj due to the risk of interactions that lead to either a decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in blood concentrations of tacrolimus and risk of tacrolimus toxicity (see section 4.5)

The combined administration of ciclosporinand tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin(see sections 4.2 and 4.5).

High potassium intake or potassium-sparing diuretics should be avoided (see section 4.5).

Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see section 4.5).

Vaccination

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

Gastrointestinal disorders

Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur.

Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.

Cardiac disorders

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients, particularly young children and those receiving substantial immunosuppression should be monitored, using such procedures as        echocardiography or ECG pre- and       post-transplant (e.g. initially at three months and then at 9-12 months). If abnormalities develop, dose reduction of tacrolimus therapy, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure,     bradyarrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte         abnormalities or known to increase tacrolimus exposure ( see section 4.5).

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been         reported to develop Epstein-Barr Virus EBV-associated lymphoproliferative disorders (see section 4.8). Patients switched to tacrolimus therapy should not receive            anti-lymphocyte treatment concomitantly. Very young (< 2 years), EBV-VCA-negative children have been reported to have an increased risk of developing  lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with       tacrolimus. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or         lymphoma.

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

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be       limited by wearing protective clothing and using a sunscreen with a high protection factor.

Opportunistic infections

Patients treated with immunosuppressants, including tacrolimus are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). 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.

Pure red cell aplasia

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.

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.

Excipients

Tacrotaj contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

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 medicinal       products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. It is therefore strongly recommended to closely monitor tacrolimus           blood levels, as well as QT prolongation (with ECG), renal function and other side effects, whenever substances which have the potential to alter CYP3A metabolism are used concomitantly and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).

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 or HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir) or HCV protease inhibitors (e.g. telaprevir, boceprevir).

Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.

Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole nefazodone and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera, also known as southern Magnolia vine or five- flavour berry.

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, norethisterone, quinidine, tamoxifen, troleandomycin.

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.

Protien binding considerations

Other interactions potentially leading to increased tacrolimus blood levels

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

Other potential interactions that may increase systemic exposure of tacrolimus include the prokinetic agent metoclopramide, cimetidine and magnesium-aluminium-hydroxide

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 medicinal products

Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolized by CYP3A4 may affect the metabolism of such medicinal products.

The half-life of ciclosprin 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 (see sections 4.2 and 4.4).

Tacrolimus has 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 co-administration of tacrolimus.

Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and phenazone.

Other interactions which have led to clinically detrimental effects

Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase these effects (e.g. aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole+trimethoprim, 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 (see section 4.4).

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 (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Human data show that tacrolimus is able to cross the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse effects on the course and outcome of pregnancy under tacrolimus treatment compared with 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 of treatment, tacrolimus treatment can be considered in pregnant women when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse effects of          tacrolimus is recommended (in particular the     effects on the kidneys). There is a risk for         premature delivery (<37 week) as well as for     hyperkalaemia in the newborn, which, however, normalises spontaneously.

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3).

Breast-feeding

Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Tacrotaj.

Fertility

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if Tacrotaj is administered in association with alcohol.

4.8 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.

Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction.

Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use. Adverse drug reactions are listed below in descending order by frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Infections and infestations

As is well known for other potent          immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur.

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

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.

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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via www.mhra.gov.uk/yellowcard ].

4.9 Overdose

Symptoms

Experience with over dosage is limited. Several cases of accidental over dosage have been reported; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy, increased blood urea nitrogen and elevated serum creatinine concentrations, and increase in alanine aminotransferase levels.

Management

No specific antidote to Tacrotaj therapy is available. If over dosage occurs, general supportive measures and symptomatic treatment should be conducted.

Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with very high plasma levels, haemofiltration or -diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcineurin inhibitors

Mechanism of action and pharmacodynamic effects

At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes.

Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.

In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly 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, -3, and γ-interferon) and the expression of the interleukin-2 receptor.

Results from published data in other primary organ transplantation

Tacrolimus has evolved into an accepted treatment as primary immunosuppressive medicinal product following pancreas, lung and intestinal transplantation. In prospective published studies tacrolimus was investigated as primary immunosuppressant in approximately 175 patients following lung, 475 patients following pancreas and 630 patients following intestinal transplantation. Overall, the safety profile of tacrolimus in these published studies appeared to be similar to what was reported in the large studies, where tacrolimus was used as primary treatment in liver, kidney and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.

Lung transplantation

The interim analysis of a recent multicentre study discussed 110 patients who underwent 1:1 randomisation to either tacrolimus or ciclosporin. Tacrolimus was started as continuous intravenous infusion at a dose of 0.01 to 0.03 mg/kg/day and oral tacrolimus was administered at a dose of 0.05 to 0.3 mg/kg/day. A lower incidence of acute rejection episodes for tacrolimus- versus ciclosporin-treated patients (11.5 % versus 22.6 %) and a lower incidence of chronic rejection, the bronchiolitis obliterans syndrome (2.86 % versus 8.57 %), was reported within the first year after transplantation. The 1-year patient survival rate was 80.8 % in the tacrolimus and 83 % in the ciclosporin.

Another randomized study included 66 patients on tacrolimus versus 67 patients on ciclosporin. Tacrolimus was started 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 ng/ml. The 1-year patient survival was 83 % in the tacrolimus and 71 % in the ciclosporin group, the 2-year survival rates were 76 % and 66 %, respectively. Acute rejection episodes per 100 patient-days were numerically fewer in the tacrolimus (0.85 episodes) than in the ciclosporin group (1.09 episodes). Obliterative bronchiolitis developed in 21.7 % of patients in the tacrolimus group compared with 38.0 % of patients in the ciclosporin group (p = 0.025). Significantly more ciclosporin-treated patients (n = 13) required a switch to tacrolimus than tacrolimus-treated    patients to ciclosporin(n = 2) (p = 0.02)

In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 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 ng/ml. The 1-year survival rates were 73.1 % in the tacrolimus versus 79.2 % in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6 months (57.7 % versus 45.8 %) and at 1 year after lung transplantation (50 % versus 33.3 %).

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 reported a significantly lower incidence of bronchiolitis obliterans syndrome with tacrolimus.

Pancreas transplantation

A multicentre study included 205 patients undergoing simultaneous pancreas-kidney transplantation who were randomized to tacrolimus (n=103) or to ciclosporin (n=102). The initial oral per protocol dose of tacrolimus was 0.2 mg/kg/day with subsequent dose adjustments to target trough levels of 8 to 15 ng/ml by Day 5 and 5 to 10 ng/ml after Month 6. Pancreas survival at 1 year was significantly superior with tacrolimus: 91.3 % versus 74.5 % with ciclosporin(p < 0.0005), whereas renal graft survival was similar in both groups. In total 34 patients switched treatment from ciclosporinto tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.

Intestinal transplantation

Published clinical experience from a single centre on the use of tacrolimus for primary treatment following intestinal transplantation showed that the actuarial survival rate of 155 patients (65 intestine alone, 75 liver and intestine, and 25 multivisceral) receiving tacrolimus and prednisone 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. Results continuously improved with increasing experience over the course of 11 years.

A variety of innovations, such as techniques for early detection of Epstein-Barr (EBV) and CMV infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, lower initial tacrolimus doses with target trough levels of 10 to 15ng/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.

5.2 Pharmacokinetic properties

Absorption

In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Following oral administration of tacrolimus capsules peak concentrations (C_max) of tacrolimus in blood are achieved in approximately 1 – 3 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 (0.30mg/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 0.5mg, tacrolimus 1mg and tacrolimus 5mg capsules, hard have been shown to be bioequivalent, when administered as equivalent dose.

Pharmacokinetics studies have indicated that increase in blood levels is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced.

The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of food decreases 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 C_max (50 %), and an increase in t_max (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 C_max (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. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.

Distribution and elimination

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 proteins, 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 and biotransformation

Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolizsed 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.

Elimination

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.

5.3 Preclinical safety data

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus. When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with tacrolimus in clinical transplantation.

Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic dosages and the offspring showed reduced birth weights, viability and growth.

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content:

Povidone K-30, Croscarmellose sodium, Lactose anhydrous, Magnesium stearate

Tacrotaj 0.5mg, 1mg, 2mg, 5mg Capsule shells:

Titanium dioxide, Yellow Iron Oxide, Gelatin

6.2 Incompatibilities

Tacrolimus is not compatible with PVC. Tubing, syringes and other equipment used to prepare or administer a suspension of Tacrotaj capsule contents should not contain PVC.

6.3 Shelf life

24 months

After opening the aluminium wrapper: 1 year.

6.4 Special precautions for storage

Store below 30°C, in the original package, to protect from moisture & light.

6.5 Nature and contents of container

PVC/PVdC-Aluminium blister pack

10 capsules per blister. Blisters placed with a desiccant in an aluminium foil sachet.

Pack sizes:

10, 30, 50, 60, 90 and 100 capsules

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India By:

TAJ PHARMACEUTICALS LIMITED

At Plot No.: 220, Mahagujarat Industrial Estate, At & Post: Moraiya, Tal – Sanand, Dist. Ahmedabad, Gujarat, INDIA.

Tacrolimus Capsules IP 0.5mg, 1mg, 2mg, 5mg (Tacrotaj) Taj Pharma

Tacrolimus

Package leaflet: Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it
• If you have any further questions, ask your doctor or
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet:

1. What Tacrotaj is and what it is used for
2. What you need to know before you take Tacrotaj
3. How to take Tacrotaj
4. Possible side effects
5. How to store Tacrotaj
6. Contents of the pack and other information

1 WHAT TACROTAJ IS AND WHAT IT IS USED FOR

Tacrotaj contains the active substance tacrolimus which is an immunosuppressant. Following your organ transplant (e.g. liver, kidney, heart), your body’s immune system will try to reject the new organ.

Tacrotaj is used to control your body’s immune response enabling your body to accept the transplanted organ.

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

You may also be given Tacrotaj for an ongoing rejection of your transplanted liver, kidney, heart or other organ when any previous treatment you were taking was unable to control this immune response after your transplantation.

2 WHAT YOU NEED TO KNOW BEFORE YOU TAKE TACROTAJ

Do not take Tacrotaj:

• If you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 6)
• If you are allergic to sirolimus or to any macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin).

Warnings and precautions

Talk to your doctor or pharmacist before taking Tacrotaj

• if you are taking any medicines mentioned below under ‘Other medicines’ and
• if you have or have had liver problems
• if you need to receive any vaccinations
• if you or a family member have been diagnosed with heart problems (e.g. congestive heart failure, bradyarrhythmias)
• if you have been diagnosed with a heart condition called “Congenital Long QT Syndorme” or “QT prolongation”.

Your doctor may need to adjust your dose of Tacrotaj. During treatment tell your doctor or pharmacist:

• if you have diarrhoea for more than one day
• if you feel strong abdominal pain accompanied with or without other symptoms, such as chills, fever, feeling sick (nausea) or being sick (vomiting)
• if you have a change of the electrical activity of your heart called “QT prolongation”.

You should keep in regular contact with your doctor. From time to time, your doctor may need to do blood, urine, heart, eye and neurological tests, to set the right dose of Tacrotaj.

Patients treated with tacrolimus have been reported to have an increased risk of developing lymphoproliferative disorders (see section 4). Ask your doctor for specific advice on these disorders.

You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Tacrotaj. This is because immunosuppressants could increase the risk of skin cancer. Wear appropriate protective clothing and use a sunscreen with a high sun protection factor.

Other medicines and Tacrotaj

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription and herbal preparations.

Tacrotaj must not be taken with ciclosporin.

Tacrotaj blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking Tacrotaj which may require an increase or decrease in dose. In particular, you should tell your doctor if you are taking or have recently taken medicines like:

• antifungal medicines and antibiotics, particularly so-called macrolide antibiotics, used to treat infections, such as ketoconazole, fluconazole, itraconazole, telithromycin, voriconazole, clotrimazole, erythromycin, clarithromycin, josamycin, rifabutin and rifampicin
• HIV medicines (e.g. ritonavir, nelfinavir, saquinavir), used to treat HIV infection
• HCV protease inhibitors (e.g. telaprevir, boceprevir), used to treat hepatitis C infection
• medicines for stomach ulcer and acid reflux (e.g. omeprazole, lansoprazole or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn
• the contraceptive pill or other hormone treatments with
• hormone treatments with danazol
• medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem and verapamil)
• amiodarone, used to control arrhythmia (uneven beating of the heart) phenytoin, phenobarbital or carbamazepine, used to treat epilepsy
• the corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids used to treat inflammations or suppress the immune system (e.g. in transplant rejection)
• isoniazid, used to treat tuberculosis
• nefazodone, used to treat depression
• herbal preparations containing St. John’s wort (Hypericum perforatum) or extracts of Schisandra sphenanthera.
• Tell your doctor if you are taking or need to take ibuprofen, amphotericin B or antivirals (e.g. ganciclovir, aciclovir). These may worsen kidney or nervous system problems when taken together with Tacrotaj.
• Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, hypertension and kidney disease, (e.g. amiloride, triamterene, or spironolactone), non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation and pain, anticoagulants (blood thinners), or oral medicines for diabetes, while you take Tacrotaj.
• If you need vaccinations, tell your doctor in advance that you are taking this medicine.

Taking Tacrotaj with food and drink

• Avoid grapefruit (also as juice) while on treatment with Tacrotaj since it can affect its levels.

Pregnancy and breast-feeding

• If you plan to become pregnant or think that you may be pregnant, ask your doctor or pharmacist for advice before taking any medicine.
• Tacrolimus passes into breast milk. Therefore you should not breast-feed whilst using Tacrotaj.

Driving and using machines

• Do not drive or use any tools or machines if you feel dizzy or sleepy, or have problems seeing clearly after taking this medicine. These effects are more frequently observed if you also drink alcohol.

Tacrotaj contains lactose

• If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3 HOW TO TAKE TACROTAJ

• Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
• Make sure that you receive the same tacrolimus medicine every time you collect your prescription, unless your transplant specialist has agreed to change to a different tacrolimus medicine.
• This medicine should be taken twice a day. If the appearance of this medicine is not the same as usual, or if dosage instructions have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine.
• The starting dose to prevent the rejection of your transplanted organ will be determined by your doctor calculated according to your body weight. Initial doses just after transplantation will generally be in the range of 0.075 – 0.30 mg per kg body weight per day depending on the transplanted organ.
• Your dose depends on your general condition and on which other immunosuppressive medication you are taking. Regular blood tests by your doctor will be required to define the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your Tacrotaj dose once your condition has stabilised. Your doctor will tell you exactly how many capsules to take and how often.
• Tacrotaj is taken orally twice daily, usually in the morning and evening. You should generally take Tacrotaj on an empty stomach or at least 1 hour before or 2 to 3 hours after the meal. The capsules should be swallowed whole with a glass of water. Avoid grapefruit and grapefruit juice while taking Tacrotaj. Do not swallow the desiccant contained in the foil wrapper.

If you take more Tacrotaj than you should

• If you have accidentally taken too much see your doctor or contact your nearest hospital emergency department immediately. Someone who has taken an overdose of Tacrotaj may have any of these symptoms: shaking, headache, feeling or being sick, itchy rash (hives), feeling tired and increased infections.

If you forget to take Tacrotaj

• Do not take a double dose to make up for forgotten individual doses.
• If you have forgotten to take your capsules, wait until it is time for the next dose, and then continue as before.

If you stop taking Tacrotaj

• Stopping your treatment may increase the risk of rejection of your transplanted organ. Do not stop your treatment unless your doctor tells you to do so.
• If you have any further questions on the use of this product, ask your doctor or pharmacist.

4 POSSIBLE SIDE EFFECTS

• Like all medicines, this medicine can cause side effects, although not everybody gets them.
• Tacrotaj reduces your body’s own defence mechanism to stop you rejecting your transplanted organ. Consequently, your body will not be as good as usual at fighting infections. So if you are taking Tacrotaj you may therefore catch more infections than usual, such as infections of the skin, mouth, stomach and intestines, lungs and urinary tract.

If you think you may have any of the following side effects, contact your doctor or go to your nearest hospital emergency room immediately:

Very common (may affect more than 1 in 10 people):

• diabetes mellitus, you may notice increased thirst, needing to urinate more often than usual and increased hunger
• kidney problems

Common (may affect up to 1 in 10 people):

• yellowing of the skin due to liver problems, liver tissue damage and inflammation of the liver
• insufficient function of the kidneys with reduced production of urine, impaired or painful urination
• gastrointestinal perforation, you may have strong abdominal pain accompanied with other symptoms, such as chills, fever, feeling sick and being sick
• inflammations or ulcers causing abdominal pain or diarrhoea, bleedings in the stomach
• fits

Uncommon side effects (may affect up to 1 in 100 people):

• bleeding in the brain, stroke
• difficulties in breathing
• reduction in the number of all types of blood cells
• inflammation of the pancreas
• partial or complete paralysis
• obstruction of the gut

• haemolytic uraemic syndrome, a condition with the following symptoms: low or no urine output (acute renal failure), extreme tiredness, yellowing of the skin or eyes (jaundice) and abnormal bruising or bleeding and signs of
  • inflammation of the membrane lining of the stomach wall
  • severe mental disorder that can cause abnormal thinking and perceptions
  • heart attack
  • insufficient function of your transplanted organ
  • coma, shock

Rare (may affect up to 1 in 1,000 people):

• Thrombotic Thrombocytopenic Purpura, a condition with the following symptoms: fever and bruising under the skin that may appear as red pinpoint dots, you may feel unexplained extreme tiredness, confusion, and notice yellowing of the skin or eyes (jaundice), with symptoms of kidney problems (low or no urine output).
• Toxic epidermal necrolysis: erosion and blistering of skin or mucous membranes, red swollen skin that can detach in large parts of the
• severe shortness of breath
• blindness
• collection of fluid around the heart
• deafness
• problems with blood flow in the liver

Very rare (may affect up to 1 in 10,000 people):

• liver failure
• Stevens-Johnson syndrome: unexplained widespread skin pain, facial swelling, serious illness with blistering of skin, mouth, eyes and genitals, hives, tongue swelling, red or purple skin rash that spreads, skin shedding
• Torsades de Pointes: change in the heart frequency that can be accompanied by symptoms, such as chest pain (angina), fainting, dizziness or feeling sick (nausea), palpitations (feeling the heartbeat) and difficulty
• painful urination with blood in the urine
• abnormal heart scan
• narrowing of the bile vessel

Not known (frequency cannot be estimated from the available data):

• allergic and anaphylactic reactions with the following symptoms: a sudden itchy rash (hives), swelling of hands, feet, ankle, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing) and you may feel you are going to
• benign and malignant tumours have been reported following treatment as a result of immunosuppression
• Posterior Reversible Encephalopathy Syndromes (PRES): headache, altered mental status, fits, and visual
• pure red cell aplasia (a very severe reduction in red blood cell counts) and haemolytic anaemia (decreased number of red blood cells due to abnormal breakdown accompanied with tiredness) have been reported. You may have no symptoms or depending on the severity of the condition, you may notice: fatigue, apathy, abnormal paleness of the skin, shortness of breath, dizziness, headache, chest pain and coldness in hands and
• agranulocytosis (a severely lowered number of white blood cells accompanied with ulcers in the mouth, fever and infections). You may have no symptoms or you may feel sudden fever, chills and sore

Other possible side effects

Very common (may affect more than 1 in 10 people):

• increased blood sugar, increased potassium in the blood
• difficulty in sleeping
• trembling, headache
• diarrhoea, nausea

Common (may affect up to 1 in 10 people):

• reduced magnesium, phosphate, potassium, calcium or sodium in the blood, fluid overload, increased uric acid or lipids in the blood, decreased appetite, increased acidity of the blood, other changes in the blood salts (seen in blood tests)
• anxiety symptoms, confusion and disorientation, depression, mood changes, nightmares, hallucination, mental disorders
• disturbances in consciousness, tingling and numbness (sometimes painful) in the hands and feet, dizziness, impaired writing ability, nervous system disorders
• blurred vision, increased sensitivity to light, eye disorders
• ringing sound in your ears
• reduced blood flow in the heart vessels, faster heartbeat
• bleeding, partial or complete blocking of blood vessels, reduced blood pressure
• shortness in breath, changes in the lung tissue, collection of liquid around the lung, inflammation of the throat, cough, flu-like symptoms inflammation or ulcers in the mouth, collection of fluid in the belly, vomiting, abdominal pains, indigestion, constipation, passing wind, bloating, loose stools, stomach problems
• changes in liver enzymes and function
• itching, rash, hair loss, acne, increased sweating
• pain in joints, limbs or back, muscle cramps
• general weakness, fever, collection of fluid in your body, pain and discomfort, increase of the enzyme alkaline phosphatase in your blood, weight gain, feeling feverish
• insufficient function of your transplanted

Uncommon (may affect up to 1 in 100 people):

• changes in blood clotting
• dehydration, reduced protein or sugar in the blood, increased phosphate in the blood
• brain disorder, speech and language abnormalities, memory problems
• clouding of the eyes (cataracts)
• impaired hearing
• irregular heartbeat, skipped heartbeat, reduced performance of your heart, enlargement of the heart muscle, stronger heartbeat, abnormal ECG, heart rate and pulse abnormal
• blood clot in a vein of a limb
• respiratory tract disorders, asthma
• increased blood level of the enzyme amylase, reflux of stomach content in your throat, delayed emptying of the stomach
• dermatitis, burning sensation in the sunlight
• joint disorders
• painful menstruation and abnormal menstrual bleedings
• influenza like illness, increased sensitivity to heat and cold
• feeling of pressure on your chest, jittery or abnormal feeling
• increase of the enzyme lactate dehydrogenase in your blood
• weight loss.

Rare (may affect up to 1 in 1,000 people):

• increased muscle stiffness
• cyst formation in your pancreas
• increased hairiness
• thirst, fall
• feeling of tightness in your chest
• decreased mobility
• ulcer

Very rare (may affect up to 1 in 10,000 people):

• muscular weakness
• increase of fat

Reporting of side effects

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

5 HOW TO STORE TACROTAJ

• Keep this medicine out of the sight and reach of
• Store below 30ºC
• Store in the original package (within the foil pouch) in order to protect from moisture and light.
• Do not use Tacrotaj after the expiry date which is stated on the carton and blister after {EXP}. Once the foil pouch is opened, the product should be used within 1 year. The expiry date refers to the last day of that month.
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the

6 CONTENTS OF THE PACK AND OTHER INFORMATION

What Tacrotaj contains

Tacrotaj 0.5mg hard capsules – The active substance is tacrolimus.

For 0.5mg: Each capsule contains 0.5mg of tacrolimus. The other ingredients are:

• Capsule content: Povidone K-30, Croscarmellose Sodium, Lactose anhydrous, Magnesium
• Capsule shell: Titanium dioxide, Yellow Iron Oxide, Gelatin

Tacrotaj 1mg, 2mg hard capsules – The active substance is tacrolimus.

For 1mg, 2mg: Each capsule contains 1mg of tacrolimus. The other ingredients are:

• Capsule content: Povidone K-30, Croscarmellose Sodium, Lactose anhydrous, Magnesium
• Capsule shell: Titanium dioxide, Gelatin

Tacrotaj 5 mg hard capsules – The active substance is tacrolimus.

For 5mg: Each capsule contains 5mg of tacrolimus. The other ingredients are:

• Capsule content: Povidone K-30, Croscarmellose Sodium, Lactose anhydrous, Magnesium
• Capsule shell: Titanium dioxide, Red Iron Oxide, Gelatin

Contents of the pack

Tacrotaj is available in blister packs containing blister strips of 10 capsules each.

0.5 mg: 10, 30, 50, 60, 90 and 100 capsules

1 mg: 10, 30, 50, 60, 90 and 100 capsules

2 mg: 10, 30, 50, 60, 90 and 100 capsules

5 mg: 10, 30, 50, 60, 90 and 100 capsules

Not all pack sizes may be marketed

7. Manufactured in India By:

TAJ PHARMACEUTICALS LIMITED

At Plot No.: 220, Mahagujarat Industrial Estate, At & Post: Moraiya, Tal – Sanand, Dist. Ahmedabad, Gujarat, INDIA.