Modigraf 0.2mg & 1mg granules for oral suspension

Update headers in section 4.4:

Opportunistic infections

Posterior reversible encephalopathy syndrome (PRES) 

Update section 4.8:

Musculoskeletal and connective tissue disorders

common:              arthralgia, back pain, muscle spasms, pain in limb extremity

Description of selected adverse reactions

Pain in extremity has been described in a number of published case reports as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra-therapeutic levels of tacrolimus. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.

 

Section 4.4 & 4.5:

Addition of further information on the risk of interaction with herbal preparations including the Chinese herb Schisandra sphenanthera.

Section 4.8:

This section has been revised and now includes a section on “Investigations” which lists the side effects relating to investigations in a single section rather than throughout section 4.8.

The section on adverse event reporting has been revised to reflect the updated HPRA contact details.

The date of revision is updated to June 2015

Section 4.4 & 4.5:

Addition of further information on the risk of interaction with herbal preparations including the Chinese herb Schisandra sphenanthera.

Section 4.8:

This section has been revised and now includes a section on “Investigations” which lists the side effects relating to investigations in a single section rather than throughout section 4.8.

The section on adverse event reporting has been revised to reflect the updated HPRA contact details.

The date of revision is updated to June 2015

2.       Qualitative and quantitative composition

 

Each sachet contains 0.2 mg tacrolimus (as monohydrate).

 

Excipient with known effect:

Each sachet contains 99.494.7 mg lactose (as monohydrate).

 

For the full list of excipients, see section 6.1.

 

4.2     Posology and method of administration

 

 

Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks post‑transplant to ensure adequate drug exposure to the active substance in the immediate post‑transplant period. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before steady state is achieved (see below under “Therapeutic drug monitoring” and section 5.2).

 
Paediatric patients

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 (with Prograf 5 mg/ml concentrate for solution for infusion) as a continuous 24‑hour infusion targeted to achieve tacrolimus whole blood concentrations of 15 ‑ 25 nanogram/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 Modigraf therapy is initiated orally, the recommended starting dose is 0.10 ‑ 0.30 mg/kg/day administered as 2 divided doses (e.g. morning and evening).

 

 

Data from clinical studies suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/mlnanogram/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/mlnanogram/ml in liver transplant recipients and 10 ‑ 20 ng/mlnanogram/ml in kidney and heart transplant patients in the early post‑transplant period. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 ‑ 15 ng/mlnanogram/ml in liver, kidney and heart transplant recipients.

 

 

 

Gender

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

 

Paediatric patients

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

 

Older Elderly people patients

There is no evidence currently available to indicate that dosing should be adjusted in older people.

 

Paediatric patients

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

 

Method of administration

It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).

 

Tacrolimus therapy is generally initiated by the oral route. If necessary, tacrolimus dosing may commence by administering Modigraf granules suspended in water, via nasogastric tubing.

 

It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).

 

 

The required dose is calculated from the weight of the patient, using the minimum number of sachets possible. Use 2 ml of water (at room temperature) should be used per 1 mg tacrolimus to produce a suspension (up to a maximum of 50 ml, depending on body weight) in a cup. Do not use PVC containing materialsMaterials containing polyvinyl chloride (PVC) should not be used (see section 6.2). Granules are added to the water and stirred. It is not advised to use any liquids or utensils to empty the sachets. The suspension can be drawn up via a syringe or swallowed directly by the patient. The taste is sweet due to the lactose. Thereafter the cup is rinsed once with the same quantity of water and the rinsings consumed by the patient. The suspension should be administered immediately after preparation.

 

In patients unable to take oral medicinal products during the immediate post‑transplant period, tacrolimus therapy can be initiated intravenously (See Summary of Product Characteristics for Prograf 5 mg/ml concentrate for solution for infusion) at a dose of approximately 1/5^th of the recommended oral dose for the corresponding indication.

 

 

 4.8       Undesirable effects

 

Summary of the safety profile

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.

 

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

 

List of adverse reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effectsadverse reactions are presented in order of decreasing seriousness.

 

 

 

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;

 

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

4.9       Overdose

 

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

 

 

Another randomised 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/mlnanogram/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).

 

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/mlnanogram/ml.

 

Pancreas transplantation

A multicentre study included 205 patients undergoing simultaneous pancreas‑kidney transplantation who were randomised 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/mlnanogram/ml by Day 5 and 5 to 10 ng/mlnanogram/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 ciclosporin to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.

 

Intestinal transplantation

. 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 15 ng/nanogram/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.

 

 

 

5.3     Preclinical safety data

 

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/nanogram/mL which is more than 6-fold higher than mean peak concentrations observed with Modigraf in clinical transplantation.

 

 

 

 

6.5     Nature and contents of container

 

Sachets consisting of layers of polyethylene terephtalate (PET), aluminium (Al) and polyethylene (PE), containing granules.

 

Pack size: carton box containing 50 sachets.

 

 

 

9. Date of first authorisation/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 May 2009

Date of latest renewal: 17 February 2014

 

10. Date of revision of the text

 

February 2014

 

2.       Qualitative and quantitative composition

 

Each sachet contains 0.2 mg tacrolimus (as monohydrate).

 

Excipient with known effect:

Each sachet contains 99.494.7 mg lactose (as monohydrate).

 

For the full list of excipients, see section 6.1.

 

4.2     Posology and method of administration

 

 

Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks post‑transplant to ensure adequate drug exposure to the active substance in the immediate post‑transplant period. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before steady state is achieved (see below under “Therapeutic drug monitoring” and section 5.2).

 
Paediatric patients

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 (with Prograf 5 mg/ml concentrate for solution for infusion) as a continuous 24‑hour infusion targeted to achieve tacrolimus whole blood concentrations of 15 ‑ 25 nanogram/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 Modigraf therapy is initiated orally, the recommended starting dose is 0.10 ‑ 0.30 mg/kg/day administered as 2 divided doses (e.g. morning and evening).

 

 

Data from clinical studies suggests that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20 ng/mlnanogram/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/mlnanogram/ml in liver transplant recipients and 10 ‑ 20 ng/mlnanogram/ml in kidney and heart transplant patients in the early post‑transplant period. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 ‑ 15 ng/mlnanogram/ml in liver, kidney and heart transplant recipients.

 

 

 

Gender

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

 

Paediatric patients

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

 

Older Elderly people patients

There is no evidence currently available to indicate that dosing should be adjusted in older people.

 

Paediatric patients

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

 

Method of administration

It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).

 

Tacrolimus therapy is generally initiated by the oral route. If necessary, tacrolimus dosing may commence by administering Modigraf granules suspended in water, via nasogastric tubing.

 

It is recommended that the oral daily dose of Modigraf be administered in 2 divided doses (e.g. morning and evening).

 

 

The required dose is calculated from the weight of the patient, using the minimum number of sachets possible. Use 2 ml of water (at room temperature) should be used per 1 mg tacrolimus to produce a suspension (up to a maximum of 50 ml, depending on body weight) in a cup. Do not use PVC containing materialsMaterials containing polyvinyl chloride (PVC) should not be used (see section 6.2). Granules are added to the water and stirred. It is not advised to use any liquids or utensils to empty the sachets. The suspension can be drawn up via a syringe or swallowed directly by the patient. The taste is sweet due to the lactose. Thereafter the cup is rinsed once with the same quantity of water and the rinsings consumed by the patient. The suspension should be administered immediately after preparation.

 

In patients unable to take oral medicinal products during the immediate post‑transplant period, tacrolimus therapy can be initiated intravenously (See Summary of Product Characteristics for Prograf 5 mg/ml concentrate for solution for infusion) at a dose of approximately 1/5^th of the recommended oral dose for the corresponding indication.

 

 

 4.8       Undesirable effects

 

Summary of the safety profile

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.

 

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

 

List of adverse reactions

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effectsadverse reactions are presented in order of decreasing seriousness.

 

 

 

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;

 

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

4.9       Overdose

 

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

 

 

Another randomised 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/mlnanogram/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).

 

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/mlnanogram/ml.

 

Pancreas transplantation

A multicentre study included 205 patients undergoing simultaneous pancreas‑kidney transplantation who were randomised 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/mlnanogram/ml by Day 5 and 5 to 10 ng/mlnanogram/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 ciclosporin to tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.

 

Intestinal transplantation

. 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 15 ng/nanogram/ml, and most recently allograft irradiation were considered to have contributed to improved results in this indication over time.

 

 

 

5.3     Preclinical safety data

 

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/nanogram/mL which is more than 6-fold higher than mean peak concentrations observed with Modigraf in clinical transplantation.

 

 

 

 

6.5     Nature and contents of container

 

Sachets consisting of layers of polyethylene terephtalate (PET), aluminium (Al) and polyethylene (PE), containing granules.

 

Pack size: carton box containing 50 sachets.

 

 

 

9. Date of first authorisation/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 May 2009

Date of latest renewal: 17 February 2014

 

10. Date of revision of the text

 

February 2014

 

4.2       Posology and method of administration

 

 

Elderly Older patients people

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

 

4.4     Special warnings and precautions for use

 

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.

 

 

Cardiac disorders

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring 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 3 months and then at 9‑12 months). If abnormalities develop, dose reduction of Modigraf, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may but at this time lacks substantial evidence for causeing 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).

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

It is strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG), as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels 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).

 

4.8       Undesirable effects

 

Cardiac disorders

common:	ischaemic coronary artery disorders, tachycardia
uncommon:	heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy, palpitations, heart rate and pulse investigations abnormal
rare:	pericardial effusion
very rare:	echocardiogram abnormal, electrocardiogram QT prolonged, Torsades de Pointes

 

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 the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

 

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

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 Modigraf 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 doses 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

4.2       Posology and method of administration

 

 

Elderly Older patients people

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

 

4.4     Special warnings and precautions for use

 

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.

 

 

Cardiac disorders

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring 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 3 months and then at 9‑12 months). If abnormalities develop, dose reduction of Modigraf, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may but at this time lacks substantial evidence for causeing 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).

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

It is strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG), as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels 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).

 

4.8       Undesirable effects

 

Cardiac disorders

common:	ischaemic coronary artery disorders, tachycardia
uncommon:	heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy, palpitations, heart rate and pulse investigations abnormal
rare:	pericardial effusion
very rare:	echocardiogram abnormal, electrocardiogram QT prolonged, Torsades de Pointes

 

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 the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

 

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

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 Modigraf 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 doses 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

4.4     Special warnings and precautions for use

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.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

It is strongly recommended to closely monitor tacrolimus blood levels, as well as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels 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).

 

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 and nefazodone.

 

 

 

7.           marketing authorisation Holder

 

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

Netherlands

4.4     Special warnings and precautions for use

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.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

It is strongly recommended to closely monitor tacrolimus blood levels, as well as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels 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).

 

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 and nefazodone.

 

 

 

7.           marketing authorisation Holder

 

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

Netherlands

 

2.       Qualitative and quantitative composition

 

Each sachet contains 0.2 mg tacrolimus (as monohydrate).

 

Excipient with known effect:

Each sachet contains 99.4 mg lactose monohydrate.

 

For the a full list of excipients, see section 6.1.

 

4.2     Posology and method of administration

 

Modigraf should not be switched with the prolonged-release formulation (Advagraf) as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. In general, inadvertent, unintentional or unsupervised switching of immediate‑ or prolonged‑release formulations of tacrolimus is unsafe.

 

 

Therapeutic drug monitoring

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.

 

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. 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. The relationship between tacrolimus trough levels (C₁₂) and systemic exposure (AUC_0‑12) is similar between the 2 formulations Modigraf granules and Prograf capsules.

 

Blood trough levels of tacrolimus should be monitored during the post‑transplantation period. Tacrolimus blood trough levels should be determined approximately 12 hours post‑dosing of Modigraf granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels should be monitored at least twice weekly during the early post‑transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored when clinical signs of toxicity or acute rejection are observed, following conversion between Modigraf granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co‑administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).

 

Data from clinical studies 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. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 ‑ 15 ng/ml in liver, kidney and heart transplant recipients.

 

Dose Adjustmetns in Special populations

Hepatic impairment

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

 

Renal impairment

As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), 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).

 

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.

 

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.

 

Therapeutic drug monitoring

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.

 

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. 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. The relationship between tacrolimus trough levels (C₁₂) and systemic exposure (AUC_0‑12) is similar between the 2 formulations Modigraf granules and Prograf capsules.

 

Blood trough levels of tacrolimus should be monitored during the post‑transplantation period. Tacrolimus blood trough levels should be determined approximately 12 hours post‑dosing of Modigraf granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels should be monitored at least twice weekly during the early post‑transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored when clinical signs of toxicity or acute rejection are observed, following conversion between Modigraf granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co‑administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).

 

Data from clinical studies 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. During subsequent 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 tacrolimus or to any of the excipients (see listed in section 6.1.)

Hypersensitivity to other macrolides.

 

4.4     Special warnings and precautions for use

 

Modigraf should not be switched with Advagraf as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. 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 reactions, including graft rejection, or other side effects adverse reactions which could be a consequence of either under‑ or over‑exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulations or regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8).

 

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been reported to develop Epstein-BarrVirus (EBV)‑associated lymphoproliferative disorders (see section 4.8).

 

Special populations

There is limited experience in non‑Caucasian patients and patients at elevated immunological risk (e.g. retransplantation, evidence of panel reactive antibodies, PRA).

 

Excipients

Modigraf granules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose‑galactose malabsorption should not take this medicinal product.

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse events reactions on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported.

 

Lactation Breast-feeding

Human data demonstrate that tacrolimus is excreted into breast milk.

 

4.8       Undesirable effects

 

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.

 

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 reactions stated below are reversible and/or respond to dose reduction. The frequency of adverse reactions is defined as follows:

Blood and lymphatic system disorders

common:	anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis
uncommon:	coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses abnormal
rare:	thrombotic thrombocytopenic purpura, hypoprothrombinaemia
not known:	pure red cell aplasia, agranulocytosis, haemolytic anaemia

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: Immunosuppressants, C calcineurin inhibitors, ATC code: L04AD02

 

 8. Marketing authorisation number(s)

 

EU/1/09/523/001

 

 9. Date of first authorisation/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 15 May 2009

 

 10. Date of revision of the text

 

August 2012

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

 

2.       Qualitative and quantitative composition

 

Each sachet contains 0.2 mg tacrolimus (as monohydrate).

 

Excipient with known effect:

Each sachet contains 99.4 mg lactose monohydrate.

 

For the a full list of excipients, see section 6.1.

 

4.2     Posology and method of administration

 

Modigraf should not be switched with the prolonged-release formulation (Advagraf) as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. In general, inadvertent, unintentional or unsupervised switching of immediate‑ or prolonged‑release formulations of tacrolimus is unsafe.

 

 

Therapeutic drug monitoring

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.

 

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. 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. The relationship between tacrolimus trough levels (C₁₂) and systemic exposure (AUC_0‑12) is similar between the 2 formulations Modigraf granules and Prograf capsules.

 

Blood trough levels of tacrolimus should be monitored during the post‑transplantation period. Tacrolimus blood trough levels should be determined approximately 12 hours post‑dosing of Modigraf granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels should be monitored at least twice weekly during the early post‑transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored when clinical signs of toxicity or acute rejection are observed, following conversion between Modigraf granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co‑administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).

 

Data from clinical studies 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. During subsequent maintenance therapy, blood concentrations have generally been in the range of 5 ‑ 15 ng/ml in liver, kidney and heart transplant recipients.

 

Dose Adjustmetns in Special populations

Hepatic impairment

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

 

Renal impairment

As the pharmacokinetics of tacrolimus are unaffected by renal function (see section 5.2), 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).

 

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.

 

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.

 

Therapeutic drug monitoring

Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring.

 

As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. 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. The relationship between tacrolimus trough levels (C₁₂) and systemic exposure (AUC_0‑12) is similar between the 2 formulations Modigraf granules and Prograf capsules.

 

Blood trough levels of tacrolimus should be monitored during the post‑transplantation period. Tacrolimus blood trough levels should be determined approximately 12 hours post‑dosing of Modigraf granules, just prior to the next dose. Frequent trough level monitoring in the initial 2 weeks post transplantation is recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels should be monitored at least twice weekly during the early post‑transplant period and then periodically during maintenance therapy. Blood trough levels of tacrolimus should also be closely monitored when clinical signs of toxicity or acute rejection are observed, following conversion between Modigraf granules to Prograf capsules, dose adjustments, changes in the immunosuppressive regimen, or co‑administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, it may take several days after adjustments to the Modigraf dose regimen before the targeted steady state is achieved (see section 5.2).

 

Data from clinical studies 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. During subsequent 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 tacrolimus or to any of the excipients (see listed in section 6.1.)

Hypersensitivity to other macrolides.

 

4.4     Special warnings and precautions for use

 

Modigraf should not be switched with Advagraf as a clinically relevant difference in bioavailability between the two formulations cannot be excluded. 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 reactions, including graft rejection, or other side effects adverse reactions which could be a consequence of either under‑ or over‑exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulations or regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8).

 

Lymphoproliferative disorders and malignancies

Patients treated with tacrolimus have been reported to develop Epstein-BarrVirus (EBV)‑associated lymphoproliferative disorders (see section 4.8).

 

Special populations

There is limited experience in non‑Caucasian patients and patients at elevated immunological risk (e.g. retransplantation, evidence of panel reactive antibodies, PRA).

 

Excipients

Modigraf granules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose‑galactose malabsorption should not take this medicinal product.

 

4.6     Fertility, pregnancy and lactation

 

Pregnancy

Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse events reactions on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported.

 

Lactation Breast-feeding

Human data demonstrate that tacrolimus is excreted into breast milk.

 

4.8       Undesirable effects

 

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products.

 

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 reactions stated below are reversible and/or respond to dose reduction. The frequency of adverse reactions is defined as follows:

Blood and lymphatic system disorders

common:	anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis
uncommon:	coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses abnormal
rare:	thrombotic thrombocytopenic purpura, hypoprothrombinaemia
not known:	pure red cell aplasia, agranulocytosis, haemolytic anaemia

 

5.         PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: Immunosuppressants, C calcineurin inhibitors, ATC code: L04AD02

 

 8. Marketing authorisation number(s)

 

EU/1/09/523/001

 

 9. Date of first authorisation/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 15 May 2009

 

 10. Date of revision of the text

 

August 2012

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

4.4     Special warnings and precautions for use

 

 

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.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Lansoprazole

 

 

 

4.8       Undesirable effects

 

Blood and lymphatic system disorders

 

not known:

pure red cell aplasia

 

4.4     Special warnings and precautions for use

 

 

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.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Lansoprazole

 

 

 

4.8       Undesirable effects

 

Blood and lymphatic system disorders

 

not known:

pure red cell aplasia

 

None provided

None provided