ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Modigraf 0.2 mg granules for oral suspension
2.
Each sachet contains 0.2 mg tacrolimus (as monohydrate).
Excipient:
Each sachet contains 99.4 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Granules for oral suspension.
White granules.
4.
Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products in adult and paediatric patients.
This medicinal product should only be prescribed, and changes in immunosuppressive therapy
initiated, by physicians experienced in immunosuppressive therapy and the management of transplant
patients. Modigraf is a granular formulation of tacrolimus, for twice-a-day administration. Modigraf
therapy requires careful monitoring by adequately qualified and equipped personnel.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Modigraf is
routinely administered in conjunction with other immunosuppressive agents in the initial
post-operative period. The dose may vary depending upon the immunosuppressive regimen chosen.
Modigraf dosing should primarily be based on clinical assessments of rejection and tolerability in each
patient individually aided by blood level monitoring (see below under “Therapeutic drug
monitoring”). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen
should be considered.
Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks
post-transplant to ensure adequate drug exposure 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).
Modigraf should not be switched with 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. This
can lead to graft rejection or increased incidence of undesirable effects, including under- or
overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus.
2
Patients should be maintained on a single formulation of tacrolimus with the corresponding 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.
Prophylaxis of kidney transplant rejection
Adults
Oral Modigraf therapy should commence at 0.20 - 0.30 mg/kg/day administered as 2 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 0.05 - 0.10 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should
be initiated as a continuous 24-hour infusion.
Paediatric patients
An initial oral dose of 0.30
mg/kg/day should be administered in 2 divided doses (e.g. morning and
evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of
0.075
–
0.100 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be
administered as a continuous 24-hour infusion.
Dose adjustment during post-transplant period in adults and paediatric patients
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.
Prophylaxis of liver transplant rejection
Adults
Oral Modigraf therapy should commence at 0.10 - 0.20 mg/kg/day administered as 2 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 0.01 - 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should
be initiated as a continuous 24-hour infusion.
Paediatric patients
An initial oral dose of 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and
evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of
0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as
a continuous 24-hour infusion.
Dose adjustment during post-transplant period in adults and paediatric patients
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.
Prophylaxis of heart transplant rejection
Adults
Modigraf 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 Modigraf therapy should commence at a dose of 0.075 mg/kg/day
administered as 2 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
3
therapy of 0.01 to 0.02 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) 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.
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 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 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).
Dose adjustment during post-transplant period in adults and paediatric patients
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.
Conversion between Modigraf and Prograf tacrolimus formulations
In healthy subjects the systemic exposure to tacrolimus (AUC) for Modigraf was approximately 18%
higher than that for Prograf capsules when administered as single doses. There are no safety data
available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in
critically ill patients.
Stable allograft recipients maintained on Modigraf granules, requiring conversion to Prograf capsules,
should be converted on a 1:1 mg:mg total daily dose basis. If equal doses are not possible, the total
daily dose of Prograf should be rounded-up to the nearest amount possible, with the higher dose given
in the morning and the lower dose in the evening.
Similarly, for conversion of patients from Prograf capsules to Modigraf granules, the total daily
Modigraf dose should preferably be equal to the total daily Prograf dose. If conversion on the basis of
equal quantities is not possible, the total daily dose of Modigraf should be rounded down to the nearest
total daily dose possible with sachets 0.2 mg and 1 mg.
The total daily dose of Modigraf granules should be administered in 2 equal doses. If equal doses are
not possible, then the higher dose should be administered in the morning and the lower dose in the
evening. Modigraf sachets must not be used partially.
Example: Total daily dose Prograf capsules given as 1 mg in the morning and 0.5 mg in the evening.
Then give a total daily dose of Modigraf 1.4 mg divided as 0.8 mg in the morning and 0.6 mg in the
evening.
Tacrolimus trough levels should be measured prior to conversion and within 1 week after conversion.
Dose adjustments should be made to ensure that similar systemic exposure is maintained.
Conversion from ciclosporin to tacrolimus
Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy
(see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not
recommended. 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-based therapy has been initiated
12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be
continued following conversion as the clearance of ciclosporin might be affected.
4
Treatment of allograft rejection
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 such
as severe adverse reactions are noted (see section 4.8), the dose of Modigraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation – adults and paediatric patients
For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with
the initial oral dose recommended for primary immunosuppression.
Treatment of allograft rejection after heart transplantation therapy – adults and paediatric patients
In adult patients converted to Modigraf, an initial oral dose of 0.15 mg/kg/day should be administered
in 2 divided doses (e.g. morning and evening).
In paediatric patients converted to tacrolimus, an initial oral dose of 0.20 - 0.30 mg/kg/day should be
administered in 2 divided doses (e.g. morning and evening).
Treatment of allograft rejection after transplantation of other allografts
The dose recommendations for lung, pancreas and intestinal transplantation are based on limited
prospective clinical trial data with the Prograf formulation. Prograf has been used in lung-transplanted
patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial
oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.
Dose adjustments 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.
5
The relationship between tacrolimus trough levels (C
12
) 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.
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.
Modigraf granules 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).
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) 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 materials (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.
Hypersensitivity to tacrolimus or to any of the excipients (see section 6.1).
Hypersensitivity to other macrolides.
There are no safety data available on the use of Modigraf granules following a temporary switch from
Prograf or Advagraf in critically ill patients.
6
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, including graft rejection, or
other side effects 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).
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.
When substances with a potential for interaction (see section 4.5) – particularly strong inhibitors of
CYP3A4 (such as 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
) should be avoided when
taking Modigraf due to the risk of interactions that lead to decrease in blood concentrations of
tacrolimus and reduced clinical effect of tacrolimus (see section 4.5).
The combined administration of ciclosporin and 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 risks of these effects (see section 4.5).
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.
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 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 but at this time lacks substantial evidence for causing
Torsades de Pointes
.
Caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome.
Lymphoproliferative disorders and malignancies
Patients treated with tacrolimus have been reported to develop EBV-associated lymphoproliferative
disorders (see section 4.8). A combination of immunosuppressives such as antilymphocytic antibodies
7
(e.g. basiliximab, daclizumab) given concomitantly increases the risk of EBV-associated
lymphoproliferative disorders. EBV-Viral Capsid Antigen (VCA)-negative patients 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 Modigraf.
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.
Patients treated with immunosuppressants, including Modigraf, 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.
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.
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).
Dose reduction may be necessary in patients with severe liver impairment (See section 4.2).
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.
4.5
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of
gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known
to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or
decrease tacrolimus blood levels.
It is recommended to monitor tacrolimus blood levels whenever substance which have the potential to
alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and
to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see
sections 4.2 and 4.4).
CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels
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). Concomitant use of these substances may require decreased tacrolimus doses in nearly all
patients.
8
Pharmacokinetics studies have indicated that the 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.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine,
nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.
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.
Lansoprazol and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and
thereby increase tacrolimus whole blood concentrations.
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 prokinetic
agents (such as metoclopramide and cisapride), cimetidine and magnesium-aluminium-hydroxide.
CYP3A4 inducers potentially leading to decreased tacrolimus blood levels
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 metabolised by CYP3A4 may affect the metabolism of such medicinal products.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition,
synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of
ciclosporin and tacrolimus is not recommended and care should be taken when administering
tacrolimus to patients who have previously received ciclosporin (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. Clinical data suggest
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).
9
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).
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 on the course and outcome of pregnancy
under tacrolimus treatment compared with other immunosuppressive medicinal products. To date, no
other relevant epidemiological data are available. 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 events of
tacrolimus is recommended (in particular effects on the kidneys).There is a risk for premature delivery
(<37 week) (incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the
newborns had normal birth weight for their gestational age) as well as for hyperkalaemia in the
newborn (incidence 8 of 111 neonates, i.e. 7.2%) which, however normalises spontaneously.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal
toxicity (see section 5.3). Tacrolimus affected fertility in male rats (see section 5.3).
Lactation
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 tacrolimus.
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).
Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus
is administered in association with alcohol.
No studies on the effects of tacrolimus (Modigraf) on the ability to drive and use machines have been
performed.
4.8
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: 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
effects are presented in order of decreasing seriousness.
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.
10
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 Modigraf.
Neoplasms benign, malignant and unspecified (inl. 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.
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
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see
section 4.4).
Endocrine disorders
rare:
hirsutism
Metabolism and nutrition disorders
very common:
diabetes mellitus, hyperglycaemic conditions, hyperkalaemia
common:
anorexia, metabolic acidoses, other electrolyte abnormalities, hyponatraemia,
fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia,
hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia,
hypertriglyceridaemia, hypophosphataemia
uncommon:
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
Psychiatric disorders
very common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental
disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
Nervous system disorders
very common:
headache, tremor
common:
nervous system disorders, seizures, disturbances in consciousness, peripheral
neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired
uncommon:
encephalopathy, central nervous system haemorrhages and cerebrovascular
accidents, coma, speech and language abnormalities, paralysis and paresis,
amnesia
rare:
hypertonia
very rare:
myasthenia
Eye disorders
common:
eye disorders, vision blurred, photophobia
uncommon:
blindness
Ear and labyrinth disorders
common:
tinnitus
uncommon:
hypoacusis
very rare:
deafness neurosensory
11
common:
insomnia
rare:
cataract
rare:
hearing impaired
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
very rare:
echocardiogram abnormal
Vascular disorders
very common:
hypertension
common:
thromboembolic and ischaemic events, vascular hypotensive disorders,
haemorrhage, peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
Respiratory, thoracic and mediastinal disorders
common:
parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal
congestion and inflammations
uncommon:
respiratory failures, respiratory tract disorders, asthma
Gastrointestinal disorders
very common:
diarrhoea, nausea
common:
gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal
pains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages,
gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration,
constipation, dyspeptic signs and symptoms, flatulence, bloating and distension,
loose stools
uncommon:
acute and chronic pancreatitis, peritonitis, blood amylase increased, ileus
paralytic, gastrooesophageal reflux disease, impaired gastric emptying
rare:
pancreatic pseudocyst, subileus
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
very rare:
venoocclusive liver disease, hepatic artery thrombosis
Skin and subcutaneous tissue disorders
common:
rash, pruritus, alopecias, acne, sweating increased
uncommon:
toxic epidermal necrolysis (Lyell’s syndrome)
very rare:
Stevens Johnson syndrome
Musculoskeletal and connective tissue disorders
common:
arthralgia, back pain, muscle cramps, pain in limb
uncommon:
joint disorders
Renal and urinary disorders
very common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary
abnormalities, oliguria, bladder and urethral symptoms
uncommon:
haemolytic uraemic syndrome, anuria
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
12
rare:
pericardial effusion
rare:
acute respiratory distress syndrome
rare:
hepatic failure
rare:
dermatitis, photosensitivity
common:
renal impairment
very rare:
nephropathy, cystitis haemorrhagic
General disorders and administration site conditions
common:
febrile disorders, pain and discomfort, asthenic conditions, oedema, body
temperature perception disturbed, blood alkaline phosphatase increased, weight
increased
uncommon:
weight decreased, influenza like illness, blood lactate dehydrogenase increased,
feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation,
temperature intolerance
rare:
fall, ulcer, chest tightness, mobility decreased, thirst
very rare:
fat tissue increased
Injury, poisoning and procedural complications
common:
primary graft dysfunction
4.9
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.
No specific antidote to tacrolimus therapy is available. If overdose 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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02
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 lymphokine 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.
Clinical efficacy and safety of tacrolimus administered twice daily in other primary organ
transplantation
In prospective published studies oral tacrolimus (given as Prograf capsules) 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 oral
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.
13
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 group.
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/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 2-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 3 studies demonstrated similar survival rates. The incidences of acute rejection were numerically
lower with tacrolimus in all 3 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 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/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 ciclosporin to
tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.
Intestinal transplantation
Published clinical experience from a single centre on the use of oral 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 15 ng/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.
Available tacrolimus is generally rapidly absorbed.
14
Modigraf granules are an immediate-release formulation of tacrolimus for twice daily dosing.
Following oral administration of Modigraf granules peak concentrations (C
max
) of tacrolimus in blood
are on average achieved in approximately 2 to 2.5 hours.
Absorption of tacrolimus is variable. Results of a single dose bioequivalence study with adult healthy
volunteers showed that Modigraf granules were approximately 20% more bioavailable than the
Prograf capsules. Mean oral bioavailability of tacrolimus (investigated with the Prograf capsules
formulation) is in the range of 20 - 25% (individual range in adult patients 6 - 43%, in paediatric
kidney transplant patients 3 - 77%). The oral bioavailability of tacrolimus was reduced when it was
administered after a meal.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Modigraf
granules may commence orally.
In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a
relatively flat absorption profile.
The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of
food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced
after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.
In stable liver transplant patients, the oral bioavailability of tacrolimus was reduced when it was
administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and
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 t
max
(38 to 80%) in whole blood were
evident.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Modigraf.
Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
Distribution
In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1
distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound
(> 98.8%) to plasma 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.
Metabolism
Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is
also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one
of these has been shown
in vitro
to have immunosuppressive activity similar to that of tacrolimus. The
other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one
of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to
pharmacological activity of tacrolimus.
Excretion
Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance
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. 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
was 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.
15
Following intravenous and oral administration of
14
C-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.
Paediatric data
In paediatric liver transplant patients the mean oral bioavailability of tacrolimus (investigated with the
Modigraf granules) is 26%± 23% (individual range in paediatric liver transplant patients 4 - 80%).
Data on oral bioavailability of Modigraf in other indications is not available.
After oral administration (0.30 mg/kg/day) to paediatric liver transplant patients, steady-state
concentrations of tacrolimus were achieved within 3 days in the majority of patients.
In paediatric liver and kidney transplant patients, values for total body clearance of
2.3 ± 1.2 ml/min/kg and 2.1 ± 0.6 ml/min/kg, respectively, have been observed. Highly variable age
dependent total body clearance and half life were observed in limited paediatric clinical investigations,
especially in early childhood.
The half-life in paediatric transplant patients averages approximately 12 hours.
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.
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.
6.
6.1 List of excipients
Lactose monohydrate
Hypromellose (E464)
Croscarmellose sodium (E468)
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride) plastics. Materials used to prepare and
administer the suspension, e.g. drinking vessels, cups, or tubing, must not contain PVC.
6.3 Shelf life
3 years.
After preparation, the suspension should be administered immediately.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Sachets consisting of layers of polyethylene terephtalate (PET), aluminium (Al) and polyethylene
(PE), containing granules.
16
Pack size: carton box containing 50 sachets.
6.6 Special precautions for disposal and other handling
No special requirements.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/09/523/001
15/05/2009
17
1.
Modigraf 1 mg granules for oral suspension
2.
Each sachet contains 1 mg tacrolimus (as monohydrate).
Excipient:
Each sachet contains 497 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Granules for oral suspension.
White granules.
4.
Prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products in adult and paediatric patients.
This medicinal product should only be prescribed, and changes in immunosuppressive therapy
initiated, by physicians experienced in immunosuppressive therapy and the management of transplant
patients. Modigraf is a granular formulation of tacrolimus, for twice-a-day administration. Modigraf
therapy requires careful monitoring by adequately qualified and equipped personnel.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Modigraf is
routinely administered in conjunction with other immunosuppressive agents in the initial
post-operative period. The dose may vary depending upon the immunosuppressive regimen chosen.
Modigraf dosing should primarily be based on clinical assessments of rejection and tolerability in each
patient individually aided by blood level monitoring (see below under “Therapeutic drug
monitoring”). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen
should be considered.
Careful and frequent monitoring of tacrolimus trough levels is recommended in the first 2 weeks
post-transplant to ensure adequate drug exposure 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).
Modigraf should not be switched with 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. This
can lead to graft rejection or increased incidence of undesirable effects, including under- or
overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus.
18
Patients should be maintained on a single formulation of tacrolimus with the corresponding 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.
Prophylaxis of kidney transplant rejection
Adults
Oral Modigraf therapy should commence at 0.20 - 0.30 mg/kg/day administered as 2 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 0.05 - 0.10 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should
be initiated as a continuous 24-hour infusion.
Paediatric patients
An initial oral dose of 0.30
mg/kg/day should be administered in 2 divided doses (e.g. morning and
evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of
0.075
–
0.100 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be
administered as a continuous 24-hour infusion.
Dose adjustment during post-transplant period in adults and paediatric patients
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.
Prophylaxis of liver transplant rejection
Adults
Oral Modigraf therapy should commence at 0.10 - 0.20 mg/kg/day administered as 2 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 0.01 - 0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should
be initiated as a continuous 24-hour infusion.
Paediatric patients
An initial oral dose of 0.30 mg/kg/day should be administered in 2 divided doses (e.g. morning and
evening). If the clinical condition of the patient prevents oral dosing, an initial intravenous dose of
0.05 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) should be administered as
a continuous 24-hour infusion.
Dose adjustment during post-transplant period in adults and paediatric patients
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.
Prophylaxis of heart transplant rejection
Adults
Modigraf 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 Modigraf therapy should commence at a dose of 0.075 mg/kg/day
administered as 2 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
19
therapy of 0.01 to 0.02 mg/kg/day (with Prograf 5 mg/ml concentrate for solution for infusion) 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.
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 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 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).
Dose adjustment during post-transplant period in adults and paediatric patients
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.
Conversion between Modigraf and Prograf tacrolimus formulations
In healthy subjects the systemic exposure to tacrolimus (AUC) for Modigraf was approximately 18%
higher than that for Prograf capsules when administered as single doses. There are no safety data
available on the use of Modigraf granules following a temporary switch from Prograf or Advagraf in
critically ill patients.
Stable allograft recipients maintained on Modigraf granules, requiring conversion to Prograf capsules,
should be converted on a 1:1 mg:mg total daily dose basis. If equal doses are not possible, the total
daily dose of Prograf should be rounded-up to the nearest amount possible, with the higher dose given
in the morning and the lower dose in the evening.
Similarly, for conversion of patients from Prograf capsules to Modigraf granules, the total daily
Modigraf dose should preferably be equal to the total daily Prograf dose. If conversion on the basis of
equal quantities is not possible, the total daily dose of Modigraf should be rounded down to the nearest
total daily dose possible with sachets 0.2 mg and 1 mg.
The total daily dose of Modigraf granules should be administered in 2 equal doses. If equal doses are
not possible, then the higher dose should be administered in the morning and the lower dose in the
evening. Modigraf sachets must not be used partially.
Example: Total daily dose Prograf capsules given as 1 mg in the morning and 0.5 mg in the evening.
Then give a total daily dose of Modigraf 1.4 mg divided as 0.8 mg in the morning and 0.6 mg in the
evening.
Tacrolimus trough levels should be measured prior to conversion and within 1 week after conversion.
Dose adjustments should be made to ensure that similar systemic exposure is maintained.
Conversion from ciclosporin to tacrolimus
Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy
(see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not
recommended. 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-based therapy has been initiated
12 - 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be
continued following conversion as the clearance of ciclosporin might be affected.
20
Treatment of allograft rejection
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 such
as severe adverse reactions are noted (see section 4.8), the dose of Modigraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation – adults and paediatric patients
For conversion from other immunosuppressants to twice daily Modigraf, treatment should begin with
the initial oral dose recommended for primary immunosuppression.
Treatment of allograft rejection after heart transplantation therapy – adults and paediatric patients
In adult patients converted to Modigraf, an initial oral dose of 0.15 mg/kg/day should be administered
in 2 divided doses (e.g. morning and evening).
In paediatric patients converted to tacrolimus, an initial oral dose of 0.20 - 0.30 mg/kg/day should be
administered in 2 divided doses (e.g. morning and evening).
Treatment of allograft rejection after transplantation of other allografts
The dose recommendations for lung, pancreas and intestinal transplantation are based on limited
prospective clinical trial data with the Prograf formulation. Prograf has been used in lung-transplanted
patients at an initial oral dose of 0.10 - 0.15 mg/kg/day, in pancreas-transplanted patients at an initial
oral dose of 0.2 mg/kg/day and in intestinal transplantation at an initial oral dose of 0.3 mg/kg/day.
Dose adjustments 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.
21
The relationship between tacrolimus trough levels (C
12
) 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.
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.
Modigraf granules 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).
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) 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 materials (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.
Hypersensitivity to tacrolimus or to any of the excipients (see section 6.1).
Hypersensitivity to other macrolides.
There are no safety data available on the use of Modigraf granules following a temporary switch from
Prograf or Advagraf in critically ill patients.
22
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, including graft rejection, or
other side effects 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).
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.
When substances with a potential for interaction (see section 4.5) – particularly strong inhibitors of
CYP3A4 (such as 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
) should be avoided when
taking Modigraf due to the risk of interactions that lead to decrease in blood concentrations of
tacrolimus and reduced clinical effect of tacrolimus (see section 4.5).
The combined administration of ciclosporin and 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 risks of these effects (see section 4.5).
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.
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 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 but at this time lacks substantial evidence for causing
Torsades de Pointes
.
Caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome.
Lymphoproliferative disorders and malignancies
Patients treated with tacrolimus have been reported to develop EBV-associated lymphoproliferative
disorders (see section 4.8). A combination of immunosuppressives such as antilymphocytic antibodies
23
(e.g. basiliximab, daclizumab) given concomitantly increases the risk of EBV-associated
lymphoproliferative disorders. EBV-Viral Capsid Antigen (VCA)-negative patients 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 Modigraf.
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.
Patients treated with immunosuppressants, including Modigraf, 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.
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.
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).
Dose reduction may be necessary in patients with severe liver impairment (See section 4.2).
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.
4.5
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of
gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known
to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or
decrease tacrolimus blood levels.
It is recommended to monitor tacrolimus blood levels whenever substance which have the potential to
alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and
to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see
sections 4.2 and 4.4).
CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels
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). Concomitant use of these substances may require decreased tacrolimus doses in nearly all
patients.
24
Pharmacokinetics studies have indicated that the 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.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine,
nicardipine, diltiazem, verapamil, danazol, ethinylestradiol, omeprazole and nefazodone.
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.
Lansoprazol and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and
thereby increase tacrolimus whole blood concentrations.
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 prokinetic
agents (such as metoclopramide and cisapride), cimetidine and magnesium-aluminium-hydroxide.
CYP3A4 inducers potentially leading to decreased tacrolimus blood levels
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 metabolised by CYP3A4 may affect the metabolism of such medicinal products.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition,
synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of
ciclosporin and tacrolimus is not recommended and care should be taken when administering
tacrolimus to patients who have previously received ciclosporin (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. Clinical data suggest
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).
25
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).
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 on the course and outcome of pregnancy
under tacrolimus treatment compared with other immunosuppressive medicinal products. To date, no
other relevant epidemiological data are available. 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 events of
tacrolimus is recommended (in particular effects on the kidneys).There is a risk for premature delivery
(<37 week) (incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the
newborns had normal birth weight for their gestational age) as well as for hyperkalaemia in the
newborn (incidence 8 of 111 neonates, i.e. 7.2%) which, however normalises spontaneously.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal
toxicity (see section 5.3). Tacrolimus affected fertility in male rats (see section 5.3).
Lactation
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 tacrolimus.
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).
Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus
is administered in association with alcohol.
No studies on the effects of tacrolimus (Modigraf) on the ability to drive and use machines have been
performed.
4.8
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: 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
effects are presented in order of decreasing seriousness.
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.
26
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 Modigraf.
Neoplasms benign, malignant and unspecified (inl. 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.
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
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see
section 4.4).
Endocrine disorders
rare:
hirsutism
Metabolism and nutrition disorders
very common:
diabetes mellitus, hyperglycaemic conditions, hyperkalaemia
common:
anorexia, metabolic acidoses, other electrolyte abnormalities, hyponatraemia,
fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia,
hypocalcaemia, appetite decreased, hypercholesterolaemia, hyperlipidaemia,
hypertriglyceridaemia, hypophosphataemia
uncommon:
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
Psychiatric disorders
very common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental
disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
Nervous system disorders
very common:
headache, tremor
common:
nervous system disorders, seizures, disturbances in consciousness, peripheral
neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired
uncommon:
encephalopathy, central nervous system haemorrhages and cerebrovascular
accidents, coma, speech and language abnormalities, paralysis and paresis,
amnesia
rare:
hypertonia
very rare:
myasthenia
Eye disorders
common:
eye disorders, vision blurred, photophobia
uncommon:
blindness
Ear and labyrinth disorders
common:
tinnitus
uncommon:
hypoacusis
very rare:
deafness neurosensory
27
common:
insomnia
rare:
cataract
rare:
hearing impaired
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
very rare:
echocardiogram abnormal
Vascular disorders
very common:
hypertension
common:
thromboembolic and ischaemic events, vascular hypotensive disorders,
haemorrhage, peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
Respiratory, thoracic and mediastinal disorders
common:
parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal
congestion and inflammations
uncommon:
respiratory failures, respiratory tract disorders, asthma
Gastrointestinal disorders
very common:
diarrhoea, nausea
common:
gastrointestinal signs and symptoms, vomiting, gastrointestinal and abdominal
pains, gastrointestinal inflammatory conditions, gastrointestinal haemorrhages,
gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration,
constipation, dyspeptic signs and symptoms, flatulence, bloating and distension,
loose stools
uncommon:
acute and chronic pancreatitis, peritonitis, blood amylase increased, ileus
paralytic, gastrooesophageal reflux disease, impaired gastric emptying
rare:
pancreatic pseudocyst, subileus
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
very rare:
venoocclusive liver disease, hepatic artery thrombosis
Skin and subcutaneous tissue disorders
common:
rash, pruritus, alopecias, acne, sweating increased
uncommon:
toxic epidermal necrolysis (Lyell’s syndrome)
very rare:
Stevens Johnson syndrome
Musculoskeletal and connective tissue disorders
common:
arthralgia, back pain, muscle cramps, pain in limb
uncommon:
joint disorders
Renal and urinary disorders
very common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary
abnormalities, oliguria, bladder and urethral symptoms
uncommon:
haemolytic uraemic syndrome, anuria
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
28
rare:
pericardial effusion
rare:
acute respiratory distress syndrome
rare:
hepatic failure
rare:
dermatitis, photosensitivity
common:
renal impairment
very rare:
nephropathy, cystitis haemorrhagic
General disorders and administration site conditions
common:
febrile disorders, pain and discomfort, asthenic conditions, oedema, body
temperature perception disturbed, blood alkaline phosphatase increased, weight
increased
uncommon:
weight decreased, influenza like illness, blood lactate dehydrogenase increased,
feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation,
temperature intolerance
rare:
fall, ulcer, chest tightness, mobility decreased, thirst
very rare:
fat tissue increased
Injury, poisoning and procedural complications
common:
primary graft dysfunction
4.9
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.
No specific antidote to tacrolimus therapy is available. If overdose 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.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02
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 lymphokine 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.
Clinical efficacy and safety of tacrolimus administered twice daily in other primary organ
transplantation
In prospective published studies oral tacrolimus (given as Prograf capsules) 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 oral
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.
29
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 group.
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/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 2-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 3 studies demonstrated similar survival rates. The incidences of acute rejection were numerically
lower with tacrolimus in all 3 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 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/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 ciclosporin to
tacrolimus, whereas only 6 tacrolimus patients required alternative therapy.
Intestinal transplantation
Published clinical experience from a single centre on the use of oral 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 15 ng/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.
Available tacrolimus is generally rapidly absorbed.
30
Modigraf granules are an immediate-release formulation of tacrolimus for twice daily dosing.
Following oral administration of Modigraf granules peak concentrations (C
max
) of tacrolimus in blood
are on average achieved in approximately 2 to 2.5 hours.
Absorption of tacrolimus is variable. Results of a single dose bioequivalence study with adult healthy
volunteers showed that Modigraf granules were approximately 20% more bioavailable than the
Prograf capsules. Mean oral bioavailability of tacrolimus (investigated with the Prograf capsules
formulation) is in the range of 20 - 25% (individual range in adult patients 6 - 43%, in paediatric
kidney transplant patients 3 - 77%). The oral bioavailability of tacrolimus was reduced when it was
administered after a meal.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Modigraf
granules may commence orally.
In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a
relatively flat absorption profile.
The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of
food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced
after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.
In stable liver transplant patients, the oral bioavailability of tacrolimus was reduced when it was
administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and
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 t
max
(38 to 80%) in whole blood were
evident.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Modigraf.
Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
Distribution
In man, the disposition of tacrolimus after intravenous infusion may be described as biphasic.
In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1
distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly bound
(> 98.8%) to plasma 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.
Metabolism
Tacrolimus is widely metabolised in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is
also considerably metabolised in the intestinal wall. There are several metabolites identified. Only one
of these has been shown
in vitro
to have immunosuppressive activity similar to that of tacrolimus. The
other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one
of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to
pharmacological activity of tacrolimus.
Excretion
Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance
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. 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
was 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.
31
Following intravenous and oral administration of
14
C-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.
Paediatric data
In paediatric liver transplant patients the mean oral bioavailability of tacrolimus (investigated with the
Modigraf granules) is 26%± 23% (individual range in paediatric liver transplant patients 4 - 80%).
Data on oral bioavailability of Modigraf in other indications is not available.
After oral administration (0.30 mg/kg/day) to paediatric liver transplant patients, steady-state
concentrations of tacrolimus were achieved within 3 days in the majority of patients.
In paediatric liver and kidney transplant patients, values for total body clearance of
2.3 ± 1.2 ml/min/kg and 2.1 ± 0.6 ml/min/kg, respectively, have been observed. Highly variable age
dependent total body clearance and half life were observed in limited paediatric clinical investigations,
especially in early childhood.
The half-life in paediatric transplant patients averages approximately 12 hours.
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.
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.
6.
6.1 List of excipients
Lactose monohydrate
Hypromellose (E464)
Croscarmellose sodium (E468)
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride) plastics. Materials used to prepare and
administer the suspension, e.g. drinking vessels, cups, or tubing, must not contain PVC.
6.3 Shelf life
3 years.
After preparation, the suspension should be administered immediately.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Sachets consisting of layers of polyethylene terephtalate (PET), aluminium (Al) and polyethylene
(PE), containing granules.
32
Pack size: carton box containing 50 sachets.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/09/523/002
9.
15/05/2009
33
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
34
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Astellas Ireland Co. Ltd
Killorglin
Co. Kerry
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 4 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 3.2 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
35
ANNEX III
LABELLING AND PACKAGE LEAFLET
36
A. LABELLING
37
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Modigraf 0.2 mg granules for oral suspension
tacrolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sachet contains 0.2 mg tacrolimus (as monohydrate).
3.
LIST OF EXCIPIENTS
Also contains lactose. See package leaflet for further information.
4.
50 sachets containing granules for oral suspension.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Suspend the granules in water.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After preparation, the suspension should be administered immediately.
9.
SPECIAL STORAGE CONDITIONS
38
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
12.
EU/1/09/523/001
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
modigraf 0.2 mg
39
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SACHET FOIL
1.
Modigraf 0.2 mg granules for oral suspension
tacrolimus
oral use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Modigraf 1 mg granules for oral suspension
tacrolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sachet contains 1 mg tacrolimus (as monohydrate).
3.
LIST OF EXCIPIENTS
Also contains lactose. See package leaflet for further information.
4.
50 sachets containing granules for oral suspension.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Suspend the granules in water.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
After preparation, the suspension should be administered immediately.
9.
SPECIAL STORAGE CONDITIONS
41
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
12.
EU/1/09/523/002
13.
BATCH NUMBER
Batch
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
modigraf 1 mg
42
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SACHET FOIL
1.
Modigraf 1 mg granules for oral suspension
tacrolimus
oral use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
43
B. PACKAGE LEAFLET
44
PACKAGE LEAFLET: INFORMATION FOR THE USER
Modigraf 0.2 mg, granules for oral suspension
Modigraf 1 mg, granules for oral suspension
Tacrolimus
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you / your child. Do not pass it on to others. It may harm
them, even if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Modigraf is and what it is used for
2.
How to take Modigraf
3.
Before you take Modigraf
5.
How to store Modigraf
6.
Further information
1. WHAT MODIGRAF IS AND WHAT IT IS USED FOR
Modigraf is an immunosuppressant. Following your organ transplant (e.g. liver, kidney, heart), your
body’s immune system will try to reject the new organ. Modigraf is used to control your body’s
immune response enabling your body to accept the transplanted organ.
You may also be given Modigraf for an ongoing rejection of your transplanted liver, kidney, heart or
other organ or if any previous treatment you were taking was unable to control this immune response
after your transplantation.
2. BEFORE YOU TAKE MODIGRAF
Do not take Modigraf
-
If you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Modigraf (see
section 6).
-
If you are allergic (hypersensitive) to sirolimus (another substance used to prevent rejection of
your transplanted organ) or to any macrolide antibiotic (e.g. erythromycin, clarithromycin,
josamycin).
Take special care with Modigraf
Tell your doctor if any of the following apply to you:
- if you are taking any medicines mentioned below under ‘Using other medicines’.
- if you have or have had liver problems.
- if you have diarrhoea for more than one day.
- if you need to receive any vaccinations.
Your doctor may need to adjust your dose of Modigraf.
You should keep in regular contact with your doctor. From time to time, your doctor may need to do
blood, urine, heart, eye tests, to set the right dose of Modigraf.
45
4.
Possible side effects
You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Modigraf. 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.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription and herbal preparations.
It is not recommended that Modigraf is taken with ciclosporin. Modigraf blood levels can be affected
by other medicines you take, and blood levels of other medicines can be affected by taking Modigraf,
which may require an increase or decrease in Modigraf 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 e.g. ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole,
erythromycin, clarithromycin, josamycin, and rifampicin
-
medicines for stomach ulcer and acid reflux (e.g. omeprazol, lansoprazol or cimetidine)
-
anti-emetics, used to treat nausea and vomiting (e.g. metoclopramide)
-
cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn
-
the contraceptive pill, hormone treatments with ethinylestradiol, or hormone treatments with
danazol
-
medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine,
diltiazem and verapamil)
-
medicines known as “statins” used to treat elevated cholesterol and triglycerides
-
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)
-
nefazodone, used to treat depression
-
Herbal preparations containing St. John’s Wort (
Hypericum perforatum
)
Tell your doctor if you are taking or need to take ibuprofen, amphotericin B or antivirals (e.g.
aciclovir). These may worsen kidney or nervous system problems when taken together with Modigraf.
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 Modigraf.
If you need to have any vaccinations, please tell your doctor before.
Taking Modigraf with food and drink
Take Modigraf on an empty stomach or 2 to 3 hours after a meal. Wait at least 1 hour until the next
meal. Avoid grapefruit (also as juice) while on treatment with Modigraf, since it can affect its levels.
Pregnancy and breast-feeding
If you are, think you might be or are planning to become pregnant, ask your doctor for advice before
using Modigraf.
Modigraf passes into breast milk. Therefore, you should not breast-feed whilst using Modigraf.
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 Modigraf. These effects are more frequent if you also drink alcohol.
Important information about some of the ingredients of Modigraf
Modigraf contains lactose (milk sugar). If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
46
-
HIV protease inhibitors (e.g. ritonavir), used to treat HIV infection
-
phenytoin or phenobarbital, used to treat epilepsy
3. HOW TO TAKE MODIGRAF
Always take Modigraf exactly as your doctor has told you. You should 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.
Following the initiation of your treatment with Modigraf, frequent blood tests will be taken by your
doctor to define the correct dose and to adjust the dose from time to time. Your doctor will usually
reduce your Modigraf dose once your condition has stabilised. Your doctor will tell you exactly how
many sachets to take.
You will need to take Modigraf every day as long as you need immunosuppression to prevent rejection
of your transplanted organ. You should keep in regular contact with your doctor.
Modigraf is taken orally twice daily, usually in the morning and evening. See also “Taking Modigraf
with food and drink”.
How to prepare the Modigraf sachets for use?
Your doctor will advise you on the number of sachets that you need to open and the volume of water
that is required to make a suspension. For accurate measuring the volume of water you can use a
syringe or graduated cylinder.
Carefully open the prescribed number of sachets, e.g. with a pair of scissors.
Pour the prescribed volume of water (at room temperature) into a glass or cup, up to a maximum of
50 ml. Place the cup with water on a stable surface. Do not use cups or spoons that are made of PVC
(polyvinylchloride) to take Modigraf because the active substance in Modigraf may stick to PVC.
Open the sachet at the point indicated with an arrow. Hold the opened sachet between thumb and
index finger above the cup with the open side of the sachet facing downwards. Gently tap on the
closed end of the sachet and pour the contents of each sachet into the glass or cup containing the
water. Do not use any utensils or liquids to empty the sachet. If you follow these instructions, you will
get the right amount of granules from the sachet. It is normal that some granules stay behind; the
sachet was designed that way.
Stir, or swirl gently until the granules have been suspended completely. The suspension can be drawn
up with a syringe or swallowed directly by the patient. The liquid has a sweet taste. Rinse the glass or
cup once with the same amount of water and drink this, too. The liquid should be drunk immediately
after preparation.
If you take more Modigraf than you should
If you have accidentally taken too much Modigraf, contact your doctor or nearest hospital emergency
department immediately.
If you forget to take Modigraf
Do not take a double dose to make up for forgotten individual doses.
47
If you have forgotten to take your Modigraf, wait until it is time for the next dose, and then continue as
before.
If you stop taking Modigraf
Stopping your treatment with Modigraf 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 medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Modigraf can cause side effects, although not everybody gets them.
Modigraf reduces your body’s defence mechanism (immune system), which will not be as good at
fighting infections. Therefore, you may be more prone to infections while you are taking Modigraf.
Severe effects may occur, including allergic and anaphylactic reactions (a very serious type of allergic
reaction with fainting and difficulty breathing, which needs immediate medical attention). Benign and
malignant tumours have been reported following Modigraf treatment.
Possible side effects are listed according to the following categories:
-
very common: affects more than 1 user in 10
-
uncommon: affects 1 to 10 users in 1,000
-
rare: affects 1 to 10 users in 10,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
Very common side effects:
-
Increased blood sugar, diabetes mellitus, increased potassium in the blood
-
Difficulty in sleeping
-
Increased blood pressure
-
Liver function tests abnormal
-
Diarrhoea, nausea
-
Kidney problems
Common side effects:
-
Reduction in blood cell counts (platelets, red or white blood cells), increase in white blood cell
counts, changes in red blood cell counts (seen in blood tests)
-
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, nightmare,
hallucination, mental disorders
-
Fits, 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
-
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
-
Stomach problems such as inflammation or ulcer causing abdominal pain or diarrhoea, bleeding
in the stomach, inflammation or ulcer in the mouth, collection of fluid in the belly, vomiting,
abdominal pain, indigestion, constipation, passing wind, bloating, loose stools
48
-
common: affects 1 to 10 users in 100
-
Trembling, headache
-
Ringing sound in your ears
-
Bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage and
inflammation of the liver
-
Itching, rash, hair loss, acne, increased sweating
-
Insufficient function of the kidneys, reduced production of urine, impaired or painful urination
-
General weakness, fever, collection of fluid in your body, pain and discomfort, increase of the
enzyme alkaline phosphatase in your blood, weight gain, feeling of temperature disturbed
-
Insufficient function of your transplanted organ
Uncommon side effects:
-
Changes in blood clotting, reduction in the number of all types of blood cells (seen in blood
tests)
-
Abnormal blood test results: reduced protein or sugar, increased phosphate, increase of the
enzyme lactate dehydrogenase
-
Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language
abnormalities, memory problems
-
Clouding of the eye lens, impaired hearing
-
Irregular heartbeat, stop of heartbeat, reduced performance of your heart, disorder of the heart
muscle, enlargement of the heart muscle, stronger heartbeat, abnormal ECG, heart rate and
pulse abnormal
-
Blood clot in a vein of a limb, shock
-
Difficulties in breathing, respiratory tract disorders, asthma
-
Obstruction of the gut, increased blood level of the enzyme amylase, reflux of stomach content
in your throat, delayed emptying of the stomach
-
Inflammation of the skin, burning sensation in the sunlight
-
Painful menstruation and abnormal menstrual bleeding
-
Failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure
on your chest, jittery or abnormal feeling, weight loss
Rare side effects:
-
Small bleedings in your skin due to blood clots
-
Blindness, deafness
-
Collection of fluid around the heart
-
Acute breathlessness
-
Cyst formation in your pancreas
-
Problems with blood flow in the liver
-
Serious illness with blistering of skin, mouth, eyes and genitals; increased hairiness
-
Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer
Very rare side effects:
-
Abnormal heart scan
-
Liver failure
-
Painful urination with blood in the urine
-
Increase of fat tissue
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5. HOW TO STORE MODIGRAF
Keep out of the reach and sight of children.
49
-
Pain in joints, limbs or back, muscle cramps
-
Dehydration, inability to urinate
-
Joint disorders
-
Increased muscle stiffness
-
Muscular weakness
Do not use Modigraf after the expiry date which is stated on the carton and sachet after EXP. The
expiry date refers to the last day of that month.
This medicinal product does not require any special temperature storage conditions.
After preparation, the suspension should be taken immediately.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Modigraf contains
-
The active substance is tacrolimus.
Each sachet of Modigraf 0.2 mg granules contains 0.2 mg of tacrolimus (as monohydrate).
Each sachet of Modigraf 1 mg granules contains 1 mg of tacrolimus (as monohydrate).
-
The other ingredients are: lactose monohydrate, hypromellose (E464) and croscarmellose
sodium (E468).
What Modigraf looks like and contents of the pack
Modigraf granules for oral suspension are white granules supplied in sachets.
Packs containing 50 sachets are available.
Marketing Authorisation Holder
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
Manufacturer
Astellas Ireland Co. Ltd.
Killorglin
County Kerry
Ireland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Astellas Pharma B.V. Branch
Erasmus Park/Parc Erasme
Square Marie Curie 50
B-1070 Brüssel/Bruxelles
Tél/Tel: + 32 (0)2 5580710
Luxembourg/Luxemburg
Astellas Pharma B.V.Branch
Erasmus Park/Parc Erasme
Square Marie Curie 50
B-1070 Brüssel/Bruxelles
Belgique/Belgien
Tél/Tel: + 32 (0)2 5580710
България
Астелас Фарма ЕООД
ул. ”Бигла” 6
София 1407
Teл.: + 359 2 862 53 72
Magyarország
Astellas Pharma Kft.
Kelenhegyi út 43
H-1118 Budapest
Tel.: + 36 (06)1 3614673
50
Česká republika
Astellas Pharma s.r.o.
Sokolovská 100/94
CZ – 18600 Praha 8
Tel: +420 236 080300
Malta
E.J. Busuttil Ltd.
Niche
Triq ix-Xorrox
MT-B'Kara BKR 1633
Tel: +356 21447184
Danmark
Astellas Pharma a/s
Naverland 4
DK-2600 Glostrup
Tlf: + 45 43 430355
Nederland
Astellas Pharma B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Tel: + 31 (0)71 5455745
Deutschland
Astellas Pharma GmbH
Georg-Brauchle-Ring 64 – 66
D-80992 München
Tel: + 49 (0)89 454401
Norge
Astellas Pharma
Solbråveien 47
N-1383 Asker
Tlf: + 47 66 76 46 00
Eesti
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Holland
Tel: +31 (0)71 5455745
Österreich
Astellas Pharma Ges.m.b.H.
Linzer Straße 221/E02
A-1140 Wien
Tel: + 43 (0)1 8772668
Ελλάδα
Astellas Pharmaceuticals AEBE
Θουκυδίδου 1
GR-14565 Άγιος Στέφανος Αττικής
Τηλ: +30 210 8189900
Polska
Astellas Pharma Sp.z.o.o.
ul. Poleczki 21
PL – 02-822 Warszawa
Tel.: + 48 (0) 225451 111
España
Astellas Pharma S.A.
Paseo del Club Deportivo n° 1
Bloque 14-2
a
E-28223 Pozuelo de Alarcón, Madrid
Tel: + 34 91 4952700
Portugal
Astellas Farma, Lda.
Edifício Cinema
Rua José Fontana, n.°1, 1°Andar
P-2770−101 Paço de Arcos
Tel: + 351 21 4401320
France
Astellas Pharma S.A.S.
114 rue Victor Hugo
F-92300 Levallois Perret
Tél: + 33 (0)1 55917500
România
S.C.Astellas Pharma SRL
Detalii de contact pentru România
Şoseaua Bucureşti-Ploieşti 42-44
Clădire 1, Parter
013696-Bucureşti - RO
Tel: +40 (0)21 361 04 95
Ireland
Astellas Pharma Co. Ltd.
25, The Courtyard
Kilcarbery Business Park, Clondalkin
IRL – Dublin 22
Tel: + 353 (0)1 4671555
Slovenija
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Nizozemska
Tel: +31 (0)71 5455745
51
Ísland
Vistor hf
Hörgatúni 2
IS-210 Garðabæ
Sími: + 354 535 7000
Slovenská republika
Astellas Pharma s.r.o.,
organizačná zložka
Galvániho 15/C
SK-821 04 Bratislava 2
Tel: +421 2 4444 2157
Italia
Astellas Pharma S.p.A.
Via delle Industrie 1
I-20061 Carugate (Milano)
Tel: + 39 (0)2 921381
Suomi/Finland
Astellas Pharma / Algol Pharma Oy
Ab
PL/Box 13
FIN-02611 Espoo/Esbo
Puh/Tel: + 358 9 50991
Κύπρος
Astellas Pharmaceuticals AEBE
Θουκυδίδου 1
GR-14565 Άγιος Στέφανος Αττικής
Τηλ: +30 210 8189900
Sverige
Astellas Pharma AB
Per Albin Hanssons väg 41
S-205 12 Malmö
Tel: + 46 (0)40-650 15 00
Latvija
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Nīderlande
Tel: + 31 (0)71 5455745
United Kingdom
Astellas Pharma Ltd.
Lovett House
Lovett Road, Staines
Middlesex TW18 3AZ – UK
Tel: + 44 (0) 1784 419615
Lietuva
Astellas Pharma Europe B.V.
Elisabethhof 19
NL-2353 EW Leiderdorp
Nyderlandai
Tel. +31 (0)71 5455745
This leaflet was last approved in:
Detailed information on this medicine is available on the European Medicines Agency (EMEA)
website: http://www.emea.europa.eu/.
52
Source: European Medicines Agency
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