ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Advagraf 0.5 mg prolonged-release hard capsules
2.
Each prolonged-release hard capsule contains 0.5 mg tacrolimus (as monohydrate).
Excipients:
Each capsule contains 53.64 mg lactose monohydrate.
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total printing
ink composition).
For a full list of excipients, see section 6.1.
3.
Prolonged-release hard capsule.
Gelatin capsules imprinted in red with “0.5 mg” on the light yellow capsule cap and “
647” on the
orange capsule body, containing white powder.
4.
Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products
in adult patients.
Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoring by
adequately qualified and equipped personnel. 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.
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of
tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including
under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to
tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding
daily dosing regimen; alterations in formulation or regimen should only take place under the close
supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative
formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that
systemic exposure to tacrolimus is maintained.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Advagraf 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. Advagraf dosing
should primarily be based on clinical assessments of rejection and tolerability in each patient individually
2
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.
In
de novo
kidney and liver transplant patients AUC
0-24
of tacrolimus for Advagraf on Day 1 was 30%
and 50% lower respectively, when compared with that for Prograf at equivalent doses. By Day 4,
systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients
with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in
the first two weeks post-transplant with Advagraf to ensure adequate drug exposure in the immediate
post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Advagraf dose
regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the
duration of oral therapy can be given.
Prophylaxis of kidney transplant rejection
Advagraf therapy should commence at a dose of 0.20 - 0.30 mg/kg/day administered once daily in the
morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant changes in
the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose
adjustments.
Prophylaxis of liver transplant rejection
Advagraf therapy should commence at a dose of 0.10 - 0.20 mg/kg/day administered once daily in the
morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant
improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may
necessitate further dose adjustments.
Conversion of Prograf-treated patients to Advagraf
Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to
once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should be
administered in the morning.
In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1
(mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC
0-24
) for Advagraf was
approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C
24
)
and systemic exposure (AUC
0-24
) for Advagraf is similar to that of Prograf. When converting from
Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks
after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary
dose adjustments made to maintain similar systemic exposure. 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.
Advagraf 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.
Treatment of allograft rejection
3
Increased doses of tacrolimus, 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 Advagraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation
For conversion from other immunosuppressants to once daily Advagraf, treatment should begin with the
initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of
transplant rejection.
Treatment of allograft rejection after heart transplantation
In adult patients converted to Advagraf, an initial oral dose of 0.15 mg/kg/day should be administered
once daily in the morning.
Treatment of allograft rejection after transplantation of other allografts
Although there is no clinical experience with Advagraf in lung-, pancreas- or intestine-transplanted
patients, 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 tacrolimus 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.
Elderly patients:
There is no evidence currently available to indicate that dosing should be adjusted in
elderly patients.
Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual
patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus
concentrations in whole blood. Comparisons of concentrations from the published literature to individual
values in clinical practice should be assessed with care and knowledge of the assay methods employed. In
current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship
between tacrolimus trough levels (C
24
) and systemic exposure (AUC
0-24
) is similar between the two
formulations Advagraf and Prograf.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus
blood trough levels should be determined approximately 24 hours post-dosing of Advagraf, just prior to
the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is
recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of
tacrolimus should also be closely monitored following conversion from Prograf to Advagraf, 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
4
should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments
to the Advagraf dose regimen it may take several days before the targeted steady state is achieved.
Data from clinical studies suggest 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
Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of
Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be
taken immediately following removal from the blister. Patients should be advised not to swallow the
desiccant. The capsules should be swallowed
whole
with fluid (preferably water). Advagraf 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). A forgotten morning dose should be taken as soon as
possible on the same day. A double dose should not be taken on the next morning.
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 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
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 formulation or regimen should only take place under
the close supervision of a transplant specialist (see sections 4.2 and 4.8).
Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or
efficacy.
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products in adult patients clinical data are not yet available for the prolonged-release formulation
Advagraf.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available
for Advagraf.
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.
5
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 rifampin, 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
Advagraf due to the risk of interactions that lead to a decrease in both blood concentrations and the
therapeutic 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 risk 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
in Prograf treated patients on rare occasions and may also occur with Advagraf. 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 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 Advagraf, 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
(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 Advagraf. 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.
6
Patients treated with immunosuppressants, including Advagraf 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 sever liver impairment (see section 4.2)
Advagraf capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who are
hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the
benefit of using Advagraf.
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 substances which have the potential to
alter CYP3A 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. 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, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin.
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
7
Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances
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, 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 antipyrine.
Other interactions leading 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, cotrimoxazole,
NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and
ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing
hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene, or
spironolactone) should be avoided (see section 4.4).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with
tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section 4.4).
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)
8
(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).
Lactation
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn
cannot be excluded, women should not breast-feed whilst receiving Advagraf.
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 Advagraf is
administered in association with alcohol.
No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been
performed.
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.
Cardiac disorders
common:
heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias,
cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy,
palpitations, heart rate and pulse investigations abnormal
rare:
pericardial effusion
very rare:
echocardiogram abnormal
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
Nervous system disorders
very common:
headache, tremor
9
uncommon:
ischaemic coronary artery disorders, tachycardia
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
rare:
blindness
Ear and labyrinth disorders
common:
tinnitus
uncommon:
hypoacusis
very rare:
deafnessneurosensory
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
rare:
acute respiratory distress syndrome
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:
pancreaticpseudocyst, subileus
Renal and urinary disorders
very common:
renal impairment
common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary
abnormalities, oliguria, bladder and urethral symptoms
uncommon:
haemolytic uraemic syndrome, anuria
very rare:
nephropathy, cystitis haemorrhagic
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
Endocrine disorders
rare:
hirsutism
Metabolism and nutrition disorders
10
uncommon:
cataract
rare:
hearing impaired
rare:
dermatitis, photosensitivity
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
Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently
at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections
may be aggravated. Both generalised and localised infections can occur.
Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal
leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including
Advagraf.
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
Injury, poisoning and procedural complications
common: primary graft dysfunction
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or
prolonged-release tacrolimus formulations, have been observed. A number of associated cases of
transplant rejection have been reported (frequency cannot be estimated from available data).
Neoplasms benign, malignant and unspecified
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign
as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin
malignancies have been reported in association with tacrolimus treatment.
Vascular disorders
very common: hypertension
common:
thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage,
peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
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
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section
4.4).
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
very rare:
hepatic failure
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
Psychiatric disorders
11
uncommon:
rare:
venoocclusive liver disease, hepatitic artery thrombosis
very common:
insomnia
common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental
disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
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 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
At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein
(FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-
tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-
dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete
set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both
in vitro
and
in
vivo
experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible
for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell
proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and
the expression of the interleukin-2 receptor.
Results from clinical trials performed with once-daily tacrolimus Advagraf
Liver transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared
in 471
de novo
liver transplant recipients. The event rate of biopsy confirmed acute rejection within the
first 24 weeks after transplantation was 32.6% in the Advagraf group (N=237) and 29.3% in the Prograf
group (N=234). The treatment difference (Advagraf – Prograf) was 3.3% (95% confidence interval [-
5.7%, 12.3%]).The 12-month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in
the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female,
19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.
Kidney transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil
(MMF) and corticosteroids, was compared in 667
de novo
kidney transplant recipients. The event rate for
biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the
Advagraf group (N=331) and 14.9% in the Prograf group (N=336). The treatment difference (Advagraf-
Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were
96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female, 7 male) and
12
in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf
and 92.8% for Prograf.
The efficacy and safety of Prograf, ciclosporin and Advagraf, all in combination with basiliximab
antibody induction, MMF and corticosteroids, was compared in 638
de novo
kidney transplant recipients.
The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute
rejection, or lost to follow-up) was 14.0% in the Advagraf group (N=214), 15.1% in the Prograf group
(N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (Advagraf-
ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Advagraf vs. ciclosporin and -1.9% (Prograf-
ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient
survival rates were 98.6% for Advagraf, 95.7% for Prograf and 97.6% for ciclosporin; in the Advagraf
arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the
ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Advagraf,
92.9% for Prograf and 95.7% for ciclosporin.
Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation
In prospective studies oral Prograf 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 Prograf in these published studies appeared to be similar
to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney
and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.
Lung transplantation
The interim analysis of a recent multicentre study using oral Prograf 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) (Keenan et al., Ann Thoracic Surg 1995;60:580).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the
ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day
and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments
to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus
79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6
months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).
The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically
lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of
bronchiolitis obliterans syndrome with tacrolimus.
Pancreas transplantation
A multicentre study using oral Prograf 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
13
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 Prograf 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. Advagraf is a prolonged-release formulation of
tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood
concentration (C
max
) of approximately 2 hours (t
max
).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prograf
formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral
bioavailability of Advagraf was reduced when it was administered after a meal. Both the rate and extent
of absorption of Advagraf were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf may
commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Advagraf.
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 the
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.
14
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is
approximately 43 hours.
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.
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
Capsule content:
Hypromellose
Ethylcellulose
Lactose monohydrate
Magnesium stearate.
Capsule shell:
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Sodium laurilsulfate
Gelatin.
Printing ink
(Opacode S-1-15083):
Shellac
Lecithin (soya)
Simeticone
Red iron oxide (E 172)
Hydroxypropylcellulose.
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used
to prepare a suspension of Advagraf capsule contents must not contain PVC.
6.3 Shelf life
3 years
After opening the aluminium wrapper: 1 year
6.4 Special precautions for storage
15
Store in the original package in order to protect from moisture.
6.5
Nature and contents of container
Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium
pouch with a desiccant containing 10 capsules per blister.
Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1 and 100×1
prolonged-release hard capsule in unit-dose perforated blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/07/387/001
EU/1/07/387/002
EU/1/07/387/009
EU/1/07/387/014
EU/1/07/387/015
EU/1/07/387/016
9.
23/04/2007
{MM/YYYY}
16
1.
Advagraf 1 mg prolonged-release hard capsules
2.
Each prolonged-release hard capsule contains 1 mg tacrolimus (as monohydrate).
Excipients:
Each capsule contains 107.28 mg lactose monohydrate.
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total printing
ink composition).
For a full list of excipients, see section 6.1.
3.
Prolonged-release hard capsule.
Gelatin capsules imprinted in red with “1 mg” on the white capsule cap and “
677” on the orange
capsule body, containing white powder.
4.
Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products
in adult patients.
Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoring by
adequately qualified and equipped personnel. 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.
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of
tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including
under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to
tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding
daily dosing regimen; alterations in formulation or regimen should only take place under the close
supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative
formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that
systemic exposure to tacrolimus is maintained.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Advagraf 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. Advagraf dosing
should primarily be based on clinical assessments of rejection and tolerability in each patient individually
17
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.
In
de novo
kidney and liver transplant patients AUC
0-24
of tacrolimus for Advagraf on Day 1 was 30%
and 50% lower respectively, when compared with that for Prograf at equivalent doses. By Day 4,
systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients
with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in
the first two weeks post-transplant with Advagraf to ensure adequate drug exposure in the immediate
post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Advagraf dose
regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the
duration of oral therapy can be given.
Prophylaxis of kidney transplant rejection
Advagraf therapy should commence at a dose of 0.20 - 0.30 mg/kg/day administered once daily in the
morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant changes in
the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose
adjustments.
Prophylaxis of liver transplant rejection
Advagraf therapy should commence at a dose of 0.10 - 0.20 mg/kg/day administered once daily in the
morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant
improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may
necessitate further dose adjustments.
Conversion of Prograf-treated patients to Advagraf
Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to
once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should be
administered in the morning.
In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1
(mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC
0-24
) for Advagraf was
approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C
24
)
and systemic exposure (AUC
0-24
) for Advagraf is similar to that of Prograf. When converting from
Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks
after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary
dose adjustments made to maintain similar systemic exposure. 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.
Advagraf 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.
Treatment of allograft rejection
18
Increased doses of tacrolimus, 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 Advagraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation
For conversion from other immunosuppressants to once daily Advagraf, treatment should begin with the
initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of
transplant rejection.
Treatment of allograft rejection after heart transplantation
In adult patients converted to Advagraf, an initial oral dose of 0.15 mg/kg/day should be administered
once daily in the morning.
Treatment of allograft rejection after transplantation of other allografts
Although there is no clinical experience with Advagraf in lung-, pancreas- or intestine-transplanted
patients, 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 tacrolimus 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.
Elderly patients:
There is no evidence currently available to indicate that dosing should be adjusted in
elderly patients.
Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual
patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus
concentrations in whole blood. Comparisons of concentrations from the published literature to individual
values in clinical practice should be assessed with care and knowledge of the assay methods employed. In
current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship
between tacrolimus trough levels (C
24
) and systemic exposure (AUC
0-24
) is similar between the two
formulations Advagraf and Prograf.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus
blood trough levels should be determined approximately 24 hours post-dosing of Advagraf, just prior to
the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is
recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of
tacrolimus should also be closely monitored following conversion from Prograf to Advagraf, 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
19
should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments
to the Advagraf dose regimen it may take several days before the targeted steady state is achieved.
Data from clinical studies suggest 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
Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of
Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be
taken immediately following removal from the blister. Patients should be advised not to swallow the
desiccant. The capsules should be swallowed
whole
with fluid (preferably water). Advagraf 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). A forgotten morning dose should be taken as soon as
possible on the same day. A double dose should not be taken on the next morning.
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 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
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 formulation or regimen should only take place under
the close supervision of a transplant specialist (see sections 4.2 and 4.8).
Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or
efficacy.
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products in adult patients clinical data are not yet available for the prolonged-release formulation
Advagraf.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available
for Advagraf.
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.
20
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 rifampin, 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
Advagraf due to the risk of interactions that lead to a decrease in both blood concentrations and the
therapeutic 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 risk 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
in Prograf treated patients on rare occasions and may also occur with Advagraf. 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 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 Advagraf, 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
(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 Advagraf. 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.
21
Patients treated with immunosuppressants, including Advagraf 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 sever liver impairment (see section 4.2)
Advagraf capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who are
hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the
benefit of using Advagraf.
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 substances which have the potential to
alter CYP3A 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. 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, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin.
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
22
Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances
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, 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 antipyrine.
Other interactions leading 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, cotrimoxazole,
NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and
ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing
hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene, or
spironolactone) should be avoided (see section 4.4).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with
tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section 4.4).
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)
23
(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).
Lactation
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn
cannot be excluded, women should not breast-feed whilst receiving Advagraf.
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 Advagraf is
administered in association with alcohol.
No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been
performed.
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.
Cardiac disorders
common:
heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias,
cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy,
palpitations, heart rate and pulse investigations abnormal
rare:
pericardial effusion
very rare:
echocardiogram abnormal
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
Nervous system disorders
very common:
headache, tremor
24
uncommon:
ischaemic coronary artery disorders, tachycardia
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
rare:
blindness
Ear and labyrinth disorders
common:
tinnitus
uncommon:
hypoacusis
very rare:
deafnessneurosensory
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
rare:
acute respiratory distress syndrome
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:
pancreaticpseudocyst, subileus
Renal and urinary disorders
very common:
renal impairment
common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary
abnormalities, oliguria, bladder and urethral symptoms
uncommon:
haemolytic uraemic syndrome, anuria
very rare:
nephropathy, cystitis haemorrhagic
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
Endocrine disorders
rare:
hirsutism
Metabolism and nutrition disorders
25
uncommon:
cataract
rare:
hearing impaired
rare:
dermatitis, photosensitivity
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
Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently
at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections
may be aggravated. Both generalised and localised infections can occur.
Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal
leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including
Advagraf.
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
Injury, poisoning and procedural complications
common: primary graft dysfunction
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or
prolonged-release tacrolimus formulations, have been observed. A number of associated cases of
transplant rejection have been reported (frequency cannot be estimated from available data).
Neoplasms benign, malignant and unspecified
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign
as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin
malignancies have been reported in association with tacrolimus treatment.
Vascular disorders
very common: hypertension
common:
thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage,
peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
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
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section
4.4).
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
very rare:
hepatic failure
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
Psychiatric disorders
26
uncommon:
rare:
venoocclusive liver disease, hepatitic artery thrombosis
very common:
insomnia
common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental
disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
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 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
At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein
(FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-
tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-
dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete
set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both
in vitro
and
in
vivo
experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible
for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell
proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and
the expression of the interleukin-2 receptor.
Results from clinical trials performed with once-daily tacrolimus Advagraf
Liver transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared
in 471
de novo
liver transplant recipients. The event rate of biopsy confirmed acute rejection within the
first 24 weeks after transplantation was 32.6% in the Advagraf group (N=237) and 29.3% in the Prograf
group (N=234). The treatment difference (Advagraf – Prograf) was 3.3% (95% confidence interval [-
5.7%, 12.3%]).The 12-month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in
the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female,
19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.
Kidney transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil
(MMF) and corticosteroids, was compared in 667
de novo
kidney transplant recipients. The event rate for
biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the
Advagraf group (N=331) and 14.9% in the Prograf group (N=336). The treatment difference (Advagraf-
Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were
96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female, 7 male) and
27
in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf
and 92.8% for Prograf.
The efficacy and safety of Prograf, ciclosporin and Advagraf, all in combination with basiliximab
antibody induction, MMF and corticosteroids, was compared in 638
de novo
kidney transplant recipients.
The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute
rejection, or lost to follow-up) was 14.0% in the Advagraf group (N=214), 15.1% in the Prograf group
(N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (Advagraf-
ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Advagraf vs. ciclosporin and -1.9% (Prograf-
ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient
survival rates were 98.6% for Advagraf, 95.7% for Prograf and 97.6% for ciclosporin; in the Advagraf
arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the
ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Advagraf,
92.9% for Prograf and 95.7% for ciclosporin.
Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation
In prospective studies oral Prograf 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 Prograf in these published studies appeared to be similar
to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney
and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.
Lung transplantation
The interim analysis of a recent multicentre study using oral Prograf 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) (Keenan et al., Ann Thoracic Surg 1995;60:580).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the
ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day
and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments
to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus
79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6
months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).
The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically
lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of
bronchiolitis obliterans syndrome with tacrolimus.
Pancreas transplantation
A multicentre study using oral Prograf 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
28
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 Prograf 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. Advagraf is a prolonged-release formulation of
tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood
concentration (C
max
) of approximately 2 hours (t
max
).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prograf
formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral
bioavailability of Advagraf was reduced when it was administered after a meal. Both the rate and extent
of absorption of Advagraf were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf may
commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Advagraf.
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 the
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.
29
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is
approximately 43 hours.
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.
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
Capsule content:
Hypromellose
Ethylcellulose
Lactose monohydrate
Magnesium stearate.
Capsule shell:
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Sodium laurilsulfate
Gelatin.
Printing ink
(Opacode S-1-15083):
Shellac
Lecithin (soya)
Simeticone
Red iron oxide (E 172)
Hydroxypropylcellulose.
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used
to prepare a suspension of Advagraf capsule contents must not contain PVC.
6.3 Shelf life
3 years
After opening the aluminium wrapper: 1 year
6.4 Special precautions for storage
30
Store in the original package in order to protect from moisture.
6.5
Nature and contents of container
Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium
pouch with a desiccant containing 10 capsules per blister.
Pack sizes: 30, 50, 60 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1, 60×1 and 100×1
prolonged-release hard capsule in unit-dose perforated blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/07/387/003
EU/1/07/387/004
EU/1/07/387/005
EU/1/07/387/006
EU/1/07/387/017
EU/1/07/387/018
EU/1/07/387/019
EU/1/07/387/020
9.
23/04/2007
{MM/YYYY}
31
1.
Advagraf 3 mg prolonged-release hard capsules
2.
Each prolonged-release hard capsule contains 3 mg tacrolimus (as monohydrate).
Excipients:
Each capsule contains 321.84 mg lactose monohydrate.
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total printing
ink composition).
For a full list of excipients, see section 6.1.
3.
Prolonged-release hard capsule.
Gelatin capsules imprinted in red with “3 mg” on the orange capsule cap and “
637” on the orange
capsule body, containing white powder.
4.
Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products
in adult patients.
Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoring by
adequately qualified and equipped personnel. 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.
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of
tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including
under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to
tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding
daily dosing regimen; alterations in formulation or regimen should only take place under the close
supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative
formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that
systemic exposure to tacrolimus is maintained.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Advagraf 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. Advagraf dosing
should primarily be based on clinical assessments of rejection and tolerability in each patient individually
32
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.
In
de novo
kidney and liver transplant patients AUC
0-24
of tacrolimus for Advagraf on Day 1 was 30%
and 50% lower respectively, when compared with that for Prograf at equivalent doses. By Day 4,
systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients
with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in
the first two weeks post-transplant with Advagraf to ensure adequate drug exposure in the immediate
post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Advagraf dose
regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the
duration of oral therapy can be given.
Prophylaxis of kidney transplant rejection
Advagraf therapy should commence at a dose of 0.20 - 0.30 mg/kg/day administered once daily in the
morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant changes in
the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose
adjustments.
Prophylaxis of liver transplant rejection
Advagraf therapy should commence at a dose of 0.10 - 0.20 mg/kg/day administered once daily in the
morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant
improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may
necessitate further dose adjustments.
Conversion of Prograf-treated patients to Advagraf
Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to
once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should be
administered in the morning.
In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1
(mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC
0-24
) for Advagraf was
approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C
24
)
and systemic exposure (AUC
0-24
) for Advagraf is similar to that of Prograf. When converting from
Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks
after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary
dose adjustments made to maintain similar systemic exposure. 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.
Advagraf 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.
Treatment of allograft rejection
33
Increased doses of tacrolimus, 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 Advagraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation
For conversion from other immunosuppressants to once daily Advagraf, treatment should begin with the
initial oral dose recommended in kidney and liver transplantation, respectively, for prophylaxis of
transplant rejection.
Treatment of allograft rejection after heart transplantation
In adult patients converted to Advagraf, an initial oral dose of 0.15 mg/kg/day should be administered
once daily in the morning.
Treatment of allograft rejection after transplantation of other allografts
Although there is no clinical experience with Advagraf in lung-, pancreas- or intestine-transplanted
patients, 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 tacrolimus 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.
Elderly patients:
There is no evidence currently available to indicate that dosing should be adjusted in
elderly patients.
Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual
patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus
concentrations in whole blood. Comparisons of concentrations from the published literature to individual
values in clinical practice should be assessed with care and knowledge of the assay methods employed. In
current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship
between tacrolimus trough levels (C
24
) and systemic exposure (AUC
0-24
) is similar between the two
formulations Advagraf and Prograf.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus
blood trough levels should be determined approximately 24 hours post-dosing of Advagraf, just prior to
the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is
recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of
tacrolimus should also be closely monitored following conversion from Prograf to Advagraf, 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
34
should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments
to the Advagraf dose regimen it may take several days before the targeted steady state is achieved.
Data from clinical studies suggest 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
Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of
Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be
taken immediately following removal from the blister. Patients should be advised not to swallow the
desiccant. The capsules should be swallowed
whole
with fluid (preferably water). Advagraf 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). A forgotten morning dose should be taken as soon as
possible on the same day. A double dose should not be taken on the next morning.
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 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
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 formulation or regimen should only take place under
the close supervision of a transplant specialist (see sections 4.2 and 4.8).
Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or
efficacy.
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products in adult patients clinical data are not yet available for the prolonged-release formulation
Advagraf.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available
for Advagraf.
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.
35
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 rifampin, 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
Advagraf due to the risk of interactions that lead to a decrease in both blood concentrations and the
therapeutic 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 risk 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
in Prograf treated patients on rare occasions and may also occur with Advagraf. 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 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 Advagraf, 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
(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 Advagraf. 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.
36
Patients treated with immunosuppressants, including Advagraf 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 sever liver impairment (see section 4.2)
Advagraf capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who are
hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the
benefit of using Advagraf.
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 substances which have the potential to
alter CYP3A 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. 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, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin.
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
37
Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances
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, 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 antipyrine.
Other interactions leading 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, cotrimoxazole,
NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and
ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing
hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene or
spironolactone) should be avoided (see section 4.4).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with
tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section 4.4).
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)
38
(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).
Lactation
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn
cannot be excluded, women should not breast-feed whilst receiving Advagraf.
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 Advagraf is
administered in association with alcohol.
No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been
performed.
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.
Cardiac disorders
common:
ischaemic coronary artery disorders, tachycardia
uncommon:
heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias,
cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy,
palpitations, heart rate and pulse investigations abnormal
rare:
pericardial effusion
very rare:
echocardiogram abnormal
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
Nervous system disorders
very common:
headache, tremor
39
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
rare:
blindness
Ear and labyrinth disorders
common:
tinnitus
uncommon:
hypoacusis
very rare:
deafnessneurosensory
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
rare:
acute respiratory distress syndrome
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:
pancreaticpseudocyst, subileus
Renal and urinary disorders
very common:
renal impairment
common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary
abnormalities, oliguria, bladder and urethral symptoms
uncommon:
haemolytic uraemic syndrome, anuria
very rare:
nephropathy, cystitis haemorrhagic
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
Endocrine disorders
rare:
hirsutism
Metabolism and nutrition disorders
40
uncommon:
cataract
rare:
hearing impaired
rare:
dermatitis, photosensitivity
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
Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently
at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections
may be aggravated. Both generalised and localised infections can occur.
Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal
leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including
Advagraf.
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
Injury, poisoning and procedural complications
common: primary graft dysfunction
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or
prolonged-release tacrolimus formulations, have been observed. A number of associated cases of
transplant rejection have been reported (frequency cannot be estimated from available data).
Neoplasms benign, malignant and unspecified
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign
as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin
malignancies have been reported in association with tacrolimus treatment.
Vascular disorders
very common: hypertension
common:
thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage,
peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
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
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section
4.4).
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
very rare:
hepatic failure
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
Psychiatric disorders
41
uncommon:
rare:
venoocclusive liver disease, hepatitic artery thrombosis
very common:
insomnia
common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental
disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
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 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
At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein
(FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-
tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-
dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete
set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both
in vitro
and
in
vivo
experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible
for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell
proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and
the expression of the interleukin-2 receptor.
Results from clinical trials performed with once-daily tacrolimus Advagraf
Liver transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared
in 471
de novo
liver transplant recipients. The event rate of biopsy confirmed acute rejection within the
first 24 weeks after transplantation was 32.6% in the Advagraf group (N=237) and 29.3% in the Prograf
group (N=234). The treatment difference (Advagraf – Prograf) was 3.3% (95% confidence interval [-
5.7%, 12.3%]).The 12-month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in
the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female,
19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.
Kidney transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil
(MMF) and corticosteroids, was compared in 667
de novo
kidney transplant recipients. The event rate for
biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the
Advagraf group (N=331) and 14.9% in the Prograf group (N=336). The treatment difference (Advagraf-
Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were
96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female, 7 male) and
42
in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf
and 92.8% for Prograf.
The efficacy and safety of Prograf, ciclosporin and Advagraf, all in combination with basiliximab
antibody induction, MMF and corticosteroids, was compared in 638
de novo
kidney transplant recipients.
The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute
rejection, or lost to follow-up) was 14.0% in the Advagraf group (N=214), 15.1% in the Prograf group
(N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (Advagraf-
ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Advagraf vs. ciclosporin and -1.9% (Prograf-
ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient
survival rates were 98.6% for Advagraf, 95.7% for Prograf and 97.6% for ciclosporin; in the Advagraf
arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the
ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Advagraf,
92.9% for Prograf and 95.7% for ciclosporin.
Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation
In prospective studies oral Prograf 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 Prograf in these published studies appeared to be similar
to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney
and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.
Lung transplantation
The interim analysis of a recent multicentre study using oral Prograf 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) (Keenan et al., Ann Thoracic Surg 1995;60:580).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the
ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day
and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments
to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus
79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6
months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).
The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically
lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of
bronchiolitis obliterans syndrome with tacrolimus.
Pancreas transplantation
A multicentre study using oral Prograf 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
43
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 Prograf 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. Advagraf is a prolonged-release formulation of
tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood
concentration (C
max
) of approximately 2 hours (t
max
).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prograf
formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral
bioavailability of Advagraf was reduced when it was administered after a meal. Both the rate and extent
of absorption of Advagraf were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf may
commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Advagraf.
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 the
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.
44
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is
approximately 43 hours.
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.
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
Capsule content:
Hypromellose
Ethylcellulose
Lactose monohydrate
Magnesium stearate.
Capsule shell:
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Sodium laurilsulfate
Gelatin.
Printing ink
(Opacode S-1-15083):
Shellac
Lecithin (soya)
Simeticone
Red iron oxide (E 172)
Hydroxypropylcellulose.
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used
to prepare a suspension of Advagraf capsule contents must not contain PVC.
6.3 Shelf life
3 years
After opening the aluminium wrapper: 1 year
6.4 Special precautions for storage
45
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium
pouch with a desiccant containing 10 capsules per blister.
Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1 and 100×1
prolonged-release hard capsules in unit-dose perforated blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/07/387/011
EU/1/07/387/012
EU/1/07/387/013
EU/1/07/387/021
EU/1/07/387/022
EU/1/07/387/023
9.
46
1.
Advagraf 5 mg prolonged-release hard capsules
2.
Each prolonged-release hard capsule contains 5 mg tacrolimus (as monohydrate).
Excipients:
Each capsule contains 536.4 mg lactose monohydrate.
The printing ink used to mark the capsule contains trace amounts of soya lecithin (0.48% of total printing
ink composition).
For a full list of excipients, see section 6.1.
3.
Prolonged-release hard capsule.
Gelatin capsules imprinted in red with “5 mg” on the greyish red capsule cap and ”
687” on the orange
capsule body, containing white powder.
4.
Prophylaxis of transplant rejection in adult kidney or liver allograft recipients.
Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products
in adult patients.
Advagraf is a once-a-day oral formulation of tacrolimus. Advagraf therapy requires careful monitoring by
adequately qualified and equipped personnel. 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.
Inadvertent, unintentional or unsupervised switching of immediate- or prolonged-release formulations of
tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including
under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to
tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding
daily dosing regimen; alterations in formulation or regimen should only take place under the close
supervision of a transplant specialist (see sections 4.4 and 4.8). Following conversion to any alternative
formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that
systemic exposure to tacrolimus is maintained.
Posology
The recommended initial doses presented below are intended to act solely as a guideline. Advagraf 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. Advagraf dosing
should primarily be based on clinical assessments of rejection and tolerability in each patient individually
47
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.
In
de novo
kidney and liver transplant patients AUC
0-24
of tacrolimus for Advagraf on Day 1 was 30%
and 50% lower respectively, when compared with that for Prograf at equivalent doses. By Day 4,
systemic exposure as measured by trough levels is similar for both kidney and liver transplant patients
with both formulations. Careful and frequent monitoring of tacrolimus trough levels is recommended in
the first two weeks post-transplant with Advagraf to ensure adequate drug exposure in the immediate
post-transplant period. As tacrolimus is a substance with low clearance, adjustments to the Advagraf dose
regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the
duration of oral therapy can be given.
Prophylaxis of kidney transplant rejection
Advagraf therapy should commence at a dose of 0.20 - 0.30 mg/kg/day administered once daily in the
morning. Administration should commence within 24 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant changes in
the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose
adjustments.
Prophylaxis of liver transplant rejection
Advagraf therapy should commence at a dose of 0.10 - 0.20 mg/kg/day administered once daily in the
morning. Administration should commence approximately 12-18 hours after the completion of surgery.
Advagraf doses are usually reduced in the post-transplant period. It is possible in some cases to withdraw
concomitant immunosuppressive therapy, leading to Advagraf monotherapy. Post-transplant
improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may
necessitate further dose adjustments.
Conversion of Prograf-treated patients to Advagraf
Allograft transplant patients maintained on twice daily Prograf capsules dosing requiring conversion to
once daily Advagraf should be converted on a 1:1 (mg:mg) total daily dose basis. Advagraf should be
administered in the morning.
In stable patients converted from Prograf capsules (twice daily) to Advagraf (once daily) on a 1:1
(mg:mg) total daily dose basis, the systemic exposure to tacrolimus (AUC
0-24
) for Advagraf was
approximately 10% lower than that for Prograf. The relationship between tacrolimus trough levels (C
24
)
and systemic exposure (AUC
0-24
) for Advagraf is similar to that of Prograf. When converting from
Prograf capsules to Advagraf, trough levels should be measured prior to conversion and within two weeks
after conversion. Following conversion, tacrolimus trough levels should be monitored and if necessary
dose adjustments made to maintain similar systemic exposure. 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.
Advagraf 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.
Treatment of allograft rejection
48
Increased doses of tacrolimus, 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 Advagraf may need to be reduced.
Treatment of allograft rejection after kidney or liver transplantation
For conversion from other immunosuppressants to once daily Advagraf, treatment should begin with the
initial oral dose recommended in kidney and liver transplantation, respectively, for prophylaxis of
transplant rejection.
Treatment of allograft rejection after heart transplantation
In adult patients converted to Advagraf, an initial oral dose of 0.15 mg/kg/day should be administered
once daily in the morning.
Treatment of allograft rejection after transplantation of other allografts
Although there is no clinical experience with Advagraf in lung-, pancreas- or intestine-transplanted
patients, 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 tacrolimus 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.
Elderly patients:
There is no evidence currently available to indicate that dosing should be adjusted in
elderly patients.
Therapeutic drug monitoring
Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual
patient aided by whole blood tacrolimus trough level monitoring.
As an aid to optimise dosing, several immunoassays are available for determining tacrolimus
concentrations in whole blood. Comparisons of concentrations from the published literature to individual
values in clinical practice should be assessed with care and knowledge of the assay methods employed. In
current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship
between tacrolimus trough levels (C
24
) and systemic exposure (AUC
0-24
) is similar between the two
formulations Advagraf and Prograf.
Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus
blood trough levels should be determined approximately 24 hours post-dosing of Advagraf, just prior to
the next dose. Frequent trough level monitoring in the initial two weeks post transplantation is
recommended, followed by periodic monitoring during maintenance therapy. Blood trough levels of
tacrolimus should also be closely monitored following conversion from Prograf to Advagraf, 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
49
should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments
to the Advagraf dose regimen it may take several days before the targeted steady state is achieved.
Data from clinical studies suggest 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
Advagraf is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of
Advagraf be administered once daily in the morning. Advagraf prolonged-release hard capsules should be
taken immediately following removal from the blister. Patients should be advised not to swallow the
desiccant. The capsules should be swallowed
whole
with fluid (preferably water). Advagraf 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). A forgotten morning dose should be taken as soon as
possible on the same day. A double dose should not be taken on the next morning.
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 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
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 formulation or regimen should only take place under
the close supervision of a transplant specialist (see sections 4.2 and 4.8).
Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or
efficacy.
For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal
products in adult patients clinical data are not yet available for the prolonged-release formulation
Advagraf.
For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available
for Advagraf.
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.
50
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 rifampin, 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
Advagraf due to the risk of interactions that lead to a decrease in both blood concentrations and the
therapeutic 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 risk 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
in Prograf treated patients on rare occasions and may also occur with Advagraf. 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 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 Advagraf, 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
(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 Advagraf. 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.
51
Patients treated with immunosuppressants, including Advagraf 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 sever liver impairment (see section 4.2)
Advagraf capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who are
hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the
benefit of using Advagraf.
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 substances which have the potential to
alter CYP3A 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. 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, norethindrone, quinidine, tamoxifen, (triacetyl)oleandomycin.
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
52
Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances
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, 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 antipyrine.
Other interactions leading 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, cotrimoxazole,
NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and
ibuprofen in conjunction with tacrolimus.
As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing
hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g., amiloride, triamterene, or
spironolactone) should be avoided (see section 4.4).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with
tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section 4.4).
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)
53
(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).
Lactation
Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn
cannot be excluded, women should not breast-feed whilst receiving Advagraf.
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 Advagraf is
administered in association with alcohol.
No studies on the effects of tacrolimus (Advagraf) on the ability to drive and use machines have been
performed.
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.
Cardiac disorders
common:
ischaemic coronary artery disorders, tachycardia
uncommon:
heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias,
cardiomyopathies, ECG investigations abnormal, ventricular hypertrophy,
palpitations, heart rate and pulse investigations abnormal
rare:
pericardial effusion
very rare:
echocardiogram abnormal
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
Nervous system disorders
very common:
headache, tremor
54
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
rare:
blindness
Ear and labyrinth disorders
common:
tinnitus
uncommon:
hypoacusis
very rare:
deafnessneurosensory
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
rare:
acute respiratory distress syndrome
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:
pancreaticpseudocyst, subileus
Renal and urinary disorders
very common:
renal impairment
common:
renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary
abnormalities, oliguria, bladder and urethral symptoms
uncommon:
haemolytic uraemic syndrome, anuria
very rare:
nephropathy, cystitis haemorrhagic
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
Endocrine disorders
rare:
hirsutism
Metabolism and nutrition disorders
55
uncommon:
cataract
rare:
hearing impaired
rare:
dermatitis, photosensitivity
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
Infections and infestations
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently
at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections
may be aggravated. Both generalised and localised infections can occur.
Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal
leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including
Advagraf.
dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia
Injury, poisoning and procedural complications
common: primary graft dysfunction
Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or
prolonged-release tacrolimus formulations, have been observed. A number of associated cases of
transplant rejection have been reported (frequency cannot be estimated from available data).
Neoplasms benign, malignant and unspecified
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign
as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin
malignancies have been reported in association with tacrolimus treatment.
Vascular disorders
very common: hypertension
common:
thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage,
peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
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
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section
4.4).
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
very rare:
hepatic failure
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
Psychiatric disorders
56
uncommon:
rare:
venoocclusive liver disease, hepatitic artery thrombosis
very common:
insomnia
common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental
disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
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 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
At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein
(FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-
tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-
dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete
set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both
in vitro
and
in
vivo
experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible
for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell
proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and
the expression of the interleukin-2 receptor.
Results from clinical trials performed with once-daily tacrolimus Advagraf
Liver transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with corticosteroids, was compared
in 471
de novo
liver transplant recipients. The event rate of biopsy confirmed acute rejection within the
first 24 weeks after transplantation was 32.6% in the Advagraf group (N=237) and 29.3% in the Prograf
group (N=234). The treatment difference (Advagraf – Prograf) was 3.3% (95% confidence interval [-
5.7%, 12.3%]).The 12-month patient survival rates were 89.2% for Advagraf and 90.8% for Prograf; in
the Advagraf arm 25 patients died (14 female, 11 male) and in the Prograf arm 24 patients died (5 female,
19 male). 12-month graft survival was 85.3% for Advagraf and 85.6% for Prograf.
Kidney transplantation
The efficacy and safety of Advagraf and Prograf, both in combination with mycophenolate mofetil
(MMF) and corticosteroids, was compared in 667
de novo
kidney transplant recipients. The event rate for
biopsy-confirmed acute rejection within the first 24 weeks after transplantation was 18.6% in the
Advagraf group (N=331) and 14.9% in the Prograf group (N=336). The treatment difference (Advagraf-
Prograf) was 3.8% (95% confidence interval [-2.1%, 9.6%]). The 12-month patient survival rates were
96.9% for Advagraf and 97.5% for Prograf; in the Advagraf arm 10 patients died (3 female, 7 male) and
57
in the Prograf arm 8 patients died (3 female, 5 male). 12-month graft survival was 91.5% for Advagraf
and 92.8% for Prograf.
The efficacy and safety of Prograf, ciclosporin and Advagraf, all in combination with basiliximab
antibody induction, MMF and corticosteroids, was compared in 638
de novo
kidney transplant recipients.
The incidence of efficacy failure at 12 months (defined as death, graft loss, biopsy-confirmed acute
rejection, or lost to follow-up) was 14.0% in the Advagraf group (N=214), 15.1% in the Prograf group
(N=212) and 17.0% in the ciclosporin group (N=212). The treatment difference was -3.0% (Advagraf-
ciclosporin) (95.2% confidence interval [-9.9%, 4.0%]) for Advagraf vs. ciclosporin and -1.9% (Prograf-
ciclosporin) (95.2% confidence interval [-8.9%, 5.2%]) for Prograf vs. ciclosporin. The 12-month patient
survival rates were 98.6% for Advagraf, 95.7% for Prograf and 97.6% for ciclosporin; in the Advagraf
arm 3 patients died (all male), in the Prograf arm 10 patients died (3 female, 7 male) and in the
ciclosporin arm 6 patients died (3 female, 3 male). 12-month graft survival was 96.7% for Advagraf,
92.9% for Prograf and 95.7% for ciclosporin.
Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation
In prospective studies oral Prograf 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 Prograf in these published studies appeared to be similar
to what was reported in the large studies, where Prograf was used as primary treatment in liver, kidney
and heart transplantation. Efficacy results of the largest studies in each indication are summarised below.
Lung transplantation
The interim analysis of a recent multicentre study using oral Prograf 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) (Keenan et al., Ann Thoracic Surg 1995;60:580).
In an additional two-centre study, 26 patients were randomised to the tacrolimus versus 24 patients to the
ciclosporin group. Tacrolimus was started as continuous intravenous infusion at a dose of 0.05 mg/kg/day
and oral tacrolimus was administered at a dose of 0.1 to 0.3 mg/kg/day with subsequent dose adjustments
to target trough levels of 12 to 15 ng/ml. The 1-year survival rates were 73.1% in the tacrolimus versus
79.2% in the ciclosporin group. Freedom from acute rejection was higher in the tacrolimus group at 6
months (57.7% versus 45.8%) and at 1 year after lung transplantation (50% versus 33.3%).
The three studies demonstrated similar survival rates. The incidences of acute rejection were numerically
lower with tacrolimus in all three studies and one of the studies reported a significantly lower incidence of
bronchiolitis obliterans syndrome with tacrolimus.
Pancreas transplantation
A multicentre study using oral Prograf 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
58
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 Prograf 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. Advagraf is a prolonged-release formulation of
tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood
concentration (C
max
) of approximately 2 hours (t
max
).
Absorption is variable and the mean oral bioavailability of tacrolimus (investigated with the Prograf
formulation) is in the range of 20% - 25% (individual range in adult patients 6% - 43%). The oral
bioavailability of Advagraf was reduced when it was administered after a meal. Both the rate and extent
of absorption of Advagraf were reduced when administered with food.
Bile flow does not influence the absorption of tacrolimus and therefore treatment with Advagraf may
commence orally.
A strong correlation exists between AUC and whole blood trough levels at steady-state for Advagraf.
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 the
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.
59
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is
approximately 43 hours.
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.
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
Capsule content:
Hypromellose
Ethylcellulose
Lactose monohydrate
Magnesium stearate.
Capsule shell:
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Sodium laurilsulfate
Gelatin.
Printing ink
(Opacode S-1-15083):
Shellac
Lecithin (soya)
Simeticone
Red iron oxide (E 172)
Hydroxypropylcellulose.
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used
to prepare a suspension of Advagraf capsule contents must not contain PVC.
6.3 Shelf life
3 years
After opening the aluminium wrapper: 1 year
6.4 Special precautions for storage
60
Store in the original package in order to protect from moisture.
6.5
Nature and contents of container
Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium
pouch with a desiccant containing 10 capsules per blister.
Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30×1, 50×1 and 100×1
prolonged-release hard capsules in unit-dose perforated blisters.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
8.
EU/1/07/387/007
EU/1/07/387/008
EU/1/07/387/010
EU/1/07/387/024
EU/1/07/387/025
EU/1/07/387/026
9.
23/04/2007
{MM/YYYY}
61
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
62
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, section 4.2).
•
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
63
ANNEX III
LABELLING AND PACKAGE LEAFLET
64
A. LABELLING
65
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON Advagraf 0.5
mg prolonged-release hard capsules
1.
Advagraf 0.5 mg prolonged-release hard capsules
Tacrolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 0.5 mg tacrolimus (as monohydrate).
3.
LIST OF EXCIPIENTS
Also contains lactose and traces of soya lecithin. See package leaflet for further information.
4.
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
100 prolonged-release hard capsules
100×1 prolonged-release hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Once daily.
Read the package leaflet before use.
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
Do not swallow the desiccant.
8.
EXPIRY DATE
EXP
66
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/07/387/001 30 capsules
EU/1/07/387/002 50 capsules
EU/1/07/387/009 100 capsules
EU/1/07/387/014 30×1 capsules
EU/1/07/387/015 50×1 capsules
EU/1/07/387/016 100×1 capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Advagraf 0.5 mg
67
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER Advagraf 0.5
mg prolonged-release hard capsules
1.
Advagraf 0.5 mg prolonged-release hard capsules
Tacrolimus
2.
Astellas Pharma Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
Once daily.
68
MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS
ALUMINIUM WRAPPER Advagraf 0.5
mg prolonged-release hard capsules (30, 50 Aluminium
Wrapper)
1.
Advagraf 0.5 mg prolonged-release hard capsules
Tacrolimus
Oral use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
6.
OTHER
Once daily.
69
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON Advagraf 1
mg prolonged-release hard capsules
1.
Advagraf 1 mg prolonged-release hard capsules
Tacrolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 1 mg tacrolimus (as monohydrate).
3.
LIST OF EXCIPIENTS
Also contains lactose and traces of soya lecithin. See package leaflet for further information.
4.
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
60 prolonged-release hard capsules
60×1 prolonged-release hard capsules
100 prolonged-release hard capsules
100×1 prolonged-release hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Once daily.
Read the package leaflet before use.
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
Do not swallow the desiccant.
8.
EXPIRY DATE
70
EXP
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/07/387/003 30 capsules
EU/1/07/387/004 50 capsules
EU/1/07/387/005 60 capsules
EU/1/07/387/006 100 capsules
EU/1/07/387/017 30×1 capsules
EU/1/07/387/018 50×1 capsules
EU/1/07/387/019 60×1 capsules
EU/1/07/387/020 100×1 capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Advagraf 1 mg
71
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER Advagraf 1
mg prolonged-release hard capsules
1.
Advagraf 1 mg prolonged-release hard capsules
Tacrolimus
2.
Astellas Pharma Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
Once daily.
72
MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS
ALUMINIUM WRAPPER Advagraf 1
mg prolonged-release hard capsules (30, 50, 60, 100
Aluminium Wrapper)
1.
Advagraf 1 mg prolonged-release hard capsules
Tacrolimus
Oral use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
60 prolonged-release hard capsules
60×1 prolonged-release hard capsules
100 prolonged-release hard capsules
100×1 prolonged-release hard capsules
6.
OTHER
Once daily.
73
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON Advagraf 3 mg prolonged-release hard capsules
1.
Advagraf 3 mg prolonged-release hard capsules
Tacrolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 3 mg tacrolimus (as monohydrate).
3.
LIST OF EXCIPIENTS
Also contains lactose and traces of soya lecithin. See package leaflet for further information.
4.
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
100 prolonged-release hard capsules
100×1 prolonged-release hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Once daily.
Read the package leaflet before use.
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
Do not swallow the desiccant.
8.
EXPIRY DATE
EXP
74
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/07/387/011 30 capsules
EU/1/07/387/012 50 capsules
EU/1/07/387/013 100 capsules
EU/1/07/387/021 30×1 capsules
EU/1/07/387/022 50×1 capsules
EU/1/07/387/023 100×1 capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Advagraf 3 mg
75
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER Advagraf 3 mg prolonged-release hard capsules
1.
Advagraf 3 mg prolonged-release hard capsules
Tacrolimus
2.
Astellas Pharma Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
Once daily.
76
MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS
ALUMINIUM WRAPPER Advagraf 3 mg prolonged-release hard capsules (30, 50, 100 Aluminium
Wrapper)
1.
Advagraf 3 mg prolonged-release hard capsules
Tacrolimus
Oral use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
100 prolonged-release hard capsules
100×1 prolonged-release hard capsules
6.
OTHER
Once daily.
77
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON Advagraf 5
mg prolonged-release hard capsules
1.
Advagraf 5 mg prolonged-release hard capsules
Tacrolimus
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 5 mg tacrolimus (as monohydrate).
3.
LIST OF EXCIPIENTS
Also contains lactose and traces of soya lecithin. See package leaflet for further information.
4.
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
100 prolonged-release hard capsules
100×1 prolonged-release hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Once daily.
Read the package leaflet before use.
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
Do not swallow the desiccant.
8.
EXPIRY DATE
EXP
78
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands
EU/1/07/387/007 30 capsules
EU/1/07/387/008 50 capsules
EU/1/07/387/010 100 capsules
EU/1/07/387/024 30×1 capsules
EU/1/07/387/025 50×1 capsules
EU/1/07/387/026 100×1 capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Advagraf 5 mg
79
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER Advagraf 5
mg prolonged-release hard capsules
1.
Advagraf 5 mg prolonged-release hard capsules
Tacrolimus
2.
Astellas Pharma Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
Once daily.
80
MINIMUM PARTICULARS TO APPEAR ON BLISTER WRAPPERS
ALUMINIUM WRAPPER Advagraf 5
mg prolonged-release hard capsules (30, 50 Aluminium
Wrapper)
1.
Advagraf 5 mg prolonged-release hard capsules
Tacrolimus
Oral use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
Use all the capsules within 1 year of opening the aluminium wrapping and before the expiry date.
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 prolonged-release hard capsules
30×1 prolonged-release hard capsules
50 prolonged-release hard capsules
50×1 prolonged-release hard capsules
6.
OTHER
Once daily.
81
B. PACKAGE LEAFLET
82
PACKAGE LEAFLET: INFORMATION FOR THE USER
Advagraf 0.5
mg prolonged-release hard capsules
Advagraf 1 mg prolonged-release hard capsules
Advagraf 3 mg prolonged-release hard capsules
Advagraf 5 mg prolonged-release hard capsules
Tacrolimus
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. 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 Advagraf is and what it is used for
3.
How to take Advagraf
4.
Possible side effects
5.
How to store Advagraf
6.
Further information
1.
WHAT ADVAGRAF IS AND WHAT IT IS USED FOR
Advagraf is an immunosuppressant. Following your organ transplant (liver, kidney), your body’s immune
system will try to reject the new organ. Advagraf is used to control your body’s immune response,
enabling your body to accept the transplanted organ.
You may also be given Advagraf for an ongoing rejection of your transplanted liver, kidney, heart or
other organ when any previous treatment you were taking was unable to control this immune response
after your transplantation.
Prograf and Advagraf contain both the active substance, tacrolimus. However, Advagraf is taken once
daily, whereas Prograf is taken twice daily. This is because Advagraf capsules allow for a prolonged
release of tacrolimus.
2.
BEFORE YOU TAKE ADVAGRAF
Do not take Advagraf
-
if you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Advagraf (see
section 6).
-
if you are allergic to sirolimus or to any macrolide-antibiotic (e.g. erythromycin, clarithromycin,
josamycin).
Take special care with Advagraf
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 Advagraf.
83
-
Keep this leaflet. You may need to read it again.
2.
Before you take Advagraf
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 Advagraf.
The use of Advagraf is not recommended in children and adolescents under 18 years.
You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Advagraf. 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 Advagraf is taken with ciclosporin.
Advagraf blood levels can be affected by other medicines you take, and blood levels of other medicines
can be affected by taking Advagraf, which may require an increase or decrease in Advagraf 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
-
HIV protease inhibitors (e.g ritonavir), used to treat HIV infection
-
medicines for stomach ulcer and acid reflux (e.g. omeprazol, lansoprazol or cimetidine)
-
cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn
-
the contraceptive pill or other hormone treatments with ethinylestradiol, 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 Advagraf.
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 Advagraf.
If you need to have any vaccinations, please tell your doctor before.
Taking Advagraf with food and drink
Take Advagraf 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 Advagraf, 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 Advagraf.
Advagraf passes into breast milk. Therefore, you should not breast-feed whilst using Advagraf.
84
-
antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
-
phenytoin or phenobarbital, used to treat epilepsy
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 Advagraf. These effects are more frequent if you also drink alcohol.
Important information about some of the ingredients of Advagraf
Advagraf 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.
The printing ink used on Advagraf capsules contains soya lecithin. If you are allergic to peanut or soya,
talk to your doctor to determine whether you should use this medicine.
3.
HOW TO TAKE ADVAGRAF
Always take Advagraf 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 once 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 daily doses just after transplantation will generally be in
the range of
0.10 – 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 Advagraf, frequent blood tests will be taken by your
doctor to define the correct dose. Afterwards regular blood tests by your doctor will be required to define
the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your Advagraf
dose once your condition has stabilised. Your doctor will tell you exactly how many capsules to take.
You will need to take Advagraf every day as long as you need immunosuppression to prevent rejection of
your transplanted organ. You should keep in regular contact with your doctor.
Advagraf is taken orally once daily in the morning. Take the capsules immediately following removal
from the blister. The capsules should be swallowed
whole
with a glass of water. Do not swallow the
desiccant contained in the foil wrapper.
If you take more Advagraf than you should
If you have accidentally taken too much Advagraf, contact your doctor or nearest hospital emergency
department immediately.
If you forget to take Advagraf
If you have forgotten to take your Advagraf capsules in the morning, take them as soon as possible on the
same day. Do not take a double dose the next morning.
If you stop taking Advagraf
85
Stopping your treatment with Advagraf 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, Advagraf can cause side effects, although not everybody gets them.
Advagraf 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 Advagraf.
Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant tumours
have been reported following Advagraf treatment.
Possible side effects are listed according to the following categories:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 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 pharynx, 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
-
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
86
-
Trembling, headache
-
Ringing sound in your ears
-
Pain in joints, limbs or back, muscle cramps
-
General weakness, fever, collection of fluid in your body, pain and discomfort, increase of the
enzyme alkaline phosphatase in your blood, weight gain, feeling 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
-
Joint disorders
-
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
-
Increased muscle stiffness
-
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:
-
Muscular weakness
-
Abnormal heart scan
-
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 ADVAGRAF
Keep out of the reach and sight of children.
Do not use Advagraf after the expiry date which is stated on the carton after “Exp”. The expiry date refers
to the last day of that month. Use all the prolonged-release hard capsules within 1 year of opening the
aluminium wrapping.
87
-
Insufficient function of the kidneys, reduced production of urine, impaired or painful urination
-
Dehydration, inability to urinate
-
Painful menstruation and abnormal menstrual bleeding
-
Blindness, deafness
-
Liver failure
Store in the original package in order to protect from moisture.
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 Advagraf contains
-
The active substance is tacrolimus.
Each capsule of Advagraf 0.5 mg contains 0.5 mg of tacrolimus.
Each capsule of Advagraf 1 mg contains 1 mg of tacrolimus.
Each capsule of Advagraf 3 mg contains 3 mg of tacrolimus.
Each capsule of Advagraf 5 mg contains 5 mg of tacrolimus.
-
The other ingredients are:
Capsule content
: Hypromellose, ethylcellulose, lactose, magnesium stearate.
Capsule shell
: Titanium dioxide (E171), yellow iron oxide (E 172), red iron oxide (E 172), sodium
laurilsulfate, gelatin.
Printing ink
: Shellac, lecithin (soya), simeticone, red iron oxide (E 172), hydroxypropylcellulose.
What Advagraf looks like and contents of the pack
Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with
“0.5 mg” on the light yellow capsule cap and “
647” on the orange capsule body, containing white
powder.
Advagraf 0.5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a
protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are
available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in
perforated unit-dose blisters.
Advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “1 mg” on
the white capsule cap and “
677” on the orange capsule body, containing white powder.
Advagraf 1 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a
protective foil wrapper, including a desiccant. Packs of 30, 50, 60 and 100 prolonged-release capsules are
available in blisters and packs of 30×1, 50×1, 60×1 and 100×1 prolonged-release capsules are available in
perforated unit-dose blisters.
Advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “3 mg” on
the orange capsule cap and “
637” on the orange capsule body, containing white powder.
Advagraf 3 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a
protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are
available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in
perforated unit-dose blisters.
Advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with “5 mg” on
the greyish red capsule cap and “
687” on the orange capsule body, containing white powder.
Advagraf 5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a
protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules
are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in
perforated unit-dose blisters.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
88
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
Česká republika
Astellas Pharma s.r.o.
Sokolovská 100/94
CZ – 18600 Praha 8
Tel: +420 236 080300
Malta
E.J. Busuttil Ltd
Niche, 1,
Triq ix-Xorrox
B’Kara BKR 1633
Tel: +356 2144 7184
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
PharmaSwiss Eesti OÜ
Tammsaare tee 47
11316 Tallinn
Tel. +372 682 7403
Fax +372 682 7401
Österreich
Astellas Pharma Ges.m.b.H.
Linzer Straße 221/E02
A-1140 Wien
Tel: + 43 (0)1 8772668
89
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
Tel: +40 (0)21 361 0495
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
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
SIA PharmaSwiss Latvia
Ģertrūdes iela 54 – 5
Rīga, LV 1011
Tel: + 371 67502 185
Fakss: + 371 67502 190
United Kingdom
Astellas Pharma Ltd.
Lovett House
Lovett Road, Staines
Middlesex TW18 3AZ – UK
Tel: + 44 (0) 1784 419615
90
Lietuva
UAB „PharmaSwiss“
Šeimyniškių g. 21b
LT-09200, Vilnius
Tel.: +370 5 279 0762
Faks.: +370 5 279 0702
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/.
91
Source: European Medicines Agency
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