ENVARSUS 0.75 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

Envarsus 0.75 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 0.75 mg tacrolimus (as monohydrate).

Excipient with known effect:

Each tablet contains 41.7 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

Oval, white to off-white uncoated tablet, debossed with “0.75” on one side and “TCS” on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

4.2 Posology and method of administration

Envarsus is a once-a-day oral formulation of tacrolimus. Tacrolimus therapy requires careful monitoring by adequately qualified and equipped personnel. This medicinal product should only be prescribed, and changes in immunosuppressive therapy be 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 adverse reactions, 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. Tacrolimus 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.

Envarsus dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring (see below under “Therapeutic drug monitoring”). If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered.

As tacrolimus is a substance with low clearance, adjustments to the 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.

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

Missed dose

A forgotten dose should be taken as soon as possible on the same day. A double dose should not be taken on the next day.

Prophylaxis of kidney transplant rejection

Envarsus therapy should commence at a dose of 0.17 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.

Prophylaxis of liver transplant rejection

Envarsus therapy should commence at a dose of 0.11–0.13 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.

Conversion of Prograf- or Advagraf-treated, patients to Envarsus – allograft transplant patients

Envarsus is not interchangeable with other existing tacrolimus containing medicinal products (immediate-release or prolonged-release) on an equal dose by dose basis.

Allograft transplant patients maintained on twice daily Prograf (immediate-release) or Advagraf (once daily) dosing requiring conversion to once daily Envarsus should be converted on a 1:0.7 (mg:mg) total daily dose basis and the Envarsus maintenance dose should, therefore, be 30% less than the Prograf or Advagraf dose.

In stable patients converted from tacrolimus immediate-release products (twice daily) to Envarsus (once daily) on a 1:0.7 (mg:mg) total daily dose basis, the mean systemic exposure to tacrolimus (AUC0–24) was similar to that of immediate-release tacrolimus. The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0–24) for Envarsus is similar to that of immediate-release tacrolimus. No studies have been conducted with conversion of patients from Advagraf to Envarsus; however, data from healthy volunteers would suggest that the same conversion rate is applicable as with the conversion from Prograf to Envarsus.

When converting from tacrolimus immediate-release products (e.g. Prograf capsules) or from Advagraf prolonged-release capsules to Envarsus, trough levels should be measured prior to conversion and within two weeks after conversion. Dose adjustments should be made to ensure that similar systemic exposure is maintained after the switch. It should be noted that black patients may require a higher dose to achieve the targeted trough levels.

Conversion  from ciclosporin to tacrolimus

Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy (see sections 4.4 and 4.5). The combined administration of ciclosporin and tacrolimus is not recommended. Tacrolimus therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 to 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

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 Envarsus may need to be reduced.

Treatment of allograft rejection after kidney or liver transplantation

For conversion from other immunosuppressants to once daily tacrolimus, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection.

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 and systemic exposure (AUC0–24) is well correlated and is similar between the immediate-release formulation and Envarsus.

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 Envarsus, just prior to the next dose. Blood trough levels of tacrolimus should also be closely monitored following conversion from tacrolimus products, dose adjustments, changes in the immunosuppressive regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations (see section 4.5). The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Envarsus 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 of 5–20 ng/mL in kidney transplant patients in the early post-transplant period, and 5–15 ng/mL during subsequent maintenance therapy.

Special populations

Elderly , patients (> 65 years)

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

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. In clinical studies patients converted from twice daily Prograf were converted to Envarsus at 1:0.85 (mg:mg).

Gender

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

Paediatric population

The safety and efficacy of Envarsus in children below 18 years of age have not yet been established.

No data are available.

Method of administration

Envarsus is a once-a-day oral formulation of tacrolimus. It is recommended that the oral daily dose of Envarsus is administered once daily in the morning. The tablets should be swallowed whole with fluid (preferably water) immediately following removal from the blister. Envarsus should generally be taken on an empty stomach to achieve maximal absorption (see section 5.2). Patients should be advised not to swallow the desiccant.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to other macrolides.

4.4 Special warnings and precautions for use

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

For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients clinical studies are not yet available for the prolonged-release formulation Envarsus.

For prophylaxis of transplant rejection in adult heart, lung, pancreas, or intestine allograft recipients clinical data are not yet available for Envarsus.

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

When substances with a potential for interaction (see section 4.5), particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or inducers of CYP3A4 (such as rifampicin or 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 tacrolimus 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 substances 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.

Nephrotoxicity

Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairment without active intervention may progress to chronic renal impairment. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced. The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with drugs associated with nephrotoxicity (see section 4.5). Concurrent use of tacrolimus with drugs known to have nephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus trough blood level and renal function should be monitored closely and dosage reduction should be considered if nephrotoxicity occurs.

Gastrointestinal disorders

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

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

Eye disorders

Eye disorders, sometimes progressing to loss of vision, have been reported in patients treated with tacrolimus. Some cases have reported resolution on switching to alternative immunosuppression. Patients should be advised to report changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, and in such cases, prompt evaluation is recommended with referral to an ophthalmologist as appropriate.

Cardiac disorders

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed in tacrolimus treated patients on rare occasions. Most cases have been reversible, occurring with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload and oedema. Accordingly, high-risk patients 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 tacrolimus 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 Epstein-Barr Virus (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 Envarsus. During treatment, careful monitoring with EBV-PCR (Polymerase-Chain-Reaction) 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.

Infection including opportunistic infections

Patients treated with immunosuppressants, including Envarsus, are at increased risk for infections including opportunistic infections (bacterial, fungal, viral and protozoal) such as CMV infection, BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). Patients are also at an increased risk of infections with viral hepatitis (e.g. hepatitis B and C reactivation and de novo infection, as well as hepatitis E, which may become chronic). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions including graft rejection that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating hepatic or renal function or neurological symptoms. Prevention and management should be in accordance with appropriate clinical guidance.

Posterior reversible encephalopathy syndrome (PRES)

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

Pure red cell aplasia

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

Special populations

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

Dose reduction may be necessary in patients with severe liver impairment (see section 4.2).

Excipients

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

4.5 Interaction with other medicinal products and other forms of interaction

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 strongly recommended to closely monitor tacrolimus blood levels, as well as renal function and other undesirable effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).

Effect of other medicinal products on the metabolism of tacrolimus

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, voriconazole and isavuconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), Hepatitis C Virus (HCV) protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), or the CMV antiviral letermovir, the pharmacokinetic enhancer cobicistat, and the tyrosine kinase inhibitors nilotinib and imatinib. 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, amiodarone, 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 and (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 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:

Interactions have been observed with rifampicin, phenytoin, and 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.

Medicinal products which have effects on tacrolimus

Impact of DAA therapy

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

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.

Mycophenolic acid

Caution should be exercised when switching combination therapy from ciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Drugs which interfere with mycophenolic acid's entero­hepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa.

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). Care should be taken when tacrolimus is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sul­famethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Close monitoring of serum potassium is recommended.

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).

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Human data show that tacrolimus crosses the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse events on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. To date, no other relevant epidemiological data are available. 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 potential adverse events of tacrolimus is recommended (in particular, effects on the kidneys). There is a risk for premature delivery (<37 week) (incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the newborns had normal birth weight for their gestational age) as well as for hyperkalaemia in the newborn (incidence 8 of 111 neonates, i.e. 7.2 %) which, however normalises spontaneously. In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3).

Breast-feeding

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 Envarsus.

Fertility

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

4.7 Effects on ability to drive and use machines

Envarsus may have a minor influence on the ability to drive and use machines. Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if Envarsus is administered in association with alcohol.

4.8 Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

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

Infections and infestations

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

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

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

Immune system disorders

Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).

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.

In clinical studies in kidney transplant patients receiving Envarsus, the most frequent adverse reactions (at least in 2% of patients) were tremor, diabetes mellitus, blood creatinine increased, urinary tract infection, hypertension, BK virus infection, renal impairment, diarrhoea, toxicity to various agents, and toxic nephropathy all of which are known to occur in the respective patient population under immunosuppressive treatment. In all, there appears to be no significant difference in the pattern of adverse events suspected to be causally related to study drug between once daily Envarsus and tacrolimus immediate-release capsules (Prograf).

Among the most frequent adverse reactions (at least in 2% of patients) in clinical studies in liver transplant patients receiving Envarsus were tremor, headache, fatigue, hyperkalaemia, hypertension, renal failure, blood creatinine increased, dizziness, hepatitis C, muscle spasms, tinea infection, leukopenia, sinusitis, and upper respiratory tract infections (URTI), all of which are known to occur in the respective patient population under immunosuppressive treatment. As in kidney transplant recipients, there appears to be no meaningful difference in the pattern of suspected adverse drug reactions between once daily Envarsus and tacrolimus immediate-release capsules (Prograf).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

It should be noted however, that there has been no direct experience with Envarsus in overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, 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.

Pharmacodynamic effects

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 Y—interferon) and the expression of the interleukin-2 receptor.

Clinical efficacy and safety

Results  from clinical studies , performed with once-daily tacrolimus

Kidney transplantation

The efficacy and safety of Envarsus and Prograf, both in combination with mycophenolate mofetil (MMF), corticosteroids and IL-2 receptor antagonist as per the standard of care were compared in a randomised, double-blind, doubledummy study, in 543 de novo kidney transplant recipients.

The percentage of patients with one or greater than one episode of clinically-suspected and treated rejections during the 360-day study was 13.8% for the Envarsus group (N=268) and 15.6% for the Prograf group (N=275). The event rate for centrally read, biopsy-confirmed acute rejection (BPAR) during the 360-day study was 13.1% in the Envarsus group (N=268) and 13.5% in the Prograf group (N=275). The efficacy failure rate as measured by the composite endpoint of death, graft loss, centrally read BPAR and loss to follow-up was 18.3% in the Envarsus group and 19.6% in the Prograf group. The treatment difference (Envarsus-Prograf) was –1.35% (95% confidence interval [-7.94%, 5.27%]). Treatment-emergent fatal adverse events occurred in 1.8% of Envarsus patients and 2.5% of Prograf patients.

The efficacy and safety of Envarsus and Prograf, both in combination with mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) and corticosteroids, were compared in 324 stable kidney transplant recipients. The event rate for locally read BPAR during the 360-day study was 1.2% in the Envarsus group (N=162) post conversion from Prograf at a dose ratio of 1:0.7 (mg:mg) and 1.2% in the group maintained on Prograf (N=162). The efficacy failure rate as measured by the composite endpoint of death, graft loss, locally read BPAR and loss to follow-up was 2.5% in both the Envarsus and Prograf groups. The treatment difference (Envarsus-Prograf) was 0% (95% confidence interval [-4.21%, 4.21%]). The treatment failure rate using the same composite end-point with centrally read BPAR was 1.9% in the Envarsus group and 3.7% in the Prograf group (95% confidence interval [6.51%, 2.31%]). Treatment emergent fatal adverse events occurred in 1.2% of Envarsus patients and 0.6% of Prograf patients.

Liver transplantation

The pharmacokinetics, efficacy and safety of Envarsus and tacrolimus immediate-release capsules, both in combination with corticosteroids were compared in 117 liver transplant recipients, of whom 88 received treatment with Envarsus. In the de novo liver transplant study, 29 subjects were treated with Envarsus. The event rate of biopsy-confirmed acute rejection within the 360-day study period was not significantly different between the Envarsus group and the tacrolimus immediate-release group. The overall incidence of fatal treatment emergent adverse events for the combined de novo and stable liver transplant population was not significantly different between the Envarsus group and the tacrolimus immediate-release group.

5.2 Pharmacokinetic properties

Absorption

The oral bioavailability of Envarsus was decreased when the medicinal product was administered after a meal; the extent of absorption was decreased by 55% and the maximum plasma concentration was decreased by 22% when taken directly after a high-fat meal. Therefore, Envarsus should generally be taken on an empty stomach to achieve maximal absorption.

In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Available tacrolimus is generally rapidly absorbed. Envarsus is a prolonged-release formulation of tacrolimus resulting in an extended oral absorption profile with an average time to maximum blood concentration (Cmax) of approximately 6 hours (tmax) at steady state.

Absorption is variable and the mean oral bioavailability of tacrolimus is in the range of 20%-25% (individual range in adult patients 6%-43%). The oral bioavailability is approximately 40% higher for Envarsus as compared to the same dose of tacrolimus immediate-release formulation (Prograf) in kidney transplant patients.

Higher Cavg (~50%), reduced peak trough fluctuation (Cmax/Cmin) and a longer Tmax were seen for Envarsus when compared with both, tacrolimus immediate-release formulation (Prograf) and a tacrolimus once daily formulation (Advagraf). Mean values for Cmax, percentage degree of fluctuation and percentage degree of swing were significantly lower with administration of Envarsus tablets.

A strong correlation exists between AUC and whole blood trough levels at steady-state for Envarsus. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.

In vitro test results indicate that there is no risk of in vivo dose dumping related to alcohol intake.

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 a-1-acid glycoprotein.

Tacrolimus is extensively distributed in the body. The steady-state volume of distribution based on plasma concentrations is approximately 1,300 L (healthy subjects). Corresponding data based on whole blood averaged 47.6 L.

Biotransformation

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.

Elimination

Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 L/h. In adult liver, kidney, and heart transplant patients, values of 4.1 L/h, 6.7 L/h, and 3.9 L/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be responsible for the higher clearance rates observed following transplantation.

The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 30 hours.

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

5.3 Preclinical safety data

The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus. 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 count and motility was observed in rats.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hypromellose

Lactose monohydrate

Macrogol 6000

Poloxamer 188

Magnesium stearate

Tartaric acid (E334)

Butylated hydroxytoluene (E321)

Dimethicone 350

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

After opening the aluminium foil wrapper: 45 days.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original aluminium foil wrapper in order to protect from light.

6.5 Nature and contents of container

PVC/alu blisters containing 10 prolonged-release tablets. 3 blisters are packed together in an aluminium foil wrapper containing a desiccant.

Pack sizes of 30, 60 and 90 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Chiesi Limited

333 Styal Road

Manchester

M22 5LG

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 08829/0183