Mycophenolate Mofetil 250 Mg Hard Capsules
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Mycophenolate mofetil 250 mg hard Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 250 mg mycophenolate mofetil.
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Capsule, hard
White to off white powder filled in Oblong, size ‘1’ hard gelatin capsule of opaque blue coloured cap and opaque brown coloured body imprinted ‘MCM’ on cap and ‘250’ on body with black ink
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Mycophenolate is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
4.2 Posology and method of administration
Treatment with mycophenolate should be initiated and maintained by appropriately qualified transplant specialists.
Use in renal transplant:
Adults: oral mycophenolate should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).
Children and adolescents (aged 2 to 18 years): the recommended dose of mycophenolate mofetil is 600 mg/m administered orally twice daily (up to a maximum of 2 g daily). Mycophenolate capsules should only be prescribed to patients with a body surface area of at least 1.25 m . Patients with a body surface area of 1.25 to 1.5 m2 may be prescribed mycophenolate at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m2 may be prescribed mycophenolate at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8) compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.
Children (< 2 years): there are limited safety and efficacy data in children below the age of 2 years. These are insufficient to make dosage recommendations and therefore use in this age group is not recommended.
Use in cardiac transplant:
Adults: oral mycophenolate should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).
Children: no data are available for paediatric cardiac transplant patients.
Use in hepatic transplant:
Adults: IV mycophenolate should be administered for the first 4 days following hepatic transplant, with oral mycophenolate initiated as soon after this, as it can be tolerated. The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).
Children: no data are available for paediatric hepatic transplant patients.
Use in elderly (> 65 years): the recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.
Use in renal impairment: in renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml.min-1 1.73 m-2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Use in severe hepatic impairment: no dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
Treatment during rejection episodes: MPA (mycophenolic acid) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of mycophenolate is not required. There is no basis for mycophenolate dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.
4.3 Contraindications
Hypersensitivity reactions to mycophenolate have been observed (see section 4.8). Therefore, Mycophenolate is contraindicated in patients with hypersensitivity to mycophenolate mofetil or mycophenolic acid.
Mycophenolate is contraindicated in women who are breastfeeding (see section 4.6).
For information on use in pregnancy and contraceptive requirements see section 4.6.
4.4 Special warnings and precautions for use
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Patients receiving mycophenolate should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients treated with immunosuppressants, including mycophenolate, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants 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.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on [invented name] who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.
There have been published reports of bronchiectasis in adults and children who received mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
Patients receiving mycophenolate should be monitored for neutropenia, which may be related to mycophenolate itself, concomitant medications, viral infections, or some combination of these causes. Patients taking mycophenolate should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 103/pl) it may be appropriate to interrupt or discontinue mycophenolate.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolate therapy. Changes to mycophenolate therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8).
Patients should be advised that during treatment with mycophenolate vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Because mycophenolate has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation, mycophenolate should be administered with caution in patients with active serious digestive system disease.
Mycophenolate is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
It is recommended that mycophenolate should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.
In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of mycophenolate with medicinal products that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate.
The risk:benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established (see also section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Aciclovir: higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur.
Antacids and proton pump inhibitors (PPIs): Decreased mycophenolic acid (MPA) exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with mycophenolate mofetil. When comparing rates of transplant rejection or rates of graft loss between mycophenolate mofetil patients taking PPIs vs. mycophenolate mofetil patients not taking PPIs, no significant differences were seen. These data support extrapolation of this finding to all antacids because the reduction in exposure when mycophenolate mofetil was co- administered with magnesium and aluminium hydroxides is considerably less than when mycophenolate mofetil was coadministered with PPIs.
Cholestyramine: following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of mycophenolate.
Medicinal products that interfere with enterohepatic circulation: caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of mycophenolate mofetil.
Ciclosporin A: ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil.
In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.
Ganciclovir; based on the results of a single dose administration study of recommended doses of oral mycophenolate and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of mycophenolate (see section 4.2) and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and mycophenolate dose adjustment is not required. In patients with renal impairment in which mycophenolate and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.
Oral contraceptives: the pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by co-administration of mycophenolate (see also section 5.2).
Rifampicin: in patients not also taking ciclosporin, concomitant administration of mycophenolate mofetil and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust mycophenolate doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.
Sirolimus: in renal transplant patients, concomitant administration of mycophenolate mofetil and CsA resulted in reduced MPA exposures by 30-50% compared with patients receiving the combination of sirolimus and similar doses of mycophenolate mofetil (see also section 4.4).
Sevelamer: decrease in MPA Cmax and AUC0_12 by 30% and 25%, respectively, were observed when mycophenolate mofetil was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer mycophenolate mofetil at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There is no data on mycophenolate with phosphate binders other than sevelamer.
Trimethoprim/sulfamethoxazole: no effect on the bioavailability of MPA was observed.
Norfloxacin and metronidazole: in healthy volunteers, no significant interaction was observed when mycophenolate mofetil was concomitantly administered with norfloxacin and metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 % following a single dose of mycophenolate mofetil.
Ciprofloxacin and amoxicillin plus clavulanic acid: reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of their discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
Tacrolimus: in hepatic transplant patients initiated on mycophenolate and tacrolimus, the AUC and Cmax of MPA, the active metabolite of mycophenolate, were not significantly affected by coadministration with tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of mycophenolate mofetil (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by mycophenolate mofetil (see also section 4.4).
Other interactions: co-administration of probenecid with mycophenolate mofetil in
monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.
Live vaccines: live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy
It is recommended that mycophenolate therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning mycophenolate therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.5). Patients should be instructed to consult their physician immediately should pregnancy occur.
The use of mycophenolate is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. Mycophenolate should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There is limited data from the use of mycophenolate mofetil in pregnant women. However, congenital malformations including ear malformations i.e. abnormally formed or absent external/middle ear have been reported in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil. Studies in animals have shown reproductive toxicity (see section 5.3).
Lactation
Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, mycophenolate are contraindicated in nursing mothers (see section 4.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.
4.8 Undesirable effects
The following undesirable effects cover adverse reactions from clinical trials:
The principal adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections (see section 4.4).
Malignancies:
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4).
Lymphoproliferative disease or lymphoma developed in 0.6% of patients receiving
mycophenolate (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6% of patients; other types of malignancy occurred in 1.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.
Opportunistic infections:
All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in patients receiving mycophenolate (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%.
Children and adolescents (aged 2 to 18 years):
The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m2 mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g mycophenolate twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.
Elderly patients ( 65 years):
Elderly patients ( . 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving mycophenolate as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.
Other adverse reactions:
Adverse reactions, probably or possibly related to mycophenolate, reported in >1/10 and in >1/100 to <1/10 of patients treated with mycophenolate in the controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients are listed in the following table.
Adverse reactions, probably or possibly related to mycophenolate mofetil, reported in patients treated with mycophenolate mofetil in renal, cardiac and hepatic clinical trials when used in combination with ciclosporin and corticosteroids
Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: 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.
|
System organ class |
Frequency |
Adverse drug reactions |
|
Infections and infestations |
Very common |
Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster |
|
Common |
Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis | |
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
Very common |
- |
|
Common |
Skin cancer, benign neoplasm of skin | |
|
Blood and lymphatic system disorders |
Very common |
Leukopenia, thrombocytopenia, anaemia |
|
Common |
Pancytopenia, leukcytosis | |
|
Metabolism and nutrition disorders |
Very common |
- |
|
Common |
Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, hyperuricaemia, gout, anorexia | |
|
Psychiatric disorders |
Very common |
- |
|
Common |
Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia | |
|
Nervous system disorders |
Very common |
- |
|
Common |
Convulsion, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paraesthesia, dysgeusia | |
|
Cardiac disorders |
Very common |
- |
|
Common |
Tachycardia | |
|
Vascular disorders |
Very common |
- |
|
Common |
Hypotension, hypertension, vasodilatation | |
|
Respiratory, thoracic and mediastinal disorders |
Very common |
- |
|
Common |
Pleural effusion, dyspnoea, cough | |
|
Gastrointestinal disorders |
Very common |
Vomiting, abdominal pain, diarrhoea, nausea |
|
Common |
Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence, eructation | |
|
Hepatobiliary disorders |
Very common |
- |
|
Common |
Hepatitis, jaundice, hyperbilirubinaemia | |
|
Skin and subcutaneous tissue disorders |
Very common |
- |
|
Common |
Skin hypertrophy, rash, acne, alopecia | |
|
Musculoskeletal and connective tissue |
Very common |
' |
|
disorders |
Common |
Arthralgia |
|
Renal and urinary disorders |
Very common |
- |
|
Common |
Renal impairment | |
|
General disorders and administration site conditions |
Very common |
- |
|
Common |
Oedema, pyrexia, chills, pain, malaise, asthenia | |
|
Investigations |
Very common |
- |
|
Common |
Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased, blood alkaline phosphatase increased, weight decreased |
Note:
501 (2 g mycophenolate daily), 289 (3 g mycophenolate daily) and 277 (2 g IV/3 g oral mycophenolate daily) patients were treated in Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively.
The following undesirable effects cover adverse reactions from post-marketing experience:
The types of adverse reactions reported during post-marketing with mycophenolate are similar to those seen in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported during post-marketing are described below with the frequencies reported within brackets if known.
Gastrointestinal: gingival hyperplasia (>1/100 to <1/10), colitis including cytomegalovirus colitis, (>1/100 to <1/10), pancreatitis, (>1/100 to <1/10) and intestinal villous atrophy.
Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil. Agranulocytosis (>1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking mycophenolate is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow depression in patients treated with mycophenolate, some of which have been fatal.
Blood and lymphatic system disorder: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil (see section 4.4).
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophenolate mofetil. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive mycophenolate mofetil.
Hypersensitivity: hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction have been reported.
Congenital disorders: see further details in section 4.6.
Respiratory, thoracic and mediastinal disorders: There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with mycophenolate in combination with other immunosuppressants, some of which have been fatal.
There have also been reports of bronchiectasis in children and adults (frequency not known).
Immune system disorders:
Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants (frequency not known).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.
It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with mycophenolate should be interrupted or the dose reduced (see section 4.4).
Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug (see section 5.2).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin-II antagonists, combinations ATC code: C09DA04.
Irbesartan/Hydrochlorothiazide is a combination of an angiotensin-II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of irbesartan tends to reverse the potassium loss associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and diastolic blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hg in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When measured by ambulatory blood pressure monitoring, the trough to peak effects of irbesartan/hydrochlorothiazide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were 68% and 76% for irbesartan/hydrochlorothiazide 150 mg/12.5 mg and irbesartan/hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour effects were observed without excessive blood pressure lowering at peak and are consistent with safe and effective blood-pressure lowering over the once-daily dosing interval.
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg.
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent after the first dose and substantially present within 12 weeks, with the maximal effect occurring by 6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained for over one year. Although not specifically studied with the irbesartan/hydrochlorothiazide, rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide.
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological studies have shown that long term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
There is no difference in response to irbesartan/hydrochlorothiazide, regardless of age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of non-black patients.
Efficacy and safety of irbesartan/hydrochlorothiazide as initial therapy for severe hypertension (defined as SeDBP > 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week, parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically forcetitrated (before assessing the response to the lower dose) after one week to irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were > 65 years of age, and just 2% were > 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of the participants.
The primary objective of this study was to compare the proportion of patients whose SeDBP was controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan (p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period, there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the combination and monotherapy groups, respectively.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for other ACE- inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
5.2 Pharmacokinetic properties
Absorption
Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of mycophenolate is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.
Distribution
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.
MPA at clinically relevant concentrations, is 97% bound to plasma albumin.
Biotransformation
MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active.
Elimination
A negligible amount of substance is excreted as MPA (< 1% of dose) in the urine. Orally administered radiolabelled mycophenolate mofetil results in complete recovery of the administered dose; with 93% of the administered dose recovered in the urine and 6% recovered in the faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100 g/ml), small amounts of MPAG are removed.
In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3 - 6 months post-transplant).
Renal impairment:
In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25 ml min-1 1.73 m-2) were 28-75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, the mean single dose MPAG AUC was 3 -6fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Delayed renal graft function:
In patients with delayed renal graft function post-transplant, mean MPA AUC (0-12h) was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC (0-12h) was 2-3-fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of mycophenolate does not appear to be necessary.
Hepatic impairment:
In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
Children and adolescents (aged 2 to 18 years):
Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients given 600 mg/m2 mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving mycophenolate at a dose of 1 g bid in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.
Elderly patients (>65 years):
Pharmacokinetic behaviour of mycophenolate in the elderly has not been formally evaluated. Oral contraceptives:
The pharmacokinetics of oral contraceptives were unaffected by co-administration of mycophenolate (see also section 4.5). A study of the co-administration of mycophenolate (1 g BID) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of mycophenolate on the ovulation suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected.
5.3 Preclinical safety data
In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2-3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3-2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.
Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacoynamics mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.
Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2-3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3-2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (including anophthalmia, agnathia and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels are approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. Refer to section 4.6.
The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population (see section 4.8).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule content:
Pregelatinised starch (maize)
Povidone (PVP K-90)
Croscarmellose sodium Magnesium stearate Capsule shell:
Cap:
Indigo carmine (E132) Titanium dioxide (E171) Gelatin
Sodium laurilsulfate Body:
Red iron oxide (E172) Yellow iron oxide (E172) Titanium dioxide (E171) Gelatin
Sodium laurilsulfate Black ink containing: Shellac
Black iron oxide (E172) Potassium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture
6.5 Nature and contents of container
PVC-PVdC/ Alu blister
100 or 300 capsules per carton. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, mycophenolate capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Limited
6 Riverview Road
Beverley
East Yorkshire
HU17 OLD
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 08553/0363
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/12/2010
10 DATE OF REVISION OF THE TEXT
31/03/2015