英文药名: Myfortic(Mycophenolic Acid Tablets)

中文药名: 麦考酚酸片

生产厂家: Novartis
药品介绍
MYFORTIC gastro-resistant tablets
Myfortic 360mg gastro-resistant tablets
MYFORTIC 180mg gastro-resistant tablets

------------------------------------------------
1. Name of the medicinal product
 Myfortic ® 180 mg gastro-resistant tablets
Myfortic ® 360 mg gastro-resistant tablets
2. Qualitative and quantitative composition
 Each gastro-resistant tablet contains 180mg or 360 mg mycophenolic acid (as mycophenolate sodium).
Excipients:
Lactose, anhydrous: 45 mg or 90 mg per tablet.
For a full list of excipients, see section 6.1.
3. Pharmaceutical form
Gastro-resistant tablet
180mg: Lime green, film-coated round tablet, with bevelled edges and the imprint (debossing) “C” on one side.
360mg: Pale orange red film-coated ovaloid tablet, with imprint (debossing) “CT” on one side.
4. Clinical particulars
4.1 Therapeutic indications
Myfortic is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.
4.2 Posology and method of administration
Treatment with Myfortic should be initiated and maintained by appropriately qualified transplant specialists.
The recommended dose is 720 mg administered twice daily (1,440 mg daily dose). This dose of mycophenolate sodium corresponds to 1 g mycophenolate mofetil administered twice daily (2 g daily dose) in terms of mycophenolic acid (MPA) content.
For additional information about the corresponding therapeutic doses of mycophenolate sodium and mycophenolate mofetil, see sections 4.4 and 5.2.
In de novo patients, Myfortic should be initiated within 72 hours following transplantation.
Myfortic can be taken with or without food. Patients may select either option but must adhere to their selected option (see section 5.2).
In order to retain the integrity of the enteric coating, Myfortic tablets should not be crushed.
Where crushing of Myfortic tablets is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane.
Children and adolescents
Insufficient data are available to support the efficacy and safety of Myfortic in children and adolescents. Limited pharmacokinetic data are available for paediatric renal transplant patients (see section 5.2).
Elderly
The recommended dose in elderly patients is 720 mg twice daily.
Patients with renal impairment
In patients experiencing delayed renal graft function post-operatively, no dose adjustments are needed (see section 5.2).
Patients with severe renal impairment (glomerular filtration rate <25 ml·min-1·1.73 m-2) should be carefully monitored and the daily dose of Myfortic should not exceed 1,440 mg.
Patients with hepatic impairment
No dose adjustments are needed for renal transplant patients with severe hepatic impairment.
Treatment during rejection episodes
Renal transplant rejection does not lead to changes in mycophenolic acid (MPA) pharmacokinetics; dosage modification or interruption of Myfortic is not required.
4.3 Contraindications
Hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients (see section 6.1).
Myfortic is contraindicated in women who are breastfeeding and in women of child bearing potential (WOCBP) not using highly effective contraception methods (see section 4.6).
For information on use in pregnancy and lactation and contraceptive requirements, see section 4.6.
4.4 Special warnings and precautions for use
Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic, 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 Myfortic should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients treated with immunosuppressants, including Myfortic, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Among the opportunistic infections 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.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (which include mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants. The mechanism for MPA derivatives induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of therapy. Changes to Myfortic 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 receiving Myfortic should be monitored for blood disorders (e.g. neutropenia or anemia – see section 4.8), which may be related to MPA itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Myfortic 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 blood disorders occur (e.g. neutropenia with (absolute neutrophil count <1.5 x 103/µl or anemia) it may be appropriate to interrupt or discontinue Myfortic.
Patients should be advised that during treatment with MPA 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 MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration and haemorrhage and perforation, Myfortic should be administered with caution in patients with active serious digestive system disease.
It is recommended that Myfortic not be administered concomitantly with azathioprine because concomitant administration of these drugs has not been evaluated.
Mycophenolic acid (as sodium salt) and mycophenolate mofetil should not be indiscriminately interchanged or substituted because of their different pharmacokinetic profiles.
Myfortic has been administered in combination with corticosteroids and ciclosporin.
There is limited experience with its concomitant use with induction therapies such as anti-T-lymphocyte globulin or basiliximab. The efficacy and safety of the use of Myfortic with other immunosuppressive agents (for example, tacrolimus) have not been studied.
Myfortic contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The concomitant administration of Myfortic and drugs which interfere with enterohepatic circulation, for example cholestyramine or activated charcoal, may result in sub-therapeutic systemic MPA exposure and reduced efficacy.
Myfortic is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. 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.
Myfortic therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Myfortic therapy, during therapy and for six weeks following therapy discontinuation (see section 4.6).
4.5 Interaction with other medicinal products and other forms of interaction
The following interactions have been reported between MPA and other medicinal products:
Aciclovir and ganciclovir
The potential for myelosuppression in patients receiving both Myfortic and aciclovir or ganciclovir has not been studied. Increased levels of mycophenolic acid glucuronide (MPAG) and aciclovir/ganciclovir may be expected when aciclovir/ganciclovir and Myfortic are administered concomitantly, possibly as a result of competition for the tubular secretion pathway.
The changes in MPAG pharmacokinetics are unlikely to be of clinical significance in patients with adequate renal function. In the presence of renal impairment, the potential exists for increases in plasma MPAG and aciclovir/ganciclovir concentrations; dose recommendations for aciclovir/ganciclovir should be followed and patients carefully observed.
Gastroprotective agents:
Magnesium and aluminium containing antacids:
MPA AUC and Cmax have been shown to decrease by approximately 37% and 25%, respectively, when a single dose of magnesium-aluminium containing antacids is given concomitantly with Myfortic. Magnesium aluminium-containing antacids may be used intermittently for the treatment of occasional dyspepsia. However the chronic, daily use of magnesium-aluminium containing antacids with Myfortic is not recommended due to the potential for decreased mycophenolic acid exposure and reduced efficacy.
Proton pump inhibitors:
In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of Myfortic and pantoprazole given at 40 mg twice daily during the four previous days. No data are available with other proton pump inhibitors given at high doses.
Oral contraceptives
Interaction studies between MMF and oral contraceptives indicate no interaction. Given the metabolic profile of MPA, no interactions would be expected for Myfortic and oral contraceptives.
Cholestyramine and drugs that bind bile acids
Caution should be used when co-administering drugs or therapies that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to decrease MPA exposure and thus reduce the efficacy of Myfortic.
Ciclosporin
When studied in stable renal transplant patients, ciclosporin pharmacokinetics were unaffected by steady state dosing of Myfortic. When co-administered with mycophenolate mofetil, ciclosporin is known to decrease the exposure of MPA. When co-administered with Myfortic, ciclosporin may decrease the concentration of MPA as well (by approximately 20%, extrapolated from mycophenolate mofetil data), but the exact extent of this decrease is unknown because such an interaction has not been studied. However, as efficacy studies were conducted in combination with ciclosporin, this interaction does not modify the recommended posology of Myfortic. In case of interruption or discontinuation of ciclosporin, Myfortic dosage should be re-evaluated depending on the immunosuppressive regimen.
Tacrolimus
In a calcineurin cross-over study in stable renal transplant patients, steady-state Myfortic pharmacokinetics were measured during both Neoral and tacrolimus treatment. Mean MPA AUC was 19% higher (90% CI: -3, +47), whereas mean MPAG AUC was about 30% lower (90% CI: 16, 42) on tacrolimus compared to Neoral treatment. In addition, MPA AUC intra-subject variability was doubled when switching from Neoral to tacrolimus. Clinicians should note this increase both in MPA AUC and variability, and adjustments to Myfortic dosing should be dictated by the clinical situation. Close clinical monitoring should be performed when a switch from one calcineurin inhibitor to another is planned.
Live attenuated vaccines
Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.
4.6. Fertility, pregnancy and lactation
Women of child-bearing potential
Myfortic therapy should not be initiated until a negative pregnancy test has been obtained.
Contraception in males and females
Women of childbearing potential must use highly effective contraception methods before beginning Myfortic therapy, during Myfortic therapy and for six weeks after their last dose of Myfortic.
Sexually active men are recommended to use condoms during treatment, and for a total of 13 weeks after their last dose of Myfortic. In addition, female partners of these male patients are recommended to use highly effective contraception during treatment and for a total of 13 weeks after the last dose of Myfortic.
Pregnancy
The use of Myfortic is not recommended during pregnancy and should be reserved for cases where no alternative treatment is available.
There is limited data from the use of Myfortic in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, cleft palate and cleft lip, micrognathia and cardiopathies have been reported in children of patients exposed to mycophenolate during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to mycophenolic acid compounds. Studies in animals have shown reproductive toxicity (see section 5.3).
Breast feeding
MPA is excreted in milk in lactating rats. It is unknown whether Myfortic is excreted in human breast milk. Because of the potential for serious adverse reactions to MPA in breast-fed infants, Myfortic is contra-indicated in women who are breast-feeding (see section 4.3).
Fertility
No specific studies with Myfortic in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen up to a dose of 40 mg/kg and 20 mg/kg respectively (see section 5.3).
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 mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.
4.8 Undesirable effects
The following undesirable effects cover adverse drug reactions from clinical trials:
Malignancies
Patients receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 2 de novo (0.9%) patients and in 2 maintenance patients (1.3%) receiving Myfortic for up to 1 year. Non-melanoma skin carcinomas occurred in 0.9% of de novo and 1.8% of maintenance patients receiving Myfortic for up to 1 year; other types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.
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 de novo renal transplant patients receiving Myfortic with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were cytomegalovirus (CMV), candidiasis and herpes simplex. CMV infection (serology, viraemia or disease) was reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.
Elderly patients
Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression.
Other adverse drug reactions
Table 1 below contains adverse drug reactions possibly or probably related to Myfortic reported in the controlled clinical trials in renal transplant patients, in which Myfortic was administered together with ciclosporin microemulsion and corticosteroids at a dose of 1,440 mg/day for 12 months. It is compiled according to MedDRA system organ class.
Adverse reactions are listed according to 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) 
Table 1

Infections and infestations
Very common	Viral, bacterial and fungal infections
Common	Upper respiratory tract infections, pneumonia
Uncommon	Wound infection, sepsis*, osteomyelitis*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon	Skin papilloma*, basal cell carcinoma*, Kaposi´s sarcoma*, lymphoproliferative disorder, squamous cell carcinoma*
Blood and lymphatic system disorders
Very common	Leukopenia
Common:	Anaemia, thrombocytopenia
Uncommon:	Lymphopenia*, neutropenia*, lymphadenopathy*
Metabolism and nutrition disorders
Uncommon:	Anorexia, hyperlipidaemia, diabetes mellitus*, hypercholesterolaemia*, hypophosphataemia
Psychiatric disorders
Uncommon	Abnormal dreams*, delusional perception*, insomnia*
Nervous system disorders
Common	Headache
Uncommon:	Tremor
Eye disorders
Uncommon:	Conjunctivitis*, vision blurred*
Cardiac disorders
Uncommon:	Tachycardia, ventricular extrasystoles
Vascular disorders:
Uncommon	Lymphocele*
Respiratory, thoracic and mediastinal disorders
Common	Cough
Uncommon:	Pulmonary congestion*, wheezing*, pulmonary oedema*
Gastrointestinal disorders
Very common	Diarrhoea
Common:	Abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, nausea, vomiting
Uncommon:	Abdominal tenderness, gastrointestinal haemorrhage, eructation, halitosis*, ileus*, lip ulceration*, oesophagitis*, subileus*, tongue discolouration*, dry mouth*, gastro-oesophageal reflux disease*, gingival hyperplasia*, pancreatitis, parotid duct obstruction*, peptic ulcer*, peritonitis*
Hepato-biliary deisordrs
Common	Liver function tests abnormal
Skin and subcutaneous tissue disorders
Uncommon:	Alopecia
Musculoskeletal and connective tissue disorders
Uncommon:	Arthritis*, back pain*, muscle cramps
Renal and urinary disorders
Common	Blood creatinine increased
Uncommon:	Haematuria*, renal tubular necrosis*, urethral stricture
Reproductive system and breast disorders
Uncommon	Impotence*
General disorders and administration site conditions
Common	Fatigue, pyrexia
Uncommon	Influenza like illness, oedema lower limb*, pain, rigors*, thirst*, weakness*
Injury, poisoning and procedural complications
Uncommon:	Contusion*

* event reported in a single patient (out of 372) only.
Note: renal transplant patients were treated with 1,440 mg Myfortic daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.
Rash has been identified as an adverse drug reaction from post marketing experience.
The following additional adverse reactions are attributed to MPA derivatives as a class effect:
Infections and infestations:
serious, life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. 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 Myfortic (see section 4.4).
Blood and lymphatic system disorders:
neutropenia, pancytopenia.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (see section 4.4).
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with MPA derivatives. 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 Myfortic.
Gastrointestinal disorders:
colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.
4.9 Overdose
There have been reports of intentional or accidental overdoses with Myfortic, whereas not all patients experienced related adverse events.
In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the class (mainly blood dyscrasias, sepsis…) (see sections 4.4 and 4.8).
Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the very high plasma protein binding of MPA, 97%. By interfering with enterohepatic circulation of MPA, bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressant, ATC code: L04AA06
MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilize salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.
5.2 Pharmacokinetic properties
Absorption
Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric coated design, the time to maximal concentration (Tmax) of MPA was approximately 1.5-2 hours. Approximately 10% of all morning pharmacokinetic profiles showed a delayed Tmax, sometimes up to several hours, without any expected impact on 24 hour/daily MPA exposure.
In stable renal transplant patients on ciclosporin based immunosuppression, the gastrointestinal absorption of MPA was 93% and the absolute bioavailability was 72%. Myfortic pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2,160 mg.
Compared to the fasting state, administration of a single dose of Myfortic 720 mg with a high fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure of MPA (AUC), which is the most relevant pharmacokinetic parameter linked to efficacy. However there was a 33% decrease in the maximal concentration of MPA (Cmax). Moreover, Tlag and Tmax were on average 3-5 hours delayed, with several patients having a Tmax of >15 hours. The effect of food on Myfortic may lead to an absorption overlap from one dose interval to another. However, this effect was not shown to be clinically significant.
Distribution
The volume of distribution at steady state for MPA is 50 litres. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound (97% and 82%, respectively). The free MPA concentration may increase under conditions of decreased protein binding sites (uraemia, hepatic failure, hypoalbuminaemia, concomitant use of drugs with high protein binding). This may put patients at increased risk of MPA-related adverse effects.
Elimination
The half life of MPA is approximately 12 hours and the clearance is 8.6 l/h.
Metabolism
MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG). MPAG is the predominant metabolite of MPA and does not manifest biological activity. In stable renal transplant patients on ciclosporin-based immunosuppression, approximately 28% of the oral Myfortic dose is converted to MPAG by presystemic metabolism. The half life of MPAG is longer than that of MPA, approximately 16 hours and its clearance is 0.45 l/h.
Excretion
Although negligible amounts of MPA are present in the urine (<1.0%), the majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6-8 hours after Myfortic dosing a second peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA. There is large variability in the MPA trough levels inherent to MPA preparations, and high morning trough levels (C0 > 10 µg/ml) have been observed in approximately 2% of patients treated with Myfortic. However, across studies, the AUC at steady state (0-12h) which is indicative of the overall exposure showed a lower variability than the one corresponding to Ctrough.
Pharmacokinetics in renal transplant patients on ciclosporin based immunosuppression
Shown in Table 2 are mean pharmacokinetic parameters for MPA following the administration of Myfortic. In the early post transplant period, mean MPA AUC and mean MPA Cmax were approximately one-half of the values measured six months post transplant.
Table 2 Mean (SD) pharmacokinetic parameters for MPA following oral administration of Myfortic to renal transplant patients on ciclosporin-based immunosuppression

Adult chronic, multiple dosing 720 mg BID (Study ERLB 301) n=48	Dose	Tmax* (h)	Cmax ( μ g/ml)	AUC 0-12 ( μ g x h/ml)
14 days post-transplant	720 mg	2	13.9 (8.6)	29.1 (10.4)
3 months post -transplant	720 mg	2	24.6 (13.2)	50.7 (17.3)
6 months post-transplant	720 mg	2	23.0 (10.1)	55.7 (14.6)
Adult chronic, multiple dosing 720 mg BID 18 months post-transplant (Study ERLB 302) n=18	Dose	Tmax* (h)	Cmax ( μ g/ml)	AUC 0-12 ( μ g x h/ml)
	720 mg	1.5	18.9 (7.9)	57.4 (15.0)
Paediatric 450 mg/m2 single dose (Study ERL 0106) n=16	Dose	Tmax* (h)	Cmax ( μ g/ml)	AUC o-∞ ( μ g x h/ml)
	450 mg/m2	2.5	31.9 (18.2)	74.5 (28.3)

* median values
Renal impairment
MPA pharmacokinetics appeared to be unchanged over the range of normal to absent renal function. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8 fold higher in the setting of anuria. Clearance of either MPA or MPAG was unaffected by haemodialysis. Free MPA may also significantly increase in the setting of renal failure. This may be due to decreased plasma protein binding of MPA in the presence of high blood urea concentration.
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
Limited data are available on the use of Myfortic in children and adolescents. In Table 2 above the mean (SD) MPA pharmacokinetics are shown for stable paediatric renal transplant patients (aged 5-16 years) on ciclosporin-based immunosuppression. Mean MPA AUC at a dose of 450 mg/m2 was similar to that measured in adults receiving 720 mg Myfortic. The mean apparent clearance of MPA was approximately 6.7 l/h/m2.
Gender
There are no clinically significant gender differences in Myfortic pharmacokinetics.
Elderly
Pharmacokinetics in the elderly have not formally been studied. MPA exposure does not appear to vary to a clinically significant degree by age.
5.3 Preclinical safety data
The haematopoetic and lymphoid system were the primary organs affected in repeated-dose toxicity studies conducted with mycophenolate sodium in rats and mice. Aplastic, regenerative anemia was identified as being the dose-limiting toxicity in rodents exposed to MPA. Evaluation of myelograms showed a marked decrease in erythroid cells (polychromatic erythroblasts and normoblasts) and a dose-dependent enlargement of the spleen and increase in extramedullary hematopoiesis. These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1.44 g/day of Myfortic in renal transplant patients.
Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses.
The non-clinical toxicity profile of mycophenolic acid (as sodium salt) 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).
Three genotoxicity assays (in vitro mouse lymphoma assay, micronucleus test in V79 Chinese hamster cells and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolic acid to cause chromosomal aberrations. These effects can be related to the pharmacodynamic 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.
Mycophenolic acid (as sodium salt) was not tumourigenic in rats and mice. The highest dose tested in the animal carcinogenicity studies resulted in approximately 0.6-5 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 1.44 g/day.
Mycophenolic acid (as sodium salt) had no effect on fertility of male or female rats up to dose levels at which general toxicity and embryotoxicity were observed.
In a teratology study performed with mycophenolic acid (as sodium salt) in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day of Myfortic (see section 4.6).
In a pre- and postnatal development study in rat, mycophenolic acid (as sodium salt) caused developmental delays (abnormal pupillary reflex in females and preputial separation in males) at the highest dose of 3 mg/kg that also induced malformations.
Mycophenolic acid (as sodium salt) showed a phototoxic potential in an in vitro 3T3 NRU phototoxicity assay.
6. Pharmaceutical particulars
6.1 List of excipients
Core
Maize starch
Povidone
Crospovidone
Lactose, anhydrous
Silica, colloidal anhydrous
Magnesium stearate
Coating
Hypromellose phthalate
Titanium dioxide (E 171)
Iron oxide yellow (E 172)
Indigo Carmine (E 132) (180mg only)
Iron oxide red (E 172) (360mg only)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
The tablets are packed in polyamide/aluminium/PVC/aluminium blister packs of 10 tablets per blister in quantities of 20, (180mg only), 50, 100, 120 and 250 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
In order to retain the integrity of the enteric coating, Myfortic tablets should not be crushed (see section 4.2).
Mycophenolic acid has demonstrated teratogenic effects (see section 4.6). Where crushing of Myfortic tablets is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Novartis Pharmaceuticals UK Limited
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
United Kingdom
8. Marketing authorisation number(s)
Myfortic 180mg gastro-resistant tablets: PL 00101/0664
Myfortic 360mg gastro-resistant tablets: PL 00101/0665
9. Date of first authorisation/renewal of the authorisation
10/10/2008
10. Date of revision of the text
29/11/2012
Myfortic-是一类具有免疫抑制作用的药物
免疫抑制剂是一类具有免疫抑制作用的药物，可抑制机体异常的免疫反应，目前已广泛应用于器官移植抗排异反应和自身免疫性疾病的治疗。然而移植排异反应是目前面临的一个重要难题，这需要有一种高效安全的免疫抑制剂，霉酚酸钠作为一种新型免疫抑制剂备受国内外关注。
霉酚酸酯(MMF)和霉酚酸钠(MPS)是霉酚酸两种最重要的衍生物，并分别于1998年和2004年通过美国FDA认证，临床上主要用于治疗器官移植的排异反应。霉酚酸(MPA)属于微生物来源的具有免疫抑制作用的抗生素，由短密青霉菌发酵代谢产生，于1896年首次分离，具有抗肿瘤、抗病毒、免疫抑制、抗牛皮癣和抗炎活性等优点，尤其免疫抑制的活性较突出，但生物利用率较低。现已试图通过制造其衍生物来提高MPA的生物利用率或特异性。霉酚酸的低生物利用率可能是在胃肠腔中的络合，狭窄的吸收窗，吸收前的代谢等引起的。现已制造霉酚酸酯(MMF)将其生物利用率由MPA的43％提高到94％以上，MMF主要以口服和注射给药。
临床结果表明，患者对霉酚酸酯的顺应性不理想，最常见的是胃肠道反应，也可出现白细胞减少或某些感染的发生。而另一种衍生物霉酚酸钠(MPS)，分子式为C17H19NaO6分子量为342.32。现有最新研究表明：霉酚酸钠是通过抑制肌苷-磷酸脱氢酶起作用，MPS有更好的耐受性，有值得关注的生物利用度和稳定性，需要给药的单位剂量比MMF小，使得病人更易接受，提高病人的顺应性。而胃肠道耐受性是免疫抑制治疗的重要问题，因为它能影响植入器官生存力，从而影响病人的存活机会。作为新一代免疫抑制剂，MPS在美国的研究显示副作用少，助换肾病人轻松过新生。
天生或转基因器官、组织或细胞同种异基因移植或异种移植排异反应的治疗和预防，例如用于心脏、肺、联结的心肺、肝、肾、胰腺、皮肤、胰岛细胞、神经细胞或角膜移植的接受者的治疗；包括急性排异反应的治疗和预防，例如与异种移植有关的超急性排异反应的治疗和预防，与移植血管疾病有关的慢性排异反应的治疗和预防；其组合物也可用于治疗和预防，例如在骨髓移植之后的移植物抗宿主病。
自身免疫性疾病的治疗和预防，例如免疫调节性疾病和炎症，特别是具有包括免疫组分的病原学的炎症，例如关节炎(风湿性关节炎、关节炎慢性Progrediente和关节炎变形)和风湿病。可以使用霉酚酸钠或霉酚酸组合物的免疫调节性疾病包括，自身免疫性血液失调(包括但不限于溶血性贫血、再生障碍性贫血、纯红细胞性贫血和先天性血小板减少症)、系统性红斑狼疮、多软骨炎、Sclerodoma、Wegener颗粒团形成、皮肌炎、多肌炎、慢性主动型肝炎、原发性胆汁性肝硬化、重症肌无力、牛皮癣、斯约综合症、天疱疮、自发口炎性腹泻(Idiophatic sprue)、炎症性肠病(如溃疡性结肠炎和克隆氏病)、内分泌眼病(Endocrine ophtha1mophath )、格雷夫氏症结节病。多发性硬化、小儿糖尿病(糖尿病Mellitus型Ⅰ)、非传染性眼色素层炎(Anterior和Posterior)、干燥性角膜结膜炎和春季角膜结膜炎、肺间质纤维化、银屑病关节炎、血管炎、肾小球性炎症(具有和没有肾病结合综合症，例如包括自发肾病综合症或微小病变性肾病)和青少年性皮肌炎。
目前，诺华公司已开发了以霉酚酸钠为核心的肠溶衣片，商品名为Myfortic，此药2007年开始在亚洲区研究，香港有20多位换肾病人参与试用新药，数据仍在收集中，据称迄今反应不错。新药的肠溶衣配方令药片通过胃部至小肠后才分解，对肠胃温和，副作用较轻微。由700多位患者参与的两个全球多中心试验结果证明，Myfortic与MMF治疗肾移植患者的功效相当且副作用低，Myfortic代替MMF的肾移植维持治疗是安全有效的。并且这种延迟释放免疫抑制剂获准用于与环孢菌素[如诺华公司的Neoral(环孢菌素微乳剂)]和皮质类固醇联用，防止成人肾移植物急性排异。Myfortic是通过抑制肌苷-磷酸脱氢酶起作用，后者在T和B淋巴细胞增殖中起重要作用。它具有比Roche公司的MPA配方CellCept(Mycophenolate mofetil)更多的优点，后者由于胃肠道副作用需要调节剂量。2004年2月7日，Myfortic成功地完成了欧洲相互认可程序(MRP)，获准用于成人肾移植患者的急性排斥反应的预防，并在同年获得FDA的批准认可。2002年10月瑞士第一个批准它的应用。
我国人体器官移植始于20世纪70年代，最近10年器官移植不论在数量还是质量上都取得了迅速发展，器官移植数量已居世界第二位。目前制约器官移植发展的最大障碍是供体短缺。
据Boston Globe报道，2004年全球抗排异药物市场规模已达30亿美元。而Datamonitor Corporation认为，2005年全球七大主要市场的脏器移植件数超过5万件，用于此用途的免疫抑制剂市场将在2015年增长至43亿美元左右。
目前这一领域的领导者是诺华、罗氏、藤泽公司，这3家公司的产品占据了抗排异药全球市场的大部分份额。诺华公司宣布FDA已经批准Myfortic(霉酚酸钠)剂与环孢霉素和皮质类固醇联合应用来预防肾移植中的排异反应，霉酚酸钠已经进入市场。
器官移植被列进20世纪医学三大进步之一，每年有数以万计的病人在器官移植后得以生存。仅在我国每年有50万人需要肾移植，400万人需要角膜移植。由于器官移植患者需要终身服用免疫抑制剂药物，随着移植技术的迅猛发展，抗排异免疫抑制剂药物将面临巨大的市场机遇。然而移植排异反应是目前面临的一个重要难题，因此开发高效、低毒和有抗慢性排异作用的化学和生物药物依然是国内外学者不懈追求的方向。而霉酚酸钠的研制开发是继环孢素、雷帕、霉酚酸酯、FK506之后的又一新型免疫抑制剂，它具有高效安全、病人耐受性好的特点，具有良好的开发前景。
麦考酚酸酯缓释片（Myfortic）由Novartis公司制造，其适应症范围为：与环孢霉素及皮质类固醇联合用药预防肾移植器官排斥。
根据美国National Transplantation Pregnancy Registry药品上市后监测结果，以及妇女孕期使用吗替麦考酚酯（MMF，可转换成Myfortic的活性成分）监测结果显示，Myfortic缓释片妊娠安全级别下降，即存在确切的胎儿风险。11月27日，FDA与Novartis公司发布医生及患者告知书，Myfortic缓释片（麦考酚酸）可增加孕期妇女流产及先天畸形风险。修改后的Myfortic缓释片说明书在[黑框警告]、[禁忌症]项增加了新的信息：准备妊娠的妇女患者不应使用本品，除非没有其他有效免疫抑制剂可以选择。孕龄女患者服用本品时，必须进行避孕咨询并采取有效避孕措施。