Novartis Pharmaceuticals UK Ltd

Gastroprotective agents:

Magnesium-aluminium containing antacids:

MPA AUC and C_max 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.

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 mycophenolic acid compoundsMPA derivatives (including MMF) as a class effect:

Gastrointestinal disorders:

colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.

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 mycophenolate mofetil MPA derivatives (which contains the same active moiety as Myfortic) (see section 4.4).

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophenolate mofetilMPA derivatives (which contains the same active moiety as Myfortic). 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.

Section 5.2
as present..........

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 C_trough.

......as present.......

Changes to Myfortic SmPC   

Sections 1, 2 and 3:

The tablets were previously referred to as Myfortic^® film-coated gastro-resistant tablets.  They are now referred to as Myfortic® gastro-resistant tablets.

The formulation is unchanged, gastro-resistant tablets is the currently accepted  EU pharmaceutical terminology.  

Section 4.3 Contraindications

The following has been added:

Myfortic is contraindicated in women who are breastfeeding (see section 4.6).

4.4. Special warnings and precautions for use

Changed from:

Patients receiving Myfortic should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Oversuppression of the immune system increases the susceptibility to infection including opportunistic infections, fatal infections and sepsis (see section 4.8).

To:

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.

Section 4.6. Pregnancy and lactation

Pregnancy

Now includes the statement:

Cases of spontaneous abortions have been reported in patients exposed to mycophenolic acid compounds.

Lactation

Now cross refers to the contraindication in Section 4.3

Section 4.8. Undesirable effects

Changed from:

The following additional adverse reactions are attributed to mycophenolic acid compounds (including MMF) as a class effect:

Gastrointestinal: colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.

Disorders related to immunosuppression: serious, sometimes life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection.

Haematological: neutropenia, pancytopenia.

To:

The following additional adverse reactions are attributed to mycophenolic acid compounds (including MMF) as a class effect:

Gastrointestinal: colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.

Disorders related to immunosuppression: 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 leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Myfortic (see section 4.4).

Haematological: neutropenia, pancytopenia.

 Section 5.3. Preclinical safety data

The following information has been added:

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.

Section 10. Date of revision of the text

Changed from 29 August 2008 to  10 October 2008

"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)".

• In the 1st sentance,

• The following paragraph has been deleted

"Myfortic should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. While there are no adequate clinical data in pregnant women, animal studies have shown a teratogenic potential (central nervous system) (see section 5.3)."
 

"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, have been reported in children of patients exposed to mycophenolate in combination with other immunosuppressants during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3)."

• Mycophenolate sodium changed to mycophenolic acid (as sodium salt)

• Inetraction with tacrolimus added

• Section on malignancies and 1st para of other adverse reaction section updated
• Lip ulceration, pancreatitis, parotid duct obstruction, peptic ulcer, rigors, thirst, back pain, muscle cramps,        abnormal dreams, delusionalperception and haematuria added
• Incidence of viral, bacterial and fungal infections and abdominal tenderness changed

• Word "core" added

• "Polyamide/Aluminium/PVC" changed to "Polyuamide/Aluminium/PVC/Aluminium"
• "Not all pack sizes may be marketed" added