Mepact 4mg powder for suspension for infusion

Same SmPC uploaded as the previous version but with a file name with the correct year.

Shelf life of unopened vial of powder updated to 3 years

Local representatives added in section 6

Section 7: Marketing authorisation address change

Section 4: Possible side effects:
Not known (cannot be estimated from the available data):

• abnormal accumulation of fluid around the heart (pericardial effusion)

Section 4: How to report a side effects: Wording amended to:

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance. Website: www.hpra.ie  By reporting side effects you can help provide more information on the safety of this medicine.

- in text body: adding frequency ‘not known (cannot be estimated from the available data)’

- in Table 1: adding AE ‘pericardial effusion’ with frequency ‘not known’

- aligning to QRD the Irish details for reporting suspected adverse reactions.

The EMA have approved the Mepact renewal and as a consequence, the product information has been updated. The changes are largely administrative in nature, to align with the QRD template.

In Section 7. Marketing authorisation holder- has the name change approval to the following:      

Takeda France SAS

Immeuble Pacific

11-13 cours Valmy

92800 Puteaux

France

Additional wording to section 4.2:

Patients with impaired renal or hepatic function

There are no clinically meaningful effects of mild to moderate renal (creatinine clearance (CrCL) ≥ 30ml/min) or hepatic impairment (Child-Pugh class A or B) on the pharmacokinetics of mifamurtide; therefore, dose adjustments are not necessary for these patients. However, as the variability in pharmacokinetics of mifamurtide is greater in subjects with moderate hepatic impairment (see Section 5.2), and safety data in patients with moderate hepatic impairment is limited, caution when administering mifamurtide to patients with moderate hepatic impairment is recommended.

As no pharmacokinetic data of mifamurtide is available in patients with severe renal or hepatic impairment, caution when administering mifamurtide to these patients is recommended. Continued monitoring of the kidney and liver function is recommended if MEPACT is used beyond completion of chemotherapy until all therapy is completed.

 
Additonal wording to section 4.9
No case of overdose has been reported within the approved indication

A healthy adult volunteer accidentally received a single dose of 6.96 mg mifamurtide and experienced a reversible treatment-related event of orthostatic hypotension

Additional wording and changes to Section 5.2:

The pharmacokinetics of mifamurtide have been characterized in healthy adult subjects following a 4 mg intravenous  infusion and in paediatric and adult patients with osteosarcoma following a 2 mg/m² intravenous infusion.

In 21 healthy adult subjects mifamurtide was cleared rapidly from  serum (minutes) with a half-life of 2.05 ± 0.40 hours, resulting in a very low  serum concentration of total (liposomal and free) mifamurtide. The mean AUC was 17.0 ± 4.86 h x nM and Cmax was 15.7 ± 3.72 nM.

In 28 osteosarcoma patients aged 6 to 39 years serum total (liposomal and free) mifamurtide concentrations declined rapidly with a mean half-life of 2.04 ± 0.456 hours. BSA-normalized clearance and half-life were similar across the age range and consistent with that determined in healthy adult subjects, supporting the recommended dose of 2 mg/m².

In a separate study in 14 patients, mean serum concentration‑time curves of total and free mifamurtide that were assessed after the first infusion of MEPACT and after a last infusion 11 or 12 weeks later, were almost superimposable and the mean AUC values of the free mifamurtide after the first and last infusion were similar. These data indicate that neither total nor free mifamurtide accumulated during the treatment period.

At 6 hours after injection of radiolabelled liposomes containing 1 mg mifamurtide, radioactivity was found in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in lung. The liposomes were phagocytosed by cells of the reticuloendothelial system. In 2 of 4 patients with lung metastases, radioactivity was associated with lung metastases.

Special Populations

Renal Impairment

The pharmacokinetics of a single 4mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (n=9) or moderate (n=8) renal impairment and in age- ,sex-, and weight-matched healthy adults with normal renal function (n=16). There was no effect of mild (50 mL/min £ CLcr £80 mL/min) or moderate (30 mL/min £ CLcr < 50 mL/min) renal insufficiency on the clearance of total MTP-PE, when compared with that observed in healthy adult subjects with normal renal function (CLcr > 80 mL/min). Additionally, the systemic exposures (AUCinf) of free (non-liposome associated) MTP-PE in mild or moderate renal insufficiency were similar to those observed in healthy adult subjects with normal renal function.

Hepatic Impairment

The pharmacokinetics of a single 4mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (Child‑Pugh class A; n=9) or moderate (Child-Pugh class B; n=8) hepatic impairment and in age- ,sex-, and weight-matched healthy adults with normal hepatic function (n=19). There was no effect of mild hepatic impairment on the systemic exposure (AUCinf) of total MTP-PE. Moderate hepatic impairment resulted in a small increase in AUCinf of total MTP-PE, with the geometric least square mean ratio (expressed as %) for moderate hepatic impairment in reference to the matched normal hepatic function group being 119% (90% CI: 94.1%‑151%). Pharmacokinetic variability was higher in the moderate hepatic impairment group (co-efficient of variation in systemic exposure [AUCinf] was 50% versus <30% in the other hepatic function groups).

Mean half-lives of total and free MTP-PE in mild hepatic impairment were 2.02 hours and 1.99 hours, respectively, and were comparable to those in subjects with normal hepatic function (2.15 hours and 2.26 hours, respectively). Mean half-lives of total and free MTP-PE in moderate hepatic impairment were 3.21 hours and 3.15 hours, respectively. Additionally, the geometric mean plasma AUCinf of free (non-liposome associated) MTP-PE in mild and moderate hepatic impairment were 47% higher than the corresponding values in the matched normal hepatic function groups.These changes were not considered to be clinically meaningful as the maximum tolerated dose (4-6 mg/m²) of mifamurtide is 2-3 times the recommended dose (2 mg/m²).