MEPACT 4mg powder for concentrate for dispersion for infusion medication leaflet

MEPACT 4 mg powder for concentrate for dispersion for infusion

Each vial contains 4 mg mifamurtide*.

After reconstitution, each mL of suspension in the vial contains 0.08 mg mifamurtide.

*fully synthetic analogue of a component of Mycobacterium sp. cell wall.

For the full list of excipients, see section 6.1.

Powder for concentrate for dispersion for infusion

White to off-white homogeneous cake or powder.

MEPACT is indicated in children, adolescents and young adults for the treatment of high-graderesectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It isused in combination with post-operative multi-agent chemotherapy. Safety and efficacy have beenassessed in studies of patients 2 to 30 years of age at initial diagnosis (see section 5.1).

Mifamurtide treatment should be initiated and supervised by specialist physicians experienced inthe diagnosis and treatment of osteosarcoma.

The recommended dose of mifamurtide for all patients is 2 mg/m2 body surface area. It should beadministered as adjuvant therapy following resection: twice weekly at least 3 days apart for12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of48 infusions in 36 weeks.

Adults > 30 years

None of the patients treated in the osteosarcoma studies were 65 years or older and in the phase IIIrandomised study, only patients up to the age of 30 years were included. Therefore, there are notsufficient data to recommend the use of MEPACT in patients > 30 years of age.

There are no clinically meaningful effects of mild to moderate renal (creatinine clearance(CrCL) ≥ 30 mL/min) or hepatic impairment (Child-Pugh class A or B) on the pharmacokinetics ofmifamurtide; therefore, dose adjustments are not necessary for these patients. However, as thevariability 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, cautionwhen administering mifamurtide to patients with moderate hepatic impairment is recommended.

As no pharmacokinetic data of mifamurtide is available in patients with severe renal or hepaticimpairment, caution when administering mifamurtide to these patients is recommended. Continuedmonitoring of the kidney and liver function is recommended if mifamurtide is used beyondcompletion of chemotherapy until all therapy is completed.

Paediatric population < 2 years

The safety and efficacy of mifamurtide in children aged 0 to 2 years have not been established. Nodata are available.

MEPACT is administered by intravenous infusion over a period of 1 hour.

MEPACT must not be administered as a bolus injection.

For further instructions on reconstitution, filtering using the filter provided and dilution of themedicinal product before administration, see section 6.6.

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

Concurrent use with ciclosporin or other calcineurin inhibitors (see section 4.5).

Concurrent use with high-dose non-steroidal-anti-inflammatory drugs (NSAIDs, cyclooxygenaseinhibitors) (see section 4.5).

Respiratory distress

In patients with a history of asthma or other chronic obstructive pulmonary disease, considerationshould be given to administration of bronchodilators on a prophylactic basis. Two patients withpre-existing asthma developed mild to moderate respiratory distress associated with the treatment(see section 4.8). If a severe respiratory reaction occurs, administration of mifamurtide should bediscontinued and appropriate treatment initiated.

Administration of mifamurtide was commonly associated with transient neutropenia, usually whenused in conjunction with chemotherapy. Episodes of neutropenic fever should be monitored andmanaged appropriately. Mifamurtide may be given during periods of neutropenia, but subsequentfever attributed to the treatment should be monitored closely. Fever or chills persisting for morethan 8 hours after administration of mifamurtide should be evaluated for possible sepsis.

Inflammatory response

Association of mifamurtide with signs of pronounced inflammatory response, includingpericarditis and pleuritis, was uncommon. It should be used with caution in patients with a historyof autoimmune, inflammatory or other collagen diseases. During mifamurtide administration,patients should be monitored for unusual signs or symptoms, such as arthritis or synovitis,suggestive of uncontrolled inflammatory reactions.

Patients with a history of venous thrombosis, vasculitis or unstable cardiovascular disordersshould be closely monitored during mifamurtide administration. If symptoms are persistent andworsening, administration should be delayed or discontinued. Haemorrhage was observed inanimals at very high doses. These are not expected at the recommended dose, however monitoringof clotting parameters after the first dose and once again after several doses is recommended.

Occasional allergic reactions have been associated with mifamurtide treatment, including rash,shortness of breath and grade 4 hypertension (see section 4.8). It may be difficult to distinguishallergic reactions from exaggerated inflammatory responses, but patients should be monitored forsigns of allergic reactions.

Gastrointestinal toxicity

Nausea, vomiting and loss of appetite are very common adverse reactions to mifamurtide (seesection 4.8). Gastrointestinal toxicity may be exacerbated when mifamurtide is used incombination with high dose, multi-agent chemotherapy and was associated with an increased useof parenteral nutrition.

MEPACT contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit.

Limited studies of the interaction of mifamurtide with chemotherapy have been conducted.

Although these studies are not conclusive, there is no evidence of interference of mifamurtide withthe anti-tumour effects of chemotherapy and vice versa.

It is recommended to separate the administration times of mifamurtide and doxorubicin or otherlipophilic medicinal products if used in the same chemotherapy regimen.

The use of mifamurtide concurrently with ciclosporin or other calcineurin inhibitors iscontraindicated due to their hypothesised effect on splenic macrophages and mononuclearphagocytic function (see section 4.3).

Also, it has been demonstrated in vitro that high-dose NSAIDs (cyclooxygenase inhibitors) canblock the macrophage activating effect of liposomal mifamurtide. Therefore, the use of high-dose

NSAIDs is contraindicated (see section 4.3).

Because mifamurtide acts through stimulation of the immune system, the chronic or routine use ofcorticosteroids should be avoided during treatment with mifamurtide.

In vitro interaction studies showed that liposomal and non-liposomal mifamurtide do not inhibitthe metabolic activity of cytochrome P450 in pooled human liver microsomes. Liposomal andnon-liposomal mifamurtide do not induce the metabolic activity or the transcription of cytochrome

P450 in primary cultures of freshly isolated human hepatocytes. Mifamurtide is, therefore, notexpected to interact with the metabolism of substances that are hepatic cytochrome P450substrates.

In a large controlled randomised study, mifamurtide used at the recommended dose and schedulewith other medicinal products that have known renal (cisplatin, ifosfamide) or hepatic (high-dosemethotrexate, ifosfamide) toxicities did not exacerbate those toxicities and there was no need toadjust mifamurtide dose.

There are no data from the use of mifamurtide in pregnant women. Animal studies are insufficientwith respect to reproductive toxicity (see section 5.3). Mifamurtide is not recommended for use duringpregnancy and in women of childbearing potential not using effective contraception.

It is unknown whether mifamurtide is excreted in human milk. The excretion of mifamurtide inmilk has not been studied in animals. A decision on whether to continue/discontinuebreast-feeding or to continue/discontinue therapy should be made taking into account the benefitof breast-feeding to the child and the benefit of mifamurtide therapy to the woman.

No dedicated fertility studies have been conducted with mifamurtide (see section 5.3).

MEPACT has a moderate influence on the ability to drive and use machines. Dizziness, vertigo,fatigue and blurred vision have shown as very common or common undesirable effects ofmifamurtide treatment.

Mifamurtide was studied as a single agent in 248 patients with mostly advanced malignancies duringthe early, single arm phase I and II clinical studies. The most frequent adverse reactions are chills,pyrexia, fatigue, nausea, tachycardia and headache. Many of the very commonly reported adversereactions as shown in the following summary table are thought to be related to the mechanism ofaction of mifamurtide (see table 1). The majority of these events were reported as either mild ormoderate.

Adverse reactions are classified according to system organ class and frequency. Frequencygroupings are defined according to the following convention: very common (≥ 1/10), common(≥ 1/100 to < 1/10), not known (cannot be estimated from the available data). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

System organ class Frequency category Adverse reaction (preferred term)

Infections and infestations Common Sepsis, Cellulitis, Nasopharyngitis,

Catheter site infection, Upperrespiratory tract infection, Urinary tractinfection, Pharyngitis, Herpes simplexinfection

Neoplasms benign, malignant Common Cancer painand unspecified (incl. cysts andpolyps)

System organ class Frequency category Adverse reaction (preferred term)

Blood and lymphatic system Very Common Anaemiadisorders

Common Leukopenia, Thrombocytopenia,

Granulocytopenia, Febrile neutropenia

Metabolism and nutrition Very common Anorexiadisorders

Common Dehydration, Hypokalaemia, Decreasedappetite

Psychiatric disorders Common Confusional state, Depression,

Insomnia, Anxiety

Nervous system disorders Very common Headache, Dizziness

Common Paraesthesia, Hypoaesthesia, Tremor,

Somnolence, Lethargy

Eye disorders Common Blurred vision

Ear and labyrinth disorders Common Vertigo, Tinnitus, Hearing loss

Cardiac disorders Very common Tachycardia

Common Cyanosis, Palpitations

Not known Pericardial effusion

Vascular disorders Very common Hypertension, Hypotension

Common Phlebitis, Flushing, Pallor

Respiratory, thoracic and Very common Dyspnoea, Tachypnoea, Coughmediastinal disorders

Common Pleural effusion, Exacerbated dyspnoea,

Productive cough, Haemoptysis,

Wheezing, Epistaxis, Exertionaldyspnoea, Sinus congestion, Nasalcongestion, Pharyngolaryngeal pain

Gastrointestinal disorders Very common Vomiting, Diarrhoea, Constipation,

Abdominal pain, Nausea

Common Upper abdominal pain, Dyspepsia,

Abdominal distension, Lowerabdominal pain

Hepatobiliary disorders Common Hepatic pain

Skin and subcutaneous tissue Very common Hyperhidrosisdisorders

Common Rash, Pruritis, Erythema, Alopecia, Dryskin

Musculoskeletal and connective Very common Myalgia, Arthralgia, Back pain, Pain intissue disorders extremity

Common Muscle spasms, Neck pain, Groin pain,

Bone pain, Shoulder pain, Chest wallpain, Musculoskeletal stiffness

Renal and urinary disorders Common Haematuria, Dysuria, Pollakiuria

Reproductive system and breast Common Dysmenorrhoeadisorders

System organ class Frequency category Adverse reaction (preferred term)

General disorders and Very common Fever, Chills, Fatigue, Hypothermia,administration site conditions Pain, Malaise, Asthenia, Chest pain

Common Peripheral oedema, Oedema, Mucosalinflammation, Infusion site erythema,

Infusion site reaction, Catheter site pain,

Chest discomfort, Feeling cold

Investigations Common Weight decreased

Surgical and medical Common Post-procedural painprocedures

Anaemia has very commonly been reported when mifamurtide is used in conjunction withchemotherapeutic agents. In a randomised controlled study, the incidence of myeloid malignancy(acute myeloid leukaemia/myelodysplastic syndrome) was the same in patients receiving

MEPACT plus chemotherapy as in patients receiving only chemotherapy (2.1%).

Metabolism and nutritional disorders

Anorexia (21%) was very commonly reported in phase I and II studies of mifamurtide

Consistent with other generalised symptoms, the very common nervous system disorders wereheadache (50%) and dizziness (17%). One patient in the phase III study experienced 2 episodes ofgrade 4 seizure while on study therapy with chemotherapy and mifamurtide. The second episodeinvolved multiple grand mal seizures over the course of days. Mifamurtide treatment wascontinued for the remainder of the study without seizure recurrence.

Ear and labyrinth disorders

Although hearing loss may be attributable to ototoxic chemotherapy, like cisplatin, it is unclearwhether MEPACT in conjunction with multi-agent chemotherapy may increase hearing loss.

A higher percentage of objective and subjective hearing loss was observed overall in patients whoreceived MEPACT and chemotherapy (12% and 4%, respectively) in the phase III study (seesection 5.1 for a description of the study) compared to those patients that received onlychemotherapy (7% and 1%). All patients received a total dose of cisplatin of 480 mg/m2 as part oftheir induction (neoadjuvant) and/or maintenance (adjuvant) chemotherapy regimen.

Cardiac and vascular disorders

Mild-moderate tachycardia (50%), hypertension (26%) and hypotension (29%) were verycommonly reported in uncontrolled studies of mifamurtide. One serious incident of subacutethrombosis was reported in early studies, but no serious cardiac events were associated withmifamurtide in a large randomised controlled study (see section 4.4).

Respiratory disorders, including dyspnoea (21%), cough (18%) and tachypnoea (13%) were verycommonly reported, and 2 patients with pre-existing asthma developed mild to moderaterespiratory distress associated with MEPACT treatment in a phase II study.

Gastrointestinal disorders were frequently associated with mifamurtide administration, includingnausea (57%) and vomiting (44%) in about half of patients, constipation (17%), diarrhoea (13%)and abdominal pain (see section 4.4).

Skin and subcutaneous disorders

Hyperhidrosis (11%) was very common in patients receiving mifamurtide in uncontrolled studies.

Low grade pain was very common in patients receiving mifamurtide, including myalgia (31%),back pain (15%), extremity pain (12%) and arthralgia (10%).

The majority of patients experience chills (89%), fever (85%) and fatigue (53%). These aretypically mild to moderate, transient in nature and generally respond to palliative treatment (e.g.,paracetamol for fever). Other generalised symptoms that were typically mild to moderate and verycommon included hypothermia (23%), malaise (13%), pain (15%), asthenia (13%) and chest pain(11%). Oedema, chest discomfort, local infusion or catheter site reactions and ‘feeling cold’ wereless frequently reported in these patients, mostly with late stage malignant disease.

An osteosarcoma patient in a phase II study who had high creatinine level at enrolment showed anincrease in blood urea and blood creatinine which was associated with mifamurtide use.

In a phase I study, there was one report of severe allergic reaction occurring after the first infusionof mifamurtide at 6 mg/m2 dose level. The patient experienced shaking, chills, fever, nausea,vomiting, uncontrollable coughing, shortness of breath, cyanotic lips, dizziness, weakness,hypotension, tachycardia, hypertension and hypothermia leading to study discontinuation. Therewas also one report of a grade 4 allergic reaction (hypertension) requiring hospitalization in thephase III study (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The maximum tolerated dose in phase I studies was 4-6 mg/m2 with a high variability of adversereactions. Signs and symptoms that were associated with higher doses and/or were dose limitingwere not life-threatening, and included fever, chills, fatigue, nausea, vomiting, headache and hypo-or hypertension.

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

In the event of an overdose, it is recommended that appropriate supportive treatment be initiated.

Supportive measures should be based on institutional guidelines and the clinical symptomsobserved. Examples include paracetamol for fever, chills and headache and anti-emetics (otherthan steroids) for nausea and vomiting.

Pharmacotherapeutic group: Immunostimulants, Other immunostimulants, ATC code: L03AX15

Mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) is a fully syntheticderivative of muramyl dipeptide (MDP), the smallest naturally-occurring immune stimulatorycomponent of cell walls from Mycobacterium sp. It has similar immunostimulatory effects asnatural MDP. MEPACT is a liposomal formulation specifically designed for in vivo targeting tomacrophages by intravenous infusion.

MTP-PE is a specific ligand of NOD2, a receptor found primarily on monocytes, dendritic cellsand macrophages. MTP-PE is a potent activator of monocytes and macrophages. Activation ofhuman macrophages by mifamurtide is associated with production of cytokines, including tumournecrosis factor (TNF-), interleukin-1 (IL-1), IL-6, IL-8, and IL-12 and adhesion molecules,including lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesionmolecule-1 (ICAM-1). In vitro-treated human monocytes killed allogeneic and autologous tumourcells (including melanoma, ovarian, colon, and renal carcinoma), but had no toxicity towardsnormal cells.

In vivo administration of mifamurtide resulted in the inhibition of tumour growth in mouse and ratmodels of lung metastasis, skin and liver cancer, and fibrosarcoma. Significant enhancement ofdisease-free survival was also demonstrated in the treatment of dog osteosarcoma andhemangiosarcoma with mifamurtide as adjuvant therapy. The exact mechanism by whichmifamurtide activation of monocytes and macrophages leads to anti-tumour activity in animalsand humans is not yet known.

The safety of liposomal mifamurtide has been assessed in more than 700 patients with variouskinds and stages of cancer and in 21 healthy adult subjects (see section 4.8).

In a randomised phase III study of 678 patients (age range from 1.4 to 30.6 years) withnewly-diagnosed resectable high-grade osteosarcoma, the addition of adjuvant mifamurtide tochemotherapy (either doxorubicin cisplatin and methotrexate with or without ifosfamide),significantly increased the 6-year overall survival and resulted in a relative reduction in the risk ofdeath by 28% (p = 0.0313, hazard ratio (HR) = 0.72 [95% confidence interval (CI): 0.53, 0. 97]).

Based on the prevalence of the disease, children and young adults were studied in the pivotal trial.

However, no specific subset analyses for efficacy are available in patients < 18 years of age and≥ 18 years of age.

The pharmacokinetics of mifamurtide have been characterised in healthy adult subjects followinga 4 mg intravenous infusion and in paediatric and adult patients with osteosarcoma following a2 mg/m2 intravenous infusion.

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

In 28 osteosarcoma patients aged 6 to 39 years serum total (liposomal and free) mifamurtideconcentrations declined rapidly with a mean half-life of 2.04 ± 0.456 hours. BSA-normalisedclearance and half-life were similar across the age range and consistent with that determined inhealthy 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 freemifamurtide that were assessed after the first infusion of mifamurtide and after a last infusion11 or 12 weeks later, were almost superimposable and the mean AUC values of the freemifamurtide after the first and last infusion were similar. These data indicate that neither total norfree mifamurtide accumulated during the treatment period.

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

Metabolism of liposomal MTP-PE has not been studied in humans.

After injection of radiolabelled liposomes containing mifamurtide, mean half-life of radiolabelledmaterial was biphasic with an α-phase of about 15 minutes and a terminal half-life of approximately18 hours.

The pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenousinfusion were evaluated in adult volunteers with mild (n = 9) or moderate (n = 8) renal impairmentand in age-, sex-, and weight-matched healthy adults with normal renal function (n = 16). Therewas no effect of mild (50 mL/min ≤ creatinine clearance [CLcr] ≤ 80 mL/min) or moderate(30 mL/min ≤ CLcr < 50 mL/min) renal insufficiency on the clearance of total MTP-PE, whencompared with that observed in healthy adult subjects with normal renal function (CLcr> 80 mL/min). Additionally, the systemic exposures AUC from zero to infinity (AUCinf of free(non-liposome associated) MTP-PE in mild or moderate renal insufficiency were similar to thoseobserved in healthy adult subjects with normal renal function.

The pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenousinfusion 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 healthyadults with normal hepatic function (n = 19). There was no effect of mild hepatic impairment onthe systemic exposure (AUCinf) of total MTP-PE. Moderate hepatic impairment resulted in a smallincrease 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 being119% (90% confidence interval [CI]: 94.1%-151%). Pharmacokinetic variability was higher in themoderate hepatic impairment group (co-efficient of variation in systemic exposure [AUCinf] was50% 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 and2.26 hours, respectively). Mean half-lives of total and free MTP-PE in moderate hepatic impairmentwere 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 thanthe corresponding values in the matched normal hepatic function groups. These changes were notconsidered to be clinically meaningful as the maximum tolerated dose (4-6 mg/m2) of mifamurtide is2-3 times the recommended dose (2 mg/m2).

In sensitive species (rabbit and dog) the highest daily dose of liposomal mifamurtide that did notcause adverse effects was 0.1 mg/kg, corresponding to 1.2 and 2 mg/m2, respectively. Theno-adverse-effect level for mifamurtide in animals corresponds roughly to the 2 mg/m2recommend dose for humans.

Data from a six-month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m2)mifamurtide provide an 8- to 19-fold cumulative exposure safety margin for overt toxicity for theintended clinical dose in humans. Major toxic effects associated with these high daily andcumulative doses of mifamurtide were mainly exaggerated pharmacological effects: pyrexia, signsof pronounced inflammatory response manifested as synovitis, bronchopneumonia, pericarditisand inflammatory necrosis of the liver and bone marrow. The following events were alsoobserved: haemorrhage and prolongation of coagulation times, infarcts, morphological changes inthe wall of small arteries, oedema and congestion of the central nervous system, minor cardiaceffects, and slight hyponatraemia. Mifamurtide was not mutagenic and did not cause teratogeniceffects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels.

There were no results from general toxicity studies that suggested harmful effects on male orfemale reproductive organs. Specific studies addressing reproductive function, perinatal toxicityand carcinogenic potential have not been performed.

1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS)

This medicinal product must not be mixed with other medicinal products except those mentionedin section 6.6.

Unopened vial of powder3 years

Chemical and physical stability has been demonstrated for 6 hours up to 25 ºC.

From a microbiological point of view, immediate use is recommended.

If not used immediately, the reconstituted, filtered and diluted solution in-use storage times andconditions prior to use of the reconstituted product must not be longer than 6 hours at 25 ºC.

Do not refrigerate or freeze the solution.

Store in a refrigerator (2 °C-8 °C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

50 mL type I glass vial with a grey butyl rubber stopper, aluminium seal and plastic flip-off cap,containing 4 mg of mifamurtide.

Each carton contains 1 vial and 1 single-use, non-pyrogenic, sterile filter for MEPACT supplied in a

PVC-grade blister.

MEPACT must be reconstituted, filtered using the filter provided and further diluted using aseptictechnique, prior to administration.

Each vial should be reconstituted with 50 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection. After reconstitution, each mL suspension in the vial contains 0.08 mg mifamurtide. Thevolume of reconstituted suspension corresponding to the calculated dose is extracted through thefilter provided and further diluted with additional 50 mL sodium chloride 9 mg/mL (0.9%)solution for injection according to the detailed instructions shown below.

The reconstituted, filtered and diluted suspension for infusion is a homogenous, white to off-white,opaque liposomal suspension, free of visible particles and free of foam and lipid lumps.

Instructions for preparation of MEPACT for intravenous infusion

Materials provided in each package:

* MEPACT powder for concentrate for dispersion for infusion (vial)

* Filter for MEPACT

Materials required but not provided:

* Sodium chloride 9 mg/mL (0.9%) solution for injection, 100 mL bag

* 1 single use 60 or 100 mL sterile syringe with luer lock

* 2 medium (18) gauge sterile injection needles

It is recommended that the reconstitution of the liposomal suspension should be performed in alaminar flow cabinet utilising sterile gloves using aseptic technique.

The lyophilised powder should be allowed to reach a temperature between approximately20 °C-25 °C prior to reconstitution, filtering using the filter provided and dilution. This shouldtake approximately 30 minutes.

1. The cap of the vial should be removed and the stopper cleaned using an alcohol pad.

2. The filter should be removed from the blister pack, and the cap removed from the filterspike. The spike should then be inserted into the vial septum firmly until seated. The filterluer connector cap should not be removed at this time.

3. The 100 mL sodium chloride 9 mg/mL (0.9%) solution for injection bag, needle and syringeshould be unpacked (not provided in the pack).

4. The site of the sodium chloride 9 mg/mL (0.9%) solution for injection bag where the needleis going to be inserted should be swabbed with an alcohol pad.

5. Using the needle and syringe, 50 mL of sodium chloride 9 mg/mL (0.9%) solution forinjection should be withdrawn from the bag.

6. After removing the needle from the syringe, the syringe should be attached to the filter byopening the filter luer connector cap (figure 1).

Figure 17. The sodium chloride 9 mg/mL (0.9%) solution for injection is added to the vial by slow,firm depression of the syringe plunger. The filter and syringe must not be removed fromthe vial.

8. The vial should be allowed to stand undisturbed for 1 minute to ensure thorough hydrationof the dry substance.

9. The vial should then be shaken vigorously for 1 minute while keeping the filter andsyringe attached. During this time the liposomes are formed spontaneously (figure 2).

Figure 210. The desired dose may be withdrawn from the vial by inverting the vial and slowly pullingback on the syringe plunger (figure 3). Each mL reconstituted suspension contains 0.08 mgmifamurtide. The volume of suspension to be withdrawn for dose quantities is calculated asfollows:

Volume to withdraw = [12.5 x calculated dose (mg)] mL

For convenience, the following table of concordance is provided:

Dose Volume1.0 mg 12.5 mL2.0 mg 25 mL3.0 mg 37.5 mL4.0 mg 50 mL

Figure 311. The syringe should then be removed from the filter and a new needle placed on thesuspension-filled syringe. The bag injection site should be wiped with an alcohol pad andthe suspension in the syringe should be injected into the original bag containing theremaining 50 mL of sodium chloride 9 mg/mL (0.9%) solution for injection (figure 4).

Figure 412. The bag should be gently swirled to mix the solution.

13. Patient identification, time and date should be added to the label on the bag containing thereconstituted, filtered and diluted liposomal suspension.

14. Chemical and physical in-use stability has been demonstrated for 6 hours at roomtemperature (between approximately 20 °C-25 °C).

15. From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of theuser and would normally not be longer than 6 hours at room temperature.

16. Based on the liposomal nature of the product, use of an infusion set with an in-line filterduring administration is not recommended.

17. The liposomal suspension is infused intravenously over about 1 hour.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda France SAS112 avenue Kléber75116 Paris

France

EU/1/08/502/001

Date of first authorisation: 6 March 2009

Date of latest renewal: 20 February 2019

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu.