1. NAME OF THE MEDICINAL PRODUCT Mycamine for injection 50 mg/vial & 100 mg/vial 2, QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains 50 mg micafungin equivalent to 50.9 mg micafungin sodium. Each vial contains 100 mg micafungin equivalent to 101.7 mg micafungin sodium. For a full list of excipients, see section 6.1 3. PHARMACEUTICAL FORM Lyophilisate for solution for infusion. White compact Iyophilised powder. 4, CLINICAL PARTICULARS 4.1 Therapeutic indications ‘Mycamine is indicated for: 1) Treatment of Patients with Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses. Mycamine has not been adequately studied in patients with endocarditis, osteomyelitis and meningitis due to Candida infections. 2) Treatment of Patients with Esophageal Candidiasis, 3) Prophylaxis of Candida Infections Patients Undergoing Hematopoietic Stem Cell Transplantation. Note: The efficacy of Mycamine against infections caused by fungi other than Candida has not been established. 4.2 Posology and method of administration Treatment with Mycamine should be initiated by a physician experienced in the management of systemic fungal infections. After reconstitution and dilution, the solution should be administered by intravenous infusion over approximately 1 hour. For reconstitution instructions see section 6.6. Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly. Use in adult patients Detailed information on dosage recommendation for adult patients is provided in the following table: Indication Dose in adult patients Body weight > 40 kg Body weight < 40 kg Treatment of Patients with Candidemia, Acute | 100 mg/day* 2 mg/kg/day* Page of 4Disseminated Candidiasis, Candida Peritonitis, and Abscesses Treatment of Patients with Esophageal 150 mg/day 3 mg/kg/day Candidiasis Prophylaxis of Candida Infections Patients 50 mg/day Img/kg/day Undergoing Hematopoietic Stem Cell Transplantation “If the patient's response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, the dose may be increased to 200 mg/day in patients weighing > 40 kg or 4mg/kg/day in patients wei £40 kg Treatment duration for adult patients Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses: The treatment duration of Candida infection should be a minimum of 14 days. The antifungal treatment should continue for at least one week after two sequential negative blood cultures have been obtained and resolution of clinical signs and after symptoms of infection, Esophageal Candidiasis: For the treatment of oesophageal candidiasis, Mycamine should be administered for at least one week after resolution of clinical signs and symptoms. Prophylaxis of Candida Infections Patients Undergoing Hematopoietic Stem Cell Transplantation: For prophylaxis of Candida infection, Mycamine should be administered for at least one week after neutrophil recovery. Use in Paediatric Patients (including neonatus) and adolescent < 16 years of age Indication Dose in paediatric patients Body weight > 40 kg Body weight < 40 kg 100 mg/day* 2 me/kg/day* Prophylaxis of Candida Infections Patients 50 mg/day Img/kg/day Undergoing Hematopoietic Stem Cell ‘Transplantation *If the patient's response is inadequate, e.g persistence of cultures or if clinical condition does not improve, the dose may be increased to 200 mg/day in patients weighing > 40 kg or 4mg/kg/day in patients weighing S40 kg. ‘Treatment duration for paediatric patients Candidemia, Acute Disseminated Candidiasis, Candida Peritonitis and Abscesses: For treatment duration of Candida infection follow the recommendation as given for adult patients above. Prophylaxis of Candida Infections Patients Undergoing Hematopoietic Stem Cell ‘Transplantation: For prophylaxis of Candida infection, Mycamine should be administered for at least one week after neutrophil recovery. Experience with Mycamine in patients less than 2 years of age is limited Gender/Race Page 2 of 14No dose adjustment is necessary based on gender or race (see section 5.2). se in patients with hepatic impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The data obtained from study of pharmacokinetics of micafungin in patients with severe hepatic dysfunction are insufficient to support a dosing recommendation and its use is not recommended in these patients (see section 5.2). Use in patients with renal impairment No dose adjustment is necessary in patients with renal impairment (see section 5.2). 4.3. Contraindications Mycamine is contraindicated in persons with known hypersensitivity to micafungin any component of ‘Mycamine, or other echinocandins. 4.4 Special warnings and precautions for use Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with micafungin. In some patients with serious underlying conditions who were receiving micafungin along with multiple concomitant medications, clinical hepatic abnormalities have occurred, and isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported. Patients who develop abnormal liver function tests during micafungin therapy should be monitored for evidence of ‘worsening hepatic function and evaluated for the risk/benefit of continuing micafungin therapy. During administration of micafungin, anaphylactoid reactions including shock may occur. If these reactions ‘occur, micafungin infusion should be discontinued and appropriate treatment administered. Isolated cases of haemolysis including acute intravascular haemolysis or haemolytic anaemia have been reported in patients treated with micafungin. Patients who develop clinical or laboratory evidence of haemolysis during micafungin therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin therapy. Hepatic effects: ‘The development of foci of altered hepatocytes (FAH) and hepatocellular tumours after a treatment period of 3 months or longer were observed in rats. The assumed threshold for tumour development in rats is approximately in the range of clinical exposure. The relevance of this finding for the therapeutic use in patients cannot be excluded. Liver function should be carefully monitored during micafungin treatment. To minimise the risk of adaptive regeneration and potentially subsequent liver tumour formation, early discontinuation in the presence of significant and persistent elevation of liver function test is recommended. Micafungin treatment should be conducted on a careful risk/benefit basis, particularly in patients having severe liver function impairment or chronic liver diseases known to represent preneoplastic conditions, such as advanced liver fibrosis, cirhosis, viral hepatitis, neonatal liver disease or congenital enzyme defects, or receiving a concomitant therapy including hepatotoxic and/or genotoxic properties, Micafungin may cause kidney problems, renal failure, and abnormal renal function test. Patients should be closely monitored for worsening of renal function. ‘The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see Undesireable effects). 4.5 Interaction with other medicinal products and other forms of interaction Drug interaction studies in healthy human subjects were conducted to evaluate the potential for interaction between micafungin and mycophenolate mofetil, ciclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin B. In these studies, no evidence of altered pharmacokinetics of micafungin was observed. No micafungin dose adjustments are necessary when these medications are administered concomitantly. Exposure (AUC) of Page 3 ofitraconazole, sirolimus and nifedipine was slightly increased in the presence of micafungin (22%, 21% and 18% respectively). Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P- glycoprotein-mediated drug transport activity. Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediated pathways. Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or itraconazole dosage should be reduced if necessary. 4.6 Pregnancy and lactation ‘There are no adequate data from the use of micafungin in pregnant women, Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown. Mycamine should not be used during pregnancy unless clearly necessary. In the dog testicular toxicity was observed after prolonged treatment of 39 weeks (see section 5.3). Although a potential on male fertility cannot be excluded, the short duration of treatment with Mycamine in patients suggests that the risk for humans is minimal. Micafungin is excreted in the milk of lactating animals. It is not known whether it is excreted in human milk, Women receiving Mycamine should not breast-feed. 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. However, adverse reactions may occur, which may influence the ability to drive and use machines (see section 4.8) 4.8 Undesirable effects ‘The safety profile of micafungin is based on 3028 patients treated with micafungin in clinical studies. 2002 patients with Candida infections (including candidaemia, invasive candidiasis and oesophageal candidiasis), 375 with invasive aspergillosis (primarily refractory infections), 651 patients treated with Micafungin for prevention of systemic fungal infections (prophylaxis). The patients treated with micafungin in clinical studies represent a critically ill patient population complex underlying diseases and the requirement of multiple co-medications including antineoplastic chemotherapy, potent systemic immunosuppressants and broad spectrum antibiotics. These patients had a wide variety of underlying conditions such as haematological malignancies, were transplant recipients, had HIV-infection and/or were in intensive care. Patients treated prophylactically with Micafungin were those at high risk for fungal infections undergoing a haematopoetic stem cell transplant (HSCT). Overall 32.2% of the patients experienced adverse drug reactions assessed to be potentially related to micafungin by the investigator. The most frequently reported adverse reactions were nausea (2.8%), phlebitis (2.5%, primarily in HIV infected patients with peripheral lines), vomiting (2.5%), and aspartate aminotransferase increase (2.3%) and blood alkaline phosphatase increased (2.7%). No clinically significant differences were seen when the safety data were analysed by age, gender or race. In the following table adverse reactions assessed to be potentially related to micafungin are listed by system organ class and MedDRA preferred term (incidence > 1%). In addition, all reactions are listed, which require medical attentiveness. Paediatric patients Page dof 4 LE eeThe incidence of some adverse reactions (listed in the table below) was higher in paediatric patients than in adult patients. Additionally, paediatric patients <1 year of age experienced about two times more often an increase in ALT, AST and AP than older paediatric patients (see section 4.4). The most likely reason for these differences were different underlying conditions compared with adults or older paediatric patients observed in clinical studies. At the time of entering the study, the proportion of paediatric patients with neutropenia was several-fold higher than in adult patients (40.2% and 7.3% of children and adults, respectively), as well as allogeneic HSCT (29.4% and 13.4%, respectively) and haematological malignancy (29.1% and 8.7%, respectively). Blood and Ivmphatic system disorders Common Thrombocytopenia Cardiac disorders Common Tachycardia Vascular disorders Common hypertension, hypotension Hepatobiliary disorders Common hyperbilirubinaemia, hepatomegaly Renal and urinary disordrs ‘Common acute renal failure, blood urea increased In the following table adverse reactions are listed by system organ class and MedDRA preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. [common > 1/100 (1%), < 1/10 (10%); uncommon > 1/1000 (0.1%), < 1/100 (1%) rare > 1/10000 (0.01%), < 1/1000 (0.1%)] Blood and lymphatic system disorders common | Neutropenia, Anaemia, Leukopenia uncommon ‘Thrombocytopenia, pancytopenia, eosinophilia, hypoalbuminacmia rare Haemolytic anaemia, Haemolysis (see section 4.4) _ unknown ‘Disseminated intravascular coagulation a Immune system disorders uncommon Anaphylactic reaction (see section 4.4) unknown Anaphylactoid shock ritional disord ‘common Hypokalaemia, Hypomagnesaemia, Hypocalcaemia uncommon Hyponatraemia, hyperkalaemia, hypophosphataemia, anorexia Nervous system disorders common Headache uncommon Somnolence, tremor, dizziness, dysgeusia Vascular disorders ‘common Phiebitis uncommon Hypotension, hypertension, flushing Page Sof 14Gastrointestinal disorders, common Diarrhoea, Nausea, Vomiti uncommon Dyspepsia, constipation Hepatobiliary disorders common Hyperbilirubinaemia, blood bilirubin increased uncommon Hepatic failure (see section 4.4), gamma-glutamyltransferase increased, jaundice, cholestasis, hepatomegaly, hepatitis, unknown Hepatic function abnormal, hepatocellular damage Skin and subcutaneous tissue disorders common Rash. uncommon Urticaria, pruritus, erythema unknown Erythema Multiforme, Steven-Johnson Syndrome, Toxic Epidermal Necrolysis Renal and urinary disorders uncommon Renal failure aggravated, blood creatinine increased, blood urea increased unknown Renal impairment, renal failure acute (see section 4.4) General Disorders and Administration Site Conditions ‘common Pyrexia, Rigors uncommon Injection site thrombosis, infusion site inflammation, injection site pain, peripheral oedema Investigations Liver function analysis common Liver function tests abnormal, Alanine aminotransferase increased, Aspartate aminotransferase increased Other investigations common Blood alkaline phosphatase increased uncommon Blood lactate dehydrogenase increased Endocrine disorders uncommon hyperhidrosis Respiratory, thoracic and mediastinal disord. uncommon Dyspnoea Page 6 of 4Cardiac disorders uncommon Tachycardia, palpitations, bradycardia Hepatic adverse reactions ‘The overall incidence of hepatic adverse reactions in the micafungin clinical studies was 8.6% (260/3028) of patients treated with micafungin. The majority of hepatic adverse reactions were mild and moderate. Most frequent events were increase in AST (2.3%), ALT (2.0%), AP (2.7%) and Liver function test abnormal (1.5%), and blood bilirubin (1.6%). Isolated cases of serious hepatic dysfunction occurred. Possible histamine-mediated symptoms ‘Symptoms like rash and rigors have been reported in clinical studies. Of those the majority were of mild to ‘moderate intensity and not treatment limiting. Serious reactions (e.g. anaphylactoid reaction) have been rarely reported during therapy with micafungin and only in patients with serious underlying conditions (e.g, advanced AIDS, malignancies) requiring multiple co-medications. Besides clinical studies isolated cases of anaphylactoid shock have been recorded during post -marketing experience without fatal outcome. Hacmolytic reactions In clinical studies haemolytic reactions occurred in 3 out of 2595 patients. 2 patients had advanced AIDS and 1 patient was post heart-kidney transplantation. During post-marketing experience isolated cases of haemolysis including intravascular haemolysis have been reported (see section 4.4). Injection-site reactions 4.4% of patients had a treatment-related injection site-reaction and phlebitis was the most frequently reported local injection-site adverse reaction. None of the injection-site adverse reactions were treatment limiting. Review of safety data from post-marketing experience since 2002 has revealed no new safety signals compared with the clinical trial database. 4.9 Overdose Repeated daily doses up to 8 mg/kg (maximum total dose 896 mg) in adult patients have been administered in clinical trials with no reported dose-limiting toxicity. One case of mis-dosage of 7.8 mg/kg/day for 7 days ‘was reported in a newborn patient. No ill effects associated with this high dose were noted. Micafimgin is highly protein-bound and not dialysable. 5, PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimycotics for systemic use, ATC code: JO2AX0S Micafungin is a lipopeptide of the echinocandin class, synthesised by chemical modification of a fermentation product of Coleophoma empetri. Micafungin non-competitively inhibits the synthesis of 1,3-B- D-glucan an essential component of the fungal cell wall. 1,3-B-D-glucan is not present in mammalian cells. Micafungin exhibited fungicidal activity against most Candida species species. In vitro susceptibility testing showed that micafungin has a broad spectrum and potent activity against Candida species (C. albicans, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii, C. dubliniensis, C. Page 7 of 14lusitaniae, C. parapsilosis, C. kefyr, C. stellatoidea), including isolates with acquired or inherent resistance to flucanozole, itraconazole and amphotericin B. Micafungin has no in vitro activity against Cryptococcus neoformans, Fusarium solani, Pseudoallescheria boydii and zygomycetes. Susceptibility testing was performed with modifications according to the Clinical and Laboratory Standards Institute (CLSI) methods M27-A2 (Candida species), respectively. To date, standardised techniques for susceptibility testing for 1,3-B-D-glucan synthesis inhibitors have not been established and results of susceptibility testing do not necessarily correlate with clinical outcome. In vitro, resistance development was not induced after repeated exposure of C. albicans to subinhibitory concentrations of micafungin. Micafungin was consistently effective in immunocompromised mouse models of disseminated candidiasis and aspergillosis, and pulmonary aspergillosis. In the oropharyngeal and oesophageal candidiasis model, ‘micafungin showed an eradicative effect without relapse after cessation of treatment. Mechanismn(s) of resistance As for all antimicrobial agents, cases of reduced susceptibility and resistance have been reported and cross- resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandins has been associated with mutations in the Fks1 and Fks2 genes coding for a major subunit of glucan synthase. Clinical experience Invasive Candidiasis: Five-hundred thirty-one adult patients (= 16 years of age) and 45 paediatric patients (© 16 years of age) received at least one dose of study drug (full analysis set, FAS) in a randomised, double- blind study that compared micafungin and liposomal amphotericin B in the treatment of candidaemia and invasive candidiasis. Patients in the main efficacy population (per protocol set, PPS) had to have a confirmed Candida infection at baseline, at least five doses of study drug, efficacy data available at end of therapy, and no prohibited medication. Treatment success required both a clinical response (complete or partial) and a mycological response (eradication or presumed eradication) at the end of therapy. The PPS included 202 adult patients in the micafungin group and 190 adult patients in the liposomal amphotericin B group. Treatment groups did not significantly differ for any demographic or baseline characteristic. At baseline, 24 (11.9%) patients in the micafungin group and 15 (7.9%) patients in the liposomal amphotericin B group were neutropenic (absolute neutrophil count < 500 cells/j1L) and 39 (19.3%) and 37 (19.5%) patients, respectively had an acute physiology and chronic health evaluation (APACHE) II score that was greater than 20. Both treatment groups received study drug for a median of 15 days (PPS). The ‘median daily dose was 100 mg for micafungin and 3 mg/kg for liposomal amphotericin B. Table 1: Overall Treatment Success Including Stratification by Neutropenic Status and Candida Species for Adult Patients in the Per Protocol Set, Invasive Candidiasis Study Micafungin Liposomal ‘% Difference Amphotericin B 19s [nT No. (%) [nT No. %) Overall Treatment Success ~ [202 [181 (89.6) [190 _ | 170 (89.5) o1 Complete Response 159 (78.7) —_ [148 (7.9) (5.9, 6.1] Partial Response 2210.9) 22.(11.6) Overall Treatment Success by Neutropenic Status _ Neutropenia at baseline 24 [18(75.0) [1s [12(@0.0) 07 No neutropenia at baseline 178_[163(91.6) | 175 _ | 158 (90.3) (53,6.71+ Overall Treatment Success by Candida Species Candida albicans 86 | 76(884) [84 [75 (89.3) Non- albicans Candida species 126 [113 (89.7) _| 112 _| 100 (89.3) C.tropicalis 5248023) [43 [4105.3) Page Sof 4CC parapsilosis 37_|33(89.2) | 30 | 26 (86.7) CC. glabrata 23__|19(82.6) | 15__| 12 (80.0) ‘ff Micafungin rate minus the liposomal amphotericin B rate, two sided 95% confidence interval for the 0.999, Fisher’s exact test) (PPS). Treatment success was experienced by 76.5% (13/17) and 84.2% (16/19) of paediatric patients (<16 years of age) in the micafungin and liposomal amphotericin B groups, respectively (PPS). Oesophageal Candidiasis: Five-hundred eighteen patients received at least a single dose of study drug (full analysis set = safety set = primary analysis set for efficacy analysis) in a randomised, double-blind study that compared micafungin and fluconazole in the treatment of oesophageal candidiasis. Treatment success (endoscopic cure) was defined as an oesophageal mucosal grade of 0 at end of therapy. Demographic and baseline characteristics were similar for the two treatment groups, as was the infective Candida species. The ‘median duration of treatment was 14 days for both study groups, and the median average daily dose was 150 ‘mg for micafungin and 200 mg for fluconazole. Table 2: Success Rate (Rate of Patients with Endoscopy Grade of 0 at End of Therapy) in the Full Analysis Set, Oesophageal Candidiasis Study icafungin | Fluconazole | Treatment | 95% CI for the 260 =258 Difference + _| Difference +. Success 228 (87.7%) | _227 (88.0%) 0.3% [:5.9%, 5.3%] Failure 32 (12.3%) 31 (12.0%) Mucosal Grade > 0 7(2.7%) 10 3.9%) Not Evaluable _25 (9.6%) 21 (8.1%) +t Micafungin rate minus the fluconazole rate. +£.95% confidence interval forthe difference in overall success rate is based on the large sample normal approximation Micafungin was shown to be not inferior to fluconazole, because the lower limit of the 95% CI was above the predefined non-inferiority margin of -10%. The relapse rate during the 4-week post-treatment period for patients who had been treated successfully at the end of therapy was 15.2% (30/198) and 11.3% (22/195), in the micafungin and fluconazole groups, respectively. Prophylaxis: Eight-hundred eighty-two patients received at least a single dose of study drug (full analysis set = safety set = primary analysis set for efficacy analysis) in a randomised, double-blind study that compared micafungin and fluconazole in the prophylaxis of invasive fungal infections in adult and paediatric (> 6 months old) patients undergoing allogeneic and autologous haematopoietic stem cell transplantation (HSCT). Treatment success was defined as the absence of a proven, probable, or suspected systemic fungal infection through the end of therapy and the absence of a proven or probable systemic fungal infection through the end of the 4-week post-treatment period; both criteria had to be met in order for the patient to be considered a treatment success. The micafungin (N = 425) and fluconazole (N= 457) treatment groups were well balanced in terms of gender, race, age, weight, types of transplant or risk of transplant related mortality. The study included 84/882 (9.5%) paediatric patients (<16 years of age) and 56/882 (6.3%) elderly patients (265 years of age). Approximately half of the patients who received micafungin (220/425, 51.8%) or fluconazole (256/457, 56.0%) received an allogeneic transplant. Of the 404 Page 9 of 4patients who received an autologous HSCT, 399 (98.8%) patients received an HSCT for leukemia or lymphoma. Of the 882 patients in the FAS, 854 (96.8%) had neutropenia with an ANC <200 cells/L at baseline, and the overall median duration of neutropenia in both treatment arms was 13 days. The median duration of treatment was 18 days for adults in both treatment groups and 22 days and 21 days for paediatric patients in the micafungin and fluconazole groups, respectively. The median average daily dose of micafungin was 50 mg for adults 1.0 mg/kg for children and the median average daily dose of fluconazole ‘was 400 mg for adults and 7.7 mg/kg for children. Table 3: Treatment Success at End of Study (after Treatment and 4 Weeks of Follow-up) in the Full Analysis Set, Prophylaxis Study ‘Micafungin Fluconazole | Treatment (n=425) (n=457) Difference + | 95% CI +t Overall 340 (80.0%) 336 (73.5%) | + 6.5% (0.9%, 12.0%) ‘Type of hematopoietic stem cell transplant 175/256 Allogeneic 157/220 (71.4%) | (68.4%) +3.0% ‘Autologous or 4) | 161/201 », peste 181/203 (89.2%) | ($9,196) +9.1% ‘None 272 (100.0%) [0 = _ +t Micafiungin rate minus the Huconazole rate; +f 95% confidence interval for the difference in overall success rate is based on the large sample normal approximation. The treatment success rate was significantly higher for micafungin compared to fluconazole. A log-rank test, which tested treatment success over the study period, was significantly different between the 2 treatment arms (P = 0.025). This treatment difference was consistent for patients who underwent an allogeneic or autologous HSCT. Treatment differences were consistent, in favour of micafungin, when data were stratified for graft-versus-host disease (GVHD), age, gender or fungal colonisation, The requirement for empirical antifungal therapy was lower in the micafungin arm (64/425, 15.1%) compared with the fluconazole arm (98/457, 21.4%) (P = 0.024). Overall, this study showed that micafungin is more effective than fluconazole in preventing invasive fungal infections and in reducing the requirement for empirical antifungal therapy for patients undergoing HSCT. 5.2 Pharmacokinetic properties ‘The pharmacokinetics of micafungin have been evaluated in healthy subjects, HSCT recipients, patients with oesophageal candidiasis and patients with systemic Candida infections Absorption ‘Micafungin is an intravenously administered medication. Distr Following intravenous administration concentrations of micafungin show a biexponential decline. The drug is rapidly distributed into tissues. The relationship of the Area Under the Concentration-time curve (AUC) to micafungin dose was linear over the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg. There is no evidence of systemic accumulation with repeated administration and steady-state is generally reached within 4 to 5 days In systemic circulation, micafungin is highly bound to plasma protein (> 99%), primarily to albumin, Binding to albumin is independent of micafungin concentration (10-100 .g/mL), Metabolism Page 10 of 14Unchanged Micafungin is the principal circulating compound in systemic circulation. Micafungin has been shown to be metabolised to several compounds; of these M-I (catechol form), M-2 (methoxy form) and M-5 (hydroxylation at the side chain) of micafungin have been detected in systemic circulation. Exposure to these metabolites is low and metabolites do not contribute to the overall efficacy of micafungin. Even though micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo. Elimination and excretion ‘The mean terminal half-life is approximately 10-17 hours and stays consistent across doses up to 8 mg/kg and after single and repeated administration. Total clearance was 0.15-0.3 ml/min/kg in healthy subjects and adult patients and is independent of dose after single and repeated administration. Following a single intravenous dose of '*C-micafungin (25 mg) to healthy volunteers, 11.6% of the radioactivity was recovered in the urine and 71.0% in the faeces over 28 days. These data indicate that climination of micafungin is primarily non-renal. In plasma, metabolites M-1 and M-2 were detected only at trace concentrations and metabolite M-5, the more abundant metabolite, accounted for a total of 6.5% relative to parent compound. Special populations Paediatric patients: In paediatric patients AUC values were dose proportional over the dose range of 0.5- 4 mg/kg. Clearance was influenced by age, with mean values of clearance in younger children (2-11 years) being approximately 1.3 -fold greater than those in older children (12-17 years). Older children had mean clearance values similar to those determined in adult patients. Mean clearance in premature infants (gestational age approximately 26 weeks) is approximately 5-fold greater than adults, Elderly: When administered as a single I-hour infusion of 50 mg the pharmacokinetics of micafungin in the elderly (aged 66-78 years) were similar to those in young (20-24 years) subjects. No dose adjustment is necessary for the elderly. Patients with hepatic impairment: Moderate hepatic impairment (Child-Pugh score 7-9) did not significantly affect the pharmacokinetics of micafungin. No dose adjustment is necessary for patients with mild to moderate hepatic impairment. A single I-hour infusion of 100 mg micafungin was administered to 8 subjects with severe hepatic dysfunction (Child-Pugh score 10-12) and 8 age-, gender-, ethnic-, and weight-matched subjects with normal hepatic function. The micafungin AUC for subjects with svere hepatic dysfunction was 68.2% [(50.8, 91.5) 90% CI] of that seen in the subjects with normal hepatic function. The M-5 (hydroxide metabolite) AUC for subjects with severe hepatic dysfunction was 231.8% [(152.3, 352.7) 90% Cl] of that seen in the subjects with normal hepatic function. These data are insufficient to support a dosing recommendation in patients with severe hepatic impairment. Patients with renal impairment: Severe renal impairment (GFR < 30 ml/min) did not significantly affect the pharmacokinetics of micafungin. No dose adjustment is necessary for patients with renal impairment. Gender/Race: Gender and race (Caucasian, Black and Oriental) did not significantly influence the pharmacokinetic parameters of micafungin. No dose adjustment of micafungin is required based on gender or race. 5.3 Preclinical safety data The toxicology of micafungin following repeated dosing was evaluated in rats and dogs. At a dose of 32 mg/kg/day, signs of hepatotoxicity were present in both species. In rats, signs of hepatotoxicity consisted Page 11 of 14of degenerative changes of hepatocytes which were accompanied by signs of compensatory regeneration. In 13-week and 26-week repeat dose studies, micafungin induced foci of altered hepatocytes in rats which persisted after a 13-week withdrawal period. Signs of hepatotoxicity in the dog at 32 mg/kg/day were liver discoloration and centrilobular hypertrophy. In rats, vacuolation of the renal pelvic epithelium as well as vacuolation and thickening (hyperplasia) of the bladder epithelium were observed in 26-week repeat dose studies at 32 mg/kg/day. These changes declined after 6 to18 month withdrawal periods. Male rats treated intravenously with micafungin sodium for 9 weeks showed vacuolation of the epididymal ductal epithelial cells at 10 and 32 mg/kg/day. A dose of 32 mg/kg/day resulted in higher epididymis weights and reduced number of sperm cells. There was no impairment of fertility in rat studies with micafungin, In dogs, lower testes weight, atrophy of seminiferous tubules and decreased sperm counts were noted after prolonged treatment (39 weeks) at 10 and 32 mg/kg/day. Vacuolation of the seminiferous epithelium, affecting Sertoli cells, was noted at 32 mg/kg/day. In reproductive and developmental toxicity studies, reduced birth weight of the pups was noted. One abortion occurred in rabbits at 32/mg/kg/day. Micafungin was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and in vivo tests Standard carcinogenicity studies have not been conducted in the view of the expected short duration of treatment. Two, 2-year female rat studies were conducted at daily doses of 20 mg/kg and 32 mg/kg. The development of foci of altered hepatocytes was assessed up to 21 months after cessation of a 3-month treatment and up to 18 months after a 6-month treatment with micafungin. In the 6-month treatment study, the incidence and number of hepatocellular adenoma were significantly increased in the 32 mg/kg/day treatment group at the end of the 18 month recovery period. In the 3-month treatment study the number of adenoma in the 32 mg/kg/day group was significantly increased at the end of the 21 month recovery period ‘There was no significant increase in the incidence or number of carcinoma, 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Lactose monohydrate Citric acid anhydrous (to adjust the pH) Sodium hydroxide (to adjust the pH), 6.2 Incompatibilities This medicinal product must not be mixed or co-infused with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vial: 3 years. 64 Special precautions for storage Unopened vials: This medicinal product does not require any special storage conditions. Reconstituted concentrate in vial Chemical and physical in-use stability has been demonstrated for up to 24 hours at 30°C when reconstituted with sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion. Page 12 0f 14Diluted infusion solut Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C and under protection from light when diluted with sodium chloride 9 mg/mL (0.9 %) solution for infusion or glucose 50 mg/mL (5%) solution for infusion. Mycamine contains no preservatives. From a microbiological point of view, the reconstituted and diluted solutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the reconstitution and dilution have taken place in controlled and validated aseptic conditions. 65 Nature and contents of container 10 mL Type I glass vial with an isobutylene-isoprene (Teflon-laminated) rubber stopper and a flip-off cap. ‘The vial is wrapped with an UV-protective film, Supplied in packs of 1 vial. 6.6 Special precautions for disposal ‘No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. Mycamine must not be mixed or co-infused with other medicinal products except those mentioned below. Using aseptic techniques at room temperature, Mycamine is reconstituted and diluted as follows: 1. The plastic cap must be removed from the vial and the stopper disinfected with alcohol. 2. Five mL of sodium chloride 9 mg/mL (0.9 %) solution for infusion or glucose 50 mg/mL (5 %) solution for infusion (taken from a 100 mL bottle/bag) should be aseptically and slowly injected into each vial along the side of the inner wall. Although the concentrate will foam, every effort should be made to minimise the amount of foam generated. A sufficient number of vials of Mycamine must be reconstituted to obtain the required dose in mg (see table below). 3. The vial should be rotated gently. DO NOT SHAKE. The lyophilised powder will dissolve completely. The concentrate should be used immediately. The vial is for single use only. Therefore, please discard unused reconstituted concentrate immediately. 4, lll of the reconstituted concentrate should be withdrawn from each vial and returned into the infusion bottle/bag from which it was originally taken. The diluted infusion solution should be used immediately. Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C and under protection from light when diluted as described above. Mycamine contains no preservative. From a microbiological point of view, the solutions should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the reconstitution and dilution have taken place in controlled and validated aseptic conditions. 5. The infusion bottle/bag should be gently inverted to disperse the diluted solution but NOT agitated in order to avoid foaming. Do not use if the solution is cloudy or has precipitated, 6. The infusion bottle/bag containing the diluted infusion solution should be inserted into a closable opaque bag for protection from light. Preparation of the solution for infusion Dose ‘Mycamine vial ‘Volume Standard infusion (mg) to be used (concentration) (added up to 100 mL) (mg/vial) of reconstituted lyophilisate Final concentra 30 1x50 ~__ approx. 5 mL (10 mg/mL) 0.50 (mg/mL) Page 13 of 4100 1x100 approx. Sm (20mg/mL) 1.0 (mg/mL) 150 1x100+1x50 approx. 10 mL. 1.5 (mg/mL) 200 2x 100 approx. 10 mL 2.0 (mg/mL) PACKAGING: Mycamine® for Injection: 1 Box of 1 Vial Store below 30°C “Harus dengan resep dokter” Mycamine 50mg, Reg. No. ‘Mycamine 100mg, Reg. No.: Manufactured by: Astellas Pharma tech Co., Ltd, Toyama, Japan Imported by: PT. Combiphar, Bandung, Indonesia Repacked by: PT. Combiphar, Bandung, Indonesia Page 14 0f 4 cca acreINFORMASI UNTUK PASIEN Mycamine® 50mg serbuk untuk injeksi Mycamine® 100mg serbuk untuk injeksi Micafungin Bacalah leaflet ini dengan seksama sebelum anda mengkonsumsi obat ini karena beri informasi yang sangat penting untuk anda. - Simpanlah leaflet ini. Anda mungkin perlu untuk membacanya lagi. ~ _Jika anda memiliki pertanyaan lebih lanjut, silahkan menghubungi dokter atau apoteker anda - _Jika anda mengalami efek samping segera hubungi dokter atau apoteker anda. Termasuk jika anda mengalami efek samping yang tidak tercantum dalam leaflet ini. Lihat nomor 4 Apa saja yang terdapat dalam leaflet i . Apa itu Mycamine® dan digunakan untuk apa Apa yang perlu diketahui sebelum menggunakan Mycamine® Bagaimana cara menggunakan Mycamine® Kemungkinan efek samping yang dapat terjadi Bagaimana cara menyimpan Mycamine® Isi kemasan dan informasi lainnya 1. Apa itu Mycamine® dan digunakan untuk apa Mycamine® merupakan obat anti jamur. Mengandung micafungin sebagai zat aktif. Mycamine® digunakan untuk mengobati dan mencegah infeksi jamur termasuk infeksi sistemik (infeksi yang telah masuk keseluruh tubuh) disebabkan oleh salah satu tipe ragi yang disebut Candida. Dinding sel merupakan bagian penting dari jamur untuk dapat hidup dan berkembang. Mycamine® bekerja dengan cara mengganggu produksi dari dinding sel jamur. Dokter akan meresepkan Mycamine® untuk anda dalam situasi sebagai berikut © Untuk mengobati orang dewasa, remaja dan anak-anak yang memiliki infeksi jamur serius yang disebut invasif kandidiasis (infeksi yang telah menembus tubuh) © Untuk mengobati orang dewasa dan remaja dengan umur > 16 tahun yang menili infeksi jamur di kerongkongan (esofagus) di mana pengobatan ke melalui pembuluh darah (intravena) merupakan cara yang tepat © Untuk mencegah infeksi Candida yang dapat menembus tubuh pada orang dewasa, remaja dan anak-anak yang berada pada risiko infeksi seperti dalam masa penyembuhan selama menjalani transplantasi sel induk pada jenis tertentu 2. Apa yang perlu diketahui sebelum menggunakan Mycamine® Jangan menggunakan Mycamine® Jika anda alergi terhadap zat lain yang terkandung pada Mycamine® (dapat dilihat pada nomor 6 atau jenis echinocandin lain Peringatan dan perhatian Pada tikus, kerusakan hati dan tumor hati terlihat pada penggunaan micafungin jangka panjang. Tidak diketahui risiko potensial perkembangan tumor hati pada manusia, dan dokter anda akan menilai keuntungan dan risiko penggunaan Mycamine® sebelum mulai menggunakan. Informasikan kepada dokter anda jika anda memiliki masalah hati (contohnyagagal hati atau hepatitis) atau memiliki ketidaknormalan tes fungsi hati. Selama pengobatan, fungsi hati anda akan dimonitor secara ketat, Micafungin dapat menyebabkan masalah ginjal, gagal ginjal, dan ketidaknormalan tes fungsi sginjal. Fungsi ginjal anda akan dimonitor secara ketat. Selama penggunaan micafungin, reaksi anafilaksis dapat terjadi. Jika reaksi tersebut terjadi, infus micafungin harus dihentikan dan diberikan pengobatan yang tepat. Kejadian beberapa efek samping lebih tinggi pada pasien anak-anak dibandingkan pasien dewasa (lihat bagian Kemungkinan efek samping yang dapat terjadi). Obat-obatan lain dan Mycamine® Informasikan kepada dokter atau apoteker anda jika anda sedang menggunakan, atau baru saja akan menggunakan obat-obatan lain. Hal ini penting untuk di informasikan kepada dokter anda jika anda menggunakan antijamur (contohnya itrakonazol), anti bakteri (contohnya rifampisin), obat penekan imun (contohnya sirolimus, prednisone, ciclosporin), antivirus (contohnya ritonavir) atau obat_hipertensi golongan kalsium antaonis (contohnya nifedipine). Dokter anda mungkin akan memutuskan untuk menyesuaikan dosis obat-obatan tersebut. Mycamine® dengan makanan dan minuman Karena Mycamine® digunakan secara intravena (melalui pembuluh darah), tidak diperlukan batasan makanan dan minuman. Kehamilan dan menyusui Jika anda sedang hamil dan menyusui, atau anda berfikir sedang hamil atau berencana untuk ‘memiliki bayi, tanyakan saran kepada dokter atau apoteker sebelum menggunakan obat ini Mycamine tidak boleh digunakan selama kehamilan kecuali jika dirasakan perlu. Jika anda menggunakan Mycamine anda tidak boleh menyusui. Mengemudi dan menggunakan mesin Tidak tersedia informasi mengenai efek Mycamine® dalam mempengaruhi kemampuan menyetir atau menggunakan mesin. Informasikan kepada dokter anda jika anda mengalami efek apapun yang dapat menyebabkan anda memiliki masalah dalam mengemudi atau menggunakan mesin. 3. Bagaimana cara menggunakan Mycamine® Mycamine® harus disiapkan dan diberikan kepada anda oleh dokter atau tenaga kesehatan profesional lainnya. Mycamine® harus diberikan sehari sekali melalui intravena (kedalam pembuluh darah) secara perlahan. Dokter anda akan menentukan berapa banyak Mycamine® yang anda butuhkan setiap hari nya. Penggunaan pada pasien dewasa, remaja umur > 16 tahun dan lanjut usia. - Dosis umum untuk mengobati infeksi invasif Kandida adalah 100 mg per hari untuk pasien dengan berat badan lebih dari 40 kg dan 2 mg/kg per hari untuk pasien dengan berat badan 40 kg atau kurang,- Dosis untuk mengobati infeksi Kandida pada esofagus adalah 150 mg untuk pasien dengan berat badan lebih dari 40 kg dan 3 mg/kg per hari untuk pasien dengan berat badan 40 kg atau kurang. - Dosis umum untuk mencegah infeksi invasif Kandida adalah 50 mg per hari untuk pasien dengan berat badan lebih dari 40 kg dan 1 mg/kg per hari untuk pasien dengan berat badan 40 kg atau kurang. Penggunaan pada anak (termasuk bayi baru lahir) dan remaja umur < 16 tahun - Dosis umum untuk mengobati infeksi invasif Kandida adalah 100 mg per hari untuk pasien dengan berat badan lebih dari 40 kg dan 2 mg/kg per hari untuk pasien dengan berat badan 40 kg atau kurang. ~ Dosis umum untuk mencegah infeksi invasif Kandida adalah 50 mg per hari untuk pasien dengan berat badan lebih dari 40 kg dan 1 mg/kg per hari untuk pasien dengan berat badan 40 kg atau kurang. Jika anda menggunakan Mycamine® lebih banyak dari yang seharusnya Dokter anda akan memantau tanggapan dan kondisi anda untuk menentukan berapa dosis Mycamine® yang anda butubkan, Namun, jika anda merasa anda diberikan Mycamine® terlalu banyak, informasikan secepatnya kepada dokter anda atau tenaga kesehatan profesional lainnya. Jika anda lupa menggunakan Mycamine® Dokter anda akan memantau tanggapan dan kondisi anda untuk menentukan berapa dosis ‘Mycamine® yang anda butuhkan. Namun, jika anda merasa anda lupa diberikan Mycamine®, informasikan secepatnya kepada dokter anda atau tenega kesehatan profesional lainnya. Jika anda memiliki pertanyaan lebih lanjut mengenai penggunaan produk ini, tanyakan kepada dokter atau apoteker anda. 4. Kemungkinan efek samping yang dapat terjadi Seperti halnya obat lain, obat ini dapat menyebabkan efek samping, walaupun tidak semua orang mengalaminya Jika anda mengalami alergi, atau reaksi kulit yang berat, anda harus segera menginformasikan kepada dokter atau perawat anda. Mycamine®dapat menyebabkan beberapa kemungkinan efek samping: Umum terjadi (dapat mempengaruhi hingga | dari 10 orang) - Ketidaknormalan tes darah (penurunan sel darah putih (leukopenia, neutropenial); penurunan sel darah merah (anemia) + Penurunan kadar kalium dalam darah (hipokalemia); penurunan kadar magnesium dalam darah (hipomagnesaemia); penurunan kadar kalsium dalam darah (hipokalkaemia) - Sakit kepala - Pembengkakan pembuluh darah vena - Mual (perasaan sakit); muntah; diare; sakit perut - Peningkatan pigmen empedu dalam darah (hiperbilirubinemia), peningkatan bilirubin dalam darah - Kemerahan - Demam - Menggigil- Ketidaknormalan tes fungsi hati, peningkatan alanin aminotransferase, peningkatan aspartat aminotransferase - Alkali fosfatase darah meningkat Tidak umum terjadi (dapat mempengaruhi hingga | dari 100 orang) - Ketidaknormalan tes darah (penurunan sel darah [pansitopenia]); penurunan platelet, darah (trombositopenia); peningkatan beberapa jenis sel darah merah yang disebut eosinofil; penurunan kadar albumin dalam darah (hipoalbuminaemia) - Hipersensitif - Penurunan kadar natrium dalam darah (hiponatremia); peningkatan kadar kalium dalam darah (hiperkalemia); penurunan kadar fosfat dalam darah (hipofosfatemia); anorexia (gangguan makan) - Merasa lesu (somnolence); gemetaran; pusing; perubahan rasa - Tekanan darah menurun atau meningkat, wajah berwarna merah - Gangguan pencernaan, sulit buang air besar ~ Gagal hati, peningkatan enzim hati (gamma-glutamyltransferase); mata atau kulit menjadi berwarna Kekuningan atau putih; pengurangan kadar empedu di usus, pembengkakan hati; radang pada hati - Gata kemerahan; gatal; kulit menjadi berwarna merah ~ Ketidaknormalan tes fungsi ginjal (peningkatan kadar kreatinin dalam darah; peningkatan kadar urea dalam darah); perburukan gagal ginjal - Peningkatan enzim yang disebut dehidrogenase laktat ~ Pembekuan pembuiuh darah di tempat suntik; rada di tempat suntik; sakit di tempat suntik; pengumpulan cairan pada tubuh - Peningkatan denyut jantung, penurunan denyut jantung, detak jantung menguat, detak jantung tidak beraturan - Keringat berlebih - Kesulitan bernafas Jarang terjadi (dapat mempengaruhi hingga 1 dari 1.000 orang) - Anemia karena kerusakan sel darah merah (anemia hemolitik), kerusakan sel darah merah (hemolisis) Tidak diketahui kejadiannya (frekuensi tidak dapat dipastikan dari data yang tersedia) - Kekacauan dalam sistem pembekuan darah = Shok - Ketidaknormalan fungsi hati, kerusakan sel hati - Erythema multiforme, steven-johnson syndrome, toxic epidermal necrolysis - Masalah ginjal, gagal ginjal akut Tambahan efek samping yang terjadi pada anak dan remaja Reaksi dibawah telah dilaporkan lebih sering pada pasien anak dibandingkan pasien dewasa: Sering trjadi (dapat mempengaruhihingga 1 dari 10 orang) Penurunan platelet darah (trombisitopenia) ~ Peningakatan detak jantung (takikardi) ~ Peningkatan atau penurunan tekanan darah ~ Peningkatan kadar empedu pada darah (hiperbilirubinemia); pembesaran hati = Gagal ginjal akut; peningkatan kadar urea dalam darah Pelaporan efek sampingJika anda mengalami efek samping, segera hubungi dokter atau apoteker anda. Hal ini termasuk kemungkinan efek samping yang tidak tercantum pada leaflet ini. 5. Bagaimana cara menyimpan Mycamine® Jauhkan dari pandangan dan jangkauan anak. Jangan gunakan Mycamine® setelah tanggal kadaluarsa yang tercantum pada vial dan dus. Tanggal kadaluarsa mengacu pada hari terakhir pada bulan tersebut. Vial yang belum dibuka tidak memerlukan kondisi penyimpanan yang khusus. Larutan yang telah dibuka dan dilarutkan dalam larutan infus harus segera digunakan, karena produk ini tidak mengandung pengawet untuk mencegah kontaminan bakteri. Hanya tenaga Kesehatan profesional yang terlatih yang telah membaca pentunjuk penggunaan dengan baik yang dapat menyiapkan obat ini untuk digunakan, Jangan gunakan larutan infus yang telah diencerkan jika keruh atau telah mengendap. Untuk metindungi botol/kantung infus berisi larutan yang telah diencerkan dari cahaya harus dimasukkan kedalam kantung buram yang tertutup. Vial hanya untuk sekali penggunaan. Oleh karena itu, harap buang larutan yang tidak terpakai dengan segera. 6. Isi kemasan dan informasi lainnya Apa yang terkandung dalam Mycamine® - Zot aktifnya adalah micafungin (dalam bentuk sodium) 1 vial mengandung 50 mg atau 100 mg micafungin (dalam bentuk sodium) - Zattambahan lain adalah laktosa monohidrat, asam sitrat anhidrat dan natrium hidroksit Seperti apa tampilan Mycamine® dan isi dari kemasannya Mycamine® 50 mg atau 100 mg serbuk untuk injeksi merupakan serbuk kering berwarna putih. Mycamine® tersedia dalam dus yang berisi 1 vial. Pemegang izin edar PT. Combiphar untuk PT. Astellas Pharma Indonesia JL. Raya Simpang 383, Padalarang 40553, Jawa Barat, Indonesia Produsen Astellas Pharma Tech Co., Ltd Toyama, Japan “Harus dengan resep dokter” Mycamine 50mg No. Rej Mycamine 100mg No. Reg. Untuk informasi lebih lanjut mengenai obat ini, harap menghubungi: PT. Astellas Pharma IndonesiaWebsite: www.astellas.co.id Informasi berikut dibawah ditujukan hanya untuk dokter atau tenaga kesehatan : Mycamine® tidak boleh dicampurkan atau digunakan secara infus dengan produk lain kecuali yang telah disebutkan dibawah, Gunakan teknik aseptik pada suhu ruangan, Mycamine® direkonstitusi dan dilarutkan dengan cara sebagai berikut: 1. Tutup plastik dibuka dari vial dan stopper dibersihkan dengan alkohol 2. Lima ml natrium klorida 9 mg/ml (0.9%) larutan untuk infus atau glukosa 50 mg/ml (5%) larutan untuk infus (diambil dari 100 ml botol/kantung) harus dibersihkan dan di suntikkan secara perlahan kedalam vial melalui diding dalam vial. ‘Walaupun larutan akan terlihat berbuih, lakukan segala cara untuk dapat meminimalkan jumlah buih yang terjadi. Beberapa jumlah vial Mycamine® mungkin akan dibutuhkan untuk dilarutkan untuk mendapatkan dosis yang dibutubkan (lihat tabel dibawah) 3. Vial harus diputar perlahan. TIDAK BOLEH DIKOCOK. Serbuk akan larut sempuma Larutan harus digunakan segera. Vial hanya untuk penggunaan sekali. Sehingga, buang segera larutan yang tidak digunakan, 4, Semua larutan yang telah dicampurkan harus dipindah dari tiap vial ke dalam botoV/kantung infus yang diambil dari awal. Larutan yang telah diencerkan harus digunakan secepatnya. Stabilitas kimia dan fisika telah dilakukan selama 24 jam pada 30°C ketika terlindungi dari cahaya dan diencerkan sesuai cara diatas. 5. Botol/kantung infus harus dalam posisi terbalik untuk melarutkan laurtan tetapi TIDAK dikocok supaya tidak timbul buih. Jangan gunakan jika larutan keruh atau mengendap. 6. Botol/kantung infus yang berisi larutan yang diencerkan harus dimasukkan kedalam kantung buram yang tertutup untuk melindungi dari cahaya. Persiapan untuk melarutkan infus : Dosis | Jumlah vial Mycamine” | Volume (konsentrasi) Standar infus (mg) yang digunakan dari rekonstitusi (ditambahkan sampai (mg/vial) liofilisat dengan 100 mL) Konsentrasi akhir 30 1x50 Kurang lebih. 3 mL 0.50 (mg/mL) (10 mg/mL) 100 Tx 100 Kurang lebih. 5 mL 1.0 (ngimL) (20mg/mL) 150 Tx 100+ 1x50 Kurang lebih. 10 mL 13 (gimL) 200 2x 100 Kurang lebih. 10 mL. 2.0 (mg/mL)