SCHEDULING STATUS

PROPRIETARY NAME (and dosage form)

CASFOLRED 50 (lyophilised powder for concentrate for solution for infusion)

CASFOLRED 70 (lyophilised powder for concentrate for solution for infusion)

COMPOSITION Each vial of CASFOLRED 50 contains 55,5 mg of caspofungin acetate equivalent to 50 mg caspofungin.

Each vial of CASFOLRED 70 contains 77,7 mg of caspofungin acetate equivalent to 70 mg caspofungin.

The other ingredients of CASFOLRED are argon, glacial acetic acid, mannitol, sodium hydroxide, sucrose and water for injection.Contains mannitol.

PHARMACOLOGICAL CLASSIFICATIONA 20.2.2. Antimicrobial (chemotherapeutic agents): Fungicides

PHARMACOLOGICAL ACTIONPharmacodynamic propertiesCaspofungin acetate is a water-soluble, semi-synthetic lipopeptide (echinocandin) compound synthesised from a fermentation product of Glarea lozoyensis. Caspofungin acetate inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeast. Beta (1,3)-D-glucan is not present in mammalian cells.Fungicidal activity with caspofungin has been demonstrated against Candida and Aspergillus species.

Cross-resistanceCaspofungin acetate is active against strains of Candida with intrinsic or acquired resistance to fluconazole, amphotericin B or flucytosine, consistent with their different mechanisms of action.

ResistanceMutants of Candida with reduced susceptibility to caspofungin have been identified in some patients during treatment. A caspofungin MIC of ≤ 2 mcg/ml using the CSLI M27-A3 method indicates that the Candida isolate is likely to be inhibited if caspofungin therapeutic concentrations are achieved; there is insufficient treatment outcome information on isolates with reduced caspofungin susceptibility to define categories other than susceptible. Breakthrough infections with Candida isolates requiring caspofungin concentrations > 2 mcg/ml for growth inhibition have developed in a mouse model of C. albicans infection and in some patients with Candida infections. Some of these isolates had mutations in the FKS1 gene.Development of in vitro resistance to caspofungin by Aspergillus species has not been identified. In clinical experience, resistance in patients with invasive aspergillosis has not been observed. The incidence of resistance in various clinical isolates of Candida and Aspergillus species is unknown.

Pharmacokinetic propertiesDistributionPlasma concentrations of caspofungin decline in a polyphasic manner after intravenous infusions. A short alpha-phase occurs immediately post-infusion, which is followed by a beta-phase with a half-life of 9 to 11 hours. An additional longer gamma-phase also occurs with a half-life of 40 to 50 hours. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is highly protein bound (approximately 97 %), and distribution to red blood cells is minimal. Mass balance results showed that approximately 92 % of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70 mg dose of [3H] caspofungin acetate.There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Plasma clearance of caspofungin is dependent on distribution rather than on biotransformation or excretion.

MetabolismThere is a slow metabolism of caspofungin by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open ring peptide compound, forming two reactive intermediate products. Additional metabolism involves hydrolysis into constitutive amino acids and their derivatives, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.

EliminationIn studies conducted, approximately 75 % of the radioactivity was recovered of which 41 % was in urine and 34 % in faeces. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours post-dose; thereafter medicine levels fell more rapidly. A small amount of caspofungin (approximately 1,4 % of dose) is excreted unchanged in urine. Renal clearance of parent substance is low (approximately 0,15 ml/min).

Special populations

Paediatric PatientsCaspofungin has been studied in five prospective studies involving patients under 18 years of age, including three paediatric pharmacokinetic studies (initial study in adolescents [12 to 17 years old] and children [2 to 11 years old] followed by a study in younger patients [3 to 23 months old] and then followed by a study in neonates and infants [< 3 months]).

2· In adolescents (ages 12 to 17 years old) receiving caspofungin at 50 mg/m daily (maximum 70 mg daily), the caspofungin plasma AUC was generally comparable to that seen in adults receiving 0-24hr

caspofungin at 50 mg daily. All adolescents received doses > 50 mg daily, and in fact, 6 of 8 received the maximum dose of 70 mg/day. The caspofungin plasma concentrations in these adolescents were reduced relative to adults receiving 70 mg daily, the dose most often administered to adolescents.

2· In children (ages 2 to 11 years old) receiving caspofungin at 50 mg/m daily (maximum 70 mg daily), the caspofungin plasma AUC after multiple doses was comparable to that seen in adults receiving 0-24hr

caspofungin at 50 mg/day. On the first day of administration, AUC was somewhat higher in children 0-24hr 2 than adults for these comparisons (37 % increase for the 50 mg/m /day to 50 mg/day comparison).

However, it should be recognised that the AUC values in these children on Day 1 were still less than those seen in adults at steady-state conditions.

2· In young children and toddlers (ages 3 to 23 months) receiving caspofungin at 50 mg/m daily (maximum 70 mg daily), the caspofungin plasma AUC , after multiple doses was comparable to that seen in 0-24hr

adults receiving caspofungin at 50 mg daily. As in the older children, these young children who received 2 50 mg/m daily had slightly higher AUC values on Day 1 relative to adults receiving the standard 0-24hr

50 mg daily dose. The caspofungin pharmacokinetic results from the young children (3 to 23 months of 2 age) that received 50 mg/m caspofungin daily were similar to the pharmacokinetic results from older

children (2 to 11 years old) that received the same dosing regimen.2 · In neonates and infants (< 3 months) receiving caspofungin at 25 mg/m daily, caspofungin peak

concentration (C ) and caspofungin trough concentration (C ) after multiple doses were comparable 1hr 24hr

to that seen in adults receiving caspofungin at 50 mg daily. On Day 1, C , was comparable and C 1hr 24hr

modestly elevated (36 %) in these neonates and infants relative to adults. AUC measurements 0-24hr

were not performed in this study due to the sparse plasma sampling. Of note, the efficacy and safety of caspofungin have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.

Hepatic impairment:Plasma concentrations of caspofungin after a single 70 mg dose in patients with mild hepatic insufficiency, (Child-Pugh score 5 to 6) were increased by approximately 55 % in area under the curve (AUC), compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in patients with mild hepatic insufficiency were increased modestly (19 to 25 % in AUC) on Days 7 and 14 relative to healthy control subjects. In a multiple-dose study, a dose reduction of the daily dose to 35 mg in moderate hepatic impairment has been shown to provide an AUC, similar to that obtained in subjects with normal hepatic function receiving the standard regime. Caspofungin has not been studied in severe hepatic insufficiency.

Gender: The caspofungin plasma concentration in some women was elevated approximately 20 % relative to men.

Elderly: The plasma concentration of caspofungin in healthy older men and women (65 years of age or more) was increased (approximately 28 % in AUC), compared to young healthy males. In patients who were treated empirically or who had invasive candidiasis, a similar modest effect of age was seen in older patients relative to younger patients. However, no dosage adjustment is necessary for elderly patients (65 years of age or more).

INDICATIONSCASFOLRED is indicated for:

· Empirical therapy for presumed fungal infections in febrile, neutropenic patients.

· Treatment of invasive candidiasis, including candidaemia.

· Treatment of oesophageal candidiasis where IV antifungal therapy is appropriate.

· Treatment of oropharyngeal candidiasis where IV antifungal therapy is appropriate.

· Treatment of invasive aspergillosis patients who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and itraconazole.

Paediatric UseThe safety and effectiveness of CASFOLRED in paediatric patients 3 months to 17 years old are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in paediatric patients and additional data from studies in patients 3 months to 17 years old.The efficacy and safety of CASFOLRED have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.CASFOLRED has not been studied in paediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. CASFOLRED has also not been studied as initial therapy for invasive aspergillosis in paediatric patients.

CONTRAINDICATIONS· CASFOLRED is contraindicated in patients with a hypersensitivity to caspofungin or to any of the

excipients.· CASFOLRED has not been studied in patients with severe hepatic insufficiency.

WARNINGS AND SPECIAL PRECAUTIONSAnaphylaxis has been reported during administration of CASFOLRED. Should this occur, CASFOLRED should be discontinued and appropriate treatment administered. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment.Limited data suggest that less common non-Candida yeasts and non-Aspergillus moulds are not covered by CASFOLRED. The efficacy of CASFOLRED against these fungal pathogens has not been established.In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 % and 75 %, respectively. It is recommended for adults with moderate hepatic impairment that the daily dose be reduced to 35 mg. There is no clinical experience in adults with severe hepatic impairment or in paediatric patients with any degree of hepatic impairment. A higher exposure than in moderate hepatic impairment is expected and CASFOLRED should be used with caution in these patients (see CONTRAINDICATIONS, DOSAGE AND DIRECTIONS and Pharmacokinetic properties).Laboratory abnormalities in liver function tests have been seen in healthy volunteers and adult and paediatric patients treated with CASFOLRED. In some adult and paediatric patients with serious underlying CASFOLRED conditions who were receiving multiple concomitant medicines with CASFOLRED, cases of clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported. A causal relationship to CASFOLRED has not been established. Patients who develop abnormal liver function tests during CASFOLRED therapy should be monitored for evidence of worsening hepatic function and the risk/benefit of continuing CASFOLRED therapy.Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported after post-marketing use of CASFOLRED. Caution should apply in patients with history of allergic skin reactions (see SIDE EFFECTS).The use of CASFOLRED with ciclosporin showed transient increases in alanine transaminase (ALT) and aspartate transaminase (AST) of less than or equal to 3-fold the upper limit of normal (ULN) that resolved with discontinuation of the treatment. Close monitoring of liver enzymes should be considered.There was also an increase of approximately 35 % in the area under the curve (AUC) of CASFOLRED when co-administered with ciclosporin; blood levels of ciclosporin remained unchanged.CASFOLRED decreased the 12 hour blood concentration (C12hr) of tacrolimus (FK-506) by 26 % in healthy adult volunteers. For patients who are concomitantly treated with tacrolimus, blood concentrations have to be monitored and appropriate dosage adjustments of tacrolimus should be considered.

Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed.

CASFOLRED contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not use CASFOLRED.

CASFOLRED contains mannitol which, on rare occasions, may cause hypersensitivity reactions.

INTERACTIONSIn vitro studies have shown that caspofungin is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. Clinical studies have shown that caspofungin did not induce the CYP3A4 metabolism of other medicines. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. In vitro and in vivo studies of caspofungin in combination with amphotericin B, does not result in antagonism of antifungal activity against either A. fumigatus or C. albicans. Results from in vitro studies suggest that there was some evidence of additive/indifferent or synergistic activity against A. fumigatus and additive/indifferent activity against C. albicans. The clinical significance of these results is unknown.In two adult clinical studies, ciclosporin (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by about 35 %. The AUC increases are probably due to reduced uptake of caspofungin by liver. CASFOLRED did not increase the plasma levels of ciclosporin. There were transient increases in liver ALT and AST when CASFOLRED and ciclosporin were co-administered. (See WARNINGS AND SPECIAL PRECAUTIONS). Clinical studies in adult healthy volunteers show that medicines such as itraconazole, amphotericin B, mycophenolate, nelfinavir or tacrolimus do not alter the pharmacokinetics of caspofungin. CASFOLRED has no effect on the pharmacokinetics of itraconazole, amphotericin B, rifampicin, or the active metabolite of mycophenolate.CASFOLRED decreased the 12 hour blood concentration (C ) of tacrolimus (FK-506) by 26 % in healthy 12hr

adult volunteers. For patients who are concomitantly treated with tacrolimus, blood concentrations have to be monitored and appropriate dosage adjustments of tacrolimus should be considered.Two clinical interaction studies indicate that rifampicin induces and inhibits caspofungin disposition with net induction at a steady state. Additionally results from population pharmacokinetic screening in adults suggest that co-administration of CASFOLRED with other inducers of medicine clearance (such as efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine) may also result in clinically meaningful reductions in caspofungin concentrations. Available data suggest that the inducible medicine clearance mechanism involved in caspofungin disposition is likely an uptake transport process, rather than metabolism.Therefore, when CASFOLRED is co-administered to adult patients with inducers of medicine clearance, such as efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, use of a daily dose of 70 mg of CASFOLRED should be considered (see DOSAGE AND DIRECTIONS FOR USE). In paediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with CASFOLRED may result in clinically meaningful reductions in CASFOLRED trough concentrations. This may indicate that paediatric patients will have similar reductions with inducers as seen in adults. When CASFOLRED is co-administered to paediatric patients with inducers of medicine clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone or

2 2carbamazepine, a CASFOLRED dose of 70 mg/m daily (not to exceed an actual daily dose of 70 mg/m ) is recommended.

PREGNANCY AND LACTATIONThere are no data on the use of CASFOLRED in pregnant women, therefore, CASFOLRED should not be used during pregnancy.It is not known if CASFOLRED is excreted in the breast milk of humans, therefore, breast-feeding is not recommended.

DOSAGE AND DIRECTIONS

Adults (≥ 18 years of age):CASFOLRED should be administered by a slow infusion over approximately 1 hour.

Empirical therapyA single 70 mg loading dose should be administered on Day 1, thereafter followed by 50 mg daily. The patient's clinical response should determine the duration of treatment. Empirical therapy should be continued until the neutropenia is resolved. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If 50 mg is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg. Even though an increase in efficacy with 70 mg daily has not been demonstrated, safety data suggest that an increase in dose to 70 mg daily is tolerated.

Invasive CandidiasisA single 70 mg loading dose should be administered on Day 1, followed thereafter by 50 mg daily. Duration of treatment of invasive candidiasis should be determined by the patient's clinical and microbiological response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may require a longer course of therapy until the resolution of the neutropenia.The safety and efficacy of multiple doses up to 150 mg daily (range 1 to 51 days; median 14 days) have been studied in 100 adult patients with invasive candidiasis. CASFOLRED is generally well tolerated in these patients receiving CASFOLRED at this higher dose. The efficacy of CASFOLRED at this higher dose is generally similar to patients receiving the 50 mg daily dose.

Oesophageal and Oropharyngeal Candidiasis 50 mg should be given daily.

Invasive AspergillosisA single 70 mg loading dose should be administered on Day 1, followed thereafter by 50 mg daily. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression and clinical response. The efficacy of a 70 mg dose regimen in patients who are not clinically responding to the 50 mg daily dose is not known. Safety data suggests that an increase in dose to 70 mg daily is well tolerated. The efficacy of doses above 70 mg has not been adequately studied in patients with invasive aspergillosis. No dose adjustments are necessary for elderly patients (65 years of age or more). No dosage adjustment is necessary based on gender, race or renal impairment.When CASFOLRED is co-administered with the metabolic inducers such as efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, use of a daily dose of 70 mg of CASFOLRED should be considered (see INTERACTIONS).

Patients with Hepatic ImpairmentPatients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment (see CONTRAINDICATIONS). For adult patients with moderate hepatic insufficiency (Child-Pugh-score 7 to 9), CASFOLRED 35 mg daily is recommended based upon pharmacokinetic data. However, where recommended, a 70 mg loading dose should still be administered on Day 1. There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score > 9) and in paediatric patients with any degree of hepatic insufficiency (see CONTRAINDICATIONS).

Paediatric PatientsCASFOLRED should be administered in children and adolescents (3 months to 17 years old) by slow IV infusion over approximately 1 hour. Dosing in children and adolescents (3 months to 17 years old) should be based on the patient's body surface area (see INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS,

1 2Mosteller Formula). For all indications, a single 70 mg/m loading dose (not to exceed an actual dose of 70 2mg) should be administered on Day 1, followed by 50 mg/m daily thereafter (not to exceed an actual dose

of 70 mg daily). Duration of treatment should be individualised to the indication, as described for each indication in adults.

2If the 50 mg/m daily dose is well tolerated but does not provide an adequate clinical response, the daily 2 dose can be increased to 70 mg/m daily (not to exceed an actual daily dose of 70 mg). Although an

2increase in efficacy with 70 mg/m daily has not been demonstrated, limited safety data suggest that an 2increase in dose to 70 mg/m daily is well tolerated.

When CASFOLRED is co-administered to paediatric patients with inducers of drug clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone or carbamazepine, use of a CASFOLRED

2dose of 70 mg/m daily (not to exceed an actual daily dose of 70 mg) should be considered.

S4 Reconstitution of CASFOLREDCASFOLRED is not stable in diluents containing dextrose.DO NOT USE ANY DILUENTS CONTAINING DEXTROSE (ALPHA-D-GLUCOSE).DO NOT MIX OR CO-INFUSE CASFOLRED WITH ANY OTHER MEDICATIONS, since no data is available on the compatibility of CASFOLRED with other intravenous substances, additives or medications. Visually inspect the infusion solution for particulate matter or discolouration.

INSTRUCTION FOR USE IN ADULTS

Step 1. Reconstitution of vialsTo reconstitute CASFOLRED powder, bring the refrigerated vial of CASFOLRED to room temperature and aseptically add 10,5 ml of either 0,9 % Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0,9 % benzyl alcohol. The reconstituted product is stable for a period of 1 hour.The concentrations of the reconstituted vials will be: 5,2 mg/ml (50 mg vial) or 7,2 mg/ml (70 mg vial).The white to off-white compact powder will dissolve completely. Mix gently until a clear solution is obtained. Reconstituted solutions should be visually inspected for particulate matter or discolouration.

Step 2. Addition of Reconstituted CASFOLRED to patient infusion solution Diluents for the final patient infusion solutions are: Sterile Saline for Injection or Lactated Ringer's Solution. The standard patient infusion is prepared by aseptically adding the appropriate amount of reconstituted drug (as shown in the table below) to a 250 ml intravenous bag or bottle. Reduced volume infusions in 100 ml may be used, when medically necessary, for 50 mg or 35 mg daily doses. Do not use if the solution is cloudy or has precipitated. Although chemical and physical stability of reconstituted/diluted solutions has been demonstrated for 24 hours at 25 °C and 48 hours at 2 to 8 °C from a microbiological point of view, the product 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 reconstitution/dilution has taken place in controlled and validated aseptic conditions. CASFOLRED should be administered by slow intravenous infusion over approximately 1 hour.

PREPARATION OF THE PATIENT INFUSION SOLUTIONS

INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTSCalculation of Body Surface Area (BSA) for paediatric dosingBefore preparation of the infusion, calculate the body surface area (BSA) of the patient using the following formula (Mosteller Formula):

2Preparation of the 50 mg/m infusion for paediatric patients > 3 months of age (using a 50 mg vial)1. Determine the daily maintenance dose by using the patient's BSA (as calculated above) and the following equation:

2 2 Daily Maintenance Dose = BSA (m ) X 50 mg/m The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.

2. Bring the refrigerated vial of CASFOLRED to room temperature.

3. Aseptically add 10,5 ml of 0,9 % Sodium Chloride Injection, Sterile Water for Injection or Bacteriostatic Water for Injection with methylparaben and propylparaben or Bacteriostatic Water for Injection with 0,9 % benzyl alcohol. a This reconstituted solution may be stored for up to 24 hours at 25 °C. b This will give a final CASFOLRED concentration in the vial of 5,2 mg/ml.

4. Remove the volume of medicine equal to the calculated loading dose (Step 1) from the vial. Aseptically c transfer this volume (ml) of reconstituted CASFOLRED to an IV bag (or bottle) containing 250 ml of

0,9 %, 0,45 %, or 0,225 % Sodium Chloride Injection, or Lactated Ringers Injection. c Alternatively, the volume (ml) of reconstituted CASFOLRED can be added to a reduced volume of

0,9 %, 0,45 %, or 0,225 % Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0,5 mg/ml. This infusion solution must be used within 24 hours if stored at or below 25 °C or within 48 hours if stored refrigerated at 2 to 8 °C.

5. If the actual daily maintenance dose is > 50 mg, then the dose may be prepared from the >70 mg vial 2 [follow Steps 2 to 4 from "Preparation of the 70 mg/m infusion for paediatric patients >3 months of age

(using a 70 mg vial)"]. The final CASFOLRED concentration in the 70 mg vial after reconstitution is 7,2 mg/ml.

2Preparation of the 70 mg/m infusion for paediatric patients > 3 months of age (using a 70 mg vial)1. The actual loading dose to be used in the paediatric patient should be determined by using the patient's BSA (as calculated above) and the following equation:

2 2 Loading Dose = BSA (m ) X 70 mg/m The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient's calculated dose.

2. Bring the refrigerated vial of CASFOLRED to room temperature.

3. Aseptically add 10,5 ml of 0,9 % Sodium Chloride Injection, Sterile Water for Injection or Bacteriostatic Water for Injection with methylparaben and propylparaben or Bacteriostatic Water for Injection with

b 0,9 % benzyl alcohol. This reconstituted solution may be stored for up to 24 hours at 25° C . This will give a final CASFOLRED concentration in the vial of 7,2 mg/ml.

4. Remove the volume of medicine equal to the calculated loading dose (Step 1) from the vial. Aseptically c transfer this volume (ml) of reconstituted CASFOLRED to an IV bag (or bottle) containing 250 ml of

0,9 %, 0,45 %, or 0,225 % Sodium Chloride Injection, or Lactated Ringers Injection. Alternatively, the c volume (ml) of reconstituted CASFOLRED can be added to a reduced volume of 0,9 %, 0,45 %, or

0,225 % Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0,5 mg/ml. This infusion solution must be used within 24 hours if stored at or below 25 °C or within 48 hours if stored refrigerated at 2 to 8 °C.

5. If the calculated loading dose is less than 50 mg, then the dose may be prepared from the 50 mg vial 2 [follow Steps 2 to 4 from "Preparation of the 50 mg/m infusion for paediatric patients > 3 months of age

(using a 50 mg vial)"]. The final CASFOLRED concentration in the 50 mg vial after reconstitution is 5,2 mg/ml.

Preparation notesa The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained. b Visually inspect the reconstituted solution for particulate matter or discolouration during reconstitution and prior to infusion. Do not use solution if cloudy or has precipitated.c CASFOLRED is formulated to provide the full labelled vial dose (50 mg or 70 mg) when 10 ml is withdrawn from the vial.

SIDE-EFFECTSThe following side effects were reported for adult patients:Blood and lymphatic system disorders

· Frequent: haemoglobin decreased, haematocrit decreased, white blood cell count decreased.

· Less frequent: anaemia, thrombocytopenia, coagulopathy, leukopenia, eosinophil count increased, platelet count decreased, platelet count increased, lymphocyte count decreased, white blood cell count increased, neutrophil count decreased.

Metabolism and nutrition disorders· Frequent: hypokalemia.

· Less frequent: fluid overload, hypomagnesaemia, anorexia, electrolyte imbalance, hyperglycaemia, hypocalcaemia, metabolic acidosis.

Psychiatric disorders· Less frequent: anxiety, disorientation, insomnia.

Nervous system disorders· Frequent: headache.

· Less frequent: dizziness, dysgeusia, paraesthesia, somnolence, tremor, hypoaesthesia.

Eye disorders· Less frequent: ocular icterus, vision blurred, eyelid oedema, lacrimation increased.

Cardiac disorders· Less frequent: palpitations, tachycardia, dysrhythmia, atrial fibrillation, cardiac failure congestive.

Vascular disorders· Frequent: phlebitis.

· Less frequent: thrombophlebitis, flushing, hot flush, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders· Frequent: dyspnoea.

· Less frequent: nasal congestion, pharyngolaryngeal pain, tachypnoea, bronchospasm, cough, dyspnoea paroxysmal nocturnal, hypoxia, rales, wheezing.

Gastrointestinal disorders· Frequent: nausea, vomiting, diarrhoea.

· Less frequent: abdominal pain, abdominal pain upper, dry mouth, dyspepsia, stomach discomfort, abdominal distension, ascites, constipation, dysphagia, flatulence.

Hepatobiliary disorders· Frequent: elevated liver values (alanine aminotransferase, aspartate aminotransferase, blood

alkaline phosphatase, bilirubin conjugated, blood bilirubin).· Less frequent: cholestasis, hepatomegaly, hyperbilirubinaemia, jaundice, hepatic function

abnormal, hepatotoxicity, liver disorder, gamma-glutamyltransferase increased.

Skin and subcutaneous tissue disorders· Frequent: rash, pruritus, hyperhidrosis, erythema.

· Less frequent: erythema multiforme, rash macular, rash maculo-papular, rash pruritic, urticaria, dermatitis allergic, pruritus generalised, rash erythematous, rash generalised, rash morbilliform, skin lesion.

· Frequency unknown: toxic epidermal necrolysis and Stevens-Johnson syndrome.

Musculoskeletal, connective tissue and bone disorders· Frequent: arthralgia.

· Less frequent: back pain, pain in extremity, bone pain, muscular weakness, myalgia.

Renal and urinary disorders· Less frequent: renal failure, renal failure acute.

General disorders and administration site conditions· Frequent: pyrexia, chills, infusion-site pruritus.

· Less frequent: pain, catheter site pain, fatigue, feeling cold, feeling hot, infusion site erythema, infusion site induration, infusion site pain, infusion site swelling, injection site phlebitis, oedema peripheral, tenderness, chest discomfort, chest pain, face oedema, feeling of body temperature change, induration, infusion site extravasation, infusion site irritation, infusion site phlebitis, infusion site rash, infusion site urticaria, injection site erythema, injection site oedema, injection site pain, injection site swelling, malaise, oedema.

Investigations· Frequent: blood potassium decreased, blood albumin decreased.

· Less frequent: blood creatinine increased, red blood cells urine positive, protein total decreased, protein urine present, prothrombin time prolonged, prothrombin time shortened, blood sodium decreased, blood sodium increased, blood calcium decreased, blood calcium increased, blood chloride decreased, blood glucose increased, blood magnesium decreased, blood phosphorus decreased, blood phosphorus increased, blood urea increased, activated partial thromboplastin time prolonged, blood bicarbonate decreased, blood chloride increased, blood potassium increased, blood pressure increased, blood uric acid decreased, blood urine present, breath sounds abnormal, carbon dioxide decreased, immunosuppressant drug level increased, international normalised ratio increased, urinary casts, white blood cells urine positive, and pH urine increased.

The following side effects were reported for paediatric patients:

Blood and lymphatic system disorders· Frequent: increased eosinophil count.

Nervous system disorders· Frequent: headache.

Cardiac disorders· Frequent: tachycardia.

Vascular disorders· Frequent: flushing, hypotension.

· Frequency unknown: swelling and peripheral oedema.Hepatobiliary disorders

· Frequent: elevated liver enzyme levels (AST, ALT).

· Frequency unknown: hepatic dysfunction.Skin and subcutaneous tissue disorders

· Frequent: rash, pruritus.

· Frequency unknown: histamine-mediated symptoms (rash, facial swelling, pruritus, sensation of warmth, bronchospasm), anaphylaxis.General disorders and administration site conditions

· Frequent: fever, chills, catheter-site pain.Investigations

· Frequent: increased liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), decreased potassium, hypomagnesaemia, increased glucose, decreased phosphorus, increased phosphorus.

· Frequency unknown: hypercalcaemia, increased eosinophils.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENTIn one study 210 mg was the highest dose which was administered as a single dose to 6 healthy subjects and in another study 150 mg once a day for up to 51 days was administered to 100 subjects.CASFOLRED is not dialysable.

IDENTIFICATION�Unopened vialsEach vial of CASFOLRED contains a white to off white lyophilised cake/powder.

Reconstituted vialsClear solution, essentially free from visible particles.

Diluted product for infusionClear solution, essentially free from visible particles.

PRESENTATION � � �CASFOLRED 50 is supplied in 10 ml USP type – I clear glass tubular Lyo vials with 20 mm neck diameter and 20 mm grey bromobutyl rubber stoppers and sealed with 20 mm aluminium flip off seals.

CASFOLRED 70 is supplied in 10 ml USP type – I clear glass tubular Lyo vials with 20 mm neck diameter and 20 mm grey bromobutyl rubber stoppers and sealed with 20 mm aluminium flip off seals.The glass vial is packed in a printed outer carton along with the package insert.

STORAGE INSTRUCTIONS

Storage of unopened vialsStore at 2 °C to 8 °C.

Storage of reconstituted /diluted solutionAlthough chemical and physical stability of reconstituted/diluted solutions has been demonstrated for 24 hours at 25 °C and 48 hours at 2 to 8 °C from a microbiological point of view, the product 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 reconstitution/dilution has taken place in controlled and validated aseptic conditions. Do not freeze.KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERSCASFOLRED 50: 50/20.2.2/0945CASFOLRED 70: 50/20.2.2/0946

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATIONDr. Reddy's Laboratories (Pty) LimitedThird Floor, The Place1 Sandton DriveSandton 2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT29 September 2017

Page 1 of 2CASFOLRED South Africa 009602

Dose* Volume ofreconstituted

CASFOLRED fortransfer to

intravenous bagor bottle

Standard preparation (Reconstituted

CASFOLRED added to 250 ml)

final concentration.

Reduced volume infusion (Reconstituted

CASFOLRED added to 100 ml) final concentration.

35 mg for moderate hepatic insufficiency (from one 50 ml vial)

7 ml 0,14 mg/ml 0,34 mg/ml

35 mg for moderate hepatic insufficiency (from one 70 ml vial)

5 ml

0,14 mg/ml 0,34 mg/ml

50 mg 10 ml 0,20 mg/ml 0,47 mg/ml

70 mg 10 ml 0,28 mg/ml Not recommended

70 mg (from two 50 mg vials)**

14 ml 0,28 mg/ml Not recommended

* 10,5 ml should be used for reconstitution of all vials** If a 70 mg vial is not available, the 70 mg dose can be prepared from two 50 mg vials.

Version No: 01

Date: 21.11.2017

Change History:New Artwork: (21.11.2017)

List. of Colours:

Black

200 x 800 mm

Dimensions : LxW (800-200 mm)

Height (cm) x Weight (kg)

3600

2BSA (m ) =

SKEDULERINGSTATUS

EIENDOMSNAAM (en doseervorm)CASFOLRED 50 (gevriesdroogde poeier vir konsentraat vir oplossing vir infusie)CASFOLRED 70 (gevriesdroogde poeier vir konsentraat vir oplossing vir infusie)

SAMESTELLINGElke flessie CASFOLRED 50 bevat 55,5 mg kaspofungienasetaat wat gelykstaande is aan 50 mg kaspofungien.Elke flessie CASFOLRED 70 bevat 77,7 mg kaspofungienasetaat wat gelykstaande is aan 70 mg kaspofungien.Die ander bestanddele van CASFOLRED is argon, ysasynsuur, mannitol, natriumhidroksied, sukrose en water vir inspuiting.Bevat mannitol.

FARMAKOLOGIESE KLASSIFIKASIEA 20.2.2. Antimikrobiese (chemoterapeutiese) middels: Swamdoders

FARMAKOLOGIESE WERKINGFarmakodinamiese eienskappeKaspofungienasetaat is 'n wateroplosbare, semi-sintetiese lipopeptied (eginokandien) wat vanaf 'n fermentasieproduk van Glarea lozoyensis gesintetiseer word. Kaspofungienasetaat rem die sintese van beta-(1,3)-D-glukaan, 'n noodsaaklike komponent van die selwand van baie filamentiese swamme en giste. Beta-(1,3)-D-glukaan kom nie in soogdierselle voor nie.Swamdodende aktiwiteit van kaspofungien teen Candida- en Aspergillus-spesies is aangetoon.

KruisweerstandigheidKaspofungienasetaat is aktief teen Candida-stamme wat intrinsieke of verworwe weerstand het teen flukonasool, amfoterisien B of flusitosien, in ooreenstemming met hul verskillende werkingsmeganismes.

WeerstandigheidMutante van Candida met laer vatbaarheid vir kaspofungien is tydens behandeling in sommige pasiënte geïdentifiseer.'n MIK van ≤ 2µg/ml vir kaspofungien volgens CSLI M27-A3-metode dui dat die Candida-isolate waarskynlik gerem sal word indien terapeutiese konsentrasies van kaspofungien bereik word; daar is onvoldoende inligting oor die uitkoms van behandeling van isolate met laer vatbaarheid vir kaspofungien om kategorieë anders as vatbaar te definieer. Deurbraakinfeksies met Candida-isolate waarvoor konsentrasies van > 2 µg/ml kaspofungien nodig was vir onderdrukking van groei het in 'n muismodel met infeksie deur C. albicans en by sommige pasiënte met Candida-infeksies ontwikkel. Sommige van hierdie isolate het mutasies in die FKS1-geen.Die ontwikkeling van in vitro-weerstand teen kaspofungien deur Aspergillus spesies is nie geïdentifiseer nie. Geen weerstand is tydens kliniese ervaring in pasiënte met indringende aspergillose waargeneem nie. Die voorkoms van weerstand in verskeie kliniese isolate van Candida- en Aspergillus-spesies is onbekend.

Farmakokinetiese eienskappeVerspreidingPlasmakonsentrasies van kaspofungien daal na intraveneuse infusies op 'n polifasige wyse. 'n Kort alfa-fase kom onmiddellik na infusie voor, wat gevolg word deur 'n beta-fase met 'n halfleeftyd van 9 tot 11 uur. Daar is ook 'n verdere langer gamma-fase met 'n halfleeftyd van 40 tot 50 uur. Verspreiding, eerder as uitskeiding of biotransformasie, is die dominante meganisme wat opruiming uit plasma beïnvloed.Kaspofungien is hoogs proteïengebonde (ongeveer 97 %), en verspreiding na rooibloedselle is minimaal.Massabalans het getoon dat na 'n enkele dosis van 70 mg [3H] kaspofungienasetaat ongeveer 92 % van die toegediende radioaktiwiteit teen 36 tot 48 uur na weefsel versprei het.Daar is min uitskeiding of biotransformasie van kaspofungien gedurende die eerste 30 uur na toediening. Plasma-opruiming van kaspofungien is afhanklik van verspreiding eerder as van biotransformasie of ekskresie.

MetabolismeDaar is 'n stadige metabolisme van kaspofungien deur hidrolise en N-asetilering. Kaspofungien ondergaan ook spontane chemiese afbraak na 'n oopringpeptiedverbinding, wat twee reaktiewe intermediêre produkte vorm. Verdere metabolisme behels hidrolise na aminosuurboustene en hul derivate, waaronder dihidroksihomotirosien en N-asetiel-dihidroksihomotirosien. Hierdie twee tirosienderivate word slegs in urien aangetref, wat die vinnige opruiming van hierdie derivate deur die niere aandui.

UitskeidingIn studies is ongeveer 75 % van die radioaktiwiteit herwin, waarvan 41 % in urien en 34 % in die feses. Plasmakonsentrasies van radioaktiwiteit en van kaspofungien was in die eerste 24 tot 48 uur na die dosis dieselfde; daarna het medisynevlakke vinniger geval. 'n Klein hoeveelheid kaspofungien (ongeveer 1,4 % van die dosis) word onveranderd in die urien uitgeskei. Renale opruiming van die moederverbinding is laag (ongeveer 0,15 ml/min).

Spesiale populasiesPediatriese pasiënteKaspofungien is bestudeer in vyf verkennende studies met pasiënte onder die ouderdom van 18 jaar, waaronder drie pediatriese farmakokinetiese studies (aanvanklike studie met adolessente [12 tot 17 jaar oud] en kinders [2 tot 11 jaar oud] gevolg deur 'n studie met jonger pasiënte [3 tot 23 maande oud] en dan gevolg deur 'n studie met neonate en babas [< 3 maande]).

2· In adolessente (ouderdomme 12 tot 17 jaar oud) wat 50 mg/m kaspofungien daagliks ontvang het (maksimum 70 mg per dag), was die AOK van kaspofungien in plasma oor die algemeen 0-24h

vergelykbaar met dié van volwassenes wat kaspofungien teen 50 mg per dag ontvang. Alle adolessente het dosisse > 50 mg per dag ontvang, en 6 van die 8 het inderwaarheid die maksimum dosis van 70 mg/dag ontvang. Die plasmakonsentrasies van kaspofungien in hierdie adolessente was laer as dié van volwassenes wat 70 mg per dag ontvang het wat die dosis is wat meestal aan adolessente toegedien word.

2· In kinders (ouderdomme 2 tot 11 jaar oud) wat 50 mg/m kaspofungien daagliks ontvang het (maksimum 70 mg per dag), was die AOK van kaspofungien in plasma na veelvoudige dosisse oor die algemeen 0-24h

vergelykbaar met dié van volwassenes wat kaspofungien teen 50 mg per dag ontvang. Op die eerste dag na toediening was AOK vir hierdie vergelykings ietwat hoër in kinders as in volwassenes (37 % 0-24h

2 hoër met die 50 mg/m /Dag as met 50 mg/dag). Dit moet egter onthou word dat die AOK-waardes in hierdie kinders op Dag 1 steeds minder was as wat by gelykvlakke in volwassenes gesien word.

2· In jong kinders en kleuters (3 tot 23 maande oud) wat 50 mg/m kaspofungien daagliks ontvang het (maksimum 70 mg per dag), was die AOK van kaspofungien in plasma na veelvoudige dosisse oor 0-24hr

die algemeen vergelykbaar met dié van volwassenes wat kaspofungien teen 50 mg per dag ontvang. 2 Soos in die ouer kinders, het hierdie jong kinders wat 50 mg/m elke dag ontvang het, effens hoër

AUC op Dag 1 relatief tot volwassenes wat die standaard daaglikse dosis van 50 mg ontvang. Die 0-24h2 farmakokinetiese resultate van kaspofungien in jong kinders (3 tot 23 maande) wat daagliks 50 mg/m

kaspofungien ontvang het, was soortgelyk aan die farmakokinetiese resultate van ouer kinders (2 tot 11 jaar oud) wat dieselfde dosisregimen ontvang het.

2· In neonate en babas (< 3 maande) wat kaspofungien teen 25 mg/m per dag ontvang het, was piek konsentrasie van kaspofungien (C ) en die trogkonsentrasie (C ) na veelvoudige dosisse 1h 24h

vergelykbaar met dié wat gesien is in volwassenes wat kaspofungien teen 50 mg per dag ontvang. Op Dag 1 was C vergelykbaar en C in hierdie neonate en babas matig hoër (36 %) vergeleke met dié van 1h 24h

volwassenes. Metings van AOK is as gevolg van die yl monsterneming van plasma nie in hierdie 0-24h

studie gedoen nie. Dit is van belang om daarop te let dat die effektiwiteit en veiligheid van kaspofungien nie voldoende in verkennende kliniese proewe met neonate en babas onder die ouderdom van 3 maande bestudeer is nie.

Swak lewerfunksie:Plasmakonsentrasies van kaspofungien na 'n enkele dosis van 70 mg aan pasiënte met ligte swak lewerfunksie (Child-Pughtelling 5 tot 6) is ongeveer 55 % hoër in area onder die kromme (AOK) in vergelyking met gesonde proefpersone. In 'n studie met meervoudige dosisse oor 14 dae (70 mg op Dag 1 gevolg deur 50 mg daagliks daarna), was plasmakonsentrasies in pasiënte met ligte swak lewerfunksie effens hoër (19 tot 25 % in AOK) op Dae 7 en 14 relatief tot gesonde proefpersone. In 'n studie met meervoudige dosisse is getoon dat 'n verlaging in die daaglikse dosis na 35 mg tydens matige swak lewerfunksie 'n AOK gee wat soortgelyk is aan dié verkry in proefpersone met normale lewerfunksie wat die standaardregimen ontvang. Kaspofungien is nie in pasiënte met erge swak lewerfunksie bestudeer nie.

Geslag:Die plasmakonsentrasie van kaspofungien in party vroue was ongeveer 20 % hoër as in mans.

Bejaardes:Die plasmakonsentrasie van kaspofungien in gesonde ouer mans en vroue (65 jaar of ouer) is hoër (ongeveer 28 % in AOK) in vergelyking met jong gesonde mans. In pasiënte wat empiries behandel is of wat indringende kandidiase gehad het, was daar 'n soortgelyke klein effek van ouderdom in ouer pasiënte teenoor jonger pasiënte. Geen dosisaanpassing is egter vir bejaardes (65 jaar of ouer) nodig nie.

INDIKASIESCASFOLRED is aangedui vir:· Empiriese behandeling vir vermeende swaminfeksies in koorsige, neutropeniese pasiënte.

· Behandeling van indringende kandidiase, waaronder kandidemie.

· Behandeling van esofageale kandidiase waar IV antifungusterapie toepaslik is.

· Behandeling van orofaringeale kandidiase waar IV antifungusterapie toepaslik is.

· Behandeling van pasiënte met indringende aspergillose wat refraktêr of onverdraagsaam teenoor amfoterisien B, lipiedformulerings van amfoterisien B of itrakonasool is.

Pediatriese gebruikDie veiligheid en doeltreffendheid van CASFOLRED vir pediatriese pasiënte van 3 maande tot 17 jaar oud word ondersteun deur inligting uit voldoende en goedgekontroleerde navorsingstudies met volwassenes, farmakokinetiese data in pediatriese pasiënte en addisionele data uit studies in pasiënte van 3 maande tot 17 jaar oud.Die effektiwiteit en veiligheid van CASFOLRED is nie voldoende in verkennende kliniese proewe met neonate en babas onder die ouderdom van 3 maande bestudeer nie.CASFOLRED is nie in pediatriese pasiënte met endokarditis, osteomiëlitis of meningitis as gevolg van Candida bestudeer nie. CASFOLRED is ook nie as aanvanklike behandeling vir indringende aspergillose in pediatriese pasiënte bestudeer nie.

KONTRA-INDIKASIES

· CASFOLRED is teenaangedui vir pasiënte met bekende hipersensitiwiteit teenoor kaspofungien of enige van die hulpstowwe.· CASFOLRED is nie in pasiënte met erge swak lewerfunksie bestudeer nie.

WAARSKUWINGS EN SPESIALE VOORSORGMAATREëLSAnafilakse is tydens die toediening van CASFOLRED aangemeld. Indien dit voorkom, moet CASFOLRED gestaak en toepaslike behandeling gegee word. Nadelige reaksies moontlik vanweë histamien, waaronder veluitslag, swelling van die gesig, angioedeem, pruritus, sensasie van warmte of brongospasma, is aangemeld en staking van die middel en/of toepaslike behandeling mag nodig wees.Beperkte data dui daarop dat minder algemene nie-Candida-giste en nie-Aspergillus-swamme nie deur CASFOLRED gedek word nie. Die effektiwiteit van CASFOLRED teen hierdie swampatogene is nie bepaal nie.In volwasse pasiënte met ligte en matige swak lewerfunksie is die AOK onderskeidelik ongeveer 20 % en 75 % hoër. Dit word aanbeveel dat die daaglikse dosis vir volwassenes met matige swak lewerfunksie tot 35 mg verminder word. Daar is geen kliniese ondervinding met volwassenes met ernstige swak lewerfunksie of met pediatriese pasiënte met enige mate van swak lewerfunksie nie. 'n Hoër blootstelling as met matige swak lewerfunksie word verwag en CASFOLRED moet versigtig deur hierdie pasiënte gebruik word (kyk KONTRA-INDIKASIES, DOSIS EN AANWYSINGS en Farmakokinetiese eienskappe).Afwykings in uitslae van lewerfunksietoetse is gesien in gesonde vrywilligers en volwasse en pediatriese pasiënte wat met CASFOLRED behandel is. Gevalle van klinies beduidende lewerdisfunksie, hepatitis en lewerversaking is aangemeld in sommige volwasse en pediatriese pasiënte met ernstige onderliggende CASFOLRED-toestande wat verskeie ander middels saam met CASFOLRED ontvang het. 'n Oorsaaklike verwantskap met CASFOLRED is nie bepaal nie. Pasiënte wat tydens behandeling met CASFOLRED abnormaliteite in lewerfunksietoetse ontwikkel, moet gemonitor word vir tekens van verslegtende lewerfunksie en vir die risiko/voordeel van voortgesette behandeling met CASFOLRED.Gevalle van die Stevens-Johnsonsindroom (SJS) en toksiese epidermale nekrolise (TEN) is aangemeld na die gebruik van CASFOLRED na bemarking. Wees versigtig met pasiënte met 'n geskiedenis van allergiese velreaksies (kyk NEWE-EFFEKTE).Die gebruik van CASFOLRED saam met siklosporien het verbygaande stygings van minder as of gelyk aan drie keer die boonste grens van normaal (BGN) in vlakke van alanientransaminase (ALT) en aspartaattransaminase (AST) veroorsaak, wat na die staking van die behandeling opgeklaar het. Noukeurige monitering van lewerensieme moet oorweeg word.Daar was ook 'n toename van ongeveer 35 % in die area onder die kromme (AOK) van CASFOLRED toe dit saam met siklosporien gegee is; bloedvlakke van siklosporien het onveranderd gebly.CASFOLRED het die bloedkonsentrasie van takrolimus (FK-506) in gesonde volwasse vrywilligers na 12 uur (C ) met 26 % verlaag. Die bloedkonsentrasies van takrolimus in pasiënte wat ook met takrolimus 12h

behandel word, moet gemonitor en toepaslike dosisaanpassings moet oorweeg word.

Effek op die vermoë om motor te bestuur en masjiene te gebruikGeen studies van die effek op die vermoë om motor te bestuur of masjiene te gebruik is gedoen nie.

CASFOLRED bevat sukrose. Pasiënte met seldsame oorerflike toestande soos fruktose-onverdraagbaarheid, glukose-galaktosewanabsorpsie of sukrase-isomaltase-ontoereikendheid moet nie CASFOLRED gebruik nie.CASFOLRED bevat mannitol wat in enkele gevalle hipersensitiwiteitsreaksies kan veroorsaak.

INTERAKSIESIn vitro-studies het getoon dat kaspofungien nie 'n remmer van enige ensiem in die sitochroom P450 (CYP)-stelsel is nie. Kliniese studies het getoon dat kaspofungien nie die metabolisme deur CYP3A4 van ander medisyne induseer nie. Kaspofungien is nie 'n substraat vir P-glikoproteïen nie en is 'n swak substraat vir sitochroom P450-ensieme.In vitro- en in vivo-studies van kaspofungien in kombinasie met amfoterisien B het geen antagonisme in antifungusaktiwiteit teen óf A. fumigatus óf C. albicans getoon nie. Resultate van in vitro-studies toon dat daar tekens van additiewe/onveranderende of sinergistiese aktiwiteit teen A. fumigatus of additiewe/onveranderende aktiwiteit teen C. albicans is. Die kliniese betekenis van hierdie resultate is onbekend.In twee kliniese studies met volwassenes het siklosporien (een dosis van 4 mg/kg of twee dosisse van 3 mg/kg) die AOK van kaspofungien met ongeveer 35 % verhoog. Die toename in AOK is waarskynlik as gevolg van swakker opname van kaspofungien deur die lewer. CASFOLRED het nie die plasmavlakke van siklosporien verhoog nie. Daar was tydelike verhogings in ALT en AST van die lewer toe CASFOLRED en siklosporien saam toegedien is (kyk WAARSKUWINGS en SPESIALE VOORSORGMAATREËLS).Kliniese studies met gesonde volwasse vrywilligers wys dat middels soos itrakonasool, amfoterisien B, mikofenolaat, nelfinavir of takrolimus nie die farmakokinetika van kaspofungien verander nie. CASFOLRED het geen effek op die farmakokinetika van itrakonasool, amfoterisien B, rifampisien, of die aktiewe metaboliet van mikofenolaat nie.CASFOLRED het die bloedkonsentrasie van takrolimus (FK-506) in gesonde volwasse vrywilligers na 12 uur (C ) met 26 % verlaag. Die bloedkonsentrasies van takrolimus in pasiënte wat ook met takrolimus 12h

behandel word, moet gemonitor en toepaslike dosisaanpassings moet oorweeg word.Twee studies van kliniese interaksie dui daarop dat rifampisien verspreiding van kaspofungien induseer en inhibeer met netto induksie by gelykvlakke. Verdere resultate van farmakokinetiese sifting van 'n populasie volwassenes dui daarop dat toediening van CASFOLRED saam met ander induseerders van opruiming van medisyne (soos efavirens, nevirapien, fenitoïen, deksametasoon of karbaamasepien) ook klinies betekenisvolle verlagings in die konsentrasies van kaspofungien kan veroorsaak. Beskikbare data dui daarop dat die meganisme vir indusering van opklaring van medisyne betrokke by verspreiding van kaspofungien waarskynlik 'n proses in die opname vir transport eerder as deur metabolisme is.Daarom moet 'n daaglikse dosis van 70 mg CASFOLRED vir volwasse pasiënte oorweeg word wanneer CASFOLRED toegedien word saam met induseerders van medisyne-opruiming, soos efavirens, nevirapien, rifampisien, deksametasoon, fenitoïen of karbaamasepien (kyk DOSERING EN AANWYSINGS VIR GEBRUIK).Resultate van regressie-analises van farmakokinetiese data toon dat toediening van deksametasoon saam met CASFOLRED klinies betekenisvolle daling in konsentrasies van CASFOLRED in pediatriese pasiënte kan veroorsaak. Dit kan daarop dui dat pediatriese pasiënte soortgelyke dalings met

2induseerders sal hê soos by volwassenes gesien. 'n Dosis van 70 mg/m CASFOLRED daagliks word aanbeveel wanneer CASFOLRED aan pediatriese pasiënte gegee word saam met induseerders van medisyne-opruiming, soos rifampisien, efavirens, nevirapien, fenitoïen, deksametasoon of

2karbaamasepien ('n werklike daaglikse dosis van 70 mg/ m moet nie oorskry word nie).

SWANGERSKAP EN BORSVOEDINGDaar is geen inligting oor die gebruik van CASFOLRED deur swanger vroue nie en daarom moet CASFOLRED nie tydens swangerskap gebruik word nie.Dit is nie bekend of CASFOLRED in die borsmelk van mense uitgeskei word nie en daarom word borsvoeding nie aanbeveel nie.

DOSIS EN GEBRUIKSAANWYSINGSVolwassenes (≥ 18 jaar):CASFOLRED moet as 'n stadige infusie oor ongeveer 1 uur toegedien word.

Empiriese behandeling'n Enkele ladingsdosis van 70 mg moet op Dag 1 gegee word en 50 mg per dag daarna. Die pasiënt se kliniese respons moet die duur van die behandeling bepaal. Empiriese behandeling moet voortgesit word totdat die neutropenie opgeklaar het. Pasiënte met 'n swaminfeksie moet vir 'n minimum van 14 dae behandel word en behandeling moet ten minste 7 dae duur nadat beide neutropenie en kliniese simptome opgeklaar het. As 50 mg goed verdra word, maar nie voldoende kliniese respons bied nie, kan die daaglikse dosis tot 70 mg verhoog word. Alhoewel 'n toename in effektiwiteit met 70 mg per dag nie bewys is nie, dui veiligheidsdata daarop dat 'n toename in dosis tot 70 mg per dag verdra word.

Invallende kandidiase'n Enkele ladingsdosis van 70 mg moet op Dag 1 gegee word en 50 mg per dag daarna. Die duur van behandeling van indringende kandidiase moet deur die pasiënt se kliniese en mikrobiologiese respons bepaal word. Oor die algemeen moet antifungusbehandeling vir ten minste 14 dae na die laaste positiewe kultuur voortduur. 'n Langer kursus van behandeling kan vir die opklaring van neutropenie nodig wees vir pasiënte wat aanhoudend neutropenies bly.Die veiligheid en effektiwiteit van meervoudige dosisse tot 150 mg per dag (gebied van 1 tot 51 dae, mediaan 14 dae) is in 100 volwasse pasiënte met indringende kandidiase bestudeer. CASFOLRED word oor die algemeen goed deur hierdie pasiënte verdra wat CASFOLRED teen hierdie hoër dosis ontvang. Die effektiwiteit van CASFOLRED teen hierdie hoër dosis is oor die algemeen soortgelyk aan dié van pasiënte wat die daaglikse dosis van 50 mg ontvang.

Esofageale en orofaringeale kandidiase50 mg moet daagliks gegee word.

Invallende aspergillose'n Enkele ladingsdosis van 70 mg moet op Dag 1 gegee word en 50 mg per dag daarna. Die duur van behandeling moet gebaseer wees op die erns van die pasiënt se onderliggende siekte, herstel van immuunonderdrukking en kliniese respons. Die effektiwiteit van 'n dosisregimen van 70 mg aan pasiënte wat nie klinies op die daaglikse dosis van 50 mg reageer nie, is nie bekend nie. Veiligheidsdata dui daarop dat 'n verhoging in dosis tot 70 mg per dag goed verdra word. Die effektiwiteit van dosisse hoër as 70 mg is nog nie genoegsaam in pasiënte met invallende aspergillose bestudeer nie.Geen dosisaanpassing is egter vir bejaardes (65 jaar of ouer) nodig nie.Geen aanpassing in die dosis is nodig op grond van geslag of ras nie en ook nie vir pasiënte met swak nierfunksie nie.Daarom moet 'n daaglikse dosis van 70 mg CASFOLRED vir volwasse pasiënte oorweeg word wanneer CASFOLRED toegedien word saam met induseerders van metabolisme, soos efavirens, nevirapien, rifampisien, deksametasoon, fenitoïen of karbaamasepien (kyk DOSERING EN AANWYSINGS VIR GEBRUIK ).

Pasiënte met swak lewerfunksieGeen aanpassing in die dosis is vir pasiënte met matige swak lewerfunksie (Child-Pughtelling 5 tot 6) nodig nie (kyk KONTRA-INDIKASIES).Vir volwasse pasiënte met matige swak lewerfunksie (Child-Pughtelling van 7 tot 9), word op grond van farmakokinetiese data, CASFOLRED teen 35 mg daagliks aanbeveel; waar egter aanbeveel, moet 'n ladingsdosis van 70 mg nog steeds op Dag 1 gegee word.Daar is geen kliniese ondervinding met pasiënte met erge swak lewerfunksie (Child-Pughtelling > 9) nie en ook nie met pediatriese pasiënte met enige mate van swak lewerfunksie nie (kyk KONTRA-INDIKASIES).

Pediatriese pasiënteCASFOLRED moet as stadige IV-infusie oor ongeveer 1 uur aan kinders en adolessente (3 maande tot 17 jaar oud) gegee word. Dosering aan kinders en adolessente (3 maande tot 17 jaar oud) moet op die pasiënt se liggaamsoppervlakte gebaseer wees (kyk INSTRUKSIES VIR GEBRUIK IN PEDIATRIESE

1 2PASIËNTE, Mostellerformule ). Vir alle aanduidings moet 'n enkele ladingsdosis van 70 mg/m op Dag 1 2toegedien word ('n werklike dosis van 70 mg moet nie oorskry word nie), gevolg deur 50 mg/m daagliks

daarna ('n werklike daagliks dosis van 70 mg moet nie oorskry word nie). Die tydsduur van behandeling moet volgens die indikasie, soos beskryf vir elke aanduiding vir volwassenes, geïndividualiseer word.

2Indien die daaglikse dosis van 50 mg/m goed verdra word, maar nie voldoende kliniese respons bied nie, 2kan die daaglikse dosis tot 70 mg/m verhoog word ('n werklike daaglikse dosis van 70 mg moet nie oorskry

2word nie). Alhoewel 'n toename in effektiwiteit met 70 mg/m per dag nie bewys is nie, dui beperkte veiligheidsdata daarop dat 'n verhoging in dosis tot 70 mg per dag goed verdra word.

2'n Dosis van 70 mg/m CASFOLRED daagliks word aanbeveel wanneer CASFOLRED aan pediatriese pasiënte gegee word saam met induseerders van middelopruiming, soos rifampisien, efavirens,

2nevirapien, fenitoïen, deksametasoon of karbaamasepien ('n werklike daaglikse dosis van 70 mg/m moet nie oorskry word nie).

Aanmaak van CASFOLREDCASFOLRED is nie stabiel in verdunners wat dekstrose bevat nie.MOENIE OPLOSMIDDELS GEBRUIK WAT DEKSTROSE (α-D-GLUKOSE) BEVAT NIE.MOENIE CASFOLRED MENG OF AS INFUSIE SAAM MET ENIGE ANDER MEDIKASIE GEE NIE, aangesien daar geen inligting beskikbaar is oor die verenigbaarheid van CASFOLRED met ander intraveneuse stowwe, bymiddels of medikasie nie.Inspekteer die infusie-oplossing visueel vir deeltjies of verkleuring.

INSTRUKSIES VIR GEBRUIK DEUR VOLWASSENESStap 1. Aanmaak van flessiesOm CASFOLRED-poeier aan te maak, word die verkoelde flessie CASFOLRED na kamertemperatuur gebring en 10,5 ml van 'n 0,9 % natriumchloriedoplossing, steriele water vir inspuiting, bakteriostatiese water vir inspuiting met metielparabeen en propielparabeen, of bakteriostatiese water vir inspuiting met 0,9 % bensielalkohol word asepties bygevoeg. Die aangemaakte produk is stabiel vir 'n tydperk van 1 uur.Die konsentrasies van die aangemaakte flessies sal as volg wees: 5,2 mg/ml (50 mg-flessie) of 7,2 mg/ml (70 mg-flessie).Die wit tot geelwit kompakte poeier sal heeltemal oplos. Meng liggies totdat 'n helder oplossing verkry word. Aangemaakte oplossings moet visueel vir deeltjies of verkleuring ondersoek word.

Stap 2. Byvoeg van aangemaakte CASFOLRED in die pasiënt se infusie-oplossingVerdunners vir die finale oplossings vir infusie aan die pasiënt is: steriele soutoplossing vir inspuiting of Ringer se laktaatoplossing. Die standaard infusie vir pasiënte word berei deur die toepaslike hoeveelheid aangemaakte geneesmiddel (soos in die tabel hier onder) asepties by 'n intraveneuse sak of bottel van 250 ml te voeg. Infusies met kleiner volume in 100 ml kan gebruik word, wanneer medies nodig, vir daaglikse dosisse van 50 mg of 35 mg.Die oplossing moet nie gebruik word as dit melkerig is of 'n neerslag bevat nie.Alhoewel chemiese en fisiese stabiliteit van aangemaakte/verdunde oplossings van 24 uur by 25 °C en 48 uur by 2 tot 8 °C vanuit mikrobiologiese oogpunt aangetoon is, moet die produk dadelik gebruik word.As dit nie dadelik gebruik word nie is die bewaartyd tydens gebruik en toestande voor gebruik die verantwoordelikheid van die gebruiker en moet normaalweg nie langer as 24 uur by 2 tot 8 °C wees nie tensy aanmaak/verdunning onder gekontroleerde en gevalideerde aseptiese toestande gedoen is.CASFOLRED moet binne 1 uur met deurlopende binneaarse infusie toegedien word.

BEREIDING VAN OPLOSSINGS VIR INFUSIE AAN PASIëNTE

INSTRUKSIES VIR GEBRUIK VIR PEDIATRIESE PASIËNTE

Berekening van liggaamsoppervlakte (LO) vir pediatriese doseringVoordat u die infusie voorberei, bereken die liggaamsoppervlakte (LO) van die pasiënt deur die volgende formule (Mostellerformule) te gebruik voordat die infusie voorberei word:

2Voorbereiding van die infusie van 50 mg/m vir pediatriese pasiënte > 3 maande oud (met 'n 50 mg-flessie)1. Bepaal die daaglikse instandhoudingsdosis deur die pasiënt se LO (soos hierbo bereken) en die volgende vergelyking te gebruik:

2 2 Daaglikse instandhoudingsdosis = LO (m ) X 50 mg/m Die daaglikse instandhoudingsdosis moet nie 70 mg oorskry nie, ongeag van die pasiënt se berekende dosis.2. Bring die verkoelde flessie met CASFOLRED na kamertemperatuur.3. Voeg 10,5 ml van 'n 0,9 % natriumchloriedoplossing, steriele water vir inspuiting, bakteriostatiese water vir inspuiting by met metielparabeen en propielparabeen, of bakteriostatiese water vir inspuiting met 0,9 % bensielalkohol asepties by. a Hierdie aangemaakte oplossing mag vir tot 24 uur by 25 °C gestoor word. b Dit sal 'n finale CASFOLRED-konsentrasie van 5,2 mg/ml in die flessie gee.4. Verwyder die volume medisyne gelyk aan die berekende ladingsdosis (Stap 1) uit die flessie. Dra

c hierdie volume (ml) van aangemaakte CASFOLRED asepties na 'n IV-sak (of bottel) wat 250 ml 0,9 %, 0,45 % of 0,225 % natriumchloriedoplossing of Ringer se laktaatoplossing bevat.

c Alternatiewelik kan die volume (ml) van aangemaakte CASFOLRED gevoeg word by 'n kleiner volume van 0,9 %, 0,45 % of 0,225 % natriumchloriedoplossing of Ringer se laktaatoplossing, wat 'n finale konsentrasie van 0,5 mg/ml nie oorskry nie. Die oplossing vir infusie moet binne 24 uur gebruik word indien dit by of onder 25 °C gehou word of binne 48 uur indien dit by 2 tot 8 °C gehou word.5. Indien die werklike daaglikse instandhoudingsdosis > 50 mg is, dan kan die dosis van die flessie met

2 70 mg berei word [Volg Stappe 2 tot 4 van " Voorbereiding van die infusie van 70 mg/m vir pediatriese pasiënte > 3 maande oud (met 'n flessie van 70 mg)"]. Die finale CASFOLRED-konsentrasie in die 70 mg-flessie na aanmaak is 7,2 mg/ml.

2Voorbereiding van die infusie van 70 mg/m vir pediatriese pasiënte > 3 maande oud (met 'n 70 mg-flessie)1. Die werklike ladingsdosis wat vir die pediatriese pasiënt gebruik moet word, word bepaal deur die pasiënt se LO (soos hierbo bereken) en die volgende vergelyking te gebruik:

2 2 Ladingsdosis = LO (m ) x 70 mg/m Die maksimum ladingsdosis op Dag 1 moet nie 70 mg oorskry nie, ongeag van die pasiënt se berekende dosis.2. Bring die verkoelde flessie met CASFOLRED na kamertemperatuur.3. Voeg 10,5 ml van 'n 0,9 % natriumchloriedoplossing, steriele water vir inspuiting, bakteriostatiese water vir inspuiting by met metielparabeen en propielparabeen, of bakteriostatiese water vir inspuiting met 0,9 % bensielalkohol asepties by. Hierdie aangemaakte oplossing mag vir tot 24 uur by 25 °C gestoor

b word . Dit sal 'n finale CASFOLRED-konsentrasie van 7,2 mg/ml in die flessie gee.4. Verwyder die volume medisyne gelyk aan die berekende ladingsdosis (Stap 1) uit die flessie. Dra

c hierdie volume (ml) van aangemaakte CASFOLRED asepties na 'n IV-sak (of bottel) wat 250 ml 0,9 %, 0,45 % of 0,225 % natriumchloriedoplossing of Ringer se laktaatoplossing bevat. Alternatiewelik kan

c die volume (ml) van aangemaakte CASFOLRED gevoeg word by 'n kleiner volume van 0,9 %, 0,45 % of 0,225 % natriumchloriedoplossing of Ringer se laktaatoplossing, wat 'n finale konsentrasie van 0,5 mg/ml nie oorskry nie. Die oplossing vir infusie moet binne 24 uur gebruik word indien dit by of onder 25 °C gehou word of binne 48 uur indien dit by 2 tot 8 °C gehou word.5. Indien die berekende ladingsdosis minder as 50 mg is, dan kan die dosis van die flessie met 50 mg berei

2 word [Volg Stappe 2 tot 4 van " Voorbereiding van die infusie van 50 mg/m vir pediatriese pasiënte > 3 maande oud (met 'n flessie van 50 mg)"]. Die finale CASFOLRED-konsentrasie in die 50 mg-flessie na aanmaak is 5,2 mg/ml.

Voorbereidingsnotasa � Die wit tot geelwit kompakte poeier sal heeltemal oplos. Meng liggies totdat 'n helder oplossing verkry word.b � Inspekteer die aangemaakte oplossing visueel vir deeltjies of verkleuring tydens aanmaak en voor infusie. Moenie die oplossing gebruik as dit melkerig is of 'n neerslag bevat nie.c � CASFOLRED is geformuleer om die volle dosis soos op die etiket (50 mg of 70 mg) te lewer wanneer 10 ml uit die flessie geneem word.

NEWE-EFFEKTEDie volgende newe-effekte is in volwasse pasiënte aangemeld:Versteurings van bloed- en limfstelsel· Dikwels: minder hemoglobien, minder hematokrit, laer witbloedseltelling.

· Minder dikwels: bloedarmoede, trombositopenie, koagulopatie, leukopenie, laer eosinofieltelling, laer bloedplaatjietelling, hoër bloedplaatjietelling, laer limfosiettelling, hoër witbloedseltelling, laer neutrofieltelling.Versteurings in metabolisme en voeding· Dikwels: hipokalemie.

· Minder dikwels: vloeistofoorbelading, hipomagnesemie, anoreksie, elektrolietwanbalans, hiperglisemie, hipokalsemie, metaboliese asidose.Psigiatriese versteurings· Minder dikwels: angs, disoriëntasie, slaaploosheid.

Versteurings van die senustelsel· Dikwels: hoofpyn.

· Minder dikwels: duiseligheid, disgeusie, parestesie, lomerigheid, bewing, hipoëstesie.Oogversteurings· Minder dikwels: okulêre ikterus, dowwe visie, ooglidedeem, meer traanafskeiding.

Hartversteurings· Minder dikwels: hartkloppings, tagikardie, disritmie, atriale fibrillasie, kongestiewe hartversaking.

Vaskulêre versteurings· Dikwels: flebitis.

· Minder dikwels: tromboflebitis, gloede, warm gloede, hipertensie, hipotensie.Respiratoriese, toragiese en mediastinale versteurings· Dikwels: dispnee.

· Minder dikwels: neusverstopping, faringolaringeale pyn, tagipnee, brongospasma, hoes, paroksismale nagtelike dispnee, hipoksie, roggel, hyg.Gastro-intestinale versteurings· Dikwels: naarheid, braking, diarree.

· Minder dikwels: buikpyn, boonste buikpyn, droë mond, dispepsie, maagongemak, buikdistensie, askites, hardlywigheid, disfagie, winderigheid.Hepatobiliêre versteurings· Dikwels: hoër waardes in lewertoetse (alanienaminotransferase, aspartaataminotransferase,

alkaliese fosfatase in bloed, gekonjugeerde bilirubien, bilirubien in die bloed).· Minder dikwels: cholestase, hepatomegalie, hiperbilirubinemie, geelsug, abnormale lewerfunksie,

hepatotoksisiteit, lewerversteuring, hoër vlakke gamma-glutamieltransferase.Versteurings van die vel en subkutane weefsel· Dikwels: uitslag, pruritus, hiperhidrose, eriteem.

· Minder dikwels: multiforme eriteem, makulêre uitslag, makulo-papulêre uitslag, pruritiese uitslag, urtikarie, allergiese dermatitis, algemene pruritus, eritemiese uitslag, algemene uitslag, morbillivorme uitslag, velletsel.· Frekwensie onbekend: toksiese epidermale nekrolise en Stevens-Johnson sindroom.

Versteurings van die muskuloskeletale stelsel, bindweefsel en skeletbene· Dikwels: artralgie

· Minder dikwels: rugpyn, pyn in die ledemate, beenpyn, spierswakheid, mialgie.Versteurings van die niere en urienweg· Minder dikwels: nierversaking, akute nierdisfunksie.

Algemene versteurings en toestande by die plek van toediening· Dikwels: pireksie, kouekoors, pruritus op die infusie-plek.

· Minder dikwels: pyn, pyn by kateterplasingsarea, moegheid, koue gevoel, warm gevoel, eriteem by infusieplek, indurasie by infusieplek, pyn by infusieplek, swelling van infusieplek, flebitis by infusieplek, perifere edeem, teerheid, borsongemak, pyn op die bors, gesigsedeem, gevoel van verandering in liggaamstemperatuur, indurasie, ekstravasasie by infusieplek, irritasie by infusieplek, flebitis by infusieplek, uitslag op infusieplek, urtikarie by infusieplek, eriteem by inspuitplek, edeem by inspuitplek, pyn by inspuitplek, swelling by inspuitplek, ongesteldheid, edeem.Laboratoriumtoetse· Dikwels: minder kalium in bloed, minder albumien in bloed.

· Minder dikwels: meer kreatinien in bloed, rooibloedselle toets positief in urien, afname in totale hoeveelheid proteïen, proteïen in urien, protrombientyd langer, protrombientyd korter, minder natrium in bloed, meer natrium in bloed, minder kalsium in bloed, meer kalsium in bloed, minder chloried in bloed, meer glukose in bloed, minder magnesium in bloed, minder fosfor in bloed, meer fosfor in bloed, meer ureum in bloed, langer geaktiveerde parsiële tromboplastientyd, minder bikarbonaat in bloed, meer chloried in bloed, meer kalium in bloed, hoër bloeddruk, minder uriensuur in bloed, bloed in urien, asemhaling klink abnormaal, minder koolstofdioksied, hoër vlak immuunonderdrukkende geneesmiddels, groter internasionale genormaliseerde verhouding, uriensilinders, witbloedselle in urien en hoër pH van urien.Die volgende newe-effekte is in volwasse pasiënte aangemeld:Versteurings van bloed- en limfstelsel· Dikwels: hoër eosinofieltelling.

Versteurings van die senustelsel· Dikwels: hoofpyn.

Hartversteurings· Dikwels: tagikardie.

Vaskulêre versteurings· Dikwels: gloede, hipotensie.

· Frekwensie onbekend: swelling en perifere edeem.Hepatobiliêre versteurings· Dikwels: hoër vlakke van lewerensieme (AST, ALT)

· Frekwensie onbekend: lewerdisfunksie.Versteurings van die vel en subkutane weefsel· Dikwels: veluitslag, pruritus.

· Frekwensie onbekend: simptome vanweë histamien (uitslag, swelling in gesig, pruritus, gevoel van warmte, brongospasma), anafilakse.Algemene versteurings en toestande by die plek van toediening· Dikwels: koors, kouekoors, pyn by die kateter.

Laboratoriumtoetse· Dikwels: hoër vlakke lewerensieme, nl. alanienaminotransferase (ALT), aspartaataminotransferase

(AST), minder kalium, hipomagnesemie, meer glukose, minder fosfor, meer fosfor.· Frekwensie onbekend: hiperkalsemie, meer eosinofiele.

BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VIR DIE BEHANDELING DAARVANIn een studie was 210 mg die hoogste dosis wat as 'n enkeldosis toegedien is aan 6 gesonde proefpersone en in 'n ander studie is 150 mg een keer per dag vir tot 51 dae aan 100 proefpersone toegedien.CASFOLRED is nie dialiseerbaar nie.

IDENTIFIKASIEOnopgemaakte flessiesElke flessie CASFOLRED bevat 'n wit tot afwit gevriesdroogde koek/poeier.Aangemaakte flessiesHelder oplossing prakties vry van sigbare deeltjies.Verdunde produk vir infusieHelder oplossing prakties vry van sigbare deeltjies.

AANBIEDINGCASFOLRED 50 word verskaf in buisvormige Lyo-flessies van helder USP tipe-1-glas van 10 ml met 'n nekdeursnit van 20 mm en proppe van 20 mm van grys bromobutielrubber en verseël met 20 mm aluminiumafwipseëls.

CASFOLRED 70 word verskaf in buisvormige Lyo-flessies van helder USP tipe-1-glas van 10 ml met 'n nekdeursnit van 20 mm en proppe van 20 mm van grys bromobutielrubber en verseël met 20 mm aluminiumafwipseëls.Die glasflessie word saam met die voubiljet in 'n gedrukte buitenste karton verpak.

BEWARINGSINSTRUKSIESBerging van onoopgemaakte flessiesBêre by 2 ºC tot 8 °C.

Berging van aangemaakte / verdunde oplossingAlhoewel chemiese en fisiese stabiliteit van aangemaakte/verdunde oplossings van 24 uur by 25 °C en 48 uur by 2 tot 8 °C vanuit mikrobiologiese oogpunt aangetoon is, moet die produk dadelik gebruik word. As dit nie dadelik gebruik word nie is die bewaartyd tydens gebruik en toestande voor gebruik die verantwoordelikheid van die gebruiker en moet normaalweg nie langer as 24 uur by 2 tot 8 °C wees nie tensy aanmaak/verdunning onder gekontroleerde en gevalideerde aseptiese toestande gedoen is.Moenie vries nie.HOU BUITE BEREIK VAN KINDERS.

REGISTRASIENOMMERSCASFOLRED 50: 50/20.2.2/0945CASFOLRED 70: 50/20.2.2/0946

NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIESERTIFIKAATDr. Reddy's Laboratories (Edms) BeperkDerde Vloer, The PlaceSandtonrylaan 1Sandton2196.

DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET29 September 2017

Dosis*

Volume van aangemaakte

CASFOLRED vir oordrag na binneaarse

sak of bottel

Finale konsentrasie van standaard voorbereiding (aangemaakte CASFOLRED

gevoeg by 250 ml)

35 mg vir matige swak lewerfunksie(van een 50 ml-flessie)

7 ml

0,14 mg/ml 0,34 mg/ml

35 mg vir swak lewerfunksie (van een 70 ml-flessie) 5 ml 0,14 mg/ml 0,34 mg/ml

50 mg 10 ml 0,20 mg/ml 0,47 mg/ml

70 mg 10 ml 0,28 mg/ml Nie aanbeveel nie

70 mg (van twee 50 mg-flessies)** 14 ml 0,28 mg/ml Nie aanbeveel nie

* 10,5 ml moet vir die aanmaak van alle flessies gebruik word** Indien 'n flessie met 70 mg nie beskikbaar is nie, kan die dosis van 70 mg uit twee flessies met 50 mg berei word.

Finale konsentrasie van standaard voorbereiding (aangemaakte CASFOLRED

gevoeg by 100 ml)

lengte (cm) x gewig (kg)

3600

2LO (m ) =

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