Active ingredients: Caspofungin
Cancidas 50 mg powder for concentrate for solution for infusion
Cancidas package inserts are available for pack sizes:- Cancidas 50 mg powder for concentrate for solution for infusion
- Cancidas 70 mg powder for concentrate for solution for infusion
Why is Cancidas used? What is it for?
So is Cancidas
Cancidas contains a medicine called caspofungin. This belongs to a group of medicines called antifungals.
What Cancidas is used for
Cancidas is used to treat the following infections in children, adolescents and adults:
- severe fungal infections in tissues and organs (called "invasive candidiasis"). This infection is caused by fungal (yeast) cells called Candida. People who might get this type of infection include those who have just had an operation or those whose immune systems are weak. Fever and chills that don't respond to an antibiotic are the most common signs of this type of infection.
- fungal infections of the nose, sinuses or lungs (called 'invasive aspergillosis') if other antifungal treatments have not worked or have caused side effects. This infection is caused by a mold called Aspergillus. People who could get this type of infection include those who are on chemotherapy, those who have had a transplant, and those whose immune systems are weak.
- suspected fungal infections: if you have a fever and a low white blood cell count with no improvement after antibiotic therapy. People who are at risk of developing a "fungal infection" include those who have just had an operation or those whose immune systems are weak.
How Cancidas works
Cancidas makes the fungal cells fragile and prevents the fungus from growing properly. This stops the spread of the infection and gives the body's natural defenses the ability to completely eliminate the infection.
Contraindications When Cancidas should not be used
Do not use Cancidas
- if you are allergic to caspofungin or any of the other ingredients of this medicine (listed in section 6).
If you are not sure, talk to your doctor, nurse or pharmacist before you are given this medicine.
Precautions for use What you need to know before taking Cancidas
Talk to your doctor, nurse or pharmacist before you are given Cancidas if:
- you are allergic to any other medicines
- have ever had liver problems - you may need a different dose of this medicine
- are already taking cyclosporine (used to help prevent transplant rejection or suppress the immune system) as your doctor may need additional blood tests during treatment
- have ever had any other medical problems.
If any of the above apply to you (or if you are not sure), talk to your doctor, nurse or pharmacist before you are given Cancidas.
Cancidas can also cause severe skin adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
Interactions Which drugs or foods can modify the effect of Cancidas
Tell your doctor, nurse or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because Cancidas can affect the way Cancidas works. some other medicines Some other medicines can also affect the way Cancidas works.
Tell your doctor, nurse or pharmacist if you are taking any of the following medicines:
- cyclosporine or tacrolimus (used to help prevent transplant rejection or suppress the immune system) - as your doctor may need additional blood tests during treatment
- some HIV medicines such as efavirenz or nevirapine
- phenytoin or carbamazepine (used to treat seizures)
- dexamethasone (a steroid)
- rifampicin (an antibiotic).
If any of the above apply to you (or if you are not sure), talk to your doctor, nurse or pharmacist before you are given this medicine.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding or if you think you are pregnant, ask your doctor for advice before taking any medicine.
- Cancidas has not been studied in pregnant women. It should only be used in pregnancy if the potential benefit justifies the potential risk to the unborn baby.
- Women given Cancidas should not breastfeed.
Driving and using machines
There is no information available to suggest that Cancidas has an effect on the ability to drive or use machines.
Cancidas contains sucrose
Cancidas contains sucrose (a type of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars, talk to your doctor, nurse or pharmacist before you are given this medicine.
Dose, Method and Time of Administration How to use Cancidas: Posology
Cancidas must always be prepared and administered by a healthcare professional.
Cancidas will be given to you:
- once a day
- by slow injection into a vein (intravenous infusion)
- in about 1 hour.
Your doctor will determine the duration of treatment and the amount of Cancidas you will be given daily. Your doctor will monitor the effect this medicine has on you. If you weigh more than 80 kg you may need a different dose.
Children and adolescents
The dose for children and adolescents may be different from the dose for adults.
Overdose What to do if you have taken too much Cancidas
If you have been given more Cancidas than you should
Your doctor will decide on the daily amount of Cancidas you need and the duration of treatment. If you are concerned that you have been given too much Cancidas, tell your doctor or nurse immediately.
If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist.
Side Effects What are the side effects of Cancidas
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor or nurse immediately if you notice any of the following side effects - you may need urgent medical treatment:
- rash (redness), itching, warmth, swelling of the face, lips or throat or difficulty in breathing - you may be having a histamine reaction to the medicine.
- difficulty breathing with wheezing or a 'rash that gets worse - you may be having an allergic reaction to the medicine.
- cough, severe breathing difficulties - if you are an adult and have invasive aspergillosis it is possible that you are having a severe respiratory problem which could result in respiratory failure.
- rash, skin peeling, mucous membrane sores, hives, extensive areas of skin peeling.
As with any other prescription medicine, some side effects can be serious. For more information, ask your doctor.
Other side effects in adults include
Common: may affect up to 1 in 10 people:
- Decrease in hemoglobin (the substance in the blood that carries oxygen is decreased), decrease in white blood cells
- Decrease in blood albumin (a type of protein) in the blood, decrease in potassium or low levels of potassium in the blood
- Headache
- Phlebitis (inflammation of the vein)
- Shortness of breath
- Diarrhea, nausea, vomiting
- Changes in some values in blood tests (including increases in the values of some liver parameters)
- Itching, rash, redness of the skin or more than normal sweating
- Pain in the joints
- Chills, fever
- Itching at the injection site.
Uncommon: may affect up to 1 in 100 people:
- Changes in some blood test values (including blood clotting disease, platelets, red blood cells and white blood cells)
- Loss of appetite, increased amount of body fluids, salt imbalance in the body, high blood sugar, low blood calcium, increased blood calcium, low blood magnesium, increased blood sugar level of acids in the blood
- Disorientation, nervousness, inability to sleep
- Feeling dizzy, decreased sensation or sensitivity (especially in the skin), shaking, feeling sleepy, altered taste, tingling or numbness
- Blurred vision, increased tearing, swollen eyelid, yellow discoloration of the whites of the eyes
- Feeling of fast or irregular heartbeats, rapid heartbeat, irregular heartbeat, abnormal heart rhythm, heart failure
- Flushing, hot flashes, high blood pressure, low blood pressure, redness of a vein that is extremely painful to pressure
- Narrowing of the muscles in the respiratory tract causing dyspnoea or cough, rapid breathing, shortness of breath that wakes the patient, reduced oxygen in the blood, abnormal breathing sounds, rubbing noise in the lungs, dyspnoea, nasal congestion, cough, pain in the throat
- Pain in the abdomen, pain in the upper part of the abdomen, dilation of the abdomen, constipation, difficulty swallowing, dry mouth, indigestion, passing of gas, stomach upset, bloating caused by the formation of fluid in the abdomen
- Decreased flow of bile, enlarged liver, yellowing of the skin and / or whites of the eyes, liver damage caused by a medicine or chemical causes, liver disorder
- Abnormal skin tissue, generalized itching, hives, rash of various types, abnormal skin, often itchy red spots on the arms and legs and sometimes on the face and rest of the body
- Back pain, arm or leg pain, bone pain, muscle pain, muscle weakness
- Loss of kidney function, sudden loss of kidney function
- Pain at the catheter site, discomfort at the injection site (redness, small hard mass, pain, swelling, irritation, rash, hives, leakage of fluid from the catheter into the tissue), inflammation of the vein at the injection site
- Increased blood pressure and changes in some blood test values (including kidney electrolytes and clotting parameters) increased levels of medicines you are taking that weaken the immune system
- Chest discomfort, chest pain, perception of change in body temperature, feeling generally unwell, general pain, swelling of the face, swelling of the ankles, hands or feet, swelling, hypersensitivity, feeling tired.
Side effects in children and adolescents
Very common: may affect more than 1 in 10 people:
- Fever
Common: may affect up to 1 in 10 people
- Headache
- Tachycardia
- Redness, low blood pressure
- Changes in some values in blood tests (increase in the values of some liver-related tests)
- Itching, rash
- Pain at the catheter site
- Chills
- Changes in some values in blood tests.
Reporting of side effects
If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and vial (the first two numbers are the month, the next four numbers are the year). The expiry date refers to the last day of the month.
Store in a refrigerator (2 ° C - 8 ° C).
Once Cancidas has been prepared, it must be used right away. This is because it does not contain ingredients to stop the growth of bacteria. Only an experienced healthcare professional, who has read the complete instructions, should prepare this medicine (see below "Instructions on how to reconstitute and dilute Cancidas").
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Cancidas contains
- The active ingredient is caspofungin. Each vial of Cancidas contains 50 mg of caspofungin.
- The other ingredients are sucrose, mannitol, glacial acetic acid and sodium hydroxide (see section 2. What you need to know before you are given Cancidas).
What Cancidas looks like and contents of the pack
Cancidas is a compact, sterile, white to off-white powder.
There is a vial of powder in each pack.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CANCIDAS POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
CANCIDAS 50 mg powder for concentrate for solution for infusion
Each vial contains 50 mg caspofungin (as acetate).
Excipients with known effects:
Each 50 mg vial contains 35.7 mg of sucrose.
CANCIDAS 70 mg powder for concentrate for solution for infusion
Each vial contains 70 mg caspofungin (as acetate).
Excipients with known effects:
Each 70 mg vial contains 50.0 mg of sucrose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for concentrate for solution for intravenous infusion.
Prior to reconstitution, the powder is a white to off-white compact powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
• Treatment of invasive candidiasis, in adult or pediatric patients.
• Treatment of invasive aspergillosis in adult or pediatric patients refractory or intolerant to therapy with amphotericin B, lipid formulations of amphotericin B and / or itraconazole. Patients with infections that progress or do not improve after a minimum of 7 days of treatment with therapeutic doses of effective antifungal therapy are defined as refractory to therapy.
• Empirical therapy of presumed fungal infections (such as Candida or Aspergillus) in neutropenic adult or pediatric patients with fever.
04.2 Posology and method of administration
Caspofungin therapy should be initiated by physicians experienced in the management of invasive fungal infections.
Dosage
Adult patients
A single 70 mg loading dose should be administered on the first day of treatment followed by another 50 mg per day. In patients weighing more than 80 kg, after the 70 mg loading dose, a caspofungin 70 mg / day (see section 5.2) No dosage adjustment is necessary based on gender or race (see section 5.2).
Pediatric patients (12 months to 17 years)
In pediatric patients (12 months to 17 years of age) dosing should be based on the patient's body surface area (see Instructions for Use in Pediatric Patients, Mosteller formula [1]). For all indications, a single loading dose of 70 mg / m2 should be administered on the first day of treatment (an effective dose of 70 mg should not be exceeded), followed by 50 mg / m2 daily (should not be exceeded). an effective dose of 70 mg per day). If the daily dose of 50 mg / m2 is well tolerated but does not provide an adequate clinical response, it can be increased to 70 mg / m2 per day (an effective daily dose of 70 mg should not be exceeded).
[1] Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22; 317: 1098 (letter)
The safety and efficacy of caspofungin have not been sufficiently studied in clinical trials in newborns and infants less than 12 months of age. Caution is recommended when treating patients in this age group. Limited data suggests that therapy may be considered. with caspofungin 25 mg / m2 per day in neonates and infants (less than 3 months of age) and 50 mg / m2 per day in young children (3 to 11 months of age) (see section 5.2).
Duration of treatment
The duration of empirical therapy should be based on the patient's clinical response. Therapy should be continued for up to 72 hours after resolution of neutropenia (ANC ≥ 500). Patients diagnosed with fungal infection should be treated for a minimum of 14 days and treatment should continue for at least 7 days after both neutropenia and clinical symptoms resolve.
The duration of treatment for invasive candidiasis should be based on the patient's clinical and microbiological response. Following improvement of the signs and symptoms of invasive candidiasis and after negative culture results, a switch to oral antifungal therapy may be considered. In general, antifungal therapy should continue for at least 14 days after the last positive culture.
The duration of invasive aspergillosis treatment should be assessed on a case-by-case basis and should be based on the severity of the patient's underlying disease, the extent of clinical improvement in immunosuppression and clinical response. In general, treatment should continue for at least 7 days. days after symptoms resolve.
Safety information for treatments longer than 4 weeks is limited. However, the available data suggest that caspofungin continues to be well tolerated with longer courses of therapy (up to 162 days in adult patients and up to 87 days in pediatric patients).
Special populations
Elderly patients
In elderly patients (65 years of age and older), the area under the curve (AUC) increased by approximately 30%. However, no systematic dosage adjustment is required. Experience with treatment in patients of equal age or over the age of 65 is limited (see section 5.2).
Renal impairment
No dosage adjustment is necessary in the presence of renal impairment (see section 5.2).
Compromise hepatic
For adult patients with mild hepatic impairment (Child-Pugh score 5 to 6), no dosage adjustment is required. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), it is recommended to administer caspofungin 35 mg / day based on pharmacokinetic data. A loading dose of 70 mg on Day 1 should be administered. No clinical data are available in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and pediatric patients with any degree of hepatic impairment (see section 4.4 ).
Co-administration with inducers of metabolic enzymes
Limited data suggest that an increase in the daily dose of caspofungin up to 70 mg, following the 70 mg loading dose, should be considered when administering caspofungin to adult patients concomitantly with certain inducers of metabolic enzymes (see section 4.5). . When caspofungin is administered to pediatric patients (12 months to 17 years of age) concomitantly with the same inducers of metabolic enzymes (see section 4.5), a caspofungin dose of 70 mg / m2 per day should be considered (not an effective dose of 70 mg per day should be exceeded).
Method of administration
After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour. For instructions on reconstitution see section 6.6.
Both 50 mg and 70 mg vials are available.
Caspofungin should be administered as a single daily intravenous infusion.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Anaphylaxis has been reported during administration of caspofungin.
If this occurs, caspofungin should be discontinued and appropriate treatment administered. Adverse reactions possibly mediated by histamine release have been reported
including rash, facial swelling, angioedema, pruritus, sensation of heat or bronchospasm and these may require interruption and / or administration of appropriate treatment.
Limited data suggest that yeasts do not-Candida and molds not-Aspergillus less common are not covered by caspofungin. The efficacy of caspofungin against these pathogenic fungi has not been established.
Concomitant use of caspofungin with cyclosporine has been evaluated in healthy adult volunteers and in adult patients. Some healthy adult volunteers who received two doses of 3 mg / kg cyclosporine with caspofungin showed transient increases in alanine transaminase (ALT) and aspartate. transaminases (AST) less than or equal to 3 times the upper limit of normal (ULN), which resolved on discontinuation of treatment. In a retrospective study of 40 patients treated for 1 to 290 days (median 17.5 days) with caspofungin and ciclosporin after the marketing of the medicinal product, no serious hepatic adverse reactions were observed. These data suggest that caspofungin can be used in patients treated with ciclosporin when the potential benefits outweigh the potential risks. In case of concomitant administration of caspofungin and cyclosporine, careful monitoring of liver enzymes should be chosen.
In adult patients with mild and moderate hepatic impairment, AUC is increased by approximately 20% and 75%, respectively. In moderate hepatic impairment, a reduction of the daily dose to 35 mg is recommended for adults. There are no data. in adults with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment. Increased exposure is expected in patients with hepatic impairment therefore caspofungin should be used with caution in these patients (see sections 4.2 and 5.2).
Laboratory abnormalities in liver function tests have been observed in healthy volunteers and in adult and pediatric patients treated with caspofungin. Clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported in some adult and pediatric patients with serious underlying conditions receiving multiple concomitant therapies with caspofungin; A causal relationship with caspofungin has not been established. Patients who develop liver function test abnormalities during caspofungin therapy should be monitored for worsening liver function and the risk / benefit of continuing caspofungin therapy should be reassessed.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, or sucrase-isomaltase insufficiency should not take this medicine (see section 2).
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported after post-marketing use of caspofungin. Caution should be exercised in patients with a history of allergic skin reaction (see section 4.8).
04.5 Interactions with other medicinal products and other forms of interaction
Studies in vitro show that caspofungin is not an inhibitor of any enzyme of the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce CYP3A4 mediated metabolism of other medicinal products. Caspofungin is not a substrate for P-glycoprotein and is a weak substrate for cytochrome P450 enzymes. However, caspofungin has been shown to interact with other medicinal products in clinical and pharmacological studies (see below).
In two clinical studies conducted in healthy adult subjects, cyclosporine A (one 4 mg / kg dose or two 3 mg / kg doses 12 hours apart) increased the AUC of caspofungin by approximately 35%. These increases in AUC are likely due to reduced liver uptake of caspofungin. Caspofungin did not increase the plasma levels of cyclosporine. When caspofungin was co-administered with cyclosporine, transient elevations in hepatic ALT and AST less than or equal to 3 times the upper limit of normal (ULN) were observed and resolved on discontinuation of therapy. In a retrospective study of For 40 patients treated from 1 to 290 days (median 17.5 days) with caspofungin and cyclosporine after the product was placed on the market, no serious hepatic adverse reactions were observed (see section 4.4). In case of concomitant administration of the two medicinal products, careful monitoring of liver enzymes should be chosen.
Caspofungin reduced the trough concentration of tacrolimus in healthy adult volunteers by 26%. Standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dose adjustments are recommended for patients receiving both therapies.
Clinical studies performed in healthy volunteers have shown that caspofungin pharmacokinetics are not clinically significantly altered by itraconazole, amphotericin B, mycophenolate, nelfinavir or tacrolimus. Caspofungin did not affect the pharmacokinetics of amphotericin B, itraconazole, rifampicin or mycophenolate mofetil. Although safety data are limited, no special precautions appear to be necessary when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil are co-administered with caspofungin.
Rifampicin caused a 60% increase in AUC and a 170% increase in trough concentration of caspofungin on the first day of concomitant administration when therapy with the two medicinal products was started concurrently in healthy adult volunteers. The trough levels of caspofungin are gradually decreased after repeated administration Rifampicin had a limited effect on AUC after two weeks of dosing but trough levels were 30% lower than in adult subjects given caspofungin alone. The mechanism underlying the interaction may somehow be due to an initial inhibition and subsequent induction of transport proteins. A similar effect can be expected for other metabolic enzyme-inducing drugs. Limited population pharmacokinetic data indicate that the " Concomitant use of caspofungin with the inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine, may result in a decrease in the AUC of caspofungin. In case of concomitant administration of inducers of metabolic enzymes, an increase in metabolic enzyme inducers should be considered in adult patients. caspofungin daily dose up to 70 mg, following the 70 mg loading dose (see section 4.2).
All of the drug interaction studies described above, conducted in adults, were conducted with daily doses of 50 or 70 mg of caspofungin. The interaction of higher doses of caspofungin with other medicinal products has not been formally studied.
In pediatric patients, results from regression analyzes of pharmacokinetic data suggest that concomitant administration of dexamethasone with caspofungin may cause clinically significant decreases in caspofungin trough concentrations. This finding may indicate that pediatric patients will experience similar reductions with inducers to those seen in adults. When caspofungin is administered to pediatric patients (12 months to 17 years of age) concomitantly with inducers of drug clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg / m2 per day (an effective dose of 70 mg per day should not be exceeded).
04.6 Pregnancy and breastfeeding
Pregnancy
Data on the use of caspofungin in pregnant women are not available or are limited. Caspofungin should not be used during pregnancy unless clearly necessary. Animal studies have shown development of toxicity (see section 5.3). Caspofungin has been shown to cross the placental barrier in animal studies.
Feeding time
It is unknown whether caspofungin is excreted in human milk. Available pharmacodynamic / toxicological data in animals have shown that caspofungin is excreted in milk. Women taking caspofungin should not breastfeed.
Fertility
For caspofungin, there were no effects on fertility in studies conducted in male and female rats (see section 5.3). There are no clinical data that allow to evaluate its impact on fertility.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Hypersensitivity reactions (anaphylaxis and adverse reactions possibly mediated by histamine release) have been reported (see section 4.4).
Pulmonary edema, adult respiratory distress syndrome (ARDS) and radiographic infiltrates have also been reported in patients with invasive aspergillosis.
Adult patients
In clinical trials, 1,865 adults were treated with single or multiple doses of caspofungin: 564 neutropenic patients with fever (empirical therapy study), 382 patients with invasive candidiasis, 228 patients with invasive aspergillosis, 297 patients with localized infections Candida, and 394 people enrolled in Phase I clinical trials. In the empirical therapy study, patients had been treated with chemotherapy for malignant neoplasm or had undergone haematopoietic stem cell transplantation (including 39 allogeneic transplants). In studies involving patients with documented infections of Candida, most patients with invasive infections from Candida had serious underlying medical conditions (eg, malignant haematopathies or other oncological conditions, recent major surgery, HIV), requiring concomitant administration of several medicines. Patients in the non-comparative study on "Aspergillus they often had severe predisposing underlying diseases (eg: bone marrow or peripheral stem cell transplantation, malignant haematopathies, solid tumors or organ transplants), requiring concomitant administration of several drugs.
Phlebitis was a frequently reported adverse reaction at the injection site in all patient populations. Other localized reactions were erythema, pain / tenderness, itching, discharge and a burning sensation.
Clinical and laboratory abnormalities reported in all adults treated with caspofungin (overall 1,780 patients) were typically mild and rarely led to discontinuation of therapy.
Table of adverse reactions
The following adverse reactions have been reported during clinical trials and / or post-marketing use:
Caspofungin was evaluated at a dose of 150 mg per day (up to 51 days) in 100 adult patients (see section 5.1). The study compared caspofungin at a dose of 50 mg per day (following a 70 mg loading dose on day 1) versus 150 mg per day in the treatment of invasive candidiasis. In this patient group, the safety profile of caspofungin at this higher dose was generally similar to that of patients receiving caspofungin at a dose of 50 mg daily. The proportion of patients with a serious drug-related adverse reaction or drug-related adverse reaction leading to discontinuation of caspofungin therapy was comparable in the 2 treatment groups.
Pediatric patients
Data from 5 completed clinical trials in 171 pediatric patients suggest that the overall incidence of adverse clinical events (26.3%; 95% CI -19.9, 33.6) is no worse than that reported in treated adults. with caspofungin (43.1%; 95% CI -40.0, 46.2). However, pediatric patients likely have a different adverse event profile than adult patients. The most common adverse events related to the reported in pediatric patients treated with caspofungin were pyrexia (11.7%), rash (4.7%) and headache (2.9%).
Table of adverse reactions
The following adverse reactions have been reported:
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Accidental administration of caspofungin up to 400 mg in one day has been reported. These occurrences did not result in clinically significant adverse reactions. Caspofungin is not dialysable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antifungals for systemic use.
ATC code: J02AX04.
Mechanism of action
Caspofungin acetate is a semi-synthetic lipopeptide (echinocandin) synthesized from a fermentation product of Glarea lozoyensis. Caspofungin acetate inhibits the synthesis of beta - D - glucan, an essential component of the cell wall of many filamentous fungi and yeasts. Beta - D - glucan is not present in mammalian cells.
The fungicidal activity of caspofungin has been demonstrated against such yeasts Candida, studies in vitro and in vivo show that the exposure of Aspergillus a caspofungin causes lysis and death of the extremities of the apical hyphae and of the branching points where cell growth and division take place.
Pharmacodynamic effects
Caspofungin owns assets in vitro against the species of Aspergillus (Aspergillus fumigatus [N = 75], Aspergillus flavus [N = 111], Aspergillus niger [N = 31], Aspergillus nidulans [N = 8], Aspergillus terreus [N = 52] e Aspergillus Candidus [N = 3]). Caspofungin also owns assets in vitro against the species of Candida (Candida albicans [N = 1032], Candida dubliniensis [N = 100], Candida glabrata [N = 151], Candida guilliermondii [N = 67], Candida kefyr [N = 62], Candida krusei [N = 147], Candida lipolytica [N = 20], Candida lusitaniae [N = 80], Candida parapsilosis [N = 215]), Wrinkled Candida [N = 1] e Candida tropicalis [N = 258], including isolates with multiple resistance transport mutations and those with acquired or intrinsic resistance to fluconazole, amphotericin B and 5-flucytosine. Susceptibility tests were performed based on modifications to both M38-A2 methods (for Aspergillus) and M27-A3 (for Candida) of the Clinical and Laboratory Standards Institute (CLSI, formerly known as the National Committee for Clinical Laboratory Standards [NCCLS]).
Standardized techniques for testing susceptibility have been established for yeasts by EUCAST. EUCAST breakpoints have not yet been established for caspofungin, due to significant interlaboratory variation in the minimum inhibitory concentration ranges (minimal inhibitory concentration or MIC) for caspofungin. Instead of breakpoints, Candida isolates that are sensitive to anidulafungin and micafungin should be considered sensitive to caspofungin. Similarly, isolates of C. parapsilosis with intermediate sensitivity to anidulafungin and micafungin can be considered with intermediate sensitivity to caspofungin.
Resistance mechanism
Candida isolates with reduced susceptibility to caspofungin have been identified in a small number of patients during treatment (MICs for caspofungin> 2 mg / l (4- to 30-fold increases in MIC) have been reported using standardized MIC testing techniques. approved by CLSI). The mechanism of resistance identified consists of the genetic mutations FKS1 and / or FKS2 (per C. glabrata). These cases have been associated with poor clinical outcomes.
The development of resistance was identified in vitro to caspofungin by sort Aspergillus. In the context of limited clinical experience, resistance to caspofungin has been observed in patients with invasive aspergillosis. The resistance mechanism has not been identified. The incidence of caspofungin resistance by various clinical isolates of Aspergillus it is rare. Resistance to caspofungin by Candida has been observed, but the incidence may vary by species or region.
Clinical efficacy and safety
Invasive Candidiasis in Adult Patients: Two hundred thirty-nine patients were enrolled in an initial study comparing caspofungin and amphotericin B in the treatment of invasive candidiasis. Twenty-four patients had neutropenia. The most frequent diagnoses were bloodstream infections (candidemia) (77%, n = 186) and Candida (8%, n = 19); patients with endocarditis, osteomyelitis or meningitis from Candida were excluded from the study. Caspofungin was administered at a dose of 50 mg once daily following a loading dose of 70 mg, while amphotericin B was administered at a dose of 0.6-0.7 mg / kg / day in non-neutropenic patients or at a dose of 0.7-1.0 mg / kg / day in neutropenic patients. The mean duration of intravenous therapy was 11.9 days, ranging from 1 to 28 days. In order to consider a response as favorable, both the resolution of the symptoms and the disappearance of the infection were required Candida from a microbiological point of view. Two hundred and twenty-four patients were included in the primary efficacy analysis (MITT analysis) of response at the end of intravenous therapy; the favorable response rates for the treatment of invasive candidiasis between caspofungin (73% [80/109]) and amphotericin B (62% [71/115]) [percentage difference 12.7 (95.6% CI -0.7 , 26.0)] were comparable. Among patients with candidemia, favorable response rates at the end of study intravenous therapy were comparable between caspofungin (72% [66/92]) and amphotericin B (63% [59/94]) in the primary efficacy analysis. (MITT analysis) [10.0 percent difference (95.0% CI -4.5, 24.5)]. Data from patients with non-haematological site of infection were more limited. Favorable response rates in patients neutropenic were 7/14 (50%) in the caspofungin group and 4/10 (40%) in the amphotericin B group. These limited data are supported by the outcome of the empirical therapy study.
In a second study, patients with invasive candidiasis received caspofungin 50 mg once daily (following a 70 mg loading dose on Day 1) or 150 mg caspofungin once daily (see section 4.8). In this study, the caspofungin dose was administered over 2 hours (instead of the usual 1 hour dose). Patients with Candida endocarditis, meningitis or osteomyelitis were excluded from this study. As this was a primary therapy study, patients who were refractory to prior antifungal drug therapy were also excluded. The number of neutropenic patients enrolled in this study was also limited (8.0%). Efficacy was a secondary endpoint in this study. Patients who met the inclusion criteria and who received one or more doses of caspofungin were included in the efficacy analysis. Favorable response rates at the end of caspofungin therapy overall were similar in the 2 treatment groups: 72% (73/102) and 78% (74/95) for the caspofungin 50 mg and 150 mg treatment groups, respectively (difference 6.3% [95% CI-5, 9, 18,4]).
Invasive aspergillosis in adult patients: 69 adult patients (aged 18 to 80 years) with invasive aspergillosis were enrolled in an open-label non-comparative study to evaluate the safety, tolerability and efficacy of caspofungin. Enrolled patients were either refractory (evolving disease or failure to improve with other antifungal therapies administered for at least 7 days) (84% of enrolled patients) or intolerant (16% of enrolled patients) to other standard antifungal therapies. Most patients had underlying disease (malignant hemopathies [N = 24 ], allogeneic bone marrow transplant or stem cell transplant [N = 18], organ transplant [N = 8], solid tumor [N = 3] or other pathologies [N = 10]). Strict definitions were used for the diagnosis of invasive aspergillosis and for the response to therapy (for a favorable response, clinically significant improvement in both radiographic images and signs and symptoms) were used, formulated following the indications of the Mycoses Study Group Criteria. The mean duration of therapy was 33.7 days, with a range from 1 to 162 days. An independent panel of specialists estimated that 41% (26/63) of patients given at least one dose of caspofungin responded favorably. Among patients who had been given caspofungin for more than 7 days, 50% (26/52) had a favorable response. The favorable response rates for patients refractory or intolerant to previous therapies were 36% (19/53) and 70% (7/10), respectively.
Although in 5 patients enrolled as refractory the doses of previous antifungal therapies were lower than those often administered for the treatment of invasive aspergillosis, the rate of favorable responses during caspofungin therapy in these patients was similar to that observed in other refractory patients. (2/5 vs 17/48, respectively). The favorable response rates among patients with pulmonary and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients with certain, probable or possible CNS involvement also had a favorable response.
Empirical therapy in neutropenic adult patients with fever: A total of 1,111 patients with persistent fever and neutropenia were enrolled in a clinical study and treated either with caspofungin 50 mg once daily following a 70 mg loading dose or with liposomal amphotericin B 3.0 mg / kg / day. Eligible patients had been treated with chemotherapy for malignancies or had undergone haematopoietic stem cell transplantation, had neutropenia (3 for 96 hours) and fever (> 38.0 ° C) that had not responded at ≥ 96 hours of treatment parenteral antibacterial. Patients were to be treated for up to 72 hours after resolution of neutropenia, for up to 28 days. However, patients with documented fungal infection could be treated for longer. In case of good tolerance to the drug but persistence of fever and deterioration of clinical condition after 5 days of therapy, the dose of study drug could be increased to 70 mg / day of caspofungin (13.3% of treated patients) or to 5.0 mg / kg / day of liposomal amphotericin B (14.3% of treated patients). 1,095 patients were included in the modified intention-to-treat (MITT) primary efficacy analysis on overall favorable response; caspofungin (33.9%) was as effective as liposomal amphotericin B (33.7%) [% difference 0.2 ( 95.2% CI -5.6, 6.0)].For a favorable overall response, the following 5 criteria were required to be met: satisfactory treatment of any fungal infection at baseline (caspofungin 51.9% [14/27], liposomal amphotericin B 25.9% [7/27]), absence of new fungal infections during study drug administration or within 7 days of completion of therapy (caspofungin 94.8% [527/556], liposomal amphotericin B 95.5% [515/539]), survival for 7 days after completion of study therapy (caspofungin 92.6% [515/556], liposomal amphotericin B 89.2% [481/539]), no interruptions from study therapy due to drug-related toxicity or lack of efficacy (caspofungin 89.7% [499/556], liposomal amphotericin B 85.5% [461/539]), and resolution of fever during the period of neutropenia (caspofungin 41.2% [229/556], amphotericin B liposomal 41.4% [223/539]). Response rates to caspofungin and liposomal amphotericin B for baseline infections caused by Aspergillus sp. were, respectively, 41.7% (5/12) and 8.3% (1/12), and per Candida sp. they were 66.7% (8/12) and 41.7% (5/12). New fungal infections due to the following uncommon yeasts and molds occurred in patients in the caspofungin group: Trichosporon sp. , Fusarium sp. , Mucor sp. , And Rhizopus sp. .
Pediatric population
The safety and efficacy of caspofungin were evaluated in pediatric patients aged 3 months to 17 years in two prospective, multicenter clinical studies. Study design, diagnostic criteria, and criteria for efficacy were similar. to those of the corresponding studies in adult patients (see section 5.1).
The first study, in which 82 patients aged 2-17 years were enrolled, was a randomized, double-blind study comparing caspofungin [50 mg / m2 IV per day following a loading dose of 70 mg / m2. m2 on Day 1 (not allowed to exceed 70 mg per day)] and liposomal amphotericin B (3 mg / kg IV per day) in a 2: 1 treatment schedule (56 patients treated with caspofungin and 26 with liposomal amphotericin B) as empirical therapy in pediatric patients with persistent fever and neutropenia. The overall therapeutic success rates based on the results of the MITT analysis, adjusted for risk strata, were as follows: 46.6% (26/56) for caspofungin and 32.2% (8/25) for liposomal amphotericin B .
The second study was prospective, open-label, non-comparative to evaluate the safety and efficacy of caspofungin in pediatric patients (aged 6 months to 17 years) with invasive candidiasis, esophageal candidiasis and invasive aspergillosis (as rescue therapy) Forty-nine patients were enrolled who were treated with caspofungin 50 mg / m2 IV once daily following a loading dose of 70 mg / m2 on Day 1 (not allowed to exceed 70 mg daily), of whom 48 were were included in the MITT analysis. Of these patients, 37 had invasive candidiasis, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. The favorable response rate, by indication, at the end of caspofungin therapy was in the MITT analysis as follows: 81% (30/37) in invasive candidiasis, 50% (5/10) in invasive aspergillosis and 100% (1 / 1) in esophageal candidiasis.
05.2 Pharmacokinetic properties
Distribution
Caspofungin is extensively bound to albumin. The unbound plasma fraction of caspofungin ranges from 3.5% in healthy volunteers to 7.6% in patients with invasive candidiasis. Distribution plays a prominent role in the plasma pharmacokinetics of caspofungin and is the phase critical passage in both phases of alpha and beta disposition Tissue distribution peaked 1.5 to 2 days after dosing when 92% of the dose was distributed within the tissues.
It is probable that only a small part of the caspofungin absorbed by the tissues subsequently returns to the plasma as unchanged compound. Consequently, elimination occurs in the absence of an equilibrium of distribution and a true estimate of the volume of distribution of caspofungin is currently impossible to obtain.
Biotransformation
Caspofungin undergoes a spontaneous degradation process in an open ring compound. Subsequent metabolism includes peptide hydrolysis and N-acetylation. Two intermediates, formed during the degradation of caspofungin to this open-loop compound, form covalent adducts with plasma proteins resulting in low-level, irreversible binding with plasma proteins.
Education in vitro show that caspofungin is not an inhibitor of cytochrome P450 enzymes 1A2, 2A6, 2C9, 2C19, 2D6 or 3A4. Caspofungin did not induce or inhibit the CYP3A4-mediated metabolism of other medicinal products in clinical studies. Caspofungin is not a substrate for P-glycoprotein and has poor substrate activity for cytochrome P450 enzymes.
Elimination
Elimination of caspofungin from plasma is slow with a clearance of 10-12 ml / min. Plasma concentrations of caspofungin decrease in a polyphasic pattern following single intravenous infusions lasting 1 hour. A short alpha phase occurs immediately thereafter. the intravenous infusion, followed by a beta phase with a half-life of 9 to 11 hours. An additional gamma phase also occurs with a half-life of 45 hours. The dominant mechanism on plasma clearance is distribution rather than excretion or biotransformation.
Approximately 75% of the radioactive dose was recovered over 27 days: 41% in urine and 34% in faeces. There is low excretion or biotransformation of caspofungin during the first 30 hours after administration. Excretion is slow and the terminal half-life of radioactivity was 12 to 15 days. A small amount of caspofungin is excreted unchanged in the urine (approximately 1.4% of the dose).
Caspofungin exhibits moderate non-linear pharmacokinetics with increased accumulation with increasing dose and dose-dependence over time until equilibrium is reached with multiple dose administration.
Special populations
Increased caspofungin exposure was observed in adult patients with renal and mild hepatic impairment, women and the elderly. Generally the increase was small and not large enough to warrant a dosage adjustment. In adult patients with moderate hepatic impairment or in patients of heavier body weight, dosage adjustment may be necessary (see below).
Weight: Weight was found to influence caspofungin pharmacokinetics in the population pharmacokinetic analysis in adult candidiasis patients. Plasma concentrations decrease with weight gain. The mean exposure in an adult patient weighing 80 kg is expected to be approximately 23% lower than that in an adult patient weighing 60 kg (see section 4.2).
Hepatic impairment: In adult patients with mild and moderate hepatic impairment, AUC increased by 20 and 75%, respectively. There are no clinical data in adult patients with severe hepatic impairment and in pediatric patients with any degree of hepatic impairment. a multiple dose study, it was shown that a reduction of the daily dose to 35 mg in adult patients with moderate hepatic impairment results in AUC similar to that obtained in adult subjects with normal hepatic function administered a standard regimen (see paragraph 4.2).
Renal impairment: In a clinical study with single doses of 70 mg, the pharmacokinetics of caspofungin were similar in adult volunteers with mild renal impairment (creatinine clearance 50-80 ml / min) and in controls. Moderate (creatinine clearance 31 to 49 mL / min), advanced (creatinine clearance 5 to 30 mL / min) and end-stage (dialysis-dependent creatinine clearance) renal impairment moderately increased plasma concentrations of caspofungin following single dose administration (AUC 30 to 49%). However, for adult patients with invasive candidiasis, oesophageal candidiasis or invasive aspergillosis who received multiple daily doses of 50 mg caspofungin, mild to advanced impairment of renal function had no significant effect on caspofungin concentrations. No dosage adjustment is necessary in patients with renal impairment. Caspofungin is not dialysable, therefore no additional dosage is required after hemodialysis.
Gender: Plasma concentrations of caspofungin were on average 17-38% higher in women than in men.
Elderly: A modest increase in AUC (28%) and C24h (32%) was observed in older male compared to younger men. In patients treated with empiric therapy or with invasive candidiasis, a similar effect was observed. modest age in the elderly compared to the young.
Race: Patient pharmacokinetic data indicate that no clinically significant differences in caspofungin pharmacokinetics were observed between Caucasians, Blacks, Hispanics and Mestizos.
Pediatric patients:
In adolescents (12-17 years of age) treated with caspofungin at 50 mg / m2 per day (maximum 70 mg per day), the plasma AUC0-24h of caspofungin was generally comparable to that seen in adults treated with caspofungin. 50 mg per day.All adolescents received doses> 50 mg per day, and in fact, 6 of 8 received the maximum dose of 70 mg / day. Plasma concentrations of caspofungin in these adolescents were lower than in adults treated with 70 mg daily, the most frequently administered dose to adolescents.
In children (aged 2 to 11 years) treated with caspofungin 50 mg / m2 per day (maximum 70 mg per day), the plasma AUC0-24h of caspofungin after multiple doses was comparable to that seen in adults treated with caspofungin. to 50 mg per day.
In infants and toddlers (aged 12-23 months) treated with caspofungin 50 mg / m2 per day (maximum 70 mg per day), the plasma AUC0-24h of caspofungin after multiple doses was comparable with that found in adults treated with caspofungin at 50 mg per day and with that found in older children (2 to 11 years of age) treated with the 50 mg / m2 dose per day.
Overall, available pharmacokinetic, efficacy and safety data are limited in patients 3 to 10 months of age. Pharmacokinetic data from a 10 month old child treated with the 50 mg / m2 daily dose indicate AUC values within a similar range to that observed in older children and adults treated with 50 mg doses, respectively. / m2 and 50 mg, while in a 6-month-old child treated with the 50 mg / m2 dose, the AUC0-24h was slightly higher.
In neonates and infants (2 per day (corresponding to a mean daily dose of 2.1 mg / kg), the peak concentration of caspofungin (C1h) and trough concentration of caspofungin (C24h) after multiple doses were comparable with what found in adults treated with caspofungin 50 mg daily. In these neonates and infants compared to adults on Day 1, C1h was comparable and C24h was modestly elevated (36%). However, variability was found in both C1h (the geometric mean on Day 4 was 11.73 mcg / mL, range 2.63 to 22.05 mcg / mL) and in C24h (the geometric mean on Day 4 was 3.55 mcg / mL, range 0.13 to 7.17 mcg / ml). In this study, no measurements of AUC0-24h were made due to the scarcity of plasma samples. It should be noted that the efficacy and safety of caspofungin have not been adequately studied in prospective clinical studies. involving newborns and infants under 3 months of age.
05.3 Preclinical safety data
Repeat dose toxicity studies in rats and monkeys at doses up to 7-8 mg / kg intravenously showed injection site reactions in rats and monkeys, signs of histamine release in rats and evidence of adverse liver effects in rats. monkeys. Growth toxicity studies in rats showed that caspofungin caused decreases in fetal body weight and increases in the incidence of incomplete calcification of the vertebrae, sternebrae and skull at doses of 5 mg / kg along with adverse reactions in the dams. what signs of histamine release in pregnant rats. An increase in the incidence of cervical ribs was also observed.
Caspofungin was negative in a series of assays in vitro for potential genotoxicity and in chromosomal testing in vivo on mouse bone marrow. Long-term studies in animals have not been conducted to evaluate carcinogenic potential. For caspofungin, there were no effects on fertility in studies conducted in male and female rats up to 5 mg / kg / day.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sucrose
Mannitol
Glacial acetic acid
Sodium hydroxide (for pH adjustment)
06.2 Incompatibility
Do not mix with diluents containing glucose, as CANCIDAS is not stable in diluents containing glucose. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
2 years.
Reconstituted concentrate: should be used immediately. Stability data showed that the concentrate for solution for infusion can be stored for up to 24 hours if the vial is stored at or below 25 ° C and reconstituted with water for injections.
Diluted intravenous infusion solution for the patient: should be used immediately. Stability data showed that the product can be used within 24 hours when stored at or below 25 ° C, or within 48 hours when the intravenous infusion bag (bottle) is stored refrigerated (2 to 8 ° C) and diluted with sodium chloride 9 mg / ml (0.9%), 4.5 mg / ml (0.45%), or 2.25 mg / ml (0.225%) solution for intravenous infusion , or with a lactated Ringer's solution.
CANCIDAS does not contain preservatives. 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 operator and would normally not be longer than 24 hours at 2 - 8 ° C, unless reconstitution and dilution did not take place under controlled and validated aseptic conditions.
06.4 Special precautions for storage
Intact vials: Store in a refrigerator (2 ° C - 8 ° C).
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
CANCIDAS 50 mg powder for concentrate for solution for infusion
10 ml Type I glass vial with a gray butyl stopper and a plastic cap with a red aluminum band.
CANCIDAS 70 mg powder for concentrate for solution for infusion
10 ml Type I glass vial with a gray butyl stopper and a plastic cap with an orange aluminum band.
Supplied in packs of 1 vial.
06.6 Instructions for use and handling
Reconstitution of CANCIDAS
DO NOT USE DILUENTS CONTAINING GLUCOSE as CANCIDAS is not stable in diluents containing glucose. DO NOT MIX OR GIVE CANCIDAS IN THE SAME ROUTE WITH ANY OTHER MEDICINAL PRODUCT, as there is no data available on the compatibility of CANCIDAS with other intravenous substances, additives or medicinal products. Visually check the IV solution for particles or discolouration.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
CANCIDAS 50 mg powder for concentrate for solution for infusion
INSTRUCTIONS FOR USE IN ADULT PATIENTS
Step 1 Reconstitution of conventional vials
To reconstitute the powder, bring the vial to room temperature and aseptically add 10.5 ml of water for injections. The concentration of the reconstituted vial will be 5.2 mg / ml.
The white to off-white compact lyophilized powder will dissolve completely. Mix lightly until a clear solution is obtained. Reconstituted solutions should be checked visually for the presence of particles or color change. This reconstituted solution can be stored for up to 24 hours at temperatures of 25 ° C or below.
Step 2 Addition of reconstituted CANCIDAS to patient intravenous infusion solution
Diluents for the final intravenous infusion solution are: sodium chloride solution for injection, or lactated Ringer's solution. The solution for infusion is prepared by aseptically adding the appropriate amount of the reconstituted concentrate (as shown in the table below) to a 250 ml infusion bag or bottle. Reduced volumes of infusion to 100 ml for 50 mg or 35 mg daily doses can be used if medically necessary. Do not use if the solution has clouding or precipitates.
PREPARATION OF THE SOLUTION FOR INTRAVENOUS INFUSION IN ADULTS
* 10.5 ml should be used to reconstitute all vials.
INSTRUCTIONS FOR USE IN PEDIATRIC PATIENTS
Body Surface Area (BSA) calculation for pediatric dosing
Before preparing the infusion, calculate the patient's body surface area (BSA) using the following formula: (Mosteller's formula)
Preparation of the 70 mg / m2 infusion for pediatric patients> 3 months of age (using a 50 mg vial)
1. Determine the appropriate loading dose to be used in pediatric patients using the patient's BSA (as calculated above) and the following equation:
BSA (m2) X 70 mg / m2 = Loading Dose
The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient's calculated dose.
2. Bring the chilled CANCIDAS vial to room temperature.
3. Aseptically add 10.5 mL of water for injections. A This reconstituted solution can be stored for up to 24 hours at or below 25 ° C. B This will provide a final caspofungin concentration in the vial of 5.2 mg / mL.
4. Remove the volume of medicine corresponding to the calculated loading dose (step 1) from the vial. Aseptically transfer this volume (mL) c of reconstituted CANCIDAS 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 volume (ml) c of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45% or 0.225% Sodium Chloride Injection, or Lactated Ringer's Injection, without exceeding a final concentration of 0.5 mg / ml. This infusion solution should be used within 24 hours if stored at or below 25 ° C or within 48 hours if stored refrigerated between 2 and 8 ° C.
Preparation of the 50 mg / m2 infusion for pediatric patients> 3 months of age (using a 50 mg vial)
1. Determine the appropriate maintenance daily dose to be used in the pediatric patient using the patient's BSA (as calculated above) and the following equation:
BSA (m2) X 50 mg / m2 = Daily Maintenance Dose
The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.
2. Bring the chilled CANCIDAS vial to room temperature.
3. Aseptically add 10.5 mL of water for injections. A This reconstituted solution can be stored for up to 24 hours at or below 25 ° C. B This will provide a final caspofungin concentration in the vial of 5.2 mg / mL.
4. Remove the volume of medicine corresponding to the calculated daily maintenance dose (step 1) from the vial. Aseptically transfer this volume (mL) c of reconstituted CANCIDAS 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 volume (ml) c of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45% or 0.225% Sodium Chloride Injection, or Lactated Ringer's Injection, without exceeding a final concentration of 0.5 mg / ml. This infusion solution should be used within 24 hours if stored at or below 25 ° C or within 48 hours if stored refrigerated between 2 and 8 ° C.
Notes for preparation:
to. The white to off-white mixture will dissolve completely. Mix gently until the solution becomes clear.
b. Visually inspect the reconstituted solution for particles or discolouration during reconstitution and before infusion. Do not use if the solution is not clear or contains precipitates.
c. CANCIDAS is formulated to provide the full labeled dose (50 mg) when 10 ml is withdrawn from the vial.
CANCIDAS 70 mg powder for concentrate for solution for infusion
INSTRUCTIONS FOR USE IN ADULT PATIENTS
Step 1 Reconstitution of conventional vials
To reconstitute the powder, bring the vial to room temperature and aseptically add 10.5 ml of water for injections. The concentration of the reconstituted vial will be 7.2 mg / ml.
The white to off-white compact lyophilized powder will dissolve completely. Mix lightly until a clear solution is obtained. Reconstituted solutions should be checked visually for the presence of particles or color change. This reconstituted solution can be stored for up to 24 hours at temperatures of 25 ° C or below.
Step 2 Addition of reconstituted CANCIDAS to patient intravenous infusion solution
Diluents for the final intravenous infusion solution are: sodium chloride solution for injection, or lactated Ringer's solution. The solution for infusion is prepared by aseptically adding the appropriate amount of the reconstituted concentrate (as shown in the table below) to a 250 ml infusion bag or bottle. Reduced volume infusions of 100 ml for 50 mg or 35 mg daily doses may be used where medically necessary. Do not use if the solution has clouding or precipitates.
PREPARATION OF THE SOLUTION FOR INTRAVENOUS INFUSION IN ADULTS
* 10.5 ml should be used to reconstitute all vials.
** If the 70 mg vial is not available, the 70 mg dose can be prepared with 2 vials of 50 mg.
INSTRUCTIONS FOR USE IN PEDIATRIC PATIENTS
Body Surface Area (BSA) calculation for pediatric dosing
Before preparing the infusion, calculate the patient's body surface area (BSA) using the following formula: (Mosteller's formula)
Preparation of the 70 mg / m2 infusion for pediatric patients> 3 months of age (using a 70 mg vial)
1. Determine the appropriate loading dose to be used in pediatric patients using the patient's BSA (as calculated above) and the following equation:
BSA (m2) X 70 mg / m2 = Loading Dose
The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient's calculated dose.
2. Bring the chilled CANCIDAS vial to room temperature.
3. Aseptically add 10.5 ml of water for injections. A This reconstituted solution can be stored for up to 24 hours at or below 25 ° C. B This will provide a final concentration of caspofungin in the vial of 7.2 mg / ml.
4. Remove the volume of medicine corresponding to the calculated loading dose (step 1) from the vial. Aseptically transfer this volume (mL) c of reconstituted CANCIDAS 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 volume (ml) c of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45% or 0.225% Sodium Chloride Injection, or Lactated Ringer's Injection, without exceeding a final concentration of 0.5 mg / ml. This infusion solution should be used within 24 hours if stored at or below 25 ° C or within 48 hours if stored refrigerated between 2 and 8 ° C.
Preparation of the 50 mg / m2 infusion for pediatric patients> 3 months of age (using a 70 mg vial)
1. Determine the appropriate maintenance daily dose to be used in the pediatric patient using the patient's BSA (as calculated above) and the following equation:
BSA (m2) X 50 mg / m2 = Daily Maintenance Dose
The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.
2. Bring the chilled CANCIDAS vial to room temperature.
3. Aseptically add 10.5 ml of water for injections. A This reconstituted solution can be stored for up to 24 hours at or below 25 ° C. B This will provide a final concentration of caspofungin in the vial of 7.2 mg / ml.
4. Remove the volume of medicine corresponding to the calculated daily maintenance dose (step 1) from the vial. Aseptically transfer this volume (mL) c of reconstituted CANCIDAS 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 volume (ml) c of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45% or 0.225% Sodium Chloride Injection, or Lactated Ringer's Injection, without exceeding a final concentration of 0.5 mg / ml. This infusion solution should be used within 24 hours if stored at or below 25 ° C or within 48 hours if stored refrigerated between 2 and 8 ° C.
Notes for preparation :
to. The white to off-white mixture will dissolve completely. Mix gently until the solution becomes clear.
b. Visually inspect the reconstituted solution for particles or discolouration during reconstitution and before infusion. Do not use if the solution is not clear or contains precipitates.
c. CANCIDAS is formulated to provide the full labeled dose (70 mg) when 10 ml is withdrawn from the vial.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Ltd
Hertford Road, Hoddeson
Hertforshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/01/196/001
035493016
EU / 1/01/196/003
035493030
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 24 October 2001.
Date of last renewal: 07 September 2011.
10.0 DATE OF REVISION OF THE TEXT
23 June 2016
