Summary of medicine characteristics - NIGUFO 50 MG POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
1 NAME OF THE MEDICINAL PRODUCT
Nigufo50 mg powder for concentrate for solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 50 mg caspofungin (as acetate).
After reconstitution in 10.5 ml of water for injection, 1 mL of solution contains 5.2 mg of caspofungin.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
Before reconstitution, the powder is a white to off-white-compact, powder.
4 CLINICAL PARTICULARS
4 CLINICAL PARTICULARS4.1 Therapeutic indications
Treatment of invasive candidiasis in adult or paediatric patients.
Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and/or itraconazole. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.
Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropenic adult or paediatric patients.
4.2 Posology and method of administration
Caspofungin should be initiated by a physician experienced in the management of invasive fungal infections.
Posology
Adult patients
A single 70 mg loading dose should be administered on Day-1, followed by 50 mg daily thereafter. In patients weighing more than 80 kg, after the initial 70 mg loading dose, caspofungin 70 mg daily is recommended (see section 5.2). No dosage adjustment is necessary based on gender or race (see section 5.2).
Paediatric patients (12 months to 17 years)
In paediatric patients (12 months to 17 years of age), dosing should be based on the patient’s body surface area (see Instructions for Use in Paediatric Patients, Mosteller1 Formula). For all indications, a single 70-mg/m2 loading dose (not to exceed an actual dose of 70 mg) should be administered on Day 1, followed by 50-mg/m2 daily thereafter (not to exceed an actual dose of 70 mg daily). If the 50 mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70-mg/m2 daily (not to exceed an actual daily dose of 70 mg).
The safety and efficacy of caspofungin have not been sufficiently studied in clinical trials involving neonates and infants below 12 months of age. Caution is advised when treating this age group. Limited data suggest that caspofungin at 25-mg/m2 daily in neonates and infants (less than 3 months of age) and 50-mg/m2 daily in young children (3 to 11 months of age) can be considered (see section 5.2).
(1 Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17):1098 (letter))
Duration of treatment
Duration of empirical therapy should be based on the patient’s clinical response. Therapy should be continued until up to 72 hours after resolution of neutropenia (ANC > 500). Patients found to have a 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 are resolved.
Duration of treatment of invasive candidiasis should be based upon the patient’s clinical and microbiological response. After signs and symptoms of invasive candidiasis have improved and cultures have become negative, 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.
Duration of treatment of invasive aspergillosis is determined on a case by case basis and should be based upon the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response. In general, treatment should continue for at least 7 days after resolution of symptoms.
The safety information on treatment durations longer than 4 weeks is limited. However, 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 paediatric patients).
Special populations
Elderly patients
In elderly patients (65 years of age or more), the area under the curve (AUC) is increased by approximately 30 %. However, no systematic dosage adjustment is required. There is limited treatment experience in patients 65 years of age and older (see section 5.2).
Renal impairment
No dosage adjustment is necessary based on renal impairment (see section 5.2).
Hepatic impairment
For adult patients with mild hepatic impairment (Child-Pugh score 5 to 6), no dosage adjustment is needed. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin 35 mg daily is recommended based upon pharmacokinetic data. An initial 70 mg loading dose should be administered on Day-1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in paediatric 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 to 70 mg, following the 70 mg loading dose, should be considered when co-administering caspofungin in adult patients with certain inducers of metabolic enzymes (see section 4.5). When caspofungin is co-administered to paediatric patients (12 months to 17 years of age) with these same inducers of metabolic enzymes (see section 4.5), a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered.
Method of administration
After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour. For reconstitution directions see section 6.6.
Both 70 mg and 50 mg vials are available.
Caspofungin should be given as a single daily infusion.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Anaphylaxis has been reported during administration of caspofungin. If this occurs, caspofungin should be discontinued and appropriate treatment administered. Possibly 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 nonAspergillus moulds are not covered by caspofungin. The efficacy of caspofungin against these fungal pathogens has not been established.
Concomitant use of caspofungin with cyclosporin has been evaluated in healthy adult volunteers and in adult patients. Some healthy adult volunteers who received two 3 mg/kg doses of cyclosporin with caspofungin 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. In a retrospective study of 40 patients treated during marketed use with caspofungin and cyclosporin for 1 to 290 days (median 17.5 days), no serious hepatic adverse reactions were noted. These data suggest that caspofungin can be used in patients receiving cyclosporin when the potential benefit outweighs the potential risk. Close monitoring of liver enzymes should be considered if caspofungin and cyclosporin are used concomitantly.
In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 % and 75 %, respectively. A reduction of the daily dose to 35 mg is recommended for adults with moderate hepatic impairment. 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 caspofungin should be used with caution in these patients (see sections 4.2 and 5.2).
Laboratory abnormalities in liver function tests have been seen in healthy volunteers and adult and paediatric patients treated with caspofungin. In some adult and paediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin, cases of clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported; a causal relationship to caspofungin has not been established. Patients who develop abnormal liver function tests during caspofungin therapy should be monitored for evidence of worsening hepatic function and the risk/benefit of continuing caspofungin therapy should be re-evaluated.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance or sucrase-isomaltase insufficiency should not take this medicinal product (see section 2).
This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction Studies in vitro show that caspofungin is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other substances. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes. However, caspofungin has been shown to interact with other medicinal products in pharmacological and clinical studies (see below).
In two clinical studies performed in healthy adult subjects, cyclosporin A (one 4 mg/kg dose or two 3 mg/kg doses 12 hours apart) increased the AUC of caspofungin by approximately 35 %. These AUC increases are probably due to reduced uptake of caspofungin by the liver. Caspofungin did not increase the plasma levels of cyclosporin. There were transient increases in liver ALT and AST of less than or equal to 3-fold the upper limit of normal (ULN) when caspofungin and cyclosporin were co-administered, that resolved with discontinuation of the medicinal products. In a retrospective study of 40 patients treated during marketed use with caspofungin and cyclosporin for 1 to 290 days (median 17.5 days), no serious hepatic adverse reactions were noted (see section 4.4). Close monitoring of liver enzymes should be considered if the two medicinal products are used concomitantly.
Caspofungin reduced the trough concentration of tacrolimus by 26 % in healthy adult volunteers. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are mandatory.
Clinical studies in healthy adult volunteers show that the pharmacokinetics of caspofungin are not altered to a clinically relevant extent by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin did not influence the pharmacokinetics of amphotericin B, itraconazole, rifampicin or mycophenolate mofetil. Although safety data are limited it appears that no special precautions are needed when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil are co-administered with caspofungin.
Rifampicin caused a 60 % increase in AUC and 170 % increase in trough concentration of caspofungin on the first day of co-administration when both medicinal products were initiated together in healthy adult volunteers. Caspofungin trough levels gradually decreased upon repeated administration. After two weeks’ administration rifampicin had limited effect on AUC, but trough levels were 30 % lower than in adult subjects who received caspofungin alone. The mechanism of interaction could possibly be due to an initial inhibition and subsequent induction of transport proteins.
A similar effect could be expected for other medicinal products that induce metabolic enzymes.
Limited data from population pharmacokinetics studies indicate that concomitant use of caspofungin with the inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine may result in a decrease in caspofungin AUC. When coadministering inducers of metabolic enzymes, an increase in the daily dose of caspofungin to 70 mg, following the 70 mg loading dose, should be considered in adult patients (see section 4.2).
All adult drug-drug interaction studies described above were conducted at a 50 or 70 mg daily caspofungin dose. The interaction of higher doses of caspofungin with other medicinal products has not been formally studied.
In paediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that paediatric patients will have similar reductions with inducers as seen in adults. When caspofungin is co-administered to paediatric patients (12 months to 17 years of age) with inducers of drug clearance, such as rifampicin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited data from the use of caspofungin in pregnant women.
Caspofungin should not be used during pregnancy unless clearly necessary. Animal studies have shown developmental toxicity (see section 5.3). Caspofungin has been shown to cross the placental barrier in animal studies.
Breast-feeding
It is unknown whether caspofungin is excreted in human milk. Available pharmacodynamic/ toxicological data in animals have shown excretion of caspofungin in milk. Women receiving caspofungin should not breast-feed.
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 for caspofungin to assess its impact on fertility.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effects
Hypersensitivity reactions (anaphylaxis and possibly histamine-mediated adverse reactions) have been reported (see section 4.4).
Also reported in patients with invasive aspergillosis were pulmonary oedema, adult respiratory distress syndrome (ARDS), and radiographic infiltrates.
Adult patients
In clinical studies, 1,865 adult individuals received single or multiple doses of caspofungin: 564 febrile neutropenic patients (empirical therapy study), 382 patients with invasive candidiasis, 228 patients with invasive aspergillosis, 297 patients with localised Candida infections, and 394 individuals enrolled in Phase I studies. In the empirical therapy study patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation (including 39 allogeneic transplantations). In the studies involving patients with documented Candida infections, the majority of the patients with invasive Candida infections had serious underlying medical conditions (e.g., haematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus study often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, haematologic malignancy, solid tumours or organ transplants) requiring multiple concomitant medications.
Phlebitis was a commonly reported local injection-site adverse reaction in all patient populations.
Other local reactions included erythema, pain/tenderness, itching, discharge, and a burning sensation.
Reported clinical and laboratory abnormalities among all adults treated with caspofungin (total 1,780) were typically mild and rarely led to discontinuation.
The following adverse reactions were reported:
[Very common (> 1/10), Common (> 1/100 to < 1/10), Uncommon (> 1/1,000 to < 1/100)]
Common: haemoglobin decreased, haematocrit decreased, white blood cell count decreased.
Uncommon: anaemia, thrombocytopaenia, coagulopathy, leukopenia, eosinophil count increased, platelet count decreased, platelet count increased, lymphocyte count decreased, white blood cell count increased, neutrophil count decreased.
Common: hypokalemia.
Uncommon: fluid overload, hypomagnesaemia, anorexia, electrolyte imbalance, hyperglycaemia, hypocalcaemia, metabolic acidosis.
Uncommon: anxiety, disorientation, insomnia.
Common: headache.
Uncommon: dizziness, dysgeusia, paraesthesia, somnolence, tremor, hypoaesthesia.
Uncommon: ocular icterus, vision blurred, eyelid oedema, lacrimation increased.
Uncommon: palpitations, tachycardia, arrhythmia, atrial fibrillation, cardiac failure congestive.
Common: phlebitis.
Uncommon: thrombophlebitis, flushing, hot flush, hypertension, hypotension.
Common: dyspnoea.
Uncommon: nasal congestion, pharyngolaryngeal pain, tachypnoea, bronchospasm, cough, dyspnoea paroxysmal nocturnal, hypoxia, rales, wheezing.
Common: nausea, diarrhoea, vomiting.
Uncommon: abdominal pain, abdominal pain upper, dry mouth, dyspepsia, stomach discomfort, abdominal distension, ascites, constipation, dysphagia, flatulence.
Common: elevated liver values (alanine aminotransferase, aspartate aminotranserase, blood alkaline phosphatase, bilirubin conjugated, blood bilirubin).
Uncommon: cholestasis, hepatomegaly, hyperbilirubinaemia, jaundice, hepatic function abnormal, hepatotoxicity, liver disorder.
Common: rash, pruritus, erythema, hyperhidrosis.
Uncommon: erythema multiforme, rash macular, rash maculo-papular, rash pruritic, urticaria, dermatitis allergic, pruritus generalised, rash erythematous, rash generalised, rash morbilliform, skin lesion.
Common: arthralgia.
Uncommon: back pain, pain in extremity, bone pain, muscular weakness, myalgia.
Uncommon: renal failure, renal failure acute.
Common: pyrexia, chills, infusion-site pruritus.
Uncommon: 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.
Common: blood potassium decreased, blood albumin decreased.
Uncommon: 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, gammaglutamyltransferase 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.
Caspofungin has also been evaluated at 150 mg daily (for up to 51 days) in 100 adult patients (see section 5.1). The study compared caspofungin at 50 mg daily (following a 70-mg loading dose on Day 1) versus 150 mg daily in the treatment of invasive candidiasis. In this group of patients, the safety of caspofungin at this higher dose appeared generally similar to patients receiving the 50-mg daily dose of caspofungin. The proportion of patients with a serious drug-related adverse reaction or a drug-related adverse reaction leading to caspofungin discontinuation was comparable in the 2 treatment groups.
Paediatric Patients
Data from 5 clinical studies completed in 171 paediatric patients suggest that the overall incidence of clinical adverse experiences (26.3 % ; 95 % CI –19.9, 33.6) is not worse than reported for adults treated with caspofungin (43.1 % ; 95 % CI –40.0, 46.2). However, paediatric patients probably have a different adverse event profile compared to adult patients. The most common drug-related clinical adverse experiences reported in paediatric patients treated with caspofungin were pyrexia (11.7 %), rash (4.7 %) and headache (2.9 %).
The following adverse reactions were reported:
[Very common (> 1/10), Common (> 1/100 to < 1/10)
Common: eosinophil count increased.
Common: headache.
Common : tachycardia.
Common : flushing, hypotension.
Common : elevated liver enzyme levels (AST, ALT).
Common : rash, pruritus.
Very common : fever.
Common : chills, catheter site pain.
Common : decreased potassium, hypomagnesemia, increased glucose, decreased phosphorus, and increased phosphorus.
Post-Marketing experience:
The following post-marketing adverse reactions have been reported:
Hepatic dysfunction
Swelling and peripheral oedema
Hypercalcaemia
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
Inadvertent administration of up to 400 mg of caspofungin in one day has been reported. These occurrences did not result in clinically important adverse reactions. Caspofungin is not dialysable.