Chemical formula: C₅₂H₈₈N₁₀O₁₅ Molecular mass: 1,093.331 g/mol PubChem compound: 3035406
Caspofungin interacts in the following cases:
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.
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.
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. Close monitoring of liver enzymes should be considered if the two medicinal products are used concomitantly.
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 co-administering 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.
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.
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.
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.
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.
Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported after post-marketing use of caspofungin. Caution should apply in patients with history of allergic skin reaction.
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. Caspofungin has been shown to cross the placental barrier in animal studies.
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.
For caspofungin, there were no effects on fertility in studies conducted in male and female rats. There are no clinical data for caspofungin to assess its impact on fertility.
No studies on the effects on the ability to drive and use machines have been performed.
Hypersensitivity reactions (anaphylaxis and possibly histamine-mediated adverse reactions) have been reported.
Also reported in patients with invasive aspergillosis were pulmonary oedema, adult respiratory distress syndrome (ARDS), and radiographic infiltrates.
In clinical studies, 1,865 adult individuals received single or multiple doses of caspofungin: 564 febrile neutropaenic 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 non-comparative 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 during clinical studies and/or post-marketing use:
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Not known (cannot be estimated from available data)
Common: haemoglobin decreased, haematocrit decreased, white blood cell count decreased
Uncommon: anaemia, thrombocytopaenia, coagulopathy, leukopaenia, 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, gamma-glutamyltransferase increased
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
Not known: Toxic epidermal necrolysis and StevensJohnson syndrome
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, 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. 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.
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
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