Caspofungin
Encyclopedia
Caspofungin (brand name Cancidas worldwide) is an antifungal drug, the first of a new class termed the echinocandin
s from Merck & Co., Inc.
It shows activity against infections with Aspergillus
and Candida
, and works by inhibiting the enzyme
β(1,3)-D-Glucan synthase
and thereby disturbing the integrity of the fungal cell wall
. Caspofungin is administered intravenously.
, in Europe, in 2001. Its currently approved therapeutic indications by both organisations include the empirical therapy of presumed fungal infections in febrile, neutropenic adult patients and the treatment of invasive aspergillosis
in adult patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B
and/or itraconazole
). Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis
, pleural cavity
infections and oesophagitis) and the EMEA approval includes indication for the treatment of general invasive candidiasis
in adult patients.
The concomitant use of caspofungin and cyclosporine in healthy volunteers led to a more frequent increase of liver enzymes (ALT=SGPT and AST=SGOT) than noted with cyclosporine alone. Combination treatment is only indicated if the potential benefit for the patient outweighs the potential risk.
Dosage reduction in patients with moderately impaired liver function is recommended. No clinical data exist regarding the use of caspofungin in patients with severely impaired liver function.
Reactions due to histamine release (rash, facial swelling, pruritus, sensation of warmth and one case of anaphylaxis) have been seen. Health-care providers should carefully watch for these reactions.
In a few patients with infections caused by Candida albicans
, mutants with reduced sensitivity to caspofungin have been noticed. Currently there are no data regarding development of resistance in other fungi than C. albicans.
The drug is found in the milk of lactating rats, but it is not known whether this is seen in humans. Thus, lactating women should be treated cautiously.
Additionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen. One case of anaphylaxis
(severe allergic reaction) has also been noted.
has been described, but is currently still rare. The mechanism is probably a point mutation in the 1→3-β-D-glucan synthase gene.
Echinocandin
Echinocandins are antifungal drugs that inhibit the synthesis of glucan in the cell wall, probably via noncompetitive inhibition of the enzyme 1,3-β glucan synthase and are thus called penicillin of antifungals . Beta glucans are polymers which, linked in their tens of thousands, make up cell wall...
s from Merck & Co., Inc.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
It shows activity against infections with Aspergillus
Aspergillus
Aspergillus is a genus consisting of several hundred mold species found in various climates worldwide. Aspergillus was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli...
and Candida
Candida (genus)
Candida is a genus of yeasts. Many species are harmless commensals or endosymbionts of animal hosts including humans, but other species, or harmless species in the wrong location, can cause disease. Candida albicans can cause infections in humans and other animals, especially in immunocompromised...
, and works by inhibiting the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
β(1,3)-D-Glucan synthase
1,3-beta-glucan synthase
1,3-beta-glucan synthase is a glucosyltransferase enzyme involved in the generation of beta-glucan in fungi. It serves as a pharmacological target for antifungal drugs such as caspofungin, anidulafungin and micafungin....
and thereby disturbing the integrity of the fungal cell wall
Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is located outside the cell membrane and provides these cells with structural support and protection, and also acts as a filtering mechanism. A major function of the cell wall is to...
. Caspofungin is administered intravenously.
Indications
Caspofungin acetate for injection was originally approved by both the Food and Drug Administration (FDA), in the US, and the EMEAEMEA
EMEA may stand for:* the previous acronym of the European Medicines Agency, an EU regulatory agency for the evaluation of medicinal products* Europe, the Middle East and Africa...
, in Europe, in 2001. Its currently approved therapeutic indications by both organisations include the empirical therapy of presumed fungal infections in febrile, neutropenic adult patients and the treatment of invasive aspergillosis
Aspergillosis
Aspergillosis is the name given to a wide variety of diseases caused by fungi of the genus Aspergillus. The most common forms are allergic bronchopulmonary aspergillosis, pulmonary aspergilloma and invasive aspergillosis. Most humans inhale Aspergillus spores every day...
in adult patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
and/or itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
). Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis
Peritonitis
Peritonitis is an inflammation of the peritoneum, the serous membrane that lines part of the abdominal cavity and viscera. Peritonitis may be localised or generalised, and may result from infection or from a non-infectious process.-Abdominal pain and tenderness:The main manifestations of...
, pleural cavity
Pleural cavity
In human anatomy, the pleural cavity is the potential space between the two pleura of the lungs. The pleura is a serous membrane which folds back onto itself to form a two-layered, membrane structure. The thin space between the two pleural layers is known as the pleural cavity; it normally...
infections and oesophagitis) and the EMEA approval includes indication for the treatment of general invasive candidiasis
Candidiasis
Thrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...
in adult patients.
Clinical efficacy
About 36% of patients refractory to other therapies responded well to caspofungin therapy, while even 70% of patients intolerant to other therapies were classified as responders. Direct comparative studies to other drugs in the treatment of invasive aspergillosis have so far not been undertaken.Contraindications
Known hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation contraindicate its use.Warnings
- Hepatic effects
The concomitant use of caspofungin and cyclosporine in healthy volunteers led to a more frequent increase of liver enzymes (ALT=SGPT and AST=SGOT) than noted with cyclosporine alone. Combination treatment is only indicated if the potential benefit for the patient outweighs the potential risk.
Dosage reduction in patients with moderately impaired liver function is recommended. No clinical data exist regarding the use of caspofungin in patients with severely impaired liver function.
- Sensitivity reactions
Reactions due to histamine release (rash, facial swelling, pruritus, sensation of warmth and one case of anaphylaxis) have been seen. Health-care providers should carefully watch for these reactions.
- Drug resistance
In a few patients with infections caused by Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
, mutants with reduced sensitivity to caspofungin have been noticed. Currently there are no data regarding development of resistance in other fungi than C. albicans.
Pregnancy and lactation
Caspofungin has been shown in animal studies to have embroyotoxic properties, and therefore has been assigned to class C. It should only be given to pregnant women if the benefit to the mother clearly outweighs the potential risk to her fetus.The drug is found in the milk of lactating rats, but it is not known whether this is seen in humans. Thus, lactating women should be treated cautiously.
Pediatric patients
Caspofungin is FDA approved for pediatric patients 3 months and older. Dosing is based on body surface area (BSA) as calculated by the mostellar formula.Side effects
Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side effects. In clinical studies and postmarketing reports, the side effects seen in 1% or more of the patients were as follows:- Gastrointestinal system: nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, abdominal painAbdominal painAbdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, and diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and... - Central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
: headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the... - Whole body: feverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, phlebitisPhlebitisPhlebitis is an inflammation of a vein, usually in the legs.When phlebitis is associated with the formation of blood clots , usually in the deep veins of the legs, the condition is called thrombophlebitis...
or thrombophlebitis, complications at the intravenous cannulation site (e.g. induration), unspecified pain, flu-like syndrome, myalgia, chills, and paresthesiaParesthesiaParesthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"... - Respiratory: dyspneaDyspneaDyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
- Renal: increased plasma creatinineCreatinineCreatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
- Hematological: anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
- ElectrolyteElectrolyteIn chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s: hypokalemiaHypokalemiaHypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low... - LiverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
: increased liver enzymes (asymptomatic) - HypersensitivityHypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
: rash, facial edema, pruritus - Other: tachycardiaTachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
Additionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen. One case of anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
(severe allergic reaction) has also been noted.
Resistance
Resistance in C. albicansCandida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
has been described, but is currently still rare. The mechanism is probably a point mutation in the 1→3-β-D-glucan synthase gene.
Drug interactions
- Cyclosporine: see under Hepatic effects
- Tacrolimus: potential pharmacokinetic interactions
- Other systemic antimycotic agents: with amphotericin B, itraconazole and mycophenolate, no interactions have been seen
- Inducers of drug clearance (e.g. carbamazepine, phenytoin, rifampin, dexamethason): consider 70 mg i.v. as maintenance dose instead of 50 mg
Duration of treatment
The mean duration of therapy in previous studies was 34 days. Some patients were even healed by a 1-day treatment. However, a few patients were treated for as long as 162 days and tolerated the drug well, indicating that longtime use may be indicated and tolerated favourably in complicated cases of aspergillosis. Generally, the duration of treatment is dictated by the severity of the disease, the clinical response and the improvement of immunecompetence in immunecompromised patients.Dosage
An initial dose of 70 mg by i.v.-infusion is given followed by 50 mg i.v. daily. If no response is seen or if inducers of caspofungin clearance (see above) are coadministered the daily dose may be increased to 70 mg i.v. An infusion should take approximately 1 hour.Dosage forms
- Cancidas 50 mg for i.v.-infusion (manufacturer Merck)
- Cancidas 70 mg for i.v.-infusion (manufacturer Merck)
- Brand names in countries other than the US may vary.