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Caspofungin

Pronunciation

(kas poe FUN jin)

Index Terms

  • Caspofungin Acetate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous, as acetate:

Cancidas: 50 mg (1 ea); 70 mg (1 ea)

Brand Names: U.S.

  • Cancidas

Pharmacologic Category

  • Antifungal Agent, Parenteral
  • Echinocandin

Pharmacology

Inhibits synthesis of β(1,3)-D-glucan, an essential component of the cell wall of susceptible fungi. Highest activity is in regions of active cell growth. Mammalian cells do not require β(1,3)-D-glucan, limiting potential toxicity.

Distribution

CSF concentrations: Nondetectable [<10 ng/mL (n=1)] (Sáez-Llorens 2009)

Metabolism

Slowly, via hydrolysis and N-acetylation as well as by spontaneous degradation, with subsequent metabolism to component amino acids. Overall metabolism is extensive.

Excretion

Urine (41%; primarily as metabolites, ~1% of total dose as unchanged drug); feces (35%; primarily as metabolites)

Half-Life Elimination

Beta (distribution): 9 to 11 hours (~8 hours in children <12 years); Terminal: 40 to 50 hours; beta phase half-life is 32% to 43% lower in pediatric patients than in adult patients

Protein Binding

~97% to albumin

Special Populations: Renal Function Impairment

AUC is increased 30% to 49% in patients with Clcr ≤49 mL/minute after administration of a single 70 mg dose. No effect on caspofungin concentrations was seen in patients with mild-to-end-stage renal impairment after administration of multiple daily doses.

Special Populations: Hepatic Function Impairment

AUC is increased by ~55% in patients with mild hepatic impairment (Child-Pugh class A) and by 76% in patients with moderate hepatic impairment (Child-Pugh class B).

Special Populations: Elderly

AUC is increased by ~28%.

Special Populations: Gender

AUC in women was ~22% higher than in men after repeat dosing.

Use: Labeled Indications

Aspergillosis, invasive: Treatment of invasive aspergillosis in patients 3 months and older who are refractory to or intolerant of other therapies (eg, amphotericin B, lipid formulations of amphotericin B, itraconazole).

Candidemia and other Candida infections:Treatment of candidemia and the following Candida infections in patients 3 months and older: intra-abdominal abscesses, peritonitis, and pleural space infections.

Esophageal candidiasis: Treatment of esophageal candidiasis in patents 3 months and older.

Fungal infections, empiric therapy: Empiric therapy for presumed fungal infections in febrile, neutropenic patients 3 months and older.

Use: Unlabeled

Alternate agent in the prophylaxis against Candida infection in neutropenic cancer patients with substantial risk (eg, allogeneic transplant or undergoing induction therapy for acute leukemia)

Contraindications

Hypersensitivity to caspofungin or any component of the formulation

Documentation of allergenic cross-reactivity for echinocandin antifungals is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Duration of caspofungin treatment should be determined by patient status and clinical response.

Aspergillosis (invasive): IV: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg once daily. Duration of therapy should be a minimum of 6 to 12 weeks or throughout period of immunosuppression and until lesions have resolved (Walsh 2008). Salvage treatment with 70 mg once daily (off-label dosing) has been reported (Maertens 2006).

Aspergillosis (invasive) in HIV-infected patients (off-label use): Adolescents and Adults: IV: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg once daily. Continue until infection resolution and CD4 count >200 cells/mm3 (HHS [OI adult 2015]).

Candidemia and other Candida infections: IV: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg once daily; generally continue for at least 14 days after the last positive culture or longer if neutropenia warrants. Higher doses (150 mg once daily infused over ~2 hours) compared to the standard adult dosing regimen (50 mg once daily) have not demonstrated additional benefit or toxicity in patients with invasive candidiasis (Betts 2009). Note: IDSA Candidiasis guidelines recommend transition to fluconazole (usually after 5 to 7 days in non-neutropenic patients) in clinically stable patients with fluconazole-susceptible isolates and negative repeat cultures (IDSA [Pappas 2016]).

Candidiasis, chronic disseminated (hepatosplenic) (off-label use): IV: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg daily for several weeks, followed by oral fluconazole therapy (IDSA [Pappas 2016])

Candidiasis, esophageal: IV:

Manufacturer’s labeling: 50 mg once daily; continue for 7 to 14 days after symptom resolution. Note: The majority of patients studied for this indication also had oropharyngeal involvement.

Alternate recommendations: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg daily; may transition to oral fluconazole therapy once oral intake tolerable. In patients with fluconazole-refractory disease, continue caspofungin for 14 to 21 days (Pappas [IDSA 2016])

Candidiasis, esophageal, in HIV-infected patients (off-label use): IV: 50 mg once daily; continue for 14 to 21 days (HHS [OI adult 2015]).

Candidiasis, intravascular infections (native or prosthetic valve endocarditis, infection of implantable cardiac devices, suppurative thrombophlebitis) (off-label use): IV: 150 mg daily. For native or prosthetic valve endocarditis, therapy should continue for at least 6 weeks after valve replacement surgery (longer durations in patients with abscesses or other complications); for patients with implantable cardiac devices, therapy should continue for 4 to 6 weeks after surgery (4 weeks for infections limited to generator pockets and at least 6 weeks for infections involving the wires); for suppurative thrombophlebitis, continue for at least 2 weeks after candidemia has cleared. Note: Step-down to fluconazole therapy is recommended in clinically stable patients with fluconazole-susceptible isolates and negative repeat cultures (IDSA [Pappas 2016]).

Candidiasis, osteoarticular infections (osteomyelitis or septic arthritis) (alternative therapy) (off-label use): IV: 50 to 70 mg daily for at least 14 days, followed by fluconazole (IDSA [Pappas 2016])

Candidiasis, prophylaxis against invasive candidiasis (high-risk ICU patients in units with a high rate of invasive candidiasis ) (alternative therapy; off-label use): IV: Loading dose: 70 mg on day 1, then 50 mg daily (IDSA [Pappas 2016])

Candidiasis, oropharyngeal (refractory disease) (alternative therapy) (off-label use): IV: Initial dose: 70 mg on day 1; subsequent doses: 50 mg once daily (Pappas [IDSA 2016])

Fungal infections, empiric therapy: IV: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg once daily; continue until resolution of neutropenia; if fungal infection confirmed, continue for a minimum of 14 days (continue for at least 7 days after resolution of both neutropenia and clinical symptoms); if clinical response inadequate, may increase up to 70 mg once daily if tolerated, but increased efficacy not demonstrated. Note: IDSA Candidiasis guidelines recommend to consider discontinuing after 4 to 5 days in patients with no clinical response (Pappas [IDSA 2016])

Dosage adjustment with concomitant use of an enzyme inducer:

Patients receiving rifampin: 70 mg caspofungin once daily

Patients receiving carbamazepine, dexamethasone, efavirenz, nevirapine, or phenytoin (and possibly other enzyme inducers): May require an increased dose of caspofungin 70 mg once daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Aspergillosis (invasive), candidemia, esophageal candidiasis, fungal infections (empiric therapy): Infants ≥3 months, Children, and Adolescents ≤17 years: IV: Initial dose: 70 mg/m2 on day 1, subsequent dosing: 50 mg/m2 once daily, if clinical response inadequate, may increase to 70 mg/m2 once daily if tolerated, but increased efficacy not demonstrated (maximum daily dose, loading or maintenance: 70 mg). Duration of caspofungin treatment should be determined by patient status and clinical response; refer to adult dosing for indication-specific recommended durations.

Aspergillosis (invasive) in HIV-infected patients (off-label use): Adolescents: IV: Refer to adult dosing.

Candidiasis, esophageal, in HIV-infected patients (off-label use): Adolescents: IV: Refer to adult dosing.

Dosage adjustment with concomitant use of an enzyme inducer: Patients receiving carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin, or rifampin (and possibly other enzyme inducers): Consider 70 mg/m2 once daily (maximum daily dose: 70 mg/day)

Dosing: Renal Impairment

No dosage adjustment necessary.

End-stage renal disease (ESRD) requiring dialysis: Poorly dialyzed; no supplemental dose or dosage adjustment necessary in patients on intermittent hemodialysis (IHD). No supplemental dose or dosage adjustment needed in peritoneal dialysis or continuous renal replacement therapy (eg, CVVHD) (Aronoff 2007, Heintz 2009).

Dosing: Hepatic Impairment

Adults:

Mild insufficiency (Child-Pugh class A): No dosage adjustment necessary.

Moderate insufficiency (Child-Pugh class B): 70 mg on day 1 (where recommended), followed by 35 mg once daily

Severe insufficiency (Child-Pugh class C): No dosage adjustment provided in manufacturer's labeling (has not been studied).

Children: Mild-to-severe insufficiency (Child-Pugh classes A, B, or C): No dosage adjustment provided in manufacturer's labeling (has not been studied).

Reconstitution

Bring intact vial to room temperature. Reconstitute vials using 10.8 mL NS for injection, SWFI, or bacteriostatic water for injection, resulting in a concentration of 5 mg/mL for the 50 mg vial, and 7 mg/mL for the 70 mg vial (vials contain overfill). Mix gently to dissolve until clear solution is formed; do not use if cloudy or contains particles. Solution should be further diluted with 0.9%, 0.45%, or 0.225% sodium chloride or LR (do not exceed final concentration of 0.5 mg/mL).

Administration

Infuse slowly, over ~1 hour. Do not administer by IV bolus.

Compatibility

Stable in NS, 1/2NS, 1/4NS, LR. Do not mix with dextrose-containing solutions.

Y-site administration: Incompatible with amphotericin B, amphotericin B lipid complex, amphotericin B liposome, ampicillin, cefazolin, cefepime, ceftazidime, ceftriaxone, clindamycin, cytarabine, ertapenem, furosemide, heparin, methylprednisolone sodium succinate, nafcillin, piperacillin/tazobactam, potassium phosphate, sulfamethoxazole/trimethoprim.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Reconstituted solution may be stored at ≤25°C (≤77°F) for up to 1 hour prior to preparation of infusion solution. Solutions diluted in NS, 1/2NS, 1/4NS, or LR for infusion should be used within 24 hours when stored at ≤25°C (≤77°F) or within 48 hours when stored at 2°C to 8°C (36°F to 46°F).

Drug Interactions

CycloSPORINE (Systemic): May enhance the adverse/toxic effect of Caspofungin. CycloSPORINE (Systemic) may increase the serum concentration of Caspofungin. Management: Weigh potential benefits of caspofungin against a possible elevated risk of hepatotoxicity. Monitor liver function and re-evaluate treatment in patients with abnormal values. Mild transaminase elevations may occur relatively commonly. Consider therapy modification

Inducers of Drug Clearance: May decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Consider therapy modification

RifAMPin: May decrease the serum concentration of Caspofungin. Management: Caspofungin prescribing information recommends using a dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) who are also receiving rifampin. Consider therapy modification

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Tacrolimus (Systemic): Caspofungin may decrease the serum concentration of Tacrolimus (Systemic). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypotension (adults: 3% to 20%; infants, children, and adolescents: 9%), peripheral edema (adults: 6% to 11%), tachycardia (7% to 11%)

Central nervous system: Chills (adults: 9% to 23%; infants, children, and adolescents: 13%), headache (9% to 15%)

Dermatologic: Skin rash (4% to 23%)

Gastrointestinal: Diarrhea (adults: 6% to 27%; infants, children, and adolescents: 7%), vomiting (6% to 17%), nausea (adults: 5% to 15%; infants, children, and adolescents: 4%)

Hematologic & oncologic: Decreased hemoglobin (adults: 18% to 21%), decreased hematocrit (adults: 13% to 18%), decreased white blood cell count (adults: 12%), anemia (adults: 11%)

Hepatic: Increased serum alkaline phosphatase (adults: 9% to 22%), increased serum ALT (adults: 4% to 18%; infants, children, and adolescents: 5%), increased serum AST (adults: 6% to 16%; infants, children, and adolescents: 2%), increased serum bilirubin (adults: 5% to 13%)

Local: Localized phlebitis (adults: 18%)

Renal: Increased serum creatinine (adults: 3% to 11%)

Respiratory: Respiratory failure (adults: 2% to 20%), cough (adults: 6% to 11%), pneumonia (adults: 4% to 11%)

Miscellaneous: Infusion related reaction (20% to 35%), fever (6% to 30%), septic shock (adults: 11% to 14%)

1% to 10%:

Cardiovascular: Hypertension (5% to 9%), atrial fibrillation (<5%), bradycardia (<5%), cardiac arrhythmia (<5%), edema (<5%), flushing (<5%), myocardial infarction (<5%)

Central nervous system: Anxiety (<5%), confusion (<5%), depression (<5%), dizziness (<5%), drowsiness (<5%), fatigue (<5%), insomnia (<5%), seizure (<5%)

Dermatologic: Erythema (5% to 9%), pruritus (infants, children, and adolescents: 6%), skin lesion (<5%), urticaria (<5%), decubitus ulcer (adults: 3% to 5%)

Endocrine & metabolic: Hypomagnesemia (adults: 7%), hyperglycemia (adults: 6%), hypokalemia (5% to 6%), hypercalcemia (<5%), hypervolemia (<5%)

Gastrointestinal: Abdominal pain (4% to 9%), mucosal inflammation (4% to 6%), abdominal distention (<5%), anorexia (<5%), constipation (<5%), decreased appetite (<5%), dyspepsia (<5%), upper abdominal pain (<5%)

Genitourinary: Urinary tract infection (<5%), nephrotoxicity (adults: 3%; serum creatinine ≥2 x baseline value or ≥1 mg/dL in patients with serum creatinine above ULN range)

Hematologic & oncologic: Blood coagulation disorder (<5%), febrile neutropenia (<5%), neutropenia (<5%), petechia (<5%), thrombocytopenia (<5%)

Hepatic: Decreased serum albumin (adults: 7%), hepatic failure (<5%), hepatomegaly (<5%), hepatotoxicity (<5%), hyperbilirubinemia (<5%), jaundice (<5%)

Infection: Sepsis (adults: 5% to 7%), bacteremia (<5%)

Local: Catheter infection (infants, children, and adolescents: 9%), infusion site reaction (<5%; pain/pruritus/swelling)

Neuromuscular & skeletal: Arthralgia (<5%), back pain (<5%), limb pain (<5%), tremor (<5%), weakness (<5%)

Renal: Hematuria (adults: 10%), increased blood urea nitrogen (adults: 4% to 9%), renal failure (<5%)

Respiratory: Dyspnea (adults: 9%), pleural effusion (adults: 9%), respiratory distress (adults: ≤8%), rales (adults: 7%), epistaxis (<5%), hypoxia (<5%), tachypnea (<5%)

<1% (Limited to important or life-threatening): Anaphylaxis, erythema multiforme, hepatitis, histamine release (including facial swelling, bronchospasm, sensation of warmth), increased gamma-glutamyl transferase, pancreatitis, Stevens-Johnson syndrome, swelling, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Anaphylaxis and histamine-related reactions (eg, angioedema, facial swelling, bronchospasm, rash, sensation of warmth) have been reported. Discontinue if anaphylaxis occurs; consider discontinuation if histamine-related reactions occur. Administer supportive treatment if needed.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; increased transaminases and rare cases of clinically significant hepatic dysfunction (including failure and hepatitis) have been reported in pediatric and adult patients. Monitor liver function tests during therapy; if tests become abnormal or worsen, consider discontinuation. Dosage reduction required in adults with moderate hepatic impairment (Child-Pugh class B); safety and efficacy have not been established in children with any degree of hepatic impairment and adults with severe hepatic impairment (Child-Pugh class C).

Concurrent drug therapy issues:

• Cyclosporine: Concurrent use of cyclosporine should be limited to patients for whom benefit outweighs risk, due to a high frequency of hepatic transaminase elevations observed during concurrent use.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Liver function; anaphylaxis or histamine-related reactions (eg, facial swelling, bronchospasm, sensation of warmth)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. When treatment of invasive Aspergillus or Candida infections is needed during pregnancy, other agents are preferred (DHHS [adult] 2014; IDSA [Pappas 2016]). Use may be considered in HIV-infected pregnant women with invasive Aspergillus or Candida infections when refractory to other agents (DHHS [adult] 2014)

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of low magnesium (mood changes; muscle pain or weakness; muscle cramps or spasms; seizures; tremors; lack of appetite; severe nausea or vomiting; or an abnormal heartbeat), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), feeling of warmth, severe dizziness, passing out, tachycardia, cough, vision changes, severe loss of strength and energy, chills, injection site pain or irritation, shortness of breath, severe headache, swelling of arms or legs, or flushing (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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