Caspofungin

J02A - Antimycotics for systemic use ATC J02AX04 Small molecule approved 2001 Parenteral Natural product

JFDA label: Cancidas Vial

Mechanism of Action

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.

Indications

Approved

Aspergillosis, invasive
Candidemia and other Candida infections
Candidiasis, esophageal
Fungal infections, empiric therapy (neutropenic patients)

Off-label

Candida infection, prophylaxis in neutropenic cancer patients at substantial risk
Candidiasis, chronic disseminated (hepatosplenic)
Candidiasis, empiric therapy (non-neutropenic ICU patients)
Candidiasis, esophageal, in HIV-infected patients (adolescents and adults)
Candidiasis, intravascular infections
Candidiasis, oropharyngeal (refractory disease)
Candidiasis, osteoarticular infections

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Fungi

Organism	Activity	MIC
Aspergillus flavus	Active	—
Aspergillus fumigatus	Active	—
Aspergillus terreus	Active	—
Candida albicans	Active	—
Candida glabrata	Active	—
Candida guilliermondii	Active	—
Candida krusei	Active	—
Candida parapsilosis	Active	—
Candida tropicalis	Active	—

Class profile

antifungalClass	Echinocandin
targetMolecule	Beta-1,3-glucan synthase (FKS1/FKS2 subunit)
isFungicidal	1
spectrumCandida	S (fungicidal)
spectrumAspergillus	S (fungistatic)
spectrumCryptococcus	Intrinsically resistant
spectrumDermatophytes	Resistant
resistanceMechanisms	FKS1 hot-spot mutations,FKS2 mutations in Candida glabrata
source	Pappas2016/Lass-Florl2011

Contraindications

Source: Lexicomp

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 Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Very Common Hypotension · peripheral edema · tachycardia

Common atrial fibrillation, pruritus, skin lesion, hyperglycemia, hypokalemia, hypercalcemia, mucosal inflammation, abdominal distention, hepatic failure, bacteremia, infusion site reaction, increased blood · Hypertension

Nervous system disorders (2)

Very Common Chills · headache

Hepatobiliary disorders (4)

Very Common Increased serum alkaline phosphatase · increased serum ALT · increased serum AST · increased serum bilirubin

Renal and urinary disorders (1)

Very Common Increased serum creatinine

Blood and lymphatic system disorders (4)

Very Common anemia · decreased hematocrit · Decreased hemoglobin · decreased white blood cell count

Gastrointestinal disorders (3)

Very Common Diarrhea · nausea · vomiting

Skin and subcutaneous tissue disorders (1)

Very Common Skin rash

General disorders and administration site conditions (4)

Very Common fever · Infusion related reaction · Localized phlebitis · septic shock

Respiratory, thoracic and mediastinal disorders (3)

Very Common cough · pneumonia · Respiratory failure

Dosing

Source: Lexicomp

Note: Duration of caspofungin treatment should be determined by patient status and clinical response. Aspergillosis, invasive (salvage therapy): 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 and depends on site of infection, extent of disease, and level/duration of immunosuppression (IDSA [Patterson 2016]). 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]). Candida infection, prophylaxis in neutropenic cancer patients at substantial risk (off-label use): IV: 50 mg once daily (Mattiuzzi 2006). 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, empiric therapy (non-neutropenic ICU patients) (off-label use): IV: Initial dose: 70 mg on day 1; subsequent dosing: 50 mg once daily. Consider discontinuing after 4 to 5 days in patients with no clinical response; continue treatment for 2 weeks in patients who improve on antifungal 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 (alternative agent) (off-label use): IV: 50 mg once daily; continue for 14 to 21 days. Note: A higher rate of relapse has been reported with echinocandins than with fluconazole (HHS [OI adult 2017]). 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 lim

(For additional information see "Caspofungin: Pediatric drug information") Aspergillosis (invasive), candidemia, esophageal candidiasis, and fungal infections (empiric therapy, neutropenic patients): 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 (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. Candidiasis, esophageal, in HIV-infected patients (alternative agent) (off-label use): Adolescents: IV: Refer to adult dosing. Dosage adjustment with concomitant use of an enzyme inducer: Patients receiving rifampin: 70 mg/m2 once daily (maximum daily dose: 70 mg/day) Patients receiving carbamazepine, dexamethasone, efavirenz, nevirapine, or phenytoin (and possibly other enzyme inducers): Consider 70 mg/m2 once daily (maximum daily dose: 70 mg/day)

Refer to adult dosing.

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).

Adults: Mild impairment (Child-Pugh class A): No dosage adjustment necessary. Moderate impairment (Child-Pugh class B): 70 mg on day 1 (where recommended), followed by 35 mg once daily Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the labeling (has not been studied). Children: Mild to severe impairment (Child-Pugh classes A, B, or C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Hepatic effects

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.

Hypersensitivity

Anaphylaxis, other hypersensitivity reactions, histamine-related reactions (eg, angioedema, facial swelling, bronchospasm, rash, sensation of warmth), and cases of Stevens-Johnson syndrome and toxic epidermal necrolysis (some fatal) have been reported. Discontinue if a hypersensitivity reaction occurs. Administer supportive treatment if needed. Disease-related concerns:

Hepatic impairment

Use with caution in patients with hepatic impairment. 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:

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.

Pregnancy & Lactation

Pregnancy

FDA category C

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 (HHS [adult] 2017; IDSA [Pappas 2016]).

Lactation

It is not known if caspofungin is present in breast milk. The manufacturer recommends that caution be exercised when administering caspofungin to nursing women.

Monitoring

Efficacy	Fungal culture and species identification; minimum inhibitory concentration (MIC) where available; clinical response (temperature, imaging for invasive fungal disease)
Toxicity	LFTs (hepatotoxicity — azoles in particular); renal function; ECG for QT prolongation (azoles); drug levels if available (itraconazole, voriconazole)
Clinical pearl	Voriconazole levels are highly variable due to CYP2C19 polymorphism — TDM recommended (target trough 2–5 mg/L). Check for drug interactions with CYP3A4 substrates.
Counseling	Report visual disturbances (voriconazole), jaundice, or rash. Take azoles with food or as directed to optimise absorption.

Chemistry & Properties

Formula	C52H88N10O15
Molecular weight	1093.33 g/mol
IUPAC name	(10R,12S)-N-[(3S,6S,9S,11R,15S,18S,20R,21S,24S,25S)-21-(2-aminoethylamino)-3-[(1R)-3-amino-1-hydroxypropyl]-6-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,25-trihydroxy-15-[(1R)-1-hydroxyethyl]-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]-10,12-dimethyltetradecanamide
CAS	162808-62-0
PubChem CID	16119814
InChIKey	`JYIKNQVWKBUSNH-WVDDFWQHSA-N`

SMILES

CC[C@H](C)C[C@H](C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CCN)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.358 h
Volume of distribution	0.572 L/kg
Protein binding	64.1%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)NTCP (Inhibitor)OAT (Inhibitor)OAT1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OATP2B1 (Substrate)P-gp (Substrate)

Drug–drug interactions (30, DDInter)

Interacting drug	Severity	Management
Dexamethasone	major
Leflunomide	major
Teriflunomide	major
Apalutamide	moderate
Asparaginase Escherichia coli	moderate
Bexarotene	moderate
Brentuximab vedotin	moderate
Clofarabine	moderate
Cyclosporine	moderate
Dabrafenib	moderate
Elagolix	moderate
Enzalutamide	moderate
Epirubicin	moderate
Griseofulvin	moderate
Idelalisib	moderate
Interferon beta-1a	moderate
Interferon beta-1b	moderate
Ivosidenib	moderate
Lorlatinib	moderate
Lumacaftor	moderate
Methotrexate	moderate
Mitotane	moderate
Naltrexone	moderate
Pegaspargase	moderate
Peginterferon beta-1a	moderate
Somatotropin	moderate
Tacrolimus	moderate
Tioguanine	moderate
Trabectedin	moderate
Vemurafenib	moderate

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cancidas Vial	Vial 50 mg	1 vial	Adatco Drug Store	—
Cancidas Vial	Vial 70 mg	1 vial	Adatco Drug Store	—
Candigard	Vial 77.69 equ.to 70 capsofungin mg	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Candigard	Vial 55.52 mg	1 vial	شركة أدوية الحكمة / Hikma Pharmaceuticals / Not Determined	—
Cangin Powder for Concentrate for Solution for IV Infusion	Infusion 70 mg	1 vial	MS PHARMA/JORDAN	—
Cangin Powder for Concentrate for Solution for IV Infusion	Infusion 50 mg	1 vial	MS PHARMA/JORDAN	—