Micafungin

J02A - Antimycotics for systemic use ATC J02AX05 Small molecule approved 2005 Parenteral Natural product

JFDA label: Mycamine 50 Vial

Mechanism of Action

Concentration-dependent inhibition of 1,3-beta-D-glucan synthase resulting in reduced formation of 1,3-beta-D-glucan, an essential polysaccharide comprising 30% to 60% of Candida cell walls (absent in mammalian cells); decreased glucan content leads to osmotic instability and cellular lysis

Indications

Approved

Candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses
Esophageal candidiasis
Prophylaxis of Candida infections

Off-label

Aspergillosis, invasive (salvage therapy)
Candidiasis empiric therapy (non-neutropenic ICU patients)
Candidiasis, chronic disseminated (hepatosplenic)
Candidiasis, intravascular infections
Candidiasis, oropharyngeal (refractory disease)
Candidiasis, osteoarticular infections
Candidiasis, prophylaxis against invasive candidiasis (high-risk ICU patients)
Empiric antifungal therapy (neutropenic fever)
Primary antifungal prophylaxis in oncology patients (children/adolescents)

Antimicrobial Spectrum

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

Fungi

Organism	Activity	MIC
Candida albicans	Active	—
Candida glabrata	Active	—
Candida guilliermondii	Active	—
Candida krusei	Active	—
Candida meningoencephalitis	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 C.glabrata
source	Pappas2016/Lass-Florl2011

Contraindications

Source: Lexicomp

Hypersensitivity to micafungin, other echinocandins, or any component of the formulation 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 (4)

Very Common Phlebitis

Common Atrial fibrillation · Cardiac arrest · tachycardia

Nervous system disorders (3)

Very Common anxiety · insomnia

Common Headache

Hepatobiliary disorders (3)

Very Common Abnormal hepatic function tests · Abnormal hepatic function tests, infusion-related reaction

Common Increased serum alkaline phosphatase

Renal and urinary disorders (2)

Very Common Decreased urine output · hematuria

Blood and lymphatic system disorders (4)

Very Common Anemia · febrile neutropenia

Common neutropenia · Thrombocytopenia

Metabolism and nutrition disorders (4)

Common abnormal aspartate transaminase · hyperkalemia · hypernatremia · Hypoglycemia

Gastrointestinal disorders (5)

Very Common diarrhea · Vomiting

Common abdominal distention · abdominal pain · Nausea

Skin and subcutaneous tissue disorders (3)

Very Common Pruritus · urticaria

Common Skin rash

Dosing

Source: Lexicomp

Aspergillosis, invasive (salvage therapy) (off-label use): IV: 100 to 150 mg once daily. Minimum duration of therapy is 6 to 12 weeks, although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement (IDSA [Patterson 2016]) Candidemia, acute disseminated candidiasis, and Candida peritonitis and abscesses: IV: 100 mg once daily; mean duration of therapy (from clinical trials) was 15 days (range: 10 to 47 days). Note: For treatment of candidemia, IDSA Candidiasis guidelines recommend a total duration of antifungal therapy of at least 2 weeks after the documented clearance of Candida from the bloodstream and resolution of candidemia-associated symptoms in patients without metastatic complications; may transition to fluconazole (eg, 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: 100 mg daily for several weeks, followed by oral fluconazole therapy (IDSA [Pappas 2016]) Candidiasis, empiric therapy (suspected invasive candidiasis in non-neutropenic ICU patients) (off-label use): IV: 100 mg daily; treatment should continue for 14 days in patients showing clinical improvement. Consider discontinuing after 4 to 5 days in patients with no clinical response (IDSA [Pappas 2016]). 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, after catheter removal, continue for at least 2 weeks after candidemia has cleared. Note: Step-down to fluconazole therapy is recommended in clinically stable patients and fluconazole-susceptible isolates with negative repeat cultures (IDSA [Pappas 2016]). Candidiasis, osteoarticular infections (osteomyelitis or septic arthritis) (alternative therapy) (off-label use): IV: 100 mg daily for at least 14 days, followed by fluconazole therapy (IDSA [Pappas 2016]) Candidiasis, oropharyngeal (refractory disease) (alternative therapy) (off-label use): IV: 100 mg once daily (IDSA [Pappas 2016]) Empiric antifungal therapy (neutropenic fever) (off-label use): IV: 100 mg once daily (IDSA [Patterson 2016]) Esophageal candidiasis: IV: 150 mg once daily; mean duration of therapy (from clinical trials) was 15 days (range: 10 to 30 days). Note: IDSA Candidiasis guidelines suggest considering a transition to oral fluconazole therapy once

(For additional information see "Micafungin: Pediatric drug information") Candidemia, acute disseminated candidiasis, and Candida peritonitis and abscesses: Infants ≥4 months, Children, and Adolescents: IV: 2 mg/kg once daily; maximum: 100 mg once daily Esophageal candidiasis: Infants ≥4 months, Children, and Adolescents: IV: ≤30 kg: 3 mg/kg once daily >30 kg: 2.5 mg/kg once daily; maximum: 150 mg once daily Prophylaxis of Candida infection in hematopoietic stem cell transplantation: Infants ≥4 months, Children, and Adolescents: IV: 1 mg/kg once daily; maximum: 50 mg once daily Primary antifungal prophylaxis in allogeneic HSCT (when fluconazole is contraindicated; off-label dosing/population; guideline recommendation): Infants ≥1 month, Children, and Adolescents

Refer to adult dosing.

No dosage adjustment necessary. Poorly dialyzed; no supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis.

No dosage adjustment necessary.

Warnings & Precautions

Source: Lexicomp

Hemolytic anemia/hemoglobinuria

Hemolytic anemia and hemoglobinuria have been reported.

Hepatic impairment

New-onset or worsening hepatic impairment, including hepatitis and hepatic failure, has been reported. Monitor closely and evaluate appropriateness of continued use in patients who develop abnormal liver function tests during treatment.

Hypersensitivity reactions

Severe anaphylactic reactions, including shock, have been reported.

Renal impairment

Increased BUN, serum creatinine, renal dysfunction, and/or acute renal failure has been reported; use with caution in patients that develop worsening renal function during treatment; monitor closely.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in animal reproduction studies. There are no adequate and well-controlled studies in pregnant women. Use only if benefit outweighs risk.

Lactation

It is not known if micafungin is excreted in breast milk. The manufacturer recommends that caution be exercised when administering micafungin 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	C56H71N9O23S
Molecular weight	1270.29 g/mol
IUPAC name	[5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-11,20,21,25-tetrahydroxy-15-[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[[4-[5-(4-pentoxyphenyl)-1,2-oxazol-3-yl]benzoyl]amino]-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxyphenyl] hydrogen sulfate
CAS	235114-32-6
PubChem CID	477468
InChIKey	`PIEUQSKUWLMALL-YABMTYFHSA-N`

SMILES

CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)N[C@H]4C[C@@H](O)[C@@H](O)NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c5ccc(O)c(OS(=O)(=O)O)c5)NC(=O)[C@@H]5C[C@@H](O)CN5C(=O)[C@H]([C@@H](C)O)NC4=O)cc3)no2)cc1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	3.588 h
Volume of distribution	0.461 L/kg
Protein binding	92.8%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C8	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OAT (Substrate)P-gp (Substrate)

Drug–drug interactions (5, DDInter)

Interacting drug	Severity	Management
Amphotericin B	moderate
Everolimus	moderate
Nitisinone	moderate
Ribociclib	moderate
Sirolimus	moderate

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Megmento	Vial 100 mg	1 vial	The Arab Pharmaceutical Manufacturing PSC/Salt	—
Megmento	Vial 50 mg	1 vial	The Arab Pharmaceutical Manufacturing PSC/Salt	—
Mifacin 50mg/vial powder for concentrate for solution for infusion	Infusion 50 mg mg	One Vila	MS PHARMA/JORDAN	—
Mycamine 50 Vial	Vial 50 mg	1 vial	Ibn Rushd Drug Store	—