Micafungin

Micafungin belongs to the pharmacological class of Echinocandins.

Micafungin has been approved to relieve symptoms and also for treating and maintaining Aspergillosis, invasive, Candidiasis, Neutropenic fever, empiric antifungal therapy, and Prophylaxis against invasive fungal infections.

Micafungin, an antifungal medication, exhibits limited oral absorption when taken by mouth. In adult patients with esophageal candidiasis, it has a volume of distribution of approximately 0.39 ± 0.11 L/kg. The drug is highly protein bound (>99%) in vitro, primarily to albumin, but it does not competitively displace bilirubin binding to albumin even at therapeutic concentrations. Micafungin also binds to a lesser extent to a1-acid-glycoprotein. Metabolically, micafungin undergoes transformation to M-1 (catechol form) by arylsulfatase, followed by further conversion to M-2 (methoxy form) by catechol-O-methyltransferase. Another metabolite, M-5, is formed through hydroxylation at the side chain catalyzed by cytochrome P450 (CYP) isozymes. Although micafungin is a substrate for CYP3A and weakly inhibits it in laboratory settings, CYP3A is not a major pathway for micafungin metabolism in the body. The primary route of elimination for micafungin is fecal excretion, accounting for approximately 71% of the administered dose over a 28-day period

The common side effects involved in using Micafungin are Diarrhea, Fever, Chills, Abnormal liver function tests, Skin rash, Dizziness, Lightheadedness.

Micafungin is available in the form of Powder for injection .

Micafungin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Micafungin belongs to the pharmacological class of Echinocandins.

By inhibiting beta-1,3-D-glucan synthase, micafungin prevents the synthesis of beta-1,3-D-glucan, a crucial element of fungal cell walls. Unlike mammalian cells, fungal cells rely on this component, making it an effective target for micafungin's antifungal activity.

Micafungin has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, invasive, Candidiasis, Neutropenic fever, empiric antifungal therapy, Prophylaxis against invasive fungal infections.

Micafungin is found to be available in the form of Powder for injection.

Micafungin can be used in the following treatment:

• Aspergillosis, invasive
• Candidiasis
• Neutropenic fever, empiric antifungal therapy
• Prophylaxis against invasive fungal infections

Micafungin can help to relieve symptoms and also for the treatment and maintenance of Aspergillosis, invasive, Candidiasis, Neutropenic fever, empiric antifungal therapy, Prophylaxis against invasive fungal infections.

Micafungin is approved for use in the following clinical indications:

• Aspergillosis, invasive
• Candidiasis
• Neutropenic fever, empiric antifungal therapy
• Prophylaxis against invasive fungal infections

• Aspergillosis, invasive:

IV: 100 to 150 mg once daily. Reserved for salvage therapy or as part of a combination regimen. Monotherapy is further reserved for patients intolerant of or refractory to azoles and polyenes. Treatment duration is individualized, with a minimum duration of 6 to 12 weeks. Combination therapy with voriconazole may be used as initial therapy for severe or progressive infection.

• Candidiasis:

Candidemia (neutropenic and nonneutropenic patients), including disseminated candidiasis: IV: 100 mg once daily. Duration is at least 14 days after the first negative blood culture and until resolution of signs/symptoms.

• Cardiac device infection: IV: 150 mg once daily. Step down to azole therapy in clinically stable patients with susceptible isolates and negative repeat cultures. Duration is at least 4 weeks after device removal for isolated generator pocket infection and 6 weeks after device removal for wire infection.
• Chronic disseminated (hepatosplenic): IV: 100 mg once daily for several weeks, followed by oral azole step-down therapy until lesion resolution and during periods of immunosuppression.
• Empiric therapy, suspected invasive candidiasis (nonneutropenic ICU patients): IV: 100 mg once daily. Consider for critically ill patients with unexplained fever or hypotension despite broad-spectrum antimicrobial therapy and risk factors for invasive candidiasis.
• Endocarditis, native or prosthetic valve: IV: 150 mg once daily. Step down to azole therapy in clinically stable patients with susceptible isolates and negative repeat cultures. Duration is at least 6 weeks after valve replacement surgery, with longer duration for perivalvular abscesses or other complications.
• Esophageal, refractory disease: IV: 150 mg once daily. Transition to oral antifungal once patient tolerates oral intake if susceptibility allows. Total duration is 14 to 28 days.
• Intra-abdominal infection: IV: 100 mg once daily. Total duration is at least 14 days and until source control and clinical resolution.
• Oropharyngeal, refractory disease: IV: 100 mg once daily. Transition to oral antifungal once patient tolerates oral intake if susceptibility allows. Total duration is 14 to 28 days.
• Osteoarticular infection (osteomyelitis or septic arthritis): IV: 100 mg once daily for at least 2 weeks. Total duration is 6 to 12 months for osteomyelitis and at least 6 weeks for septic arthritis.
• Thrombophlebitis, suppurative: IV: 150 mg once daily. Continue antifungal therapy until the catheter is removed and the thrombus is resolved, and for at least 2 weeks after the candidemia has cleared.
• Neutropenic fever, empiric antifungal therapy:

IV: 100 mg once daily. Recommended for patients with persistent or recurrent fever after ≥4 days of antimicrobial therapy when the duration of neutropenia is expected to exceed 7 days.

• Prophylaxis against invasive fungal infections:

Hematologic malignancy or hematopoietic cell transplant: IV: 50 to 100 mg once daily. Duration is at least until the resolution of neutropenia and varies based on the degree and duration of immunosuppression.

Solid organ transplant: IV: 100 mg once daily. Duration varies based on patient risk factors and transplant center protocol.

• Powder for injection : 50mg/vial , 100mg/vial

Powder for injection.

• Dosage Adjustments in Pediatric Patients:

Aspergillosis, invasive; treatment:

• Infants, Children, and Adolescents: Limited data available. Initial doses at the higher end of the dosage range may be necessary in infants due to pharmacokinetic differences. Treatment duration should be individualized, with a minimum duration of 6 to 12 weeks.
• ≤40 kg: IV: 2 to 3 mg/kg/dose once daily; higher doses of 4 to 6 mg/kg/dose once daily have also been described.
• 40 kg: IV: 100 mg/dose once daily; may increase to 150 mg/dose if clinically indicated; maximum daily dose: 150 mg/day.

Candidiasis, esophageal:

• Non-HIV-exposed/-infected: Infants ≥4 months, Children, and Adolescents: Recommended treatment duration is 14 to 21 days.
• ≤30 kg: IV: 3 mg/kg/dose once daily.
• 30 kg: IV: 2.5 mg/kg/dose once daily; maximum dose: 150 mg/dose.
• HIV-exposed/-infected: Recommended treatment duration is 14 to 21 days.
• Infants <15 kg: IV: 5 to 7 mg/kg/dose once daily.
• Children 2 to 8 years and ≤40 kg: IV: 3 to 4 mg/kg/dose once daily.
• Children ≥9 years:
• ≤40 kg: IV: 2 to 3 mg/kg/dose once daily.
• 40 kg: IV: 100 mg/dose once daily.
• Adolescents: IV: 150 mg/dose once daily.

Candidiasis, systemic:

• Infants <4 months: IV: 10 mg/kg/dose once daily; doses as high as 15 mg/kg/dose have been reported.
• Infants ≥4 months, Children, and Adolescents: IV: Initial dose: 2 mg/kg/dose once daily; usual maximum dose: 100 mg/dose; may increase to 4 mg/kg/dose if needed; maximum dose: 200 mg/dose.

Empiric antifungal therapy (neutropenic fever):

• Infants ≥4 months, Children, and Adolescents: IV: 2 to 3 mg/kg/dose once daily; maximum dose: 200 mg/dose.

Fungal infection prophylaxis in hematopoietic stem cell transplant recipients:

• Infants <4 months: IV: 2 mg/kg/dose once daily; dose based on pharmacokinetic exposure similar to adults receiving 50 mg.
• Infants ≥4 months, Children, and Adolescents: IV: 1 mg/kg/dose once daily; maximum dose: 50 mg/dose; doses as high as 3 mg/kg/day have been used in trials.

• Alternate day dosing (very limited data available): Infants ≥7 months and Children ≤10 years: IV: 3 mg/kg/dose every 48 hours; dosing based on a pharmacokinetic modeling study.

There are no specific dietary restrictions associated with the use of Micafungin. Micafungin can be administered with or without food, and no specific foods or beverages are known to interact with Micafungin.

Micafungin may be contraindicated under the following conditions:

• Micafungin is contraindicated in patients who have demonstrated hypersensitivity to the drug.

• Serious hypersensitivity reactions (including anaphylaxis and anaphylactoid reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in patients receiving Micafungin. In such cases, Micafungin infusion should be stopped, and appropriate treatment should be administered.
• Hepatic carcinomas and adenomas were observed in rat studies evaluating the reversibility of hepatocellular lesions caused by micafungin sodium. Micafungin should not be used in higher-than-recommended doses and for prolonged durations due to the potential risk of liver tumor formation.
• Laboratory abnormalities in liver function tests have been observed in healthy volunteers and patients treated with Micafungin. Clinical hepatic abnormalities, including hepatic impairment, hepatitis, and worsening hepatic failure, have occurred in some patients with serious underlying conditions. Patients with hepatic impairment or abnormal liver function tests during Micafungin therapy should be closely monitored and evaluated for the risk/benefit of continuing treatment.
• Elevations in blood urea nitrogen (BUN) and creatinine, as well as isolated cases of significant renal impairment or acute renal failure, have been reported in patients receiving Micafungin. Patients who develop abnormal renal function tests during Micafungin therapy should be monitored for worsening renal function.
• Acute intravascular hemolysis and hemoglobinuria have been observed during Micafungin infusion. Isolated cases of significant hemolysis and hemolytic anemia have also been reported. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during Micafungin therapy should be closely monitored and evaluated for the risk/benefit of continuing treatment.
• Male rats treated with micafungin sodium showed changes in the epididymal ductal epithelial cells, epididymis weights, and reduced numbers of sperm cells in animal studies. However, no impairment of fertility was observed in these studies.

The excretion of micafungin in human milk has not been established. However, micafungin has been detected in the milk of lactating rats that received the drug. Therefore, caution should be exercised when administering Micafungin to breastfeeding women.

Pregnancy:

Teratogenic Effects - Category C

There are no sufficient and well-controlled studies conducted in pregnant women to evaluate the use of Micafungin. Therefore, the administration of Micafungin during pregnancy should only be considered if the potential benefits outweigh the potential risks.

In pregnant rabbits, the administration of micafungin sodium via intravenous dosing from days 6 to 18 of gestation resulted in visceral abnormalities and abortion at a dose of 32 mg/kg. This dose is approximately four times the recommended dose when comparing body surface areas. The observed visceral abnormalities in rabbits included lung lobation abnormalities, levocardia, retrocaval ureter, anomalous right subclavian artery, and ureter dilatation. However, it should be noted that animal studies do not always accurately predict the response in humans.

No specific food restrictions or dietary modifications are required when using Micafungin. Micafungin can be administered with or without food.

The adverse reactions related to Micafungin can be categorized as follows:

More common:

• Black, tarry stools
• Cough
• Decreased frequency or amount of urine
• Fast, pounding, or irregular heartbeat or pulse
• Fever or chills
• Increased thirst
• Loss of appetite
• Lower back or side pain
• Nausea or vomiting
• Painful or difficult urination
• Pale skin
• Pinpoint red spots on the skin
• Swelling of the face, fingers, or lower legs
• Trouble breathing
• Ulcers, sores, or white spots in the mouth
• Unusual bleeding or bruising
• Unusual tiredness or weakness
• Weight gain

Less common:

• Bone pain
• Changes in skin color, pain, tenderness, or swelling of the foot or leg
• Chest pain
• Drowsiness
• Mood or mental changes
• Muscle pain or cramps
• Muscle spasms or twitching
• Numbness or tingling in the hands, feet, or lips
• Seizures
• Swollen glands
• Trembling

Rare:

• Abdominal or stomach cramps
• Blurred vision
• Dizziness
• Headache
• Nervousness
• Pounding in the ears
• Slow or fast heartbeat
• Weakness or heaviness of the leg

A total of 14 clinical drug-drug interaction studies were conducted in healthy volunteers to assess potential interactions between Micafungin and various medications such as amphotericin B, mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, itraconazole, voriconazole, ritonavir, or rifampin. These studies did not observe any interactions that affected the pharmacokinetics of micafungin.

However, when Micafungin was co-administered with amphotericin B deoxycholate, there was a 30% increase in amphotericin B deoxycholate exposure. The clinical significance of this increase is uncertain, but the co-administration should only be used when the benefits outweigh the risks, and close monitoring of amphotericin B deoxycholate toxicities is recommended.

Co-administration of Micafungin with voriconazole led to an approximately 20% reduction in voriconazole exposure on average. However, when comparing the effect of Micafungin to placebo, it was found that Micafungin did not have a significant impact on the pharmacokinetics of voriconazole.

Single or multiple doses of Micafungin did not affect the pharmacokinetics of mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, voriconazole, or fluconazole.

In the presence of steady-state Micafungin, sirolimus exposure (AUC) increased by 21% without affecting Cmax. Nifedipine exposure (AUC) and peak concentration (Cmax) increased by 18% and 42%, respectively, when co-administered with Micafungin. Similarly, itraconazole exposure (AUC) and Cmax increased by 22% and 11%, respectively, when co-administered with Micafungin. Patients receiving sirolimus, itraconazole, or nifedipine in combination with Micafungin should be monitored for potential toxicity, and the dosage of sirolimus, itraconazole, or nifedipine may need to be adjusted if necessary.

Micafungin does not inhibit P-glycoprotein and is not expected to affect P-glycoprotein-mediated drug transport activity.

The following are the side effects involving Micafungin:

• Nausea
• Vomiting
• Stomach pain
• Indigestion
• Diarrhea
• Constipation
• Headache
• Trouble sleeping (insomnia)
• Flushing (warmth, redness, or tingly feeling)
• Itching or skin rash
• Injection site reactions (pain, swelling, or tenderness)

Pregnancy:

Teratogenic Effects - Category C

There are no sufficient and well-controlled studies conducted in pregnant women to evaluate the use of Micafungin. Therefore, the administration of Micafungin during pregnancy should only be considered if the potential benefits outweigh the potential risks.

In pregnant rabbits, the administration of micafungin sodium via intravenous dosing from days 6 to 18 of gestation resulted in visceral abnormalities and abortion at a dose of 32 mg/kg. This dose is approximately four times the recommended dose when comparing body surface areas. The observed visceral abnormalities in rabbits included lung lobation abnormalities, levocardia, retrocaval ureter, anomalous right subclavian artery, and ureter dilatation. However, it should be noted that animal studies do not always accurately predict the response in humans.

Lactation:

The excretion of micafungin in human milk has not been established. However, micafungin has been detected in the milk of lactating rats that received the drug. Therefore, caution should be exercised when administering Micafungin to breastfeeding women.

Pediatric:

In pediatric patients, the values of AUC (area under the curve) were directly proportional to the dose given within the range of 0.5-4 mg/kg. Clearance, on the other hand, was influenced by weight. Younger children (4 months to 5 years) had a mean weight-adjusted clearance 1.35 times higher than that of older children (6 to 11 years). Clearance values in older children (12-16 years) were similar to those observed in adult patients. In children less than 4 months of age, the mean weight-adjusted clearance was approximately 2.6 times higher than in older children (12-16 years) and 2.3 times higher than in adults.

A PK/PD bridging study demonstrated that micafungin penetrates the central nervous system (CNS) in a dose-dependent manner. To achieve maximum eradication of fungal burden in CNS tissues, a minimum AUC of 170 µg*hr/L was required. Population PK modeling indicated that a dose of 10 mg/kg in children less than 4 months of age would be sufficient to achieve the desired exposure for treating CNS Candida infections.

Geriatric Use:

The pharmacokinetics of micafungin were comparable between elderly individuals (aged 66-78 years) and young subjects (20-24 years) when given as a single 1-hour infusion of 50 mg. No dose adjustment is required for the elderly population.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Micafungin.

Clinical trials have administered repeated daily doses of micafungin up to 8 mg/kg (with a maximum total dose of 896 mg) in adult patients, and no dose-limiting toxicity has been reported. In one instance, a newborn patient received a dosage of 16 mg/kg/day, and no adverse reactions were observed with this high dose.

Regarding micafungin overdoses, there is no available experience or information. In the event of an overdose, it is recommended to provide general supportive measures and symptomatic treatment.

Pharmacodynamics:

Micafungin, formerly known as FK463, is an antifungal agent synthesized from a fermentation product of Coleophoma empetri. It belongs to the echinocandin structural class and acts as a glucan synthesis inhibitor. The U.S. Food and Drug Administration approved micafungin in March 2005. It works by inhibiting an enzyme that is vital for the synthesis of fungal cell walls. The fungicidal or fungistatic effects of micafungin depend on its concentration, with some Candida species being susceptible to its fungicidal action. However, it typically exhibits fungistatic activity against Apergillus. Micafungin can be used concurrently with various other medications, including the HIV protease inhibitor ritonavir and transplant drugs like cyclosporine and tacrolimus.

Pharmacokinetics:

Absorption:

• Pharmacokinetics of micafungin show linear behavior within the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg.
• There is no evidence of micafungin accumulation in the systemic circulation with repeated administration, and it generally reaches a steady-state within 4 to 5 days.

Distribution:

• After intravenous administration, micafungin concentrations exhibit a biexponential decline, indicating rapid distribution into tissues.
• Micafungin is highly bound to plasma proteins (>99%), primarily to albumin.
• The binding of micafungin to albumin remains consistent regardless of its concentration (10-100 µg/ml).
• The volume of distribution at steady state (Vss) is approximately 18-19 liters.

Biotransformation:

• Micafungin primarily circulates in its unchanged form in the systemic circulation.
• Micafungin undergoes metabolism to several compounds, including M-1 (catechol form), M-2 (methoxy form of M-1), and M-5 (hydroxylation at the side chain). However, these metabolites have minimal exposure and do not significantly contribute to the overall efficacy of micafungin.
• Although micafungin is a substrate for CYP3A in laboratory studies, CYP3A-mediated hydroxylation is not a major pathway for micafungin metabolism in vivo.

Elimination and Excretion:

• The mean terminal half-life of micafungin is approximately 10-17 hours and remains consistent across doses up to 8 mg/kg and after single or repeated administration.
• Total clearance of micafungin is 0.15-0.3 ml/min/kg in healthy subjects and adult patients, and it is independent of the dose after single or repeated administration.
• Following a single intravenous dose of 14C-micafungin (25 mg) in healthy volunteers, approximately 11.6% of the radioactivity was excreted in urine and 71.0% in feces over 28 days. These findings indicate that the elimination of micafungin is primarily non-renal. Metabolites M-1 and M-2 were detected in plasma at trace concentrations, while the more abundant metabolite M-5 accounted for a total of 6.5% relative to the parent compound.

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