Amphotericin B deoxycholate (Fungizone) is a conventional broad-spectrum antifungal drug. It is available mostly as an injection for intravenous administration. Topical and oral formulations are also available but amphotericin B dose and bioavailability via these routes are very variable.

(Fungizone) Amphotericin B Uses:

• It is used for treating Life-threatening fungal infections caused by:

  • Aspergillosis,
  • cryptococcosis (torulosis),
  • North American blastomycosis,
  • systemic candidiasis,
  • coccidioidomycosis,
  • histoplasmosis,
  • zygomycosis (including susceptible species of Absidia, Mucor, and Rhizopus that cause mucormycosis)
  • Conidiobolus,
  • Basidiobolus, and
  • sporotrichosis.

• Leishmaniasis:

  • For the treatment of patients with American mucocutaneous leishmaniasis.

• Off Label Use of Amphotericin B in Adults include:

  • endophthalmitis caused by candida
  • esophageal candidiasis
  • Fluconazole-refractory oropharyngeal Candidiasis
  • Candidiasis of the urinary tract
  • Visceral Leishmaniasis
  • Ocular aspergillosis

Amphotericin B Dose in Adults

Note: Conventional amphotericin formulations and lipid-soluble formulations are not interchangeable and the doses are different.

Note: Infusion-related immediate reactions may occur. Patients should be premedicated 30 - 60 minutes prior to the administration with the following drugs:

• NSAID and/or diphenhydramine or
• acetaminophen with diphenhydramine or
• hydrocortisone.
• Meperidine may be administered if the patient experiences rigors during the infusion.

Amphotericin B Test dose:

• 1 mg of the drug is administered intravenously over 20 to 30 minutes.

Amphotericin B Dose in the treatment of Susceptible fungal infections:

• 0.3 - 1.5 mg/kg/day intravenously.
• 1 - 1.5 mg/kg over 4 - 6 hours may be administered on alternate days once therapy is established.
• Patients with aspergillosis and rhino-cerebral mucormycosis often require higher doses of 1 to 1.5 mg/kg/day.
• The maximum dose of 1.5 mg/kg/day should not be exceeded.

Amphotericin B Dose in the treatment of disseminated Aspergillosis:

• 0.6 - 0.7 mg/kg/day Intravenously for 3 - 6 months.

Note: IDSA recommends Voriconazole as the preferred therapy for invasive aspergillosis. Conventional amphotericin B may be reserved for use in resource-limited settings.

Amphotericin B Dose in the treatment of Ocular Aspergillosis:

• Inject 5 - 10 mcg intraocular in a 0.1 ml volume as a single dose to the affected eye intravitreally or intracamerally.
• The dose may be repeated in 4 - 7 days as clinically indicated.
• Guidelines recommend concomitant use of systemic voriconazole and vitrectomy.
• Topical (0.1% to 0.2% solution) may be applied to the affected eye every 30 - 60 minutes until the symptoms resolve.

Note:  The preferred treatment is Ophthalmic natamycin.

Amphotericin B Dose in the treatment of Blastomycosis in immunocompromised patients and patients with disseminated extrapulmonary or severe pulmonary disease):

• 0.7 - 1 mg/kg/day intravenously for 1 - 2 weeks or until improvement is noted.
• This is followed by oral itraconazole for 6 - 12 months.

Amphotericin B Dose in the treatment of Candidiasis:

• CNS candidiasis in patients who fail to respond to systemic therapy and removal of the device or when the ventricular device cannot be removed:

  • 0.01 to 0.5 mg/2 mL intraventricularly via the device into the ventricle.
  • The solution should be prepared in D5W.

• Endophthalmitis due to Candida infection:

  • Patients with vitritis or with macular involvement with or without vitritis):
    • 5 to 10 mcg/0.1 mL intravitreal.
    • The solution is prepared in sterile water and administered with concomitant systemic antifungal therapy.

• Esophageal candidiasis in Non-HIV infected patients:

  • 0.3 to 0.7 mg/kg/day Intravenously.
  • Amphotericin B should be continued for 21 days in fluconazole-refractory disease.
  • Oral antifungal therapy should be initiated once the patient can tolerate orally.

• Esophageal candidiasis in HIV-infected patients:

  • 0.6 mg/kg/day Intravenous for 14 - 21 days

• Invasive candidiasis as an alternative therapy:

  • 0.5 to 0.7 mg/kg/day Intravenously.
  • The dose may be increased to 1 mg/kg/day for infections caused by C. glabrata or C. krusei.

• Oropharyngeal candidiasis in fluconazole-refractory Non-HIV-infected patients:

  • 100 mg orally of an extemporaneously compounded suspension of 100 mg/mL four times a day.

• Urinary tract candidiasis 

  • Asymptomatic candiduria in patients undergoing urologic procedures:

    • 0.3 - 0.6 mg/kg intravenously daily for several days prior to and after the procedure

  • Fungus balls (Irrigation via nephrostomy tubes):

    • Irrigate with 25 to 50 mg in 200 to 500 mL sterile water (final concentration range: 0.05 to 0.25 mg/mL).

  • Pyelonephritis caused by C. krusei or fluconazole-resistant C. glabrata:

    • • 0.3 to 0.6 mg/kg/day intravenously for 1 - 7 days with or without flucytosine.

  • Symptomatic cystitis caused by C.krusei or fluconazole-resistant C. glabrata:

    • • 0.3 to 0.6 mg/kg/day Intravenously for 1 to 7 days

  • Bladder irrigation in infections caused by Fluconazole-resistant species like C. krusei, C. glabrata):

    • Irrigate with a 0.05 mg/mL (50 mg/L) sterile water solution instilled for 5 - 7 days or until cultures are clear.

Amphotericin B Dose in the treatment of Coccidioidomycosis in HIV-infected patients with severe, non-meningeal infection (ie, diffuse pulmonary or severely ill with an extrathoracic disseminated disease):

• 0.7 to 1 mg/kg/day Intravenously until clinical improvement, then initiate fluconazole or itraconazole therapy.

Amphotericin B Dose in the treatment of Cryptococcal disease in HIV-infected patients:

• Disseminated (non-CNS disease) or severe pulmonary disease:

  • Induction phase (given with flucytosine or fluconazole): 0.7 to 1 mg/kg/day for 2 weeks. (Flucytosine is preferred).
  • Oral fluconazole is then given in the consolidation/ maintenance phase.

• Meningitis:

  • Induction phase (given with flucytosine or fluconazole): 0.7 to 1 mg/kg/day for 2 weeks. (Flucytosine is preferred).
  • Oral fluconazole is then given in the consolidation/ maintenance phase.

Amphotericin B Dose in the treatment of Histoplasmosis in patients with moderately severe to severe pulmonary or disseminated disease:

• 0.7 to 1 mg/kg/day Intravenous for 1 - 2 weeks, followed by 12 weeks treatment with oral itraconazole for pulmonary disease or 12 months oral itraconazole for disseminated disease.

Amphotericin B Dose in the treatment of Leishmaniasis (alternative agent):

• Cutaneous leishmaniasis:

  • Intravenous dose of 0.5 to 1 mg/kg once daily, or every other day, for a cumulative total of 15 to 30 mg/kg.

• Mucosal leishmaniasis:

  • Intravenous administration of 0.5 to 1 mg/kg/dosage once daily, or every other day, for a cumulative dose of 20 to 45 mg/kg.

• Visceral leishmaniasis:

  • Once daily or on alternate days, provide 1 mg/kg intravenously for a cumulative dose of 15–20 mg/kg.

• Visceral leishmaniasis in HIV-infected patients:

  • 0.5 to 1 mg/kg/dose intravenous once a day for a total cumulative dose of 1,500 to 2,000 mg

Amphotericin B Dose in the treatment of pulmonary, meningeal, osteoarticular, or disseminated Sporotrichosis:

• 0.7 - 1 mg/kg/day intravenous once a day.
• Once the patient improves, oral itraconazole may be initiated for suppressive therapy for a total duration of 12 months or more.

Amphotericin B Dose in Childrens

Note: Conventional amphotericin formulations and lipid-soluble formulations are not interchangeable and the doses are different.

Note: Infusion-related immediate reactions may occur. Patients should be premedicated 30 - 60 minutes prior to the administration with the following drugs:

• NSAID and/or diphenhydramine or
• acetaminophen with diphenhydramine or
• hydrocortisone.
• Meperidine may be administered if the patient experiences rigors during the infusion.

Amphotericin B Test dose:

• A maximum dose of 1 mg is administered intravenously during a 20- to 60-minute period.

Amphotericin B Dose in the treatment of Susceptible fungal infections in children:

• Once daily intravenously, 0.25 to 0.5 mg/kg.
• The dose is increased incrementally by 0.25 mg/kg up to a daily maximum of 1.5 mg/kg.
• A 0.25 to 1 mg/kg/dose intravenous dose given once daily is the typical maintenance dosage.
• It can also be given every other day at a dose of 1 to 1.5 mg/kg.
• You shouldn't go beyond the 1.5 mg/kg/day upper limit.

Amphotericin B Dose for Bladder irrigation:

• 50 mcg/mL solution is administered as continuous or intermittent irrigation three times a day with a dwell time of 60 - 90 minutes

Amphotericin B Dose in the treatment of Aspergillosis:

• For prophylaxis in immunocompromised patients: 

  • Intranasal: 7 mg amphotericin B in 7 mL sterile water was placed in a De Vilbiss atomizer and the aerosolized solution was instilled intranasally to each nostril four times daily delivering an average of 5 mg amphotericin/day to reduce the frequency of invasive aspergillosis in neutropenic patients [Ref].

• Endocarditis:

  • 1 mg/kg/dose Intravenous once a day with or without flucytosine.

Amphotericin B Dosein the treatment of moderately severe to severe Blastomycosis independent of HIV status:

• 0.7 - 1 mg/kg/dose Intravenous once a day as initial therapy for 1 - 2 weeks.
• This is followed by oral itraconazole for a total of 12 months.

Amphotericin B Dose in the treatment of Candidiasis:

• Invasive candidiasis:

  • One intravenous dose of 0.5 to 1 mg/kg/day.
  • The intensity and location of the infection will determine how long the treatment will last.

• Endocarditis:

  • 1 mg/kg/dose Intravenous once a day with or without flucytosine.

• Esophageal candidiasis in Non-HIV exposed patients:

  • 0.3 - 0.7 mg/kg/dose intravenous once a day.
  • Oral antifungal therapy may be administered once the patient can tolerate orally.
  • Amphotericin B may be continued for 21 days in fluconazole-refractory disease.

• Esophageal candidiasis in HIV exposed patients:

  • Infants and Children:
    • 0.3 - 0.7 mg/kg/dose Intravenous once a day.

  • Adolescents:

    • 0.6 mg/kg/dose Intravenous once a day for 14 - 21 days.

• Oropharyngeal candidiasis in fluconazole-refractory patients:

  • Non-HIV-exposed/-positive:

    • 0.3 mg/kg/dose Intravenous once a day

  • HIV-exposed/-positive:

    • Infants and Children:

      • 0.3 - 0.5 mg/kg/dose Intravenous once a day.

    • Adolescent:

      • 0.6 mg/kg/dose Intravenous once a day for 14 to 21 days.

• Urinary tract infections:

  • For prophylaxis in urologic procedures in patients with candiduria:

    • 0.3 to 0.6 mg/kg/dose Intravenous once a day for several days before and after the procedure

  • For Treatment:

    • Cystitis:

      • High-risk asymptomatic patients:
        • 1 mg/kg/dose Intravenous once daily
      • Symptomatic (C. krusei or fluconazole-resistant C. glabrata):
        • 0.3 to 0.6 mg/kg/dose Intravenous once daily for 1 to 7 days

    • Pyelonephritis:

      • 0.3 - 0.6 mg/kg/dose Intravenous once a day for 1 to 7 days.
      • Flucytosine may be added in some cases.

Amphotericin B Dose in the treatment of Coccidioidomycosis:

• Non-HIV-exposed/-positive:

  • Disseminated (non-CNS) disease:

    • 0.5 - 1.5 mg/kg/dose Intravenous every day or on alternate days with or without concomitant azole antifungal treatment.
    • The duration of the treatment is determined by clinical response.

  • CNS disease:

    • 0.1 to 1.5 mg/dose intrathecally administered as daily, or on alternate days, to weekly in some cases with or without azole therapy.
    • The duration of the treatment depends on the clinical response.

  • Pulmonary disease, diffuse:

    • 0.5 - 1.5 mg/kg/dose Intravenous every day or on alternate days for several weeks,
    • This is followed by an oral azole antifungal for a total of 12 months or more.

• HIV-exposed/-positive:

  • Disseminated (non-CNS) disease, diffuse pulmonary disease in severely ill patients:

    • Infants and Children:

      • 0.5 to 1 mg/kg/dose Intravenous once a day until clinical improvement
      • Treatment is continued for several weeks.

    • Adolescents:

      • 0.7 - 1 mg/kg/dose Intravenous once a day until clinical improvement.
      • This is followed by fluconazole or itraconazole orally.

Amphotericin B Dose in the treatment of Cryptococcal disease in HIV-infected patients:

• Disseminated (non-CNS disease) or severe pulmonary disease:

  • Induction phase (given with flucytosine or fluconazole): 0.7 to 1 mg/kg/day for 2 weeks. (Flucytosine is preferred).
  • Oral fluconazole is then given in the consolidation/ maintenance phase.

• Meningitis in non-HIV exposed patients:

  • Induction phase (given with flucytosine): 0.7 to 1 mg/kg/day for 2 - 4 weeks.
  • Oral maintenance therapy is then given in the consolidation phase.
  • The dose of amphotericin B may be increased to 1.5 mg/kg/day if flucytosine is not well tolerated.

• Meningitis in HIV exposed patients:

  • Infants and Children:

    • 1 mg/kg/dose intravenously once a day plus flucytosine or fluconazole for a minimum of two weeks.
    • This is followed by the consolidation phase and chronic suppressive therapy.
    • The induction therapy may be prolonged it the CSF is not negative and the patient does not show clinical improvement.
    • The dose of amphotericin B may be increased to 1.5 mg/kg/day administered alone or in combination with fluconazole if flucytosine is not well tolerated.

  • Adolescents:

    • Induction phase (given with or without flucytosine): 0.7 to 1 mg/kg/day for 2 weeks.
    • Oral maintenance therapy is then given in the consolidation phase.

Amphotericin B Dose in the treatment of Histoplasmosis in patients with moderately severe to severe pulmonary or disseminated disease:

•  0.7 to 1 mg/kg/day Intravenous once a day for 1 - 2 weeks, followed by 12 weeks treatment with oral itraconazole for pulmonary disease or 12 months oral itraconazole for disseminated disease.
• In patients with CNS involvement and patients with a delayed response, the induction phase is prolonged to a total of 4 - 6 weeks.

Amphotericin B Dose in the treatment of visceral Leishmaniasis in HIV-exposed or HIV-positive patients:

• 0.5 - 1 mg/kg/dose Intravenous once a day for a total cumulative dose of 1,500 - 2,000 mg.

Amphotericin B Dose in the treatment of Peritonitis (CAPD):

• Intraperitoneal administration:

  • 1 - 4 mg per liter of dialysate has been used in children.
  • It may be associated with severe abdominal pain especially at doses greater than 2 mg per liter of dialysate.

• Intravenous administration:

  • 1 mg/kg/dose Intravenous once a day.

Amphotericin B Dose in the treatment of Severe Sporotrichosis:

• 0.7 mg/kg/dose intravenously once a day.
• This is followed by oral itraconazole therapy once the patient improves amphotericin therapy.

Pregnancy Risk Factor B

• It crosses the placental boundary and enters the foetus circulation.
• In animal reproduction studies, there were no adverse events.
• It is advised for pregnant women with severe systemic fungal diseases.

Amphotericin use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Breastfeeding is safe for the infant because it does not cause any systemic exposure due to its poor oral absorption.
• However, the manufacturer does not recommend breastfeeding while receiving amphotericin treatment.

Amphotericin B dose in renal impairment:

• Patients who develop drug-related renal dysfunction may be advised to reduce the total daily dose by 50% or the same dose may be given on alternate days.
• It is poorly dialyzable and the supplemental dosage is usually not required.
• Dose adjustment is not necessary including in patients on CRRT and hemodialysis.

Amphotericin dose in liver disease:

• The manufacturer has not  recommended any adjustments in the dose in patients with liver disease.

Common Side Effects of Amphotericin B Include:

• Cardiovascular:

  • Hypotension

• Central nervous system:

  • Chills
  • Headache
  • Malaise
  • Pain

• Endocrine & metabolic:

  • Hypokalemia
  • Hypomagnesemia

• Gastrointestinal:

  • Anorexia
  • Diarrhea
  • Epigastric pain
  • Heartburn
  • Nausea
  • Stomach cramps
  • Vomiting

• Hematologic & oncologic:

  • Anemia (normochromic-normocytic)

• Local:

  • Pain at the injection site

• Renal:

  • Renal function abnormality
  • Renal insufficiency

• Respiratory:

  • Tachypnea

• Miscellaneous:

  • Fever

Less Common Side Effects of Amphotericin B Include:

• Cardiovascular:

  • Flushing
  • Hypertension

• Central nervous system:

  • Arachnoiditis
  • Delirium
  • Neuralgia
  • Paresthesia

• Genitourinary:

  • Urinary retention

• Hematologic & oncologic:

  • Leukocytosis

Contraindication to Amphotericin B Include:

• Allergy to amphotericin, or any component of this formulation

Prevention of errors: [US Boxed Warning]

• If the dosage exceeds 1.5 mg/kg, it is important to verify the product name and dosage.

Interrupting therapy:

• If treatment is stopped for more than 7 days, it should be restarted at the lowest dose. Then, gradually increase the dose to the maximum.

Amphotericin B deoxycholate (conventional): Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• Monitor BUN and serum creatinine levels on alternate days (at least weekly)
• Serum electrolytes especially potassium and magnesium,
• Liver function tests,
• Temperature,
• Coagulation profile,
• CBC
• Input and output
• Clinical features of hypokalemia including muscle weakness, cramping, drowsiness, and ECG changes

How to administer Amphotericin B?

• Oral amphotericin B:

  • Oral amphotericin B is poorly absorbed and may be used for mucosal disease only.
  • It ought to be given continuously to encourage minimal variance in peak and trough levels.

• Oral Extended-release formulation:

  • The oral extended-release tablet should be taken whole without chewing or crushing the tablet.
  • It should be administered within one hour of finishing a meal.

• Amphotericin B Suspension:

  • The suspension should be shaken well prior to its use.
  • It may be mixed with formula, milk, fruit juice, water, ginger ale, or cold drinks and administered immediately after mixing.

• Intravenous Amphotericin B:

  • Amphotericin B injection should be diluted in 1 liter or 500 ml of dextrose water and infused over a period of 4 - 6 hours.

Mechanism of action of Amphotericin B:

• It alters cell membrane permeability in susceptible fungi by binding with ergosterol.
• Cellular leakage and cell death can result. It can also cause oxidation-dependent stimulation macrophages.

It isabsorbedIt can cause serious side effects if ingested orally. It is therefore mainly used intravenously. It isdistributedMany substances are found in tissues and body fluids. These fluids include bile, pericardial, pleural, and synovial fluids. In children, the penetration into cerebrospinal fluid can be as high as 40% to 90%. Adult penetration is very poor. 90% of the drug must be consumed within 90 daysplasma proteinsIt is. It has been ahalf-life eliminationPremature neonates receive 14.8 hours, while infants and children receive 18 hours (ranging between 11.9 hours and 40.3 hours). It has a biphasic half life in adults. It has a terminal half-life of 15 to 48 hours, and a initial half-life of 15 to 15 days. It takes time to get therepeak serum concentrationIt is 1 hour after a 4-6 hours infusion. It is excreted mainly via urine.

Amphotericin B Injection Brand Names (International):

• Amfucin
• Ampho-Moronal
• Amphocil
• Ampholin
• Amphotret
• Anfotericina B
• Fungizone IV
• Fungilin
• Fungilin Lozenges
• Fungitericin
• Fungizon
• Fungizona
• Fungizone
• Fungso-B
• Photericin B
• Tericin
• Terix

Amphotericin B Brand Names in Pakistan: