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Trade Names:
Amphotec
- Powder for injection 50 mg (as cholesteryl)
- Powder for injection 100 mg (as cholesteryl)

Trade Names:
Amphocin
- Powder for injection 50 mg (as desoxycholate)

Trade Names:
Abelcet
- Suspension for injection 100 mg per 20 mL (as lipid complex)

Trade Names:
AmBisome
- Powder for injection 50 mg (as liposomal)

Mechanism of Action

Pharmacology

Alters fungal cell membrane permeability.

Pharmacokinetics

Absorption

C _max is approximately 2.6 to 2.9 mcg/mL.

C _max is approximately 0.5 to 2 mcg/mL.

C _max is approximately 1.7 mcg/mL ( Abelcet ) and approximately 7.3 to 83 mcg/mL ( Ambisome ; 1 to 5 mg/kg/day).

Distribution

Vd is approximately 3.8 to 4.1 L/kg; distribution t _½ is approximately 3.5 min.

More than 90% protein bound.

Vd is approximately 131 L/kg ( Abelcet ) and 0.1 to 0.44 L/kg ( Ambisome ; 1 to 5 mg/kg/day).

Metabolism

Not known.

Elimination

The t _½ is approximately 27.5 to 28.2 h; Cl is approximately 0.105 to 0.112 L/h/kg.

Elimination t _½ is approximately 15 days and plasma t _½ is approximately 24 h; excreted very slowly by the kidneys with 2% to 5% of a dose excreted in the active form.

The t _½ is approximately 173.4 h ( Abelcet ), approximately 7 to 10 h ( Ambisome ; measured within 24-h dosing interval), and approximately 100 to 153 h ( Ambisome ; measured up to 49 days after dosing). Cl is approximately 436 mL/h/kg ( Abelcet ) and 11 to 51 mL/h/kg ( Ambisome ).

Indications and Usage

Treatment of progressive, potentially fatal infections caused by certain fungal species.

Treatment of invasive aspergillosis.

Treatment of American mucocutaneous leishmaniasis.

Treatment of invasive fungal infections in patients refractory to conventional amphotericin B desoxycholate or when renal function impairment or unacceptable toxicity precludes use of the desoxycholate formulation (lipid complex); treatment of infections caused by Aspergillus , Candida , or Cryptococcus species (liposomal); empirical treatment of febrile, neutropenic patients with presumed fungal infections (liposomal); treatment of visceral leishmaniasis (liposomal).

Unlabeled Uses

Prophylaxis of fungal infections in patients with bone marrow transplantation; treatment of primary amoebic meningoencephalitis caused by Naegleria fowleri ; subconjunctival or intravitreal treatment of ocular aspergillosis; bladder irrigation for candidal cystitis; chemoprophylaxis of aspergillosis; intrathecal treatment of severe meningitis unresponsive to IV therapy; intra-articular or IM treatment of coccidioidal arthritis.

Contraindications

Standard considerations.

Dosage and Administration

IV Test dose advisable (eg, 10 mL containing 1.6 to 8.3 mg infused over 15 to 30 min); recommended treatment dose is 3 to 4 mg/kg/day.

IV Test dose of 0.05 mg/mL infused slowly over 20 to 30 min. Record patient's temperature, pulse, respiration, and BP every 30 min for 2 to 4 h. Recommended concentration is 0.1 mg/mL.

IV Initial recommended dose is 0.25 to 0.3 mg/kg/day infused slowly over 2 to 6 h. Dose is increased gradually up to 0.5 to 0.7 mg/kg/day and up to 1 mg/kg/day for some mycoses (max daily dose, 1 mg/kg/day or 1.5 mg/kg on alternate days). Daily dose varies with type of infection, ranging from 0.5 to 1.5 mg/kg for 4 to 12 wk. However, aspergillosis regimen is 1 mg/kg/day up to a total treatment dose of 3.6 g over 11 mo; rhinocerebral phycomycosis regimen is 0.25 to 1 mg/kg/day up to a total treatment dose of 3 to 4 g; sporotrichosis regimen is 0.5 mg/kg/day up to a total treatment dose of 2.5 g over 9 mo.

IV 0.5 mg/kg/day on alternate days for 14 doses.

IV 5 mg/kg/day as a single infusion at a rate of 2.5 mg/kg/h. If infusion time exceeds 2 h, mix contents of infusion bag by shaking every 2 h. Dilute to 2 mg/mL for patients with CV disease.

IV 3 mg/kg/day.

IV 3 to 5 mg/kg/day as a 1 to 2 mg/mL dilution.

IV 3 to 5 mg/kg/day as a 0.2 to 0.5 mg/mL dilution.

IV 6 mg/kg/day.

IV 3 mg/kg/day on days 1 through 5 (days 14 and 21 for immunocompetent patients); administer 4 mg/kg/day on days 1 through 5 (days 10, 17, 24, 31, and 38 for immunosuppressed patients).

General Advice

• Amphotericin B cholesteryl
• Administer diluted in dextrose 5% injection by IV infusion rate of 1 mg/kg/h.
• Follow manufacturer's instructions for reconstitution and administration. Reconstitute by using sterile water for injection. Do not reconstitute with saline or dextrose solutions or admix with saline or electrolytes.
• Do not filter or use an in-line filter.
• Do not mix with other IV medications.

• Amphotericin B desoxycholate
• Follow manufacturer's instructions for reconstitution and administration. Use sterile water for injection without a bacteriostatic agent. Do not reconstitute with saline. Preservatives, bacteriostatic agents, and saline may cause precipitation.
• Use volumetric IV pump to regulate delivery over the recommended 6-h period. Shorter infusion times have also been used.
• Use IV filter (at least 1 micron) during administration.
• Agitate hanging solution to mix every 30 to 60 min.
• Do not mix with other IV medications.
• Do not administer if solution is discolored or if precipitate is present.

• Amphotericin B lipid-based
• Administer IV at a rate of 2.5 mg/kg/h. If infusion time exceeds 2 h, mix contents by shaking the infusion bag every 2 h.
• Follow manufacturer's instructions for reconstitution and administration. Use dextrose 5% injection for reconstitution. Do not reconstitute with other drugs or electrolytes because compatibility of liposomal amphotericin B has not been established. Flush an existing IV line with dextrose 5% injection before infusion of liposomal amphotericin B, or use a separate infusion line.
• Shake the vial gently until there is no yellow sediment at the bottom.
• Do not use an in-line filter less than 5 microns.

Storage/Stability

• Medication is stable for 24 h at room temperature or 7 days if kept refrigerated.
• Store in a dark area. Protect from light during administration.

• Do not freeze. Retain in the carton until time of use.
• May be stored for 15 h if refrigerated or 6 h at room temperature.
• Discard any unused material.

• Use within 24 h after reconstitution.
• Store unopened vials at 59° to 86°F.
• Refrigerate after reconstitution.

Drug Interactions

Concurrent use may enhance potential for arrhythmias, bronchospasm, renal toxicity, and shock.

Antagonism between amphotericin B and the antifungal agent may occur.

Increased potential for hypokalemia.

May increase nephrotoxic effects.

Amphotericin B–induced hypokalemia may potentiate digitalis toxicity.

Increased risk of flucytosine toxicity.

Acute pulmonary toxicity has been reported in patients receiving IV amphotericin B and leukocyte transfusions. Do not give concurrently.

Possible synergistic nephrotoxicity.

Amphotericin B–induced hypokalemia may enhance curariform effect of skeletal muscle relaxant.

Closely monitor renal and hematologic function if used with amphotericin B.

Incompatibility

Do not mix with other IV medications.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension, tachycardia (10%); hypertension (9%); hemorrhage, postural hypotension (at least 5%); arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, CHF, phlebitis, shock, supraventricular tachycardia, syncope, vasodilation, venoocclusive liver disease, ventricular extrasystoles (1% to less than 5%); ventricular fibrillation.

CNS

Headache (8%); abnormal thinking, confusion, dizziness, insomnia, somnolence, tremor (at least 5%); asthenia (1% to less than 5%); agitation, anxiety, convulsion, depression, hallucinations, hypertonia, nervousness, neuropathy, paresthesia, psychosis, speech disorder, stupor (1% to less than 5%); malaise, peripheral nephropathy.

Dermatologic

Maculopapular rash, pruritus, rash, sweating (at least 5%); acne, alopecia, petechial rash, skin discoloration, skin disorder, skin nodule, skin ulcer, urticaria, vesiculobullous rash (1% to less than 5%).

EENT

Eye hemorrhage (at least 5%); amblyopia, deafness, ear disorder, pharyngitis, tinnitus (1% to less than 5%).

GI

Nausea (12%); nausea and vomiting, vomiting (11%); diarrhea, dry mouth, hematemesis, stomatitis (at least 5%); anorexia, bloody diarrhea, constipation, dyspepsia, fecal incontinence, GI disorder, GI hemorrhage, gingivitis, glossitis, increased gamma glutamyl transpeptidase, melena, mouth ulceration, oral moniliasis, rectal disorder (1% to less than 5%); cramping, epigastric pain.

Genitourinary

Hematuria (at least 5%); albuminuria, dysuria, glycosuria, kidney failure, oliguria, urinary incontinence, urinary retention, urinary tract disorder (1% to less than 5%); anuria, azotemia, hematuria, hypostenuria, nephrocalcinosis, renal tubular acidosis.

Hematologic-Lymphatic

Thrombocytopenia (7%); anemia, coagulation disorder, decreased prothrombin (at least 5%); decreased thromboplastin, ecchymosis, hypochromic anemia, increased fibrinogen, leukocytosis, leukopenia, petechiae (1% to less than 5%); agranulocytosis, eosinophilia, normochromic anemia, normocytic anemia.

Hepatic

Abnormal LFTs (11%); jaundice (at least 5%).

Local

Injection-site inflammation (at least 5%); injection-site pain with phlebitis and thrombophlebitis.

Metabolic-Nutritional

Increased creatinine (34%); hypokalemia (29%); hyperbilirubinemia (19%); hypomagnesemia (11%); hyperglycemia (9%); increased alkaline phosphatase (8%); hypophosphatemia, peripheral edema, weight gain (at least 5%); acidosis, dehydration, hyperkalemia, hyperlipemia, hypernatremia, hypervolemia, hypoglycemia, hyponatremia, hypoproteinemia, increased ALT and AST, increased BUN, increased lactic dehydrogenase, weight loss (1% to less than 5%).

Musculoskeletal

Back pain (at least 5%); arthralgia, myalgia, neck pain (1% to less than 5%); joint pain, muscle pain.

Respiratory

Dyspnea, hypoxia (9%); apnea, asthma, epistaxis, hyperventilation, increased cough, lung disorder, rhinitis (at least 5%); hemoptysis, lung edema, pleural effusion, respiratory disorder, sinusitis (1% to less than 5%); respiratory failure.

Miscellaneous

Chills (77%); fever (55%); abdominal pain, chest pain, enlarged abdomen, face edema, mucous membrane disorder, pain, sepsis (at least 5%); accidental injury, allergic reaction (including anaphylactoid reactions and anaphylaxis), death, hypothermia, immune system disorder, infection (1% to less than 5%).

Precautions

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established (amphotericin B desoxycholate). Safety and efficacy in children younger than 1 mo of age not established (amphotericin B lipid-based, amphotericin B cholesteryl).

Nephrotoxicity

Drug is toxic and should be used with caution under close supervision. Renal damage is most important toxic effect. Despite its dangerous adverse reactions, amphotericin B frequently is the only effective treatment for potentially fatal fungal diseases.

Overdosage

Symptoms

Cardiorespiratory arrest.

Patient Information

• Explain need for prolonged therapy and for close monitoring during course of therapy.
• Encourage patient to increase fluid intake to 2,000 to 3,000 mL/day, if allowed.
• Inform patient to report any discomfort at injection site immediately.
• Instruct patient to report symptoms of chills, malaise, or fever.