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AMPHOTERICIN B

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Amphotericin B is a polyene antifungal agent produced by the microorganism Streptomyces nodosus. It has been available in the United States since 1956.
    B) Amphotericin B liposome is a formulation of amphotericin B encapsulated in small unilamellar liposomes. Lipid components are hydrogenated phosphatidylcholine, cholesterol, and dimyristoyl phosphatidylglycerol.
    C) Amphotericin B cholesteryl sulfate is a complex of amphotericin B and cholesteryl sulfate.
    D) Amphotericin B lipid complex is a formulation of amphotericin B complexed with two phospholipids, dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG).

Specific Substances

    1) Amphotericin B
    2) Anfotericina B
    3) Ampho-moronal
    4) Amphotericine B
    5) Amphozone
    6) Fungilin
    7) Fungizone
    8) Mysteclin-F
    9) NS 718
    10) NSC 527017
    11) Molecular Formula: C47-H73-N-O17
    12) CAS 1397-89-3 (Amphotericin B)
    1.2.1) MOLECULAR FORMULA
    1) C47H73NO17

Available Forms Sources

    A) FORMS
    1) Amphotericin B is available as 50 mg lyophilized powder for intravenous administration (Prod Info FUNGIZONE(R) IV injection, 2009).
    2) Amphotericin B cholesteryl sulfate complex is available in single use vials as 50 mg in a 20 mL vial and 100 mg in a 50 mL vial for intravenous administration (Prod Info AMPHOTEC(R) IV injection, 2009).
    3) Amphotericin B lipid complex is available in single-use vials as 100 mg in 20 mL suspension for intravenous administration (Prod Info ABELCET(R) IV injection, 2009).
    4) Amphotericin B liposome is available as 50 mg intravenous powder for injection (Prod Info AmBisome(R) intravenous injection, 2012).
    B) USES
    1) Amphotericin B is effective for the treatment of serious infections including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, paracoccidioidomycosis, and sporotrichosis. Due to its significant toxicity, amphotericin B is reserved for life-threatening infections (Prod Info FUNGIZONE(R) IV injection, 2009).
    2) Amphotericin B lipid complex, amphotericin B cholesteryl sulfate complex, and amphotericin B liposome have been effective in the treatment of severe fungal infections in patients refractory to or intolerant of conventional amphotericin B (Prod Info AmBisome(R) intravenous injection, 2012; Prod Info ABELCET(R) IV injection, 2009; Prod Info AMPHOTEC(R) IV injection, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Amphotericin B is an antifungal agent derived from the microorganism Streptomyces nodosus. Amphotericin B is utilized for the treatment of fungal infections.
    B) PHARMACOLOGY: Amphotericin B binds with ergosterol on fungal cytoplasmic membranes causing pores to leak, facilitating organelle death. Human cells are less affected because cell walls contain cholesterol instead of sterols.
    C) TOXICOLOGY: Amphotericin B is known to cause some degree of renal insufficiency. Distal renal tubule damage and altering blood flow and smooth muscle function are thought to be the etiology of renal dysfunction resulting in nephrocalcinosis. It is also thought that the vehicle for amphotericin B delivery, deoxycholate, may play a role in renal insufficiency. Although amphotericin B has a greater affinity for binding to the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell, thus resulting in cytotoxicity.
    D) EPIDEMIOLOGY: Poisoning is usually the result of dosing error. Notable poisoning is uncommon, but may cause significant morbidity and mortality.
    E) WITH THERAPEUTIC USE
    1) IV infusion has been implicated in phlebitis, arthralgias, myalgias, fever, rigors, headache, nausea, vomiting, diarrhea, anemia, thrombocytopenia, leukopenia, tinnitus, renal injury, hypotension, tachycardia, dyspnea, and peripheral neuropathy. Intrathecal administration has caused paresthesia, delirium, flaccid paralysis, and parkinsonism. Chest pain is a known side effect after infusion of amphotericin B liposomal formulations. Oral exposures can occur with topical formulations, or lozenges, but toxicity is limited. Dermatitis can also occur with topical exposure.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, bloody stool, fever, chills, hypokalemia, hyperkalemia, hypomagnesemia, increase in liver enzymes, and renal insufficiency.
    2) SEVERE TOXICITY: Disseminated intravascular coagulation, hypotension, dysrhythmias, renal failure, respiratory failure, and cardiac arrest.
    0.2.20) REPRODUCTIVE
    A) Amphotericin B is rated FDA Pregnancy Category B. No teratogenic or fertility effects have been reported in animal studies.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, creatine phosphokinase, urinalysis, and creatinine clearance.
    D) Specific drug concentrations are not clinically useful, but can confirm overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For mild to moderate overdose, administer IV fluids, and antiemetics for nausea or vomiting. Replace electrolytes or treat hyperkalemia. Salt loading and mannitol have been utilized to prevent renal injury; efficacy in overdose is unknown.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is supportive with attention to the airway, breathing, and circulation. Strategies to reduce renal toxicity include IV saline, magnesium, and potassium supplementation for low magnesium or potassium. Treat hyperkalemia and cardiac dysrhythmias per protocol.
    C) INTRATHECAL INJECTION
    1) After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as amphotericin B is highly protein bound.
    D) DECONTAMINATION
    1) Significant toxicity has not been reported after ingestion. Gastrointestinal decontamination is generally not indicated.
    E) AIRWAY MANAGEMENT
    1) Generally not necessary. Intubate patients with severe hypotension or dysrhythmias, pulmonary edema, or respiratory failure.
    F) ANTIDOTE
    1) None
    G) ENHANCED ELIMINATION
    1) Exchange transfusion may be utilized in neonates and infants after large IV overdoses. In adults, hemodialysis is not useful given the low water solubility and high protein binding of amphotericin B.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Most exposures will occur in a hospital setting, but small oral unintentional overdoses that are asymptomatic may be managed at home.
    2) OBSERVATION CRITERIA: Any symptomatic patient or one with an intentional ingestion should be sent to the hospital and observed.
    3) ADMISSION CRITERIA: Any symptomatic patient with a suspected or known significant overdose should be admitted to the ICU.
    4) CONSULT CRITERIA: Nephrology should be consulted if acute renal failure develops. Consult a medical toxicologist or poison center for patients with significant overdose or severe toxicity.
    I) PITFALLS
    1) Failure to consider amphotericin B in patients presenting with renal insufficiency. Overdose commonly occurs when the non-lipid formulation is administered at doses intended for the lipid formulation.
    J) PHARMACOKINETICS
    1) Amphotericin B is poorly absorbed orally and IM. Protein binding is greater than 90%. Volume of distribution varies depending on the amphotericin B formulation: Amphotericin B 3.3 to 4 L/kg, Amphotericin B cholesteryl sulfate complex 3.8 to 4.1 L/kg, Amphotericin B lipid complex 131 L/kg, Amphotericin B liposome 0.1 to 0.16 L/kg. Elimination half-life also varies with formulation: Amphotericin B 15 days, Amphotericin B cholesteryl sulfate complex 28 hours, Amphotericin B lipid complex 173 hours, Amphotericin B liposome 7 to 153 hours, depending on duration of therapy.
    K) TOXICOKINETICS
    1) Half-life may be extended in renal failure, overdose, and various co-morbidities. In one 50-fold overdose, the elimination half-life was 148 days.
    L) DIFFERENTIAL DIAGNOSIS
    1) Consider other nephrotoxic agents in patients treated with Amphotericin B as patients may likely be on other chemotherapeutic agents.
    0.4.3) INHALATION EXPOSURE
    A) Move to fresh air and monitor for respiratory distress. Administer oxygen and treat with beta-2 agonists as needed.
    0.4.4) EYE EXPOSURE
    A) Irrigate copiously with tap water or normal saline.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed skin with soap and water.

Range Of Toxicity

    A) TOXIC DOSE: No specific toxic dose is known. Minimum lethal exposure has not been established. Dysrhythmias and cardiac arrest have occurred in pediatric patients following doses of approximately 4 to 41 mg/kg of amphotericin B.
    B) THERAPEUTIC DOSE: ADULT: AMPHOTERICIN B: IV, 0.25 to 0.3 mg/kg/day initially, up to 0.5 to 0.7 mg/kg/day, depending on cardio-renal status; intrathecal, 0.1 to 1.5 mg per dose at intervals ranging from daily to weekly, starting with a low dose and titrating up as tolerated. AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX: 3 to 4 mg/kg/day IV infusion at a rate of 1 mg/kg/hr. AMPHOTERICIN B LIPID COMPLEX: 5 mg/kg/day IV infusion at a rate of 2.5 mg/kg/hr. AMPHOTERICIN B LIPOSOME: 3 to 5 mg/kg/day IV infusion over a period of 2 hours. PEDIATRIC: AMPHOTERICIN B: 0.5 to 1 mg/kg/day IV depending on infection. AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX: 3 to 4 mg/kg/day IV infusion at a rate of 1 mg/kg/hr. AMPHOTERICIN B LIPID COMPLEX: 3 to 6 mg/kg/day IV depending on infection. AMPHOTERICIN B LIPOSOME: 3 to 5 mg/kg/day IV infusion over a period of 2 hours.

Clinical Effects

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CHILLS have been reported with amphotericin B therapy (Chabot et al, 1989; Garnacho-Montero et al, 1998). This reaction did not vary significantly whether the infusion rate was slow (2 hour) or rapid (45 minute) (Cleary et al, 1988). Chills have also been reported with liposomal amphotericin B infusion (Lopez-Berstein et al, 1989).
    2) FEVER has been reported with amphotericin B therapy (Chabot et al, 1989). This reaction was not dependent on infusion rate (ie, slow-2 hours or rapid-45 minutes) (Cleary et al, 1988). Fever has also been reported with liposomal amphotericin B or amphotericin lipid complex infusions (Lopez-Berestein et al, 1985; Garnacho-Montero et al, 1998).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: Blindness was the final outcome when a one milligram test dose was given intravenously to an adult with systemic lupus erythematous and cryptococcal meningitis (Li & Lai, 1989).
    a) Ten hours after administration the patient complained of visual loss and within 3 days was blind. Four days later she developed ophthalmoplegia with failure of abduction of both eyes and impaired upward and downward gaze of the left eye. No brain lesion was found.
    b) The ophthalmoplegia subsided by 5 weeks post exposure, but the blindness persisted. Bilateral optic atrophy developed 10 weeks after the initial administration.
    2) CASE REPORT: SUBCONJUNCTIVAL NODULES were reported in an adult three weeks following 2 days of subconjunctival amphotericin B (total dose, 7.5 mg). The conjunctiva was painful, injected with yellow and with blanched areas. The nodules disappeared spontaneously after 8 weeks but the yellow coloring was permanent (Bell & Ritchey, 1973).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Hearing loss and tinnitus have been reported in patients receiving amphotericin B (Prod Info FUNGIZONE(R) IV injection, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Only a few cases of dysrhythmias (sinus tachycardia, multifocal atrial and ventricular premature contractions, ventricular fibrillation, asystole) have been reported during therapeutic administration of amphotericin B; may be related to hyperkalemia.
    b) CASE REPORTS (TACHYCARDIA, PVCS): Sinus tachycardia with frequent multifocal atrial and ventricular premature contractions were reported in one case of a 66-year-old patient (Gross et al, 1978), and in other cases following the use of liposomal amphotericin B or amphotericin lipid complex (Garnacho-Montero et al, 1998; Levine et al, 1991).
    c) CASE REPORT (PVCS): Premature ventricular contractions unrelated to the time of administration of amphotericin B were reported in a 1.5-month-old infant given 1 mg/kg/day (8.5 mg/kg total). When amphotericin was temporarily discontinued, the PVC's decreased. When it was restarted, the PVC's again increased. When the therapy was finally discontinued, the dysrhythmias ceased (Googe & Walterspiel, 1988). Electrolytes were normal in this case.
    d) CASE REPORT (VENTRICULAR FIBRILLATION): Ventricular fibrillation was reported after infusion of 1.4 mg/kg over 45 minutes in an anuric patient. This dysrhythmia was associated with hyperkalemia (8 to 8.4 mEq/liter) (Craven & Gremillion, 1985). Similar hyperkalemic ventricular dysrhythmias have been described in dog experiments.
    e) Asystole has been reported with amphotericin B therapy (El-Dawlatly et al, 1999; DeMonaco & McGovern, 1983).
    1) CASE REPORT: A case of transient asystole was temporally related and confirmed on rechallenge, in a patient who was administered therapeutic amounts of amphotericin B (DeMonaco & McGovern, 1983).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Two preterm infants (30-week and 25-week) received amphotericin B for treatment of candidal infections that were reported on day of life 19 and 27, respectively. Both infants were initially started on amphotericin B at a dose of 0.5 mg/kg/day, which was increased to 1 mg/kg/day after 2 days of therapy. The first infant (30-week) received a total amphotericin B dose of 14.5 mg/kg by day of life 35; however, on day 35, the patient developed acute bradycardia (50 bpm) and marked desaturation to 60% to 70% per pulse oximetry. Despite aggressive resuscitative measures, the patient's condition continued to deteriorate and he died approximately 2 hours later. The second infant received a total amphotericin B dose of 20.5 mg/kg by day of life 49, without any previous complications of therapy; however on day 49, approximately 75 minutes after the last infusion, the patient developed bradycardia (80 to 100 bpm) and increased nasopharyngeal secretions. A chest x-ray demonstrated a right upper lobe infiltrate. The patient continued to deteriorate clinically, necessitating cardiopulmonary resuscitation. Despite intensive supportive measures, the patient died approximately 2 hours later. In both patients, serum amphotericin concentrations at the time of death were 6.7 and 7.4 mcg/mL, respectively (normal 0.3 to 3 mcg/mL). Further investigation revealed that the amphotericin B concentration that both infants received was 5 mg/mL, instead of 0.1 mg/mL (a 50-fold overdose) (Perlman et al, 1991).
    b) CASE REPORT: A 3-month-old infant developed wide-complex bradycardia (20 bpm) with cardiogenic shock, requiring cardiopulmonary resuscitation, hyperkalemia (potassium 9.8 mmol/L), and metabolic acidosis after receiving 2 doses of amphotericin B deoxycholate 20 mg, each dose given as a 1 hour intravenous infusion, instead of the prescribed liposomal amphotericin B formulation to be given as 6-hour infusions. Four hours after resuscitation, laboratory data showed improvement in his potassium concentration (4.4 mmol/L); however, his liver enzyme concentrations were elevated. Although the patient's laboratory values gradually improved over the next several days, he continued to demonstrate irreversible damage to his liver and kidneys, resulting in his death 17 days later (Groeneveld et al, 2008).
    B) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Phlebitis may occur with the therapeutic administration of amphotericin B (Schneiderman et al, 1987). Filtering with a 1 micrometer filter did not affect the incidence or severity of the phlebitis (Gotz et al, 1985).
    C) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 4-year-old boy developed hyperkalemia and a fatal cardiopulmonary arrest with rapid infusion of amphotericin B: lipid complex (5 mg/kg over 1 hour) (Barcia, 1998).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Cardiac arrests occurred in 5 pediatric patients (3 children ages ranging from 2 to 7-years-old, and 2 infants, ages of 4.5 weeks and 7 weeks) after receiving amphotericin overdoses, in doses ranging from 3.8 to 40.8 mg/kg/day. Only 1 of the 5 patients survived, the 2-year-old, who received amphotericin B of 4.6 mg/kg over a 2-hour period, instead of the prescribed 0.46 mg/kg dose, and who had been given IV hydrocortisone 10 mg and acetaminophen suppositories 120 mg prior to the amphotericin B infusion as standard protocol. Immediately following the amphotericin B infusion, the patient experienced one episode of vomiting, generalized seizures, and cardiac arrest, with a subsequent 15-second episode of asystole followed by bradycardia and conversion to a wide QRS complex tachycardia. With supportive care, including continuation of the hydrocortisone, the patient gradually recovered without sequelae. It is suggested that hydrocortisone therapy may decrease amphotericin B-induced cytokine expression resulting in decreased toxicity of amphotericin B, although further studies are warranted (Cleary et al, 1993).
    D) RAYNAUD'S PHENOMENON
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Three cases of painful cyanotic Raynaud's phenomenon after intravenous administration or inhalation of amphotericin B have been reported. Intravenous amphotericin B liposome was used in all patients without any side-effects. It is suggested that spasms of peripheral vessels mediated by thromboxane A2 could be responsible for the Raynaud's phenomenon. The authors suggest the use of inhibitors of prostaglandin synthesis for therapy (Zernikow et al, 1997).
    E) HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT A 41-year-old woman experienced chest pain approximately 2 hours after beginning the infusion of her second 300-mg dose (5 mg/kg) of amphotericin B for treatment of cryptococcal meningitis. Laboratory studies showed elevated creatine kinase (3485 Units/L, normal range 12-191 Units/L), troponin T (18.7 ng/mL, normal range 0-0.1 ng/mL), troponin I (1100 ng/mL, normal range 0-0.5 ng/mL), and potassium (9.5 mEq/: L, normal range 3.5-5 mEq/L) levels. On hospital day 3, after receiving her third dose of amphotericin B, the patient became severely hypotensive and an ECG showed wide-complex tachycardia with several episodes of asystole. The patient responded to resuscitative measures; however, her condition continued to deteriorate with development of disseminated intravascular coagulation, acute renal failure, and circulatory shock. Despite aggressive supportive measures, the patient died, with multi-organ failure, 3 days after receiving her third dose of amphotericin B. It was determined that the patient had been receiving amphotericin B deoxycholate (a non-lipid formulation) instead of liposomal amphotericin B. Concentrations of amphotericin B, measured in undiscarded blood samples obtained 5 and 18 hours after receiving the second 300-mg dose of amphotericin B deoxycholate were 7.0 and 5.3 mcg/mL (normal range 0.1 to 2.0 mcg/mL), respectively(Burke et al, 2006; Mohr et al, 2005).
    F) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension is a commonly reported adverse event in patients receiving amphotericin B (Prod Info FUNGIZONE(R) IV injection, 2009).
    G) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain was reported in 12% of patients who received amphotericin B liposome 1.5 to 6 mg/kg/day (n=343) compared with 11.6% of patients who received amphotericin B deoxycholate 0.3 to 1.2 mg/kg/day (n=344) in a multicenter, randomized, double-blind trial in adult (n=592) and pediatric (n=95) patients with febrile neutropenia (Prod Info AmBisome(R) intravenous injection, 2012).
    b) In a multicenter, randomized, double-blind trial in adult (n=202) and pediatric (n=42) patients with febrile neutropenia, chest pain was reported in 8.2% and 11.1% of patients who received amphotericin B liposome 3 mg/kg/day (n=85) and 5 mg/kg/day (n=81), respectively, compared with 6.4% of patients who received amphotericin B lipid complex 5 mg/kg/day (n=78) (Prod Info AmBisome(R) intravenous injection, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) Acute dyspnea, hemoptysis, and bilateral airway disease have associated with the therapeutic administration of amphotericin B. They have been associated with granulocyte transfusions and with transfusions of blood products other than granulocytes (Haber et al, 1986; Dutcher et al, 1989). The causes and relationship of these symptoms is still unclear.
    b) CASE REPORT: A 63-year-old man with a history of ischemic cardiopathy developed fever, chills, tachycardia, tachypnea, and severe hypoxemia with the first dose of amphotericin B lipid complex despite previous uneventful treatment with amphotericin B deoxycholate (Garnacho-Montero et al, 1998).
    B) PULMONARY HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Pulmonary hypertension was reported in a patient with candida infection treated with liposomal amphotericin B (Levine et al, 1991).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been reported in patients receiving amphotericin B (Prod Info FUNGIZONE(R) IV injection, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported as a common adverse reaction with amphotericin B (Prod Info FUNGIZONE(R) IV injection, 2009).
    B) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) Parkinsonism has rarely been associated with the intraventricular administration of amphotericin. This is usually reversible, but may be permanent (Fisher & Dewald, 1983).
    C) DEPRESSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Confusion and depression were associated with a course of amphotericin. A psychotic reaction associated with phlebitis was reported in a 61-year-old following a 50-mg infusion. The reaction persisted for 4 hours. These reactions appear to be rare side effects (Weddington, 1982; Altschuler & Wadleigh, 1972).
    D) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy has been reported with use of amphotericin B (Prod Info FUNGIZONE(R) IV injection, 2009)
    E) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 28-year-old man was restless, incoherent, and responsive to his name only approximately 6 hours following intrathecal administration of amphotericin B 0.25 mg for treatment of coccidioidal meningitis. An EEG demonstrated diffuse slowing. With supportive care, the patient gradually recovered over the next 2 days, with a repeat EEG indicating significant improvement. Following a 5-day interval, the patient was restarted on intrathecal amphotericin B therapy at a lower dose of 0.025 mg and titrated up to a maintenance dose of 0.5 mg intrathecally without complications (Winn et al, 1979).
    F) NEUROLOGICAL DEFICIT
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Neurologic deficits, including leg weakness and numbness and flaccid paralysis of the leg, and urinary retention were reported in 2 patients (a 64-year-old man and a 61-year-old woman) who received intrathecal amphotericin B therapy 0.5 mg for treatment of coccidioidal meningitis. Despite discontinuation of amphotericin B, the neurologic deficits in the male patient only minimally improved. He became non-ambulatory, and two months later, he died of aspiration pneumonia. An autopsy revealed focal necrosis of his spinal cord. The authors speculate that amphotericin B may exert a direct toxic effect on the spinal cord or its vascular supply when given intrathecally (Carnevale et al, 1980).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea, anorexia, and vomiting are seen with therapeutic administration (Raymond, 1988; Lopez-Berestein et al, 1989) .
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-year-old boy developed nausea, vomiting, fever, diarrhea, hypokalemia, and acute renal insufficiency after receiving 3 doses of amphotericin B deoxycholate 5 mg/kg/day, for treatment of a suspected fungal infection, instead of the prescribed liposomal amphotericin B formulation. With supportive care, the patient gradually recovered and was restarted on liposomal amphotericin B 3 mg/kg/day without complications (Groeneveld et al, 2008).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is a commonly reported adverse effect in patients receiving amphotericin B (Prod Info FUNGIZONE(R) IV injection, 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-year-old boy developed nausea, vomiting, fever, diarrhea, hypokalemia, and acute renal insufficiency after receiving 3 doses of amphotericin B deoxycholate 5 mg/kg/day, for treatment of a suspected fungal infection, instead of the prescribed liposomal amphotericin B formulation. With supportive care, the patient gradually recovered and was restarted on liposomal amphotericin B 3 mg/kg/day without complications (Groeneveld et al, 2008).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One adult initially given 1 mg, then 10 mg, 20 mg, and finally 30 mg/day, developed abnormal liver function tests after 18 days (total dose of 571 mg). Amphotericin B was discontinued 3 days later with increases in SGOT, SGPT, alkaline phosphatase, LDH, and bilirubin. At that time a total of 721 mg had been given. Rechallenge with amphotericin B worsened liver function tests. However, the effects were reversible (Miller, 1984).
    b) CASE REPORT: Hepatotoxicity developed in a 26-year-old man with life-threatening pulmonary blastomycosis after the addition of amphotericin B to his itraconazole therapy. Symptoms resolved upon discontinuation of amphotericin B (Gill et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: ALT and AST levels of 3350 Units/L (normal range 0 to 40 Units/L) and 3390 Units/L (normal range 0 to 37 Units/L), respectively, were reported in a 41-year-old woman who inadvertently received amphotericin B deoxycholate (a non-lipid formulation) instead of the prescribed liposomal formulation (Mohr et al, 2005).
    b) CASE REPORT (INFANT): Elevated AST and ALT concentrations of 3146 units/L (normal, less than 80 units/L) and 1356 units/L (normal, less than 45 units/L), respectively, and elevated lactate dehydrogenase and gamma-glutamyl transferase concentrations of 10089 units/L (normal, less than 450 units/L) and 477 units/L (normal, less than 50 units/L), respectively, were reported in a 3-month-old infant who received amphotericin B deoxycholate 20 mg as 1-hour intravenous infusions, instead of the prescribed liposomal amphotericin B formulation to be administered as 6-hour infusions (Groeneveld et al, 2008).
    B) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Acute toxic hepatic degeneration was demonstrated at autopsy in a man who was given a total dose of amphotericin B 4.82 grams over 1 year for the treatment of cryptococcal meningoencephalitis (Carnecchia & Kurtzke, 1960).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) As many as 80% to 88% of patients receiving therapeutic amphotericin B doses experience decrease in renal function. Much of this damage is reversible (Chabot et al, 1989; Butler, 1964; Sabra & Branch, 1990; Garnacho-Montero et al, 1998; Johnson et al, 1998).
    b) The kidney damage appears to be dose related (Butler, 1964).
    c) The nephrotoxic effects appear to be secondary to renal tubular lesions, decreased glomerular filtration rate, and reduced renal plasma flow (Butler, 1964; Butler, 1964a).
    d) During initial treatment, creatinine clearance may decline. However, this effect may normalize over the next several months (Miller & Bates, 1969).
    e) CHANGES IN PROXIMAL TUBULAR FUNCTION (Burgess & Birchall, 1972):
    1) Increased clearance of uric acid (varied inversely with the glomerular filtration rate).
    2) Increased potassium clearance as the amphotericin B dose increased.
    3) Development of renal tubular acidosis.
    4) A rise in urine pH or fall in hydrogen ion excretion which usually preceded a significant reduction in the glomerular filtration rate.
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-year-old boy developed nausea, vomiting, fever, diarrhea, hypokalemia, and acute renal insufficiency after receiving 3 doses of amphotericin B deoxycholate 5 mg/kg/day, for treatment of a suspected fungal infection, instead of the prescribed liposomal amphotericin B formulation. Laboratory data, obtained 3 days after the infusion, revealed serum creatinine concentration of 303 mcmol/L (normal range 30 to 90 mcmol/L), urea concentration of 15.9 mmol/L (normal range 1.8 to 6.4 mmol/L), potassium concentration of 2.7 mmol/L (normal range 3.7 to 5.9 mmol/L), and a creatinine clearance of 23 mL/min/1.73 m(2). With supportive care, the patient gradually recovered and was restarted on liposomal amphotericin B 3 mg/kg/day without complications (Groeneveld et al, 2008).
    b) CASE REPORT: A 41-year-old woman developed disseminated intravascular coagulation, acute renal failure, and circulatory shock, and subsequently died, from multisystem organ failure, after inadvertently receiving several 300 mg (5 mg/kg) doses of amphotericin B deoxycholate (a non-lipid formulation) instead of the prescribed liposomal formulation. Concentrations of amphotericin B, measured in undiscarded blood samples obtained 5 and 18 hours after receiving the second 300-mg dose of amphotericin B deoxycholate, were 7.0 and 5.3 mcg/mL (normal range 0.1 to 2.0 mcg/mL), respectively (Burke et al, 2006; Mohr et al, 2005).
    C) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Urinary retention was reported in 2 patients who developed acute myelopathy with leg weakness and sensory loss after they received amphotericin B 0.5 mg intrathecally for treatment of coccidioidal meningitis (Carnevale et al, 1980).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Metabolic acidosis (pH 6.98) was reported in a 3-month-old infant who received 2 doses of amphotericin B deoxycholate 20 mg as 1-hour infusions instead of the prescribed liposomal amphotericin B formulation to be administered as 6-hour infusions (Groeneveld et al, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was reported after therapeutic doses of amphotericin B (Brandriss, 1964). Amphotericin B can severely depress erythropoieses (McKee, 1969) which may result in normochromic, normocytic anemia (Goodpasture et al, 1972), which is reversible.
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been associated with therapeutic doses of amphotericin B (Stein & Tolle, 1983).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia may occur after therapeutic doses of amphotericin B (Chan et al, 1982; Swanson & Cook, 1977).
    D) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 41-year-old woman developed disseminated intravascular coagulation, acute renal failure, and circulatory shock after inadvertently receiving several 300 mg (5 mg/kg) doses of amphotericin B deoxycholate instead of the prescribed liposomal formulation. Despite aggressive supportive measures, the patient died due to multi-organ failure. Concentrations of amphotericin B, measured in undiscarded blood samples obtained 5 and 18 hours after receiving the second 300 mg-dose of amphotericin B deoxycholate, were 7.0 and 5.3 mcg/mL (normal range 0.1 to 2.0 mcg/mL), respectively (Burke et al, 2006; Mohr et al, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash has been seen as a side effect with therapeutic doses (Lorber et al, 1976).
    B) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) REDMAN SYNDROME: Erythema of the hands, soles, face, and neck were reported, along with hand edema, in an 18-year-old man receiving amphotericin B 1 mg (Ellis & Tharpe, 1990).

Summary Of Exposure

    A) USES: Amphotericin B is an antifungal agent derived from the microorganism Streptomyces nodosus. Amphotericin B is utilized for the treatment of fungal infections.
    B) PHARMACOLOGY: Amphotericin B binds with ergosterol on fungal cytoplasmic membranes causing pores to leak, facilitating organelle death. Human cells are less affected because cell walls contain cholesterol instead of sterols.
    C) TOXICOLOGY: Amphotericin B is known to cause some degree of renal insufficiency. Distal renal tubule damage and altering blood flow and smooth muscle function are thought to be the etiology of renal dysfunction resulting in nephrocalcinosis. It is also thought that the vehicle for amphotericin B delivery, deoxycholate, may play a role in renal insufficiency. Although amphotericin B has a greater affinity for binding to the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell, thus resulting in cytotoxicity.
    D) EPIDEMIOLOGY: Poisoning is usually the result of dosing error. Notable poisoning is uncommon, but may cause significant morbidity and mortality.
    E) WITH THERAPEUTIC USE
    1) IV infusion has been implicated in phlebitis, arthralgias, myalgias, fever, rigors, headache, nausea, vomiting, diarrhea, anemia, thrombocytopenia, leukopenia, tinnitus, renal injury, hypotension, tachycardia, dyspnea, and peripheral neuropathy. Intrathecal administration has caused paresthesia, delirium, flaccid paralysis, and parkinsonism. Chest pain is a known side effect after infusion of amphotericin B liposomal formulations. Oral exposures can occur with topical formulations, or lozenges, but toxicity is limited. Dermatitis can also occur with topical exposure.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, bloody stool, fever, chills, hypokalemia, hyperkalemia, hypomagnesemia, increase in liver enzymes, and renal insufficiency.
    2) SEVERE TOXICITY: Disseminated intravascular coagulation, hypotension, dysrhythmias, renal failure, respiratory failure, and cardiac arrest.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgias and arthralgias are seen on therapeutic administration (Raymond, 1988).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis has occurred. A fatal reaction occurred in a 72-year-old man receiving a test dose (Murry, 1974).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) AMPHOTERICIN B LIPOSOME: Severe allergic reaction to the liposomal component of liposomal amphotericin B was reported in a 2.9-year-old girl with Hurler's syndrome who received an allogeneic cord blood stem cell transplant from an unrelated donor. She received conventional amphotericin B for 20 days without any reaction. More than 2 months later, she died of progressive respiratory and kidney failure. The authors suggest that the use of conventional amphotericin B is not contraindicated in the event of a previous allergic reaction to amphotericin B liposome (Cesaro et al, 1999).

Reproductive

    3.20.1) SUMMARY
    A) Amphotericin B is rated FDA Pregnancy Category B. No teratogenic or fertility effects have been reported in animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS, RATS: No fetal harm was reported in rabbits and rats administered doses up to 1.1 and 0.8 times the recommended human dose, respectively (Prod Info AMPHOTEC(R) IV injection, 2009; Prod Info AmBisome(R) intravenous injection, 2012; Prod Info ABELCET(R) intravenous injection, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Amphotericin B is rated FDA Pregnancy Category B (Prod Info AMPHOTEC(R) IV injection, 2009; Prod Info AmBisome(R) intravenous injection, 2012; Prod Info ABELCET(R) intravenous injection, 2013).
    2) Amphotericin B should only be used during pregnancy if the potential benefit to the mother outweighs the risk to the fetus (Prod Info AMPHOTEC(R) IV injection, 2009; Prod Info AmBisome(R) intravenous injection, 2012; Prod Info ABELCET(R) intravenous injection, 2013).
    B) LACK OF EFFECT
    1) The Collaborative Perinatal Project monitored over 50,000 mother-child pairs, 9 of which had first trimester exposure to amphotericin B (Briggs et al, 1998). Other studies have also reported amphotericin B use during various stages of pregnancy. No evidence of adverse fetal effects were reported in these studies.
    C) ANIMAL STUDIES
    1) RABBITS, RATS: No fetal harm was reported in rabbits and rats administered doses up to 1.1 and 0.8 times the recommended human dose, respectively (Prod Info AMPHOTEC(R) IV injection, 2009; Prod Info AmBisome(R) intravenous injection, 2012; Prod Info ABELCET(R) intravenous injection, 2013). However, higher rates of spontaneous abortions were reported in rabbits administered doses equivalent to 0.5 to 2 times the recommended human dose (Prod Info AmBisome(R) intravenous injection, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown if amphotericin B is excreted in human milk. Nursing mothers should discontinue either breastfeeding or amphotericin B treatment, while taking into account the importance of this drug to the patient (Prod Info AMPHOTEC(R) IV injection, 2009; Prod Info AmBisome(R) intravenous injection, 2012; Prod Info ABELCET(R) intravenous injection, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) DOGS, RATS: Ovarian and testicular histology was unaffected when dogs and rats were administered doses up to 0.4 and 0.5 times the recommended human dose, respectively, for 13 weeks (Prod Info AMPHOTEC(R) IV injection, 2009).
    2) RATS: No impact on fertility was observed in male and female rats administered doses up to 0.32 times the recommended human dose, based on body surface area (Prod Info ABELCET(R) intravenous injection, 2013). In a separate study, an abnormal estrous cycle (prolonged diestrus) and a decreased number of corpora lutea were observed in rats administered 10 mg/kg and 15 mg/kg doses (equivalent to human doses of 1.6 and 2.4 mg/kg, based on body surface area, respectively) (Prod Info AmBisome(R) intravenous injection, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, creatine phosphokinase, urinalysis, and creatinine clearance.
    D) Specific drug concentrations are not clinically useful, but can confirm overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, and creatine phosphokinase.
    2) Specific drug concentrations are not clinically useful, but can confirm overdose.
    4.1.3) URINE
    A) OTHER
    1) Twenty four hour urine for creatinine clearance.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.
    b) Institute continuous cardiac monitoring and obtain an ECG.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any symptomatic patient with a suspected or known significant overdose should be admitted to the ICU.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Most exposures will occur in a hospital setting, but small oral unintentional overdoses that are asymptomatic may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Nephrology should be consulted if acute renal failure develops. Consult a medical toxicologist or poison center for patients with significant overdose or severe toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any symptomatic patient or one with an intentional ingestion should be sent to the hospital and observed.

Monitoring

    A) Monitor vital signs.
    B) Institute continuous cardiac monitoring and obtain an ECG.
    C) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, creatine phosphokinase, urinalysis, and creatinine clearance.
    D) Specific drug concentrations are not clinically useful, but can confirm overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Significant toxicity has not been reported after ingestion. Gastrointestinal decontamination is generally not indicated.
    6.5.2) PREVENTION OF ABSORPTION
    A) Significant toxicity has not been reported after ingestion. Gastrointestinal decontamination is generally not indicated.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no specific antidote.
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Institute continuous cardiac monitoring and obtain an ECG.
    3) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, creatine phosphokinase, urinalysis, and creatinine clearance.
    4) Specific drug concentrations are not clinically useful, but can confirm overdose.
    C) TOXIC NEPHROPATHY
    1) SALT LOADING: Administration of sodium supplements during therapeutic administration of amphotericin B significantly reduced the incidence of nephrotoxicity. One liter of 0.9 percent sodium chloride was given daily to patients being given 40 milligrams/day of amphotericin (Heidemann et al, 1983; Branch et al, 1987; Branch, 1988; Anderson, 1995). The effectiveness of this method in overdose has not been examined.
    2) MANNITOL: Has also been recommended to reduce nephrotoxicity after therapeutic administration of amphotericin B. Only a small number of patients have been evaluated, some with positive results and some negative (Fuller & Hyneck, 1987). More research is required before this treatment can be recommended. This technique has not been tried in overdose.
    D) PHLEBITIS
    1) May occur with therapeutic doses of amphotericin B. Filtering with a 1 micrometer filter does not affect the incidence or severity of the phlebitis (Gotz et al, 1985).
    E) CHILL
    1) Shaking chills are often seen with therapeutic doses and are treated with:
    2) Meperidine, 50 to 70 milligrams per chill episode (Burke et al, 1980). Patients on chronic amphotericin may become addicted to meperidine (Cleary et al, 1988; Fincannon, 1988). Meperidine has also been used prophylactically to prevent chills (Oldfield et al, 1990).
    3) Dantrolene: In doses of 50 milligrams intravenously slowly has been recommended (Gross et al, 1986) but others have found it of little or no value (DaCamara, 1987)
    4) Other measures to control the chills, fever, and rigors of amphotericin have included acetaminophen, hydrocortisone, antihistamines, and phenothiazines. None of these have undergone controlled clinical trials to prove their efficacy (DaCamara, 1987).
    F) HYPOKALEMIA
    1) Administration of 5 milligrams of amiloride twice daily to 20 patients receiving amphotericin B reduced the amount of potassium wasting and resulted in higher plasma potassium as compared to patients not receiving the drug (Smith et al, 1988).
    2) Hypokalemia resolved without treatment in a premature infant exposed to a 50-fold overdose of amphotericin B over a 3-day period (Koren et al, 1990).
    G) INTRATHECAL INJECTION
    1) Intrathecal injection with amphotericin B has produced paresthesia, delirium, flaccid paralysis, and parkinsonism.
    2) POSITIONING: Keep the patient upright if possible to delay the flow of drug to the cisterna magnum (Blaney et al, 1995).
    3) CEREBROSPINAL FLUID DRAINAGE: Immediately remove at least 20 mL of CSF through a lumbar catheter. The optimal amount of CSF to remove is unknown. Adults have tolerated removal of 10 to 70 mL CSF after intrathecal methotrexate overdose (Gosselin & Isbister, 2005; Addiego et al, 1981).
    4) CSF EXCHANGE: Serial removal of 20 mL portions of CSF and replacement with corresponding volumes of warmed, preservative free normal saline or lactated ringers should be performed after CSF removal.
    5) Add fresh frozen plasma (25 mL FFP to 1 L NS or LR) or 5% albumin to the perfusate to enhance removal as amphotericin B is highly protein bound. (Addiego et al, 1981).
    H) EXPERIMENTAL THERAPY
    1) HYDROCORTISONE: A 2-year-old child survived cardiac complications after receiving an amphotericin B overdose of 4.6 mg/kg, instead of the prescribed 0.46 mg/kg, over a 2-hour period and who had been given IV hydrocortisone 10 mg and acetaminophen suppositories 120 mg prior to the amphotericin B infusion as standard protocol. Immediately following the amphotericin B infusion, the patient experienced one episode of vomiting, generalized seizures, and cardiac arrest, with a subsequent 15-second episode of asystole followed by bradycardia and conversion to a wide QRS complex tachycardia. With supportive care, including continuation of the hydrocortisone, the patient gradually recovered without sequelae. It is suggested that hydrocortisone therapy may decrease amphotericin B-induced cytokine expression resulting in decreased toxicity of amphotericin B, although further studies are warranted (Cleary et al, 1993).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move to fresh air and monitor for respiratory distress. Administer oxygen and treat with beta-2 agonists as needed.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) Irrigate copiously with tap water or normal saline.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Wash exposed skin with soap and water.

Enhanced Elimination

    A) EXCHANGE TRANSFUSION
    1) Amphotericin B is highly protein bound. Therefore, exchange transfusions in infants has been recommended as a treatment for overdose.
    2) A 2-volume exchange performed on a 5-month-old 7 kilogram child did not have a significant effect. The amphotericin B level dropped from 4.0 micrograms/milliliter, to 3.2 micrograms/milliliter. The level was 1.85 micrograms/milliliter after 48 hours (Brent et al, 1990).
    3) The observed apparent half-life (40.2 hours) calculated in the case above was within the range of the normal half-life for the distribution phase (Feldman, 1973; Louria, 1958). The plasma levels did not appear to be significantly altered.
    B) HEMODIALYSIS
    1) Hemodialysis for 4 to 6 hours does not appreciably change plasma concentrations or half-life (Block, 1974).
    C) PERITONEAL DIALYSIS
    1) Low to undetectable amphotericin B levels were measured in the peritoneal dialysate fluid of one patient with renal failure and disseminated cryptococcus neoformans. The patient received daily doses of 30 milligrams (Muther & Bennett, 1980).
    D) PLASMAPHERESIS
    1) CASE REPORT: A 60-year-old woman, with a suspected systemic fungal infection, inadvertently received IV amphotericin B deoxycholate 250 mg (4.3 mg/kg; usual dose 0.25 to 1 mg/kg) over a 2-hour period instead of the prescribed liposomal amphotericin B. Other than complaints of abdominal pain and a general feeling of malaise, the patient was asymptomatic. Her initial serum amphotericin concentration, obtained 33 hours post-overdose, was 4.9 mcg/mL (reference range 1.2 to 2.4 mcg/mL). After receiving an initial course of plasmapheresis approximately 36 hours post-overdose, her serum amphotericin concentration had decreased to less than 2 mcg/mL. Over the next 4 days , the patient received plasmapheresis daily (a total of 5 sessions) and 3 hemodialysis sessions. Two days following the overdose, the patient's serum creatinine level peaked at 2.9 mg/dL, but decreased after the first hemodialysis session and normalized 5 days post-overdose. The patient continued to remain hemodynamically stable throughout her course of therapy and was discharged home on hospital day 16 (Wang et al, 2013).

Abstracts

Case Reports

    A) INFANT
    1) Five infants receiving doses of 2.5 to 8 mg/kg developed no permanent sequelae (Brent et al, 1990).
    2) A 21-day-old baby received 2.5 mg/kg during a 5-hour infusion. No changes in BUN, serum creatinine, or serum sodium were noted (Personal Communication, 1988).
    3) A 3-kg neonate received 24 to 25 mg as an initial dose instead of the 1 mg which had been ordered. The patient experienced no symptoms and therapy was reinstituted 5 days later (Personal Communication, 1988).
    4) An 8-week-old received 14 mg instead of the 1.4 mg ordered. Abdominal distension, bloody diarrhea and a decrease in platelets from 163,000 to 43,000 in 12 hours was observed (Personal Communication, 1988).
    B) ADULT
    1) A 21-year-old comatose woman was administered 200 mg intravenously over a four hour period. Fever and chills were the only symptoms seen with amphotericin restarted 1 week later (Personal Communication, 1988).
    2) A patient received 25 mg in 250 mL of infusion instead of 5 mg in 500 mL. The patient was without symptoms 24 hours post infusion (Personal Communication, 1988).
    C) PEDIATRIC
    1) A 5-year-old boy received 3 mg/kg on his first day of therapy and experienced nausea and vomiting. No changes in renal function, were noted, but a bone scan on the following day revealed an increased uptake in the kidneys characteristic of a post-ischemic state (Personal Communication, 1988).

Range Of Toxicity

Summary

    A) TOXIC DOSE: No specific toxic dose is known. Minimum lethal exposure has not been established. Dysrhythmias and cardiac arrest have occurred in pediatric patients following doses of approximately 4 to 41 mg/kg of amphotericin B.
    B) THERAPEUTIC DOSE: ADULT: AMPHOTERICIN B: IV, 0.25 to 0.3 mg/kg/day initially, up to 0.5 to 0.7 mg/kg/day, depending on cardio-renal status; intrathecal, 0.1 to 1.5 mg per dose at intervals ranging from daily to weekly, starting with a low dose and titrating up as tolerated. AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX: 3 to 4 mg/kg/day IV infusion at a rate of 1 mg/kg/hr. AMPHOTERICIN B LIPID COMPLEX: 5 mg/kg/day IV infusion at a rate of 2.5 mg/kg/hr. AMPHOTERICIN B LIPOSOME: 3 to 5 mg/kg/day IV infusion over a period of 2 hours. PEDIATRIC: AMPHOTERICIN B: 0.5 to 1 mg/kg/day IV depending on infection. AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX: 3 to 4 mg/kg/day IV infusion at a rate of 1 mg/kg/hr. AMPHOTERICIN B LIPID COMPLEX: 3 to 6 mg/kg/day IV depending on infection. AMPHOTERICIN B LIPOSOME: 3 to 5 mg/kg/day IV infusion over a period of 2 hours.

Therapeutic Dose

    7.2.1) ADULT
    A) AMPHOTERICIN B
    1) TEST DOSE: An intravenous test dose of 1 mg is dissolved in 20 mL of 5% dextrose by slow infusion (over 20 to 30 minutes) to test for anaphylactic reactions; monitor temperature, pulse rate, blood pressure, and respiratory rate every 30 minutes for 2 to 4 hours. The next dose is determined by the severity of the reaction (Prod Info FUNGIZONE(R) IV injection, 2009).
    2) IV: Initially, in patients with good cardio-renal function and well-tolerated test dose, 0.25 to 0.3 mg/kg IV daily, depending on severity of fungal infection. For patients with poor cardio-renal function or a severe reaction to the test dose, initial therapy daily doses are smaller (ie, 5 or 10 mg). Maintenance doses are 0.5 to 0.7 mg/kg/day, depending on cardio-renal function (Prod Info FUNGIZONE(R) IV injection, 2009).
    3) INTRATHECAL: The recommended intrathecal dose of amphotericin B for coccidioidal meningitis is 0.1 to 1.5 mg per dose at intervals ranging from daily to weekly, starting with a low dose and titrating up until the appearance of patient intolerance (severe vomiting, prostration, or transient dose-related mental status) (Galgiani et al, 2005).
    4) AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX
    a) The recommended dose is 3 to 4 mg/kg/day administered as an IV infusion at a rate of 1 mg/kg/hour. A test dose is recommended prior to administration of the first dose. Infuse approximately 10 mL of the final reconstituted solution containing 1.6 to 8.3 mg of amphotericin B over 15 to 30 minutes and monitor the patient for 30 minutes following infusion (Prod Info AMPHOTEC(R) IV injection, 2009).
    1) A test dose is recommended prior to administration of the first therapy dose. Infuse approximately 10 mL of the final reconstituted solution containing 1.6 to 8.3 mg of amphotericin B over a 15- to 30- minute period and monitor the patient for an additional 30 minutes following the infusion (Prod Info AMPHOTEC(R) IV injection, 2009).
    5) AMPHOTERICIN B LIPID COMPLEX
    a) The recommended dose is 5 mg/kg/day administered as an IV infusion at a rate of 2.5 mg/kg/hour (Prod Info ABELCET(R) IV injection, 2009).
    6) AMPHOTERICIN B LIPOSOME
    a) The recommended dose is 3 to 5 mg/kg/day, depending on the type of infection, administered as an IV infusion over a period of 2 hours (Prod Info AmBisome(R) intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) NEONATE/AMPHOTERICIN B
    1) INTRAVENOUS
    a) SYSTEMIC FUNGAL INFECTIONS: 1 mg/kg/day IV (Chapman et al, 2008; Wheat et al, 2007)
    2) INTRATHECAL
    a) SEVERE FUNGAL INFECTIONS OF THE CNS: Neonatal doses have ranged from 0.5 milligram/day in 2 milliliters of 5% dextrose to 0.6 milligram/day in 0.5 milliliter of 5% dextrose. Total doses were 0.15 milligram to 8.6 milligrams (Adler et al, 1972; Klein et al, 1972). Doses of 0.125 to 0.25 milligram have been administered to children via an Ommaya reservoir (Graybill & Ellenbogen, 1973).
    B) CHILDREN
    1) AMPHOTERICIN B
    a) BLASTOMYCOSIS, SEVERE DISEASE: 0.7 to 1 mg/kg IV once daily for 1 to 2 weeks, followed by step-down therapy with oral itraconazole 10 mg/kg/day (maximum 400 mg/day) orally in 2 divided doses for a total of 12 months (Chapman et al, 2008).
    b) CANDIDIASIS, INVASIVE: 0.5 to 1 mg/kg IV once daily (Pappas et al, 2009).
    c) CRYPTOCOCCOSIS: 1 mg/kg IV daily plus flucytosine 25 mg/kg orally four times daily for a minimum of 2 weeks, followed by fluconazole 10 to 12 mg/kg orally daily for 8 weeks as consolidation therapy (Perfect et al, 2010; Grant & Junker, 2005).
    d) FEBRILE NEUTROPENIA, EMPIRIC TREATMENT: 0.6 to 1.2 mg/kg IV once daily (Walsh et al, 1999; White et al, 1998).
    e) HISTOPLASMOSIS, MODERATELY SEVERE TO SEVERE ACUTE PULMONARY: 1 mg/kg IV once daily for 1 to 2 weeks, followed by stepdown therapy with itraconazole 5 to 10 mg/kg/day (maximum 400 mg/day) orally in 2 divided doses for a total of 12 weeks (Wheat et al, 2007).
    f) PROGRESSIVE DISSEMINATED HISTOPLASMOSIS: 1 mg/kg IV once daily for 4 to 6 weeks (preferred therapy) (Wheat et al, 2007). 1 mg/kg IV once daily for 2 to 4 weeks, followed by stepdown therapy with itraconazole 5 to 10 mg/kg/day (maximum 400 mg/day) orally in 2 divided doses to complete 3 months of therapy (alternative therapy)(Wheat et al, 2007).
    g) SPOROTRICHOSIS, DISSEMINATED: 0.7 mg/kg IV once daily as initial therapy, followed by step-down therapy with itraconazole 6 to 10 mg/kg/day (maximum 400 mg/day) orally in 2 divided doses for a total of 12 months (Kauffman et al, 2007).
    2) AMPHOTERICIN CHOLESTERYL SULFATE COMPLEX
    a) The recommended dose is 3 to 4 mg/kg/day administered as an IV infusion at a rate of 1 mg/kg/hour (Prod Info AMPHOTEC(R) IV injection, 2009).
    1) A test dose is recommended prior to administration of the first therapy dose. Infuse approximately 10 mL of the final reconstituted solution containing 1.6 to 8.3 mg of amphotericin B over a 15- to 30- minute period and monitor the patient for an additional 30 minutes following the infusion (Prod Info AMPHOTEC(R) IV injection, 2009).
    3) AMPHOTERICIN B LIPID COMPLEX
    a) BLASTOMYCOSIS, SEVERE DISEASE: 3 to 5 mg/kg IV once daily for 1 to 2 weeks, followed by stepdown therapy with oral itraconazole 10 mg/kg/day( maximum dose of 400 mg/day) orally in 2 divided doses for a total of 12 months (Chapman et al, 2008)
    b) MENINGITIS: 4 to 6 mg/kg IV once daily, in combination with flucytosine 25 mg/kg orally four times daily (preferred), followed by fluconazole 6 to 12 mg/kg orally daily for 8 weeks as consolidation therapy (Perfect et al, 2010; Centers for Disease Control and Prevention et al, 2009)
    c) DISSEMINATED DISEASE (CNS NOT INVOLVED) OR SEVERE PULMONARY DISEASE: 5 mg/kg IV once daily with or without flucytosine (primary therapy) (Perfect et al, 2010; Centers for Disease Control and Prevention et al, 2009).
    d) HISTOPLASMOSIS, PROGRESSIVE DISSEMINATED HISTOPLOASMOSIS (INTOLERANT TO CONVENTIONAL AMPHOTERICIN B): 3 to 5 mg/kg IV once daily for 4 to 6 weeks (Wheat et al, 2007)
    e) SYSTEMIC FUNGAL INFECTIONS (ASPERGILLOSIS, CANDIDIASIS), INCLUDING HIV-INFECTED CHILDREN: 5 mg/kg IV once daily (Prod Info ABELCET(R) IV injection, 2009; Centers for Disease Control and Prevention et al, 2009; Wiley et al, 2005);(Walsh et al, 1999a)
    4) AMPHOTERICIN B LIPOSOME
    a) 1 MONTH TO 16 YEARS: The recommended dose is 3 to 5 mg/kg/day, depending on the type of infection, administered as an IV infusion over a period of 2 hours (Prod Info AmBisome(R) intravenous injection, 2012).
    b) LESS THAN 1 MONTH: Safety and efficacy have not been established in pediatric patients less than 1-month-old (Prod Info AmBisome(R) intravenous injection, 2012).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) A specific minimum lethal dose has not been established.
    B) PEDIATRIC
    1) CASE REPORTS: Two preterm infants (30-week and 25-week) developed acute bradycardia and respiratory insufficiency resulting in clinical deterioration and subsequent death after receiving a course of amphotericin B therapy to treat candidal infections at a concentration of 5 mg/mL instead of the desired administration concentration of 0.1 mg/mL (a 50-fold overdose) (Perlman et al, 1991).
    2) CASE SERIES: 4 pediatric patients (2 children ages 7-years-old and 3.5-years-old, and 2 infants ages 4.5 weeks and 7 weeks) developed cardiac arrest, unresponsive to resuscitative efforts, after receiving amphotericin B overdoses, in doses ranging from 3.8 to 40.8 mg/kg (Cleary et al, 1993).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) A 50-milligram dose was given in a 6 hour infusion without serious adverse effects (Personal Communication, 1988)
    B) ADULT
    1) CASE REPORT: A 60-year-old woman, with a suspected systemic fungal infection, inadvertently received IV amphotericin B deoxycholate 250 mg (4.3 mg/kg; usual dose 0.25 to 1 mg/kg) over a 2-hour period instead of the prescribed liposomal amphotericin B. Other than complaints of abdominal pain and a general feeling of malaise, the patient was asymptomatic. Her initial serum amphotericin concentration, obtained 33 hours post-overdose, was 4.9 mcg/mL (reference range 1.2 to 2.4 mcg/mL). Her serum creatinine level peaked at 2.9 mg/dL approximately 2 days post-overdose. After receiving a total of 5 plasmapheresis sessions and 3 hemodialysis sessions, the patient's serum amphotericin B concentration decreased to less than 1 mcg/mL and her serum creatinine level normalized. The patient continued to remain hemodynamically stable throughout her course of therapy and was discharged home on hospital day 16 (Wang et al, 2013).
    C) PEDIATRIC
    1) CASE REPORT: An 8-week-old baby received 14 milligrams and developed abdominal distension, bloody diarrhea and a fall in platelets from 163,000 to 43,000/microliter (Personal Communication, 1988).
    2) CASE REPORT: A premature infant received a total dose of 15 milligrams/kilogram over a 3-day period without serious adverse effects (Koren et al, 1990).
    3) CASE REPORT: A 2-year-old boy survived after receiving an amphotericin B overdose of 4.6 mg/kg over a 2-hour period and immediately developing one episode of vomiting, generalized seizures, and cardiac arrest, with a subsequent 15-second episode of asystole followed by bradycardia and conversion to a wide QRS complex tachycardia. With intensive supportive care, the patient gradually recovered without sequelae (Cleary et al, 1993).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Toxic levels are unknown. Peak serum concentration of less than 2 micrograms/milliliter occurred more than 10 days after a 50-fold overdose in a premature infant (Koren et al, 1990).
    b) Serum concentrations are not directly proportional to dose and tend to plateau at doses exceeding 50 milligrams. With usual doses, trough concentrations on alternate day or daily administration schedules are not significantly different.
    c) Peak serum concentrations are generally higher on alternate day schedules. Serum concentrations are reported to represent less than 10 percent of the administered dose (Bindschadler & Bennett, 1969).
    d) Susceptible fungi are usually inhibited or killed by less than 10 micrograms/milliliter serum concentrations (Anderson, 1976).
    e) CASE REPORT: A 41-year-old woman developed multi-organ failure and subsequently died after receiving several 300-mg (5 mg/kg) doses of amphotericin B deoxycholate (a non-lipid formulation) instead of the prescribed liposomal formulation. Concentrations of amphotericin B, measured in undiscarded blood samples obtained 5 and 18 hours after receiving the second 300 mg-dose of amphotericin B deoxycholate, were 7.0 and 5.3 mcg/mL (normal range 0.1 to 2.0 mcg/mL), respectively (Mohr et al, 2005).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) >5 gm/kg (RTECS, 2006)
    2) LD50- (ORAL)MOUSE:
    a) >8 gm/kg (RTECS, 2006)
    3) LD50- (INTRAMUSCULAR)RAT:
    a) >5 gm/kg (RTECS, 2006)
    4) LD50- (ORAL)RAT:
    a) >5 gm/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Amphotericin B is fungistatic or fungicidal, depending on the concentration achieved and the susceptibility of the organism to amphotericin B. Amphotericin B acts by binding to sterols in the fungus cell membrane, producing a change in membrane permeability that allows leakage of intracellular components from the cell (Prod Info FUNGIZONE(R) IV injection, 2009). Although amphotericin B has a greater affinity for binding to the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell, thus resulting in cytotoxicity (Prod Info AmBisome(R) intravenous injection, 2012).

Physicochemical

Physical Characteristics

    A) Amphotericin B is a sterile, nonpyrogenic, lyophilized cake (which may partially reduce to powder). Crystalline amphotericin B is insoluble in water, but the solubility is increased by the addition of sodium desoxycholate in the final product (Prod Info amphotericin B intravenous injection lyophilized powder for solution, 2009).

Molecular Weight

    A) 924.09 (Prod Info amphotericin B intravenous injection lyophilized powder for solution, 2009)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Administering amphotericin B to dogs via 6 alternate day rapid boluses (1 mg/kg in 25 mL of D5W) caused more renal lesions and side effects than administering the same dose in 1 liter of D5W over 5 hours (Rubin et al, 1989).

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