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Drug dosage identifier

Amphotericin B Deoxycholate

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Dose and administration

Intravenous1

1 mg/kg/dose every 24 hours (Maximum 1.5 mg/ kg/ dose if given on alternate days)

Note:  Approval from Infectious Diseases (ID) Team is required before starting amphotericin.
Dosing interval to be reviewed at 7 - 10 days after start of treatment
Dosing adjustments for toxicity to be discussed with ID Team
  1. Administer the first dose over 4 hours or more, then if tolerated administer subsequent doses over 1 - 2 hours or more (the exact time may vary using a drug library on pump so ensure the full dose is given).
  2. Use the first 30 minutes of the first dose as a "test dose" to observe for adverse reactions
  3. Incremental treatment is inappropriate.
  4. Amphotericin must be used under close clinical supervision. Toxicity occurs commonly - see Adverse Effects and Monitoring ("Special Considerations")
  5. May need to treat for 4-6 weeks.

Indications

  1. Systemic candidiasis.
  2. Congenital candidiasis.
  3. Other systemic fungal infections.
  4. For all indications, ID Team approval is required prior to starting therapy.

Contraindications and precautions

  1. Hypersensitivity to amphotericin B.
  2. Minor, superficial fungal infections.
  3. Caution in preterm infants, especially extreme immaturity.

Clinical pharmacology

Amphotericin B is a polyene antifungal antibiotic that is active against a wide range of yeasts and yeast-like fungi including Candida albicans. The mechanism of action depends on its binding to a sterol moiety, ergosterol, present in the membrane of sensitive fungi. May be fungicidal or fungistatic, depending on the drug concentration obtained and the sensitivity of the fungus.

Absorption from the gastrointestinal tract is negligible, even with very large doses. After IV administration only a small percentage of the drug remains in the plasma compartment. High binding (> 90%) to human plasma protein. CSF concentrations of amphotericin B are only 2-4% of the serum concentrations. Drug may accumulate in tissues to a significant concentration and be excreted renally for months.

Dosage schedules for amphotericin B have been devised following observations of toxicity with large doses and other clinical experiences. No objective data exists regarding the appropriate length of therapy required, although most infants have been treated for an average of 40 days (range 14-70 days). Amphotericin is frequently used in combination with flucytosine.

Possible adverse effects

Amphotericin B deoxycholate is rarely used in children and adults due to toxicity, but neonates seem to tolerate this drug better with fewer side effects. However any neonate receiving this drug still needs close monitoring for adverse effects.

  1. Cardiotoxicity - more common with rapid infusion rates or high doses
  2. Nephrotoxicity - assess sodium status and correct deficiency at start of and during treatment if necessary. Ensure adequate hydration.
  3. Hypokalaemia and hypomagnesaemia - monitor both electrolytes, especially potassium, and correct deficiencies.
  4. Abnormal liver function tests (stop therapy) and hyperbilirubinaemia.
  5. Anaphylaxis
  6. Anaemia
  7. Venous irritation, pain and thrombophlebitis at injection site. Extravasation may cause tissue damage.
  8. Fever, vomiting, hypotension. For other adverse effects contact the ward pharmacist.

Interactions

  1. Loop diuretics (eg. frusemide), and thiazide diuretics - potential for hypokalemia.
  2. Nephrotoxic drugs eg. Gentamicin, amikacin, vancomycin, frusemide - renal toxicity risk.
  3. Digoxin - digitalis toxicity with hypokalaemia.
  4. Flucytosine - synergistic effect and risk of flucytosine toxicity. (Monitor flucytosine levels).

Special considerations

  1. Amphotericin B should be used primarily for treatment of infants with progressive and potentially fatal fungal infections.
  2. Concommitant administration of sodium chloride at 4 mmol/kg/day reduces the risk of nephrotoxicity3.

Monitor

  • Observe for adverse reactions during first 30 minutes of administration eg. cardiotoxicity.
  • Potassium, magnesium, sodium - correct deficiencies
  • Renal function - if deteriorating, discuss dosing dose regimen adjustments with ID Team, although adjustment rarely required.
  • Liver function - stop therapy if abnormal.
  • Full blood count
  • Fluid balance

Management of Amphotericin administration

Description

  • Supplied from Pharmacy as single-use syringes. Notify Ward Pharmacist (ph: 29609) early in the day to arrange the manufacture of these syringes. These will take several hours to prepare.
  • If required after hours contact the On-Call Pharmacist through the Duty Manager. Discuss with Neonatologist first. Emphasise to Pharmacy that Amphotericin deoxycholate (conventional amphotericin) is required from Biomed. The Biomed service is only available until 8pm daily, so the amphotericin charts must be sent to Pharmacy early in the day.
  • Amphotericin at 0.1 mg/mL (1 mg/10mL) is 256 mOsm/kg and pH 5.7

Prescription

Dose of drug is charted in mg/dose on Regular section of prescription chart.

Administration

Slow IV Infusion

  • Pre-prepared syringes from Pharmacy: The supplied syringe is ready to prime through the extension tubing. Do NOT filter through a 0.22micron filter. The solution in the syringes will have been filtered by Pharmacy in the preparation process.
  • Preferably administer via a central line. Can be administered peripherally but may cause pain at infusion site with thrombophlebitis.
  • Administer first dose over 4 hours. For first 30 minutes observe baby closely for adverse reactions. Monitor ECG and B.P. If no adverse reactions observed continue remainder of first dose over remaining 3.5 hours and monitor for adverse reactions.
  • Second and subsequent doses, administer over 1 - 2 hours if tolerated.
  • Compatible with glucose 5 % and 10%. Do NOT mix with any other drug, IV solution, blood or blood products. A separate cannula is usually inserted for administration of amphotericin.
  • Flush cannula with glucose 5% before and after administration of amphotericin
  • Not compatible with lipid, sodium chloride, amikacin, calcium gluconate, dopamine, dobutamine, gentamicin, heparin, meropenem, potassium chloride, sodium bicarbonate, vancomycin.
  • Protect from light during administration.

Nursing considerations

  • Ensure patient is adequately hydrated before and during therapy.
  • Obtain baseline FBC, serum electrolytes, renal and liver function tests. Repeat these measurements regularly during therapy
  • Observe for adverse effects during the first 30 minutes of administration - especially for cardiotoxicity.
  • Monitor and document vital signs including blood pressure and fluid balance. See instructions to "Monitor" under Special Considerations.
  • Assess IV site carefully before and during infusion of amphotericin.
  • Observe for signs of adverse effects.

Storage

Syringes are single use only. Store in the fridge

References

  1. Bradley JS, Nelson JD (eds.). Nelson's Pediatric Antimicrobial Therapy (20th ed.). 2014.
  2. Brayfield A (ed). Martindale: The Complete Drug Reference (38th ed.). London: Pharmaceutical Press, 2014.
  3. Paediatric Injectable Guidelines (4th ed.). Melbourne: The Royal Children's Hospital, 2011.
  4. McEvoy G (ed). Handbook on Injectable Drugs (18th ed.). Bethesda: American Society of Health-System Pharmacists , Inc., 2015.
  5. X-Gen Amphotericin B data sheet. New York: X-Gen Pharmaceuticals, 2010

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Document Control

  • Date last published: 30 June 2015
  • Document type: Drug Dosage Guideline
  • Services responsible: ADHB Pharmacy, Neonatology, Paediatric Infectious Diseases
  • Editor: Sarah Bellhouse
  • Review frequency: 2 years