Uses and safety of acyclovir in pregnancy

Journal of Family Practice, Feb, 1994 by John G. Spangler, Julienne K. Kirk, Mark P. Knudson

Kingsley[5] reported data on 116 pregnant patients who were exposed to acyclovir in the first, second, and third trimester. In 18 of the 116 neonates, the concentrations of acyclovir in cord blood ranged from [less than] 0.5 to 1.23 [mu]mol/L, and 14 samples of amniotic fluid contained between 0.5 and 5.58 [mu]mol/L of acyclovir. In one study, five pregnant patients at term who received acyclovir 200 mg orally every 8 hours had peak maternal plasma concentrations of 2.5 [mu]mol/L approximately 1.5 hours after the dose.[6] In the same report, the drug was noted to be highly concentrated in amniotic fluid and gastric aspirate but not in fetal blood.

In comparison to healthy nonpregnant patients receiving acyclovir, mean peak plasma concentrations following 200 mg orally in pregnant patients are lower[7] and usually occurred within 1.5 to 2.5 hours following administration. Possible reasons for differences in peak concentrations found between pregnant and nonpregnant individuals include an increased volume of distribution and changes in renal clearance of the drug during pregnancy.

Teratogenicity

As an FDA category "C" drug, human data on acyclovir are incomplete, but potential benefits of drugs in this category may justify potential risks. Although no adequate and well-controlled studies have been conducted in pregnant women using acyclovir, it has not proved to be teratogenic in laboratory animals. Data among pregnant rabbits and rats given subcutaneous injections of 15, 25, and 50 mg/kg/d of acyclovir showed neither embryotoxicity nor increased risk of fetal malformations.[8] When acyclovir was administered by gavage to mice in doses up to 450 mg/kg/d (30 times human therapeutic doses), no adverse effects of toxicity appeared in reproduction or development over two generations.[8] The effect of acyclovir on mammalian embryonic development in cell culture showed that even extremely large doses did not result in individual gene damage.[9] Chromosomal damage in cultured human lymphocytes has been reported at acyclovir concentrations 25 times higher than peak levels (1100 [mu]mol/L or 250 [mu]g/mL administered intravenously).[6]

Because of the lack of prospective data on pregnancy and acyclovir, the Burroughs Wellcome Company and the Centers for Disease Control and Prevention have established the Acyclovir in Pregnancy Registry to evaluate reported cases of gestational exposure to the drug. The address for this service is: Acyclovir in Pregnancy Registry, Division of Epidemiology, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709; phone: 1-800-722-9292, ext. 8465.

Acute Toxicity

Oral acyclovir is generally well tolerated, but serious adverse effects, including crystallization within the renal tubules, have been reported when the drug is administered intravenously. This nephrotoxicity, which is thought to be cause by the precipitation of acyclovir in the nephron, occurs in less than 5% of hospitalized patients when the drug is administered intravenously.[10] Such crystallization can result in obstructive nephropathy that can lead to renal failure and anuria and may be manifested by increases in serum blood urea nitrogen (BUN) and creatinine levels. Renal insufficiency usually is completely reversible with discontinuation of acyclovir. However, if acute renal failure and anuria occur, dialysis should be considered to enhance elimination of the drug. Because of the potential of renal toxicity, the drug should be administered over 1 hour, patients should be well hydrated during intravenous therapy, a urine volume of at least 500 mL per 24 hours should be maintained, and the BUN and creatinine levels monitored closely.[11] There has been one case report of nephrotoxicity with high-dose oral acyclovir (800 mg 5 times a day) in a patient also on propoxyphene,[12] but there have been no reports of increased renal toxicity in pregnant patients receiving either form of the drug.