Ganciclovir
Risk Factor: CM
Class: ANTI-INFECTIVES
/ Antivirals
Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers
Fetal Risk Summary
Ganciclovir, a synthetic nucleoside analogue that inhibits replication of herpes viruses, is used in the treatment of cytomegalovirus (CMV) retinitis and other viral infections.
The drug is embryotoxic in mice and rabbits, causing fetal resorption in at least 85% of animals exposed to 2 times the human dose based on area under the plasma concentration curve (HD) (1). Month-old male offspring of female mice administered 1.7 times HD before and during gestation and during lactation had hypoplastic testes and seminal vesicles and pathologic changes in the nonglandular region of the stomach (1). In pregnant rabbits given doses 2 times the HD, fetal effects included growth retardation and teratogenicity (cleft palate, anophthalmia/microphthalmia, aplastic kidneys and pancreas, hydrocephaly, and brachygnathia).
Ganciclovir is both carcinogenic and mutagenic in mice (1). Moreover, inhibition of spermatogenesis has been observed in mice and dogs. One study using cultured fetal rat hepatocytes, however, found little or no toxic effects, in terms of cell growth and cell membrane permeability, of high concentrations (0.530 g/mL) of ganciclovir (2).
Passage of ganciclovir across the perfused human placenta has been reported (2,3). In a 1993 report, ganciclovir was found initially to concentrate at the maternal placental surface and then to cross passively, without metabolism, to the fetus (2). In a second study, ganciclovir and acyclovir were discovered to cross the placenta in approximately similar amounts by simple diffusion (3).
Only two reports have been located that describe the use of ganciclovir during human pregnancy (4,5). In the first case, a 31-year-old woman received a renal transplant approximately 3 weeks after her last menstrual period (LMP) (8 and 10 days after unprotected intercourse) (4). Medications related to maintaining the transplant included methylprednisolone tapered to prednisone, azathioprine, and cyclosporine. Other drugs added shortly after surgery were trimethoprim, nifedipine and acyclovir. Her worsening hypertension was controlled with nifedipine. Six weeks after surgery (9 weeks after her LMP), she developed CMV infection that was treated with IV ganciclovir (2.5 mg/kg twice daily) for 2 weeks and a single dose of IV CMV hyperimmune globulin. CMV cultures were negative after treatment and remained so throughout the reminder of the pregnancy. A normal 2640-g male infant was born at 38 weeks' gestation with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. Placental villitis consistent with CMV was noted and the infant had a positive CMV urine culture, but he remained healthy and was developing normally at 18 months of age (4).
The second case involved a 29-year-old CMV negative woman who had received a CMV positive liver transplant. She became pregnant 5 months after the transplant (5). She received ganciclovir (1-g orally three times daily), tacrolimus, and prednisone before conception and throughout the 1st trimester. Ganciclovir was discontinued when pregnancy was diagnosed at 3 months gestation. Steroid-induced hyperglycemia was not observed, but worsening preeclampsia and fetal distress resulted in delivery at 30 weeks' gestation of a 790-g female infant with Apgar scores of 4 and 7 at 1 and 5 minutes, respectively. No malformations were observed and, except for her small size and mild respiratory problems, she did well and was discharged home on day 50 of life. The author also mentioned three other, unpublished, ganciclovir-treated pregnancies that had been reported to the manufacturer. One patient had been lost to follow-up, one had been treated with IV ganciclovir during the last 4 weeks of pregnancy, and one had been treated with oral ganciclovir from 14 to 18 weeks' gestation. The two pregnancies with known outcomes resulted in normal infants (5).
CMV is the most common cause of congenital viral infection in the United States, infecting 0.2%2.2% of all liveborn infants (6). Approximately 40% of primary CMV infections occurring during pregnancy will result in transplacental passage of the virus to the fetus (6). A relatively small percentage of these infants, however, will exhibit structural damage, such as symmetric growth retardation, hepatosplenomegaly, chorioretinitis, microphthalmia, cerebral calcification, hydrocephaly, and microcephaly. Some infants who have been infected in utero will develop later toxicity as evidenced by deafness (CMV is the leading cause of congenital hearing loss), mental retardation, and impaired psychomotor development (6). The effectiveness of ganciclovir in preventing or ameliorating these effects is unknown. Only five cases of its use in human pregnancy are known, but no adverse effects attributable to ganciclovir were apparent in the four cases with outcome details, although one infant had a positive CMV urine culture without signs or symptoms of infection. Long term evaluation of the four exposed infants for late appearing toxicity, however, has not been reported. Because of the potential for fetal toxicity and the known toxic effects in animals, some investigators have recommended that ganciclovir should only be used during pregnancy for life-threatening disease or in immunocompromised patients with major cytomegalovirus infections, such as retinitis (1,3,7). Currently, the only approved indications for ganciclovir are for the treatment of CMV retinitis or prevention of CMV disease in immunocompromised patients or in solid organ transplant recipients (1).
Breast Feeding Summary
No reports describing the use of ganciclovir during lactation have been located. Because of the potential for serious toxicity in a nursing infant, mothers taking ganciclovir should probably not breast-feed. The pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections has been reported (8).
References
- Product information. Cytovene. Roche Laboratories, 2001.
- Henderson GI, Hu ZQ, Yang Y, Perez TB, Devi BG, Frosto TA, Schenker S. Ganciclovir transfer by human placenta and its effects on rat fetal cells. Am J Med Sci 1993;306:1516.
- Gilstrap LC, Bawdon RE, Roberts SW, Sobhi S. The transfer of the nucleoside analog ganciclovir across the perfused human placenta. Am J Obstet Gynecol 1994;170:96773.
- Miller BW, Howard TK, Goss JA, Mostello DJ, Holcomb WL Jr, Brennan DC. Renal transplantation one week after conception. Transplantation 1995;60:13534.
- Pescovitz MD. Absence of teratogenicity of oral ganciclovir used during early pregnancy in a liver transplant recipient. Transplantation 1999;67:7589.
- American College of Obstetricians and Gynecologists. Perinatal viral and parasitic infections. ACOG Practice Bulletin. No. 20, September 2000.
- DeArmond B. Safety considerations in the use of ganciclovir in immunocompromised patients. Transplant Proc 1991;23(Suppl 1):269.
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Trang JM, Kidd L, Gruber W, Storch G, Demmler G, Jacobs R, Dankner W, Starr S, Pass R, Stagno S, Alford C, Soong S-J, Whitley RJ, Sommadossi J-P, and the NIAID Collaborative Antiviral Study Group. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. Clin Pharmacol Ther 1993;53:1521.
Questions and Answers
why does viral THYMIDINE kinase phosphorylate the GUANINE nuceloside analogues ganciclovir and aciclovir?, two different bases with very different structure!!! i don't understand why these molecules which look like G act on the viral T-kinase. thank you!
The name of the enzyme is a bit of a misnomer since it can work on other nucleosides than thymidine (thymidine happens to be the best substrate), i.e. the enzyme is non-specific as to substrate. This is in contrast to the host cell thymidine kinase which is very specific to thymidine since the cell has other enzymes to phosphorylate the other nucleosides. This lack of specificity of the viral enzyme allows it also to work on nucleoside-analog drugs and phosphorylate them. The host enzyme, because of its greater specificity, is much less good at this (and often does not phosphorylate the drug at all).
what criteria is needed to stop the eye injection - gancyclovir/ganciclovir?,
you mean intravitreal injection ?
do you have endophthalmitis ?
I have a transplant kidny my CMV test is positive .I use ganciclovir for 14 days.please help me know about it?,
put this info in a search engine and find out from a medical site, not us
