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Valganciclovir

Classification: C

Drug products: Valcyte, Valganciclovir 2care4, Valganciclovir Accord, Valganciclovir Bluefish, Valganciclovir Medical Valley, Valganciclovir Orion, Valganciclovir Sandoz, Valganciclovir Teva, Valganciklovir Ebb

ATC code: J05AB14

Substances: valganciclovir, valganciclovir hydrochloride

Summary

No prospective, controlled studies investigating gender differences of valganciclovir treatment efficacy have been identified. Cytomegalovirus disease seems to be more common in women after solid-organ transplantation followed by antiviral prophylaxis with ganciclovir or valganciclovir. It should be noted that valganciclovir has been associated with teratogenic effects and decreased sperm density and motility during and up to six months after discontinued treatment with valganciclovir in men. Effective contraception is thus recommended for both men and women treated with (val)ganciclovir. For men, effective contraception needs to continue at least six months after discontinued (val)ganciclovir treatment.

Additional information

Pharmacokinetics and dosing

Valganciklovir is a prodrug, which is rapidly metabolized to ganciclovir upon systemic absorption. A prospective, observational study (45 men, 20 women) sought to characterize the population pharmacokinetic profile of ganciclovir administered in the form of oral valganciclovir to solid organ transplant recipients [1]. The central volume of distribution of ganciclovir was found to be almost 40% lower in women. After correcting for their lower body weight, a difference of about 20% remained and was attributed to sex as an independent covariate. Furthermore, the clearance of ganciclovir was found to be almost 25% higher than would be expected in women, after correction for sex-related differences in eGFR. In other words, the clearance of ganciclovir seemed to differ less between men and women than the clearance of creatinine, even though ganciclovir is a predominantly (>90%) renally eliminated drug. The authors suggested that the relatively higher clearance of ganciclovir in women might be explained by differences in expression of organic anion transporter (OAT) enzymes between men and women [1]. Differences between men and women of similar magnitudes were reported in another population pharmacokinetic study (37 men, 9 women) [2].

The net effect of pharmacokinetic differences between men and women on the systemic exposure of ganciclovir is not clear. A lower volume of distribution would be expected to translate into higher peak plasma concentrations (Cmax), whereas a higher clearance would be expected to reduce the overall systemic exposure (AUC) of ganciclovir. However, no studies reporting sex-based differences in the systemic exposure of (val)ganciclovir have been identified. Furthermore, no well-defined therapeutic exposure targets for ganciclovir have been characterized. Consequently, there is insufficient evidence to support dose adjustments of valganciclovir depending on patient’s sex at present. Individual clinical assessment supported by therapeutic drug monitoring in selected patients is recommended until further evidence emerges.

Effects

No studies comparing sex-related differences in valganciclovir efficacy per se have been identified. However, female sex has been associated with an increased risk of developing cytomegalovirus disease after solid-organ transplantation followed by antiviral prophylaxis with ganciclovir or valganciclovir [3, 4]. The underlying reasons for this have not been elucidated, but it has been proposed that higher estrogen levels might facilitate cytomegalovirus replication [3, 4]. It is unclear whether women would benefit from more aggressive or extended antiviral prophylaxis regimens in this context.

Adverse effects

Apart from male fertility issues (refer to separate section below), no reports of sex-related differences in adverse events have been reported.

Reproductive health issues

Decreased sperm density and motility during and up to six months after discontinued treatment with valganciclovir has been reported [5]. Male infertility is reported among less common (1/1000) adverse effects of valganciclovir [5]. This seems to be based on observed, temporary effects in humans and indications of permanent male infertility in animal studies [5]. No case reports of permanent infertility have been identified in men or women.

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2020-06-08

Date of litterature search: 2020-05-04

References

  1. Perrottet N, Csajka C, Pascual M, Manuel O, Lamoth F, Meylan P, Aubert JD, Venetz JP, Soccal P, Decosterd LA, Biollaz J, Buclin T. Population pharmacokinetics of ganciclovir in solid-organ transplant recipients receiving oral valganciclovir. Antimicrob Agents Chemother. 2009;53(7):3017-23.
  2. Wiltshire H, Hirankarn S, Farrell C, Paya C, Pescovitz MD, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N; Valganciclovir Solid Organ Transplant Study Group. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid-organ transplant recipients. Clin Pharmacokinet. 2005;44(5):495-507.
  3. Freeman RB, Paya C, Pescovitz MD, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Heaton N; Valganciclovir Solid Organ Transplant Study Group. Risk factors for cytomegalovirus viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients. Transplantation . 2004;8(12):1765-73.
  4. Arthurs SK, Eid AJ, Pedersen RA, Dierkhising RA, Kremers WK, Patel R, Razonable RR. Delayed-onset primary cytomegalovirus disease after liver transplantation. Liver transpl. 2007;13(12):1703-09.
  5. Cymevene (ganciklovir). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2020-04-22, cited 2020-05-06].
  6. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk

Authors: Gustaf Beijer

Reviewed by: Mia von Euler, Diana Rydberg, Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson