4.5 Interaction with other medicinal products and other forms of interaction
• Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase aciclovir plasma concentrations.

• Ciclosporin: There has been a small number of transplant patients with increased serum levels of ciclosporin and signs of nephrotoxicity when aciclovir is given concurrently. Renal function should be monitored closely in patients taking both drugs.

• Cimetidine and probenecid: Cimetidine and probenecid increase the AUC of aciclovir by competing for active secretion by the renal tubules and reduce aciclovir renal clearance. Dosage adjustment is usually not necessary because of the wide therapeutic index of aciclovir.

• Mycophenolate mofetil: Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are coadministered. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

• An experimental study on five male subjects indicates that concomitant therapy with aciclovir increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with aciclovir.

• Zidovudine: Although co-administration of zidovudine and aciclovir is not usually associated with toxicity, there is a single case report of overwhelming fatigue developing in a patient when given the two drugs together. This did not occur when zidovudine and aciclovir were given alone.

4.6 Fertility, pregnancy and lactation
Pregnancy

Experience in humans is limited so the use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks. Herpes simplex encephalitis and varicella pneumonia constitute a significant risk for mother and foetus and primary genital herpes may retard intrauterine growth and increase the risk of premature birth and neonatal herpes infection. (See section 5.3 Preclinical Safety Data). Aciclovir readily crosses the placenta and levels in cord blood are higher than in maternal serum.

A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of aciclovir. The registry findings have not shown an increase in the number of birth defects amongst aciclovir exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice. In a non-standard test in rats, foetal abnormalities were observed but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Breast-feeding

Following oral administration of 200mg aciclovir five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6-4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if aciclovir is to be admin