Valaciclovir

Caution is advised when administering valaciclovir to patients with impaired renal function. Adequate hydration should be maintained. The dose of valaciclovir should be reduced in patients with impaired renal function as shown in the table below.

In patients on intermittent haemodialysis, the valaciclovir dose should be administered after the haemodialysis has been performed. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after renal transplantation or engraftment. The valaciclovir dosage should be adjusted accordingly.

Dosage for renal impairment:

^a For patients on intermittent haemodialysis, the dose should be given after dialysis on dialysis days.
^b For HSV suppression in immunocompetent subjects with a history of ≥10 = recurrences/year, better results may be obtained with 250 mg twice daily.

The combination of valaciclovir with nephrotoxic medicinal products should be made with caution, especially in subjects with impaired renal function, and warrants regular monitoring of renal function. This applies to concomitant administration with aminoglycosides, organoplatinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin, and tacrolimus.

Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Following 1,000 mg valaciclovir, cimetidine and probenecid reduce aciclovir renal clearance and increase the AUC of aciclovir by about 25% and 45%, respectively, by inhibition of the active renal secretion of aciclovir. Cimetidine and probenecid taken together with valaciclovir increased aciclovir AUC by about 65%. Other medicinal products (including e.g. tenofovir) administered concurrently that compete with or inhibit active tubular secretion may increase aciclovir concentrations by this mechanism. Similarly, valaciclovir administration may increase plasma concentrations of the concurrently administered substance.

In patients receiving higher aciclovir exposures from valaciclovir (e.g. at doses for zoster treatment or CMV prophylaxis), caution is required during concurrent administration with drugs which inhibit active renal tubular secretion.

Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate motefil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are co-administered. No changes in peak concentrations or AUCs are observed with co-administration of valaciclovir and mycophenolate mofetil in healthy volunteers. There is limited clinical experience with the use of this combination.

A limited amount of data on the use of valaciclovir and a moderate amount of data on the use of aciclovir in pregnancy is available from pregnancy registries (which have documented the pregnancy outcomes in women exposed to valaciclovir or to oral or intravenous aciclovir (the active metabolite of valaciclovir); 111 and 1,246 outcomes (29 and 756 exposed during the first trimester of pregnancy, respectively) and postmarketing experience indicate no malformative or foeto/neonatal toxicity. Animal studies do not show reproductive toxicity for valaciclovir. Valaciclovir should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk.

Aciclovir, the principle metabolite of valaciclovir, is excreted in breast milk. However, at therapeutic doses of valaciclovir, no effects on the breastfed newborns/infants are anticipated since the dose ingested by the child is less than 2% of the therapeutic dose of intravenous aciclovir for treatment of neonatal herpes. Valaciclovir should be used with caution during breast feeding and only when clinically indicated.

Fertility

Valaciclovir did not affect fertility in rats dosed by the oral route. At high parenteral doses of aciclovir testicular atrophy and aspermatogenesis have been observed in rats and dogs. No human fertility studies were performed with valaciclovir, but no changes in sperm count, motility or morphology were reported in 20 patients after 6 months of daily treatment with 400 to 1000 mg aciclovir.

No studies on the effects on the ability to drive and use machines have been performed. The clinical status of the patient and the adverse reaction profile of valaciclovir should be borne in mind when considering the patient’s ability to drive or operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

The most common adverse reactions (ARs) reported in at least one indication by patients treated with valaciclovir in clinical trials were headache and nausea. More serious ARs such as thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, acute renal failure and neurological disorders are discussed in greater detail in other sections of the label.

Undesirable effects are listed below by body system organ class and by frequency.

The following frequency categories are used for classification of adverse effects: Very common ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1000, Very rare <1/10,000.

Clinical trial data have been used to assign frequency categories to ARs if, in the trials, there was evidence of an association with valaciclovir.

For ARs identified from postmarketing experience, but not observed in clinical trials, the most conservative value of point estimate (“rule of three”) has been used to assign the AR frequency category. For ARs identified as associated with valaciclovir from post-marketing experience, and observed in clinical trials, study incidence has been used to assign the AR frequency category. The clinical trial safety database is based on 5,855 subjects exposed to valaciclovir in clinical trials covering multiple indications (treatment of herpes zoster, treatment/suppression of genital herpes & treatment of cold sores).

Clinical Trial Data:

Nervous system disorders

Very common: Headache

Gastrointestinal disorders

Common: Nausea

Post Marketing Data:

Blood and lymphatic system disorders

Uncommon: Leucopenia, thrombocytopenia

Leucopenia is mainly reported in immunocompromised patients.

Immune system disorders

Rare: Anaphylaxis

Psychiatric and nervous system disorders

Common: Dizziness

Uncommon: Confusion, hallucinations, decreased consciousness, tremor, agitation

Rare: Ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms, delirium.

Neurological disorders, sometimes severe, may be linked to encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors. In organ transplant patients receiving high doses (8,000 mg daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Gastrointestinal disorders

Common: Vomiting, diarrhoea.

Uncommon: Abdominal discomfort

Hepato-biliary disorders

Uncommon: Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).

Skin and subcutaneous tissue disorders

Common: Rashes including photosensitivity, pruritus.

__Uncommon:__Urticaria

Rare: Angioedema

Renal and urinary disorders

Uncommon: Renal pain, haematuria (often associated with other renal events).

Rare: Renal impairment, acute renal failure (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses).

Renal pain may be associated with renal failure.

Intratubular precipitation of aciclovir crystals in the kidney has also been reported. Adequate fluid intake should be ensured during treatment.

Additional information on special populations

There have been reports of renal insufficiency, microangiopathic haemolytic anaemia and thrombocytopenia (sometimes in combination) in severely immunocompromised adult patients, particularly those with advanced HIV disease, receiving high doses (8,000 mg daily) of valaciclovir for prolonged periods in clinical trials. These findings have also been observed in patients not treated with valaciclovir who have the same underlying or concurrent conditions.