Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Milpharm Limited, Ares Block, Odyssey Business Park, West End Road, Ruislip HA4 6QD, United Kingdom
Hypersensitivity to valaciclovir or aciclovir or any of the excipients (listed in section 6.1).
Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.
Aciclovir is eliminated by renal clearance; therefore the dose of valaciclovir must be reduced in patients with renal impairment (see section 4.2). Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side-effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see section 4.8).
There are no data available on the use of higher doses of valaciclovir (4000 mg or more per day) in patients with liver disease. Specific studies of valaciclovir have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000 mg to these patients.
Clinical response should be closely monitored, particularly in immunocompromised patients.
Consideration should be given to intravenous antiviral therapy when response to oral therapy is considered insufficient.
Patients with complicated herpes zoster, i.e. those with visceral involvement, disseminated zoster, motor neuropathies, encephalitis and cerebrovascular complications should be treated with intravenous antiviral therapy.
Moreover, immunocompromised patients with ophthalmic zoster or those with a high risk for disease dissemination and visceral organ involvement should be treated with intravenous antiviral therapy.
Patients should be advised to avoid intercourse when symptoms are present even if treatment with an antiviral has been initiated. During suppressive treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still possible. Therefore, in addition to therapy with valaciclovir, it is recommended that patients use safer sex practices.
Clinical response should be closely monitored in these patients. Consideration should be given to intravenous antiviral therapy when response to oral therapy is unlikely to be sufficient.
Data on the efficacy of valaciclovir from transplant patients (~200) at high risk of CMV disease (e.g. donor CMV-positive/recipient CMV negative or use of anti-thymocyte globulin induction therapy) indicate that valaciclovir should only be used in these patients when safety concerns preclude the use of valganciclovir or ganciclovir.
High dose valaciclovir as required for CMV prophylaxis may result in more frequent adverse events, including CNS abnormalities, than observed with lower doses administered for other indications (see section 4.8). Patients should be closely monitored for changes in renal function, and doses adjusted accordingly (see section 4.2).
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 1000 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 1246 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 (see section 5.3). 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 (see Section 5.2). Valaciclovir should be used with caution during breast feeding and only when clinically indicated.
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 5855 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:
Very common: Headache
Common: Nausea
Post Marketing Data:
Uncommon: Leucopenia, thrombocytopenia
Leucopenia is mainly reported in immunocompromised patients.
Rare: Anaphylaxis
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 (see section 4.4). In organ transplant patients receiving high doses (8000 mg daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses used for other indications.
Uncommon: Dyspnoea
Common: Vomiting, diarrhoea.
Uncommon: Abdominal discomfort
Uncommon: Reversible increases in liver function tests (e.g. bilirubin, liver enzymes).
Common: Rashes including photosensitivity, pruritus.
__Uncommon:__Urticaria
Rare: Angioedema
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 (see section 4.4).
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 (8000 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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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