Symptoms and Signs
Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of valaciclovir. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdosing. Many of the reported cases involved renally impaired and elderly patients receiving repeated overdoses, due to lack of appropriate dosage reduction.
Treatment
Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
Not applicable.
The most common adverse reactions (ARs) reported in at least one indication by patients treated with Viramixal 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 threeâ€) 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
| 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 (8000 mg daily) of Viramixal 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 (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 of suspected adverse reactions 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 via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. | |
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Valaciclovir did not affect fertility in male or female rats dosed by the oral route.
Valaciclovir was not teratogenic in rats or rabbits. Valaciclovir is almost completely metabolised to aciclovir. Subcutaneous administration of aciclovir in internationally accepted tests did not produce teratogenic effects in rats or rabbits. In additional studies in rats, foetal abnormalities and maternal toxicity were observed at subcutaneous doses that produced plasma aciclovir levels of 100 micrograms/mL (>10-fold higher than 2000 mg single dose valaciclovir in humans with normal renal function).
Varicella zoster virus (VZV) infections - herpes zoster
Viramixal is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults.
Viramixal is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression.
Herpes simplex virus (HSV) infections
Viramixal is indicated
- for the treatment and suppression of HSV infections of the skin and mucous membranes including:
| - treatment of first-episode of genital herpes in immunocompetent adults and adolescents and in immunocompromised adults | |
| - treatment of recurrences of genital herpes in immunocompetent adults and adolescents, and in immunocompromised adults | |
| - suppression of recurrent genital herpes in immunocompetent adults and adolescents and in immunocompromised adults |
- Treatment and suppression of recurrent ocular HSV infections in immunocompetent adults and adolescents and in immunocompromised adults
Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV-infection.
Cytomegalovirus (CMV) infections:
Viramixal is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents
Antivirals for systemic use.
Pharmacotherapeutic group: Nucleosides and nucleotides excluding reverse transcriptase inhibitors, ATC code: J05AB11.
Mechanism of action
Valaciclovir, an antiviral, is the L-valine ester of aciclovir. Aciclovir is a purine (guanine) nucleoside analogue.
Valaciclovir is rapidly and almost completely converted in man to aciclovir and valine, probably by the enzyme referred to as valaciclovir hydrolase.
Aciclovir is a specific inhibitor of the herpes viruses with in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), and human herpes virus 6 (HHV-6). Aciclovir inhibits herpes virus DNA synthesis once it has been phosphorylated to the active triphosphate form.
The first stage of phosphorylation requires the activity of a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only present in virus-infected cells. Selectivity is maintained in CMV with phosphorylation, at least in part, being mediated through the phosphotransferase gene product of UL97. This requirement for activation of aciclovir by a virus-specific enzyme largely explains its selectivity.
The phosphorylation process is completed (conversion from mono- to triphosphate) by cellular kinases. Aciclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this nucleoside analogue results in obligate chain termination, halting virus DNA synthesis and thus blocking virus replication.
Pharmacodynamic effects
Resistance to aciclovir is normally due to a thymidine kinase deficient phenotype which results in a virus which is disadvantaged in the natural host. Reduced sensitivity to aciclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants resembles that of the wild-type virus.
Monitoring of clinical HSV and VZV isolates from patients receiving aciclovir therapy or prophylaxis has revealed that virus with reduced sensitivity to aciclovir is extremely rare in the immunocompetent host and is found infrequently in severely immunocompromised individuals e.g. organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).
Clinical studies
Varicella Zoster Virus Infection
Viramixal accelerates the resolution of pain: it reduces the duration of and the proportion of patients with zoster-associated pain, which includes acute and, in patients older than 50 years, also post-herpetic neuralgia. Viramixal reduces the risk of ocular complications of ophthalmic zoster.
Intravenous therapy generally is considered standard for zoster treatment in immunocompromised patients; however, limited data indicate a clinical benefit of valaciclovir in the treatment of VZV infection (herpes zoster) in certain immunocompromised patients, including those with solid organ cancer, HIV, autoimmune diseases, lymphoma, leukaemia and stem cell transplants.
Herpes Simplex Virus Infection
Valaciclovir for ocular HSV infections should be given according to applicable treatment guidelines.
Studies of valaciclovir treatment and suppression for genital herpes were performed in HIV/HSV coinfected patients with a median CD4 count of > 100cells/mm3.).
Cytomegalovirus Infection
CMV prophylaxis with valaciclovir in subjects receiving solid organ transplantation (kidney, heart) reduces the occurrence of acute graft rejection, opportunistic infections and other herpes virus infections (HSV, VZV). There is no direct comparative study versus valganciclovir to define the optimal therapeutic management of solid organ transplant patients.
Absorption
Valaciclovir is a prodrug of aciclovir. The bioavailability of aciclovir from valaciclovir is about 3.3 to 5.5-fold greater than that historically observed for oral aciclovir. After oral administration valaciclovir is well absorbed and rapidly and almost completely converted to aciclovir and valine. This conversion is probably mediated by an enzyme isolated from human liver referred to as valaciclovir hydrolase. The bioavailability of aciclovir from 1000 mg valaciclovir is 54%, and is not reduced by food. Valaciclovir pharmacokinetics is not dose-proportional. The rate and extent of absorption decreases with increasing dose, resulting in a less than proportional increase in Cmax over the therapeutic dose range and a reduced bioavailability at doses above 500 mg. Aciclovir pharmacokinetic (PK) parameter estimates following single doses of 250 to 2000 mg valaciclovir to healthy subjects with normal renal function are shown below.
| Aciclovir PK Parameter | 250 mg (N=15) | 500 mg (N=15) | 1000 mg (N=15) | 2000 mg (N=8) | |
| Cmax | micrograms/mL | 2.20 ± 0.38 | 3.37 ± 0.95 | 5.20 ± 1.92 | 8.30 ± 1.43 |
| Tmax | hours (h) | 0.75 (0.75-1.5) | 1.0 (0.75-2.5) | 2.0 (0.75-3.0) | 2.0 (1.5-3.0) |
| AUC | h.micrograms/mL | 5.50 ± 0.82 | 11.1 ± 1.75 | 18.9 ± 4.51 | 29.5 ± 6.36 |
Cmax = peak concentration; Tmax = time to peak concentration; AUC = area under the concentration-time curve. Values for Cmax and AUC denote mean ± standard deviation. Values for Tmax denote median and range.
Peak plasma concentrations of unchanged valaciclovir are only about 4% of peak aciclovir levels, occur at a median time of 30 to 100 min post-dose, and are at or below the limit of quantification 3 h after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing. Herpes zoster, herpes simplex and HIV infection do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir compared with healthy adults. In transplant recipients receiving valaciclovir 2000 mg 4 times daily, aciclovir peak concentrations are similar to or greater than those in healthy volunteers receiving the same dose. The estimated daily AUCs are appreciably greater.
Distribution
Binding of valaciclovir to plasma proteins is very low (15%). CSF penetration, determined by CSF/plasma AUC ratio, is independent of renal function and was about 25% for aciclovir and the metabolite 8-OH-ACV, and about 2.5% for the metabolite CMMG.
Biotransformation
After oral administration, valaciclovir is converted to aciclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Aciclovir is converted to a small extent to the metabolites 9(carboxymethoxy)methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxy-aciclovir (8-OH-ACV) by aldehyde oxidase. Approximately 88% of the total combined plasma exposure is attributable to aciclovir, 11% to CMMG and 1% to 8-OH-ACV. Neither valaciclovir nor aciclovir is metabolized by cytochrome P450 enzymes.
Elimination
Valaciclovir is eliminated in the urine principally as aciclovir (greater than 80% of the recovered dose) and the aciclovir metabolite CMMG (about 14% of the recovered dose). The metabolite 8-OH-ACV is detected only in small amounts in urine (< 2% of the recovered dose). Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 h.
Special Populations
Renal impairment
The elimination of aciclovir is correlated to renal function, and exposure to aciclovir will increase with increased renal impairment. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours, compared with about 3 hours for normal renal function.
Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and cerebrospinal fluid (CSF) was evaluated at steady-state after multiple-dose valaciclovir administration in 6 subjects with normal renal function (mean creatinine clearance 111 mL/min, range 91-144 mL/min) receiving 2000 mg every 6 hours and 3 subjects with severe renal impairment (mean CLcr 26 mL/min, range 17-31 mL/min) receiving 1500 mg every 12 hours. In plasma as well as CSF, concentrations of aciclovir, CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, at severe renal impairment compared with normal renal function.
Hepatic impairment
Pharmacokinetic data indicate that hepatic impairment decreases the rate of conversion of valaciclovir to aciclovir but not the extent of conversion. Aciclovir half-life is not affected.
Pregnant women
A study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy indicates that pregnancy does not affect the pharmacokinetics of valaciclovir.
Transfer into breast milk
Following oral administration of a 500 mg dose of valaciclovir, peak aciclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times the corresponding maternal aciclovir serum concentrations. The median aciclovir concentration in breast milk was 2.24 micrograms/ml (9.95 micromoles/L). With a maternal valaciclovir dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral aciclovir dosage of about 0.61 mg/kg/day. The elimination half-life of aciclovir from breast milk was similar to that for serum. Unchanged valaciclovir was not detected in maternal serum, breast milk, or infant urine.
Hydration status
Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration, particularly the elderly.
Use in patients with renal impairment and in elderly patients
Aciclovir is eliminated by renal clearance, therefore the dose of valaciclovir must be reduced in patients with renal impairment. 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.
Use of higher doses of valaciclovir in hepatic impairment and liver transplantation
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.Use for zoster treatment
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.
Transmission of genital herpes
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.
Use in ocular HSV infections
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.
Use in CMV infections
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. Patients should be closely monitored for changes in renal function, and doses adjusted accordingly.
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 Viramixal 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.
Varicella zoster virus (VZV) infections - herpes zoster and ophthalmic zoster
Patients should be advised to start treatment as soon as possible after a diagnosis of herpes zoster. There are no data on treatment started more than 72 hours after onset of the zoster rash.
Immunocompetent Adults
The dose in immunocompetent patients is 1000 mg three times daily for seven days (3000 mg total daily dose). This dose should be reduced according to creatinine clearance (see Renal impairment below).
Immunocompromised Adults
The dose in immunocompromised patients is 1000 mg three times daily for at least seven days (3000 mg total daily dose) and for 2 days following crusting of lesions. This dose should be reduced according to creatinine clearance (see Renal impairment below).
In immunocompromised patients, antiviral treatment is suggested for patients presenting within one week of vesicle formation or at any time before full crusting of lesions.
Treatment of herpes simplex virus (HSV) infections in adults and adolescents (>12 years)
Immunocompetent Adults and Adolescents (>12 years)
The dose is 500 mg of Viramixal to be taken twice daily (1000 mg total daily dose). This dose should be reduced according to creatinine clearance (see Renal impairment below).
For recurrent episodes, treatment should be for three to five days. For initial episodes, which can be more severe, treatment may have to be extended to ten days. Dosing should begin as early as possible. For recurrent episodes of herpes simplex, this should ideally be during the prodromal period or immediately upon appearance of the first signs or symptoms. Viramixal can prevent lesion development when taken at the first signs and symptoms of an HSV recurrence.
Herpes labialis
For herpes labialis (cold sores), valaciclovir 2000 mg twice daily for one day is effective treatment in adults and adolescents. The second dose should be taken about 12 h (no sooner than 6 h) after the first dose. This dose should be reduced according to creatinine clearance (see Renal impairment below). When using this dosing regimen, treatment should not exceed one day, since this has been shown not to provide additional clinical benefit. Therapy should be initiated at the earliest symptom of a cold sore (e.g. tingling, itching or burning).
Immunocompromised Adults
For the treatment of HSV in immunocompromised adults, the dosage is 1000 mg twice daily for at least 5 days, following assessment of the severity of the clinical condition and immunological status of the patient. For initial episodes, which can be more severe, treatment may have to be extended to ten days. Dosing should begin as early as possible. This dose should be reduced according to creatinine clearance (see Renal impairment below). For maximum clinical benefit, the treatment should be started within 48 hours. A strict monitoring of the evolution of lesions is advised.
Suppression of recurrences of herpes simplex virus (HSV) infections in adults and adolescents (>12 years)
Immunocompetent Adults and Adolescents (>12 years)
The dose is 500 mg of Viramixal to be taken once daily. Some patients with very frequent recurrences (> 10/year in absence of therapy) may gain additional benefit from the daily dose of 500 mg being taken as a divided dose (250 mg twice daily). This dose should be reduced according to creatinine clearance (see Renal impairment below).Treatment should be re-evaluated after 6 to 12 months of therapy.Immunocompromised Adults
The dose is 500 mg of Viramixal twice daily. This dose should be reduced according to creatinine clearance (see Renal impairment below). Treatment should be re-evaluated after 6 to 12 months of therapy.
Prophylaxis of cytomegalovirus (CMV) infection and disease in adults and adolescents (>12 years)
The dosage of Viramixal is 2000 mg four times a day, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see Renal impairment below).
The duration of treatment will usually be 90 days, but may need to be extended in high-risk patients.
Special populations
Children
The efficacy of Viramixal in children below the age of 12 years has not been evaluated.
Elderly
The possibility of renal impairment in the elderly must be considered and the dose should be adjusted accordingly (see Renal impairment below). Adequate hydration should be maintained.
Renal impairment
Caution is advised when administering Viramixal to patients with impaired renal function. Adequate hydration should be maintained. The dose of Viramixal should be reduced in patients with impaired renal function as shown in Table 1 below.
In patients on intermittent haemodialysis, the Viramixal 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 Viramixal dosage should be adjusted accordingly.
Hepatic impairment
Studies with a 1000 mg dose of valaciclovir in adult patients show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained).
Table 1: DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT
| Therapeutic Indication | Creatinine Clearance (mL/min) | Valaciclovir Dosage a |
| Varicella-Zoster Virus (VZV) Infections |
|
|
| Treatment of herpes zoster (shingles) in immunocompetent and immunocompromised adults | > 50 30 to 49 10 to 29 10 | 1000 mg three times daily 1000 mg twice daily 1000 mg once daily 500 mg once daily |
| Herpes Simplex Virus (HSV) Infections | ||
| Treatment of HSV infections | ||
| - immunocompetent adults and adolescents | > 30 < 30 | 500 mg twice daily 500 mg once daily |
| - immunocompromised adults | > 30 < 30 | 1000 mg twice daily 1000 mg once daily |
| Treatment of herpes labialis (cold sores) in immunocompetent adults and adolescents (alternative 1-day regimen) | >50 30 to 49 10 to 29 <10 | 2000mg twice in one day 1000 mg twice in one day 500 mg twice in one day 500 mg single dose |
| Suppression of HSV infections | ||
| - immunocompetent adults and adolescents | > 30 < 30 | 500 mg once daily b 250 mg once daily |
| - immunocompromised adults | > 30 < 30 | 500 mg twice daily 500 mg once daily |
| Cytomegalovirus (CMV) Infections | ||
| CMV prophylaxis in solid organ transplant recipients in adults and adolescents | >75 50 to <75 25 to <50 10 to <25 <10 or on dialysis | 2000 mg four times daily 1500 mg four times daily 1500 mg three times daily 1500 mg twice daily 1500 mg once daily |
a For patients on intermittent haemodialysis, the dose should be given after dialysis on dialysis days.
bFor HSV suppression in immunocompetent subjects with a history of >10 recurrences/year, better results may be obtained with 250 mg twice daily.
No special requirements for disposal
