Active ingredient: valaciclovir hydrochloride Chemical name: 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L- valinate hydrochloride CAS number: 124832-27-5 Molecular weight: 360.8 Molecular formula: C13H20N6O4.HCl Chemical structure:

DESCRIPTION

Valaciclovir is the L-valine ester of aciclovir. Aciclovir is a purine nucleoside analogue. Valvala tablets contain the active ingredient valaciclovir hydrochloride. The tablets also contain microcrystalline cellulose, crospovidone, povidone, magnesium stearate, and Opadry White 13B58802.

PHARMACOLOGY

Pharmacotherapeutic group: Nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05AB11

Virology

Valaciclovir is rapidly and almost completely converted in man to aciclovir probably by the enzyme 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 (IC50 0.1 - 3.0mM), varicella-zoster virus (VZV) (IC50 1.6 - 5.1mM) and human cytomegalovirus (HCMV) (IC50 10 - > 200mM). 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: thymidine kinase in HSV and VZV infected cells or protein kinase in HCMV infected cells. This requirement for activation of aciclovir by a virus specific enzyme largely explains its unique 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.

After oral administration valaciclovir is well absorbed and rapidly and almost completely converted to aciclovir and valine. This conversion is probably mediated by valaciclovir hydrolase, an enzyme isolated from human liver. Administration of a single dose of 500mg valaciclovir to healthy subjects under fasting conditions achieved a mean peak plasma concentration of aciclovir of 3.1mg/mL within approximately 1.69 hours. Mean peak aciclovir concentrations are 10-37mM (2.2 - 8.3mg/mL) following single doses of 250-2000mg valaciclovir to healthy subjects with normal renal function and occur at a median time of 1.00 - 2.00 hours post dose. The time to peak (Tmax) is 1.7 hours for 1 x 500mg tablet, 1.6 hours for 2 x 500mg tablets and 1.9 hours for a 1000mg tablet. The bioavailability of aciclovir following a dose of 1000mg of valaciclovir is 54% and is unaffected by food. Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur 30 - 100 minutes post dose, and are at or below the limit of quantification 3 hours after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing. Binding of aciclovir to plasma proteins is very low (9 to 33%). In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 hours. In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. Valaciclovir is eliminated principally as aciclovir (greater than 80% of the recovered dose) and the known aciclovir metabolite, 9-(carboxymethoxy) methylguanine (CMMG), in the urine.

Patients with Herpes Zoster or Herpes Simplex infections

The pharmacokinetics of valaciclovir and aciclovir are not altered significantly in patients with herpes zoster and herpes simplex infections after oral administration of valaciclovir tablets.

End-Stage Renal Disease (ESRD)

Following administration of valaciclovir to volunteers with ESRD, the average aciclovir half-life is approximately 14 hours. During haemodialysis, the aciclovir half-life is approximately 4 hours. Approximately one third of aciclovir in the body is removed by dialysis during a 4-hour haemodialysis session. Apparent plasma clearance of aciclovir in dialysis patients was 86.3 +- 21.3mL/min/1.73m2, compared to 679.16 +- 162.76mL/min/1.73m2 in healthy volunteers. Reduction in dosage is recommended in patients with renal impairment.

Microbiology

Resistance of HSV and VZV to aciclovir can result from qualitative and quantitative changes in the viral (thymidine kinase) TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to aciclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered. Resistance of HSV and VZV to aciclovir occurs by the same mechanisms. While most of the aciclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valaciclovir (and therefore to aciclovir) should be considered in patients who show poor clinical response during therapy.

CLINICAL TRIALS

Two doses of valaciclovir were compared to aciclovir in a double blind randomised trial in immunocompetent patients aged 50 years and over with herpes zoster (n=1141). All patients were treated within 72 hours of the appearance of the rash. Valaciclovir 1g three times daily for seven days achieved statistically significant reductions in the duration of zoster-associated pain (which is the sum of acute pain and post-herpetic neuralgia) and in the duration of post-herpetic neuralgia when compared with aciclovir (Table 1, Figure 1). There was no statistically significant difference between the three treatments for the resolution of rash.

Table 1: Randomised double blind randomised trial design for comparison of Herpes Zoster-associated pain in immunocompetent patients aged

>= 50 years with herpes zoster (n=1141)

There was no significant difference to the duration of zoster-associated pain when treatment was started within 48 hours or 72 hours. Patients treated within 48 hours of rash onset were found to have faster healing rates as measured by the duration of new lesion formation and time to crusting or healing of 50% or more of lesions. Thus, greater benefit is gained if the drug is started within 48 hours.

Valaciclovir versus Aciclovir for patients >= 50 years (n=1141)

Figure 1: Duration of Zoster-associated pain: Kaplan-Meier plots for

In a second, placebo controlled trial in patients under 50 years of age (n=399), demonstration of efficacy was restricted to a small decrease in mean time to cessation of new lesion formation. No significant effects were demonstrated for other outcomes of herpes zoster in this age group. Nevertheless, the occasional younger patient with severe herpes zoster may benefit from therapy with valaciclovir. Herpes zoster is usually a milder condition in younger patients. In ophthalmic zoster oral aciclovir has been shown to reduce the incidence of stromal keratitis and both the incidence and severity of anterior uveitis but not other ocular complications or acute pain. The recommended dose of valaciclovir produces higher plasma concentrations of aciclovir than those associated with these beneficial effects.

Four large multicentre, randomised double-blind trials were conducted in adults with herpes simplex infections. These studies included a total of 3569 treated patients of whom 1941 received valaciclovir.

One study compared valaciclovir (1000mg twice daily) with aciclovir (200mg five times daily) administered for 10 days in immunocompetent patients with initial (primary or first episode) genital herpes. Patients reported to the clinic for treatment within 72 hours of the first signs or symptoms of genital herpes. Patients were randomized to receive valaciclovir tablets (n=323) or Zovirax (n=320) for 10 days. The median time to lesion healing was 9 days in each treatment group. The median time to the cessation of viral shedding was 3 days in each treatment group. Median time to cessation of pain was 5 days in each treatment group.

The other three studies enrolled immunocompetent patients with a history of recurrent genital herpes infections. These studies compared valaciclovir (1000mg and/or 500mg twice daily) with aciclovir (200mg five times daily) and/or placebo, administered for 5 days. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode. The primary efficacy end-points in each study were:

In one study, patients were randomized to receive five days of treatment with either valaciclovir 500mg bid (n=360) or placebo (n=259).

The median time to lesion healing was four days in the group receiving valaciclovir 500mg versus six days in the placebo group.

The median time to cessation of viral shedding in patients with at least one positive culture (42% of the overall study population) was two days in the group receiving valaciclovir 500mg versus four days in the placebo group.

The median time to cessation of pain was three days in the group receiving valaciclovir 500mg versus four days in the placebo group. Results supporting efficacy were replicated in the other two studies.

Pooled analysis of the three studies also showed that the use of valaciclovir in patients who self-initiated treatment in the prodrome, increased the chances of preventing lesion development (aborting episodes) by 31% to 44% compared with placebo.

Prophylaxis of cytomegalovirus (CMV) infection and disease, following organ transplantation Three double-blind, randomised clinical studies were conducted to investigate the efficacy and safety of valaciclovir in the prophylaxis of CMV infection and disease following renal or heart transplantation. These studies included a total of 643 patients, of whom 320 received valaciclovir, 13 received aciclovir and 310 received placebo (see Table 2). The primary efficacy endpoint in renal transplant studies was the development of CMV disease and the primary endpoint in the heart transplant study was the development of CMV antigenaemia. Secondary endpoints for the studies included CMV disease (heart transplant study), CMV infection, reduced acute graft rejection, fewer opportunistic bacterial or fungal infections and reduced herpes virus disease (HSV, VZV).

The two renal transplant studies involved a total of 616 renal transplant recipients, of which 306 received a daily dose of 2g valaciclovir four times daily (adjusted according to creatinine clearance for renal function) and 310 received placebo for 90 days. The patients were stratified by donor and recipient CMV-serostatus (seropositive recipients [R+] versus seronegative recipients of a graft from a seropositive donor [D+R-]). Patients commenced study drug within 72 hours post-transplant and continued treatment for 90 days (treatment period) receiving, following adjustment for renal function, a daily average dose of 4.7g ([R+] subjects) and 5.3g ([D+R-] subjects) valaciclovir. Patients were evaluated for efficacy and safety for six months post-transplant (study period) (Table 2, Figure 2). In renal transplant recipients valaciclovir was significantly better than placebo in preventing or delaying CMV disease by 78% and 82% in the [D+R-] and [R+] strata respectively, during the six month study period. Valaciclovir was also significantly better than placebo in preventing or delaying the development of viraemia, viruria and clinical HSV disease during the study period. No valaciclovir recipient developed VZV disease, whereas 2% and 4% of placebo patients did, R+ and D+R- strata respectively. Additionally in D+R- patients, valaciclovir was shown to significantly reduce acute graft rejections (biopsy proven and clinical acute rejection by 57% and 45% respectively) and opportunistic infections (48% primarily bacterial and fungal infections). There were no significant differences in rates of chronic graft rejection. Allograft function and survival, including the proportion of patients with a functional graft at their last assessment were similar between treatment groups. Administration of valaciclovir was associated with significantly fewer hospital

Figure 2: Proportions of patients [D+R-] without confirmed CMV disease:

Kaplan-Meier plots for Valaciclovir versus placebo (n=616)

admissions and reduced use of ganciclovir and aciclovir for the treatment of CMV disease or other herpes virus infections, respectively.

Table 2: Results for the primary and secondary endpoints in the pivotal trials (results based on entire study period: 3 months treatment followed by 3 months follow up)

The third study enrolled 27 heart transplant recipients. This study compared valaciclovir (n=14, 2g four times daily, adjusted according to creatinine clearance for renal function) with aciclovir (n=13, 200mg four times daily). Treatment was commenced within 3 days post-transplant and continued for 90 days. Patients were followed up until the end of the sixth month. During the 90 day treatment period, 29% of patients on valaciclovir developed CMV antigenaemia (primary endpoint) compared to 92% of patients who received aciclovir. The time difference to CMV antigenaemia was statistically significant, with median time to CMV antigenaemia of 19 vs. 119 days in favour of valaciclovir (HR=0.422, 95% CI: 0.179, 0.992; p=0.049). At the end of the study period (3 months following the treatment period) the proportion of patients with CMV antigenaemia was similar in both treatment arms. Notable but not statistically significant reductions in the rates of CMV infection (valaciclovir 43%, aciclovir 92%), symptomatic CMV infection (valaciclovir 0%, aciclovir 38%), CMV disease (valaciclovir 0%, aciclovir 23%) and HSV disease (valaciclovir 29%, aciclovir 54%), were observed during the 90 day treatment period. The incidence of other infections (bacterial, fungal, non-herpes virus) was also lower in the valaciclovir group throughout the entire study period (valaciclovir 36%, aciclovir 62%). There were no significant differences in graft rejection and survival rates between the valaciclovir and aciclovir patients at the end of the study (3 months following treatment period).

Two additional clinical studies have been conducted to assess the safety and efficacy of valaciclovir in the prophylaxis of CMV infection in bone marrow transplant recipients. The adverse event data from these trials is consistent with the current safety profile of valaciclovir.

CONTRAINDICATIONS

Valvala is contraindicated in patients known to be hypersensitive to valaciclovir, aciclovir or any component of the formulation.

PRECAUTIONS

HIV disease

Thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome, in some cases resulting in death, has occurred in patients with advanced HIV disease who were treated with valaciclovir for prolonged periods and also in allogenic bone marrow transplant and renal transplant recipients who were treated with valaciclovir while participating in clinical trials at doses of 8 grams per day. Similar signs have been observed in patients with the same underlying or concurrent conditions who were not treated with valaciclovir.

Immunocompromised patients

Use of valaciclovir at doses of 1000mg/day in immunocompromised patients with CD4+ counts > 100x106 L has not been associated with occurrences of thrombotic microangiopathy (TMA). However use in severely immunocompromised patients (CD4+ counts < 100x106 L) has not been examined at this low dosage.

Use in genital herpes

Continuous therapy with valaciclovir in patients with recurrent genital herpes reduces the risk of transmitting genital herpes. It does not cure genital herpes or completely eliminate the risk of transmission. In addition to therapy with valaciclovir, it is recommended that patients use safer sex practices.

Information for patients

Patients should be informed that valaciclovir (or any other antiviral) is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding.

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

The dose of valaciclovir must be reduced in patients with renal impairment (see DOSAGE AND ADMINISTRATION). Aciclovir delivered by valaciclovir is eliminated by renal clearance (see PHARMACOLOGY). 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 ADVERSE EFFECTS). Precipitation of aciclovir in renal tubules may occur when the solubility (2.5mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained. In the event of acute renal failure and anuria, the patient may benefit from haemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION).

Use of high dose valaciclovir in hepatic impairment and liver transplantation

There are no data available on the use of high doses of valaciclovir (8g/day) in patients with liver disease. Caution should therefore be exercised when administering high doses of valaciclovir to these patients. Specific studies of valaciclovir have not been conducted in liver transplantation; however high dose aciclovir has been studied in this population.

Effects on ability to drive and use machines

No special precautions necessary. A detrimental effect on driving or ability to operate machinery can not be predicted from the pharmacological properties of valaciclovir or the active substance aciclovir. No studies to investigate the effect of valaciclovir on such activities have been conducted. However, the clinical status of the patient and the adverse event profile of valaciclovir should be borne in mind when considering a patient"s ability to drive or operate machinery.

Effects on fertility

Valaciclovir did not impair fertility or reproduction in rats at 200mg/kg per day, corresponding to plasma levels 2.8 (HZV) and 0.3 (CMV) times human plasma concentrations (AUC).

Teratogenesis

Valaciclovir was not teratogenic in rats or rabbits given oral doses of 400mg/kg (which results in exposures of 1.1 and 2.0 times (HZV) and 0.4 and 0.7 times (CMV) human exposure, respectively, based on body surface area) during the period of major organogenesis. Aciclovir was not teratogenic in the mouse (450mg/kg/day PO), rabbit (50mg/kg/day SC and IV) or rat (50mg/kg/day SC) when dosed throughout the period of organogenesis. Plasma concentrations of aciclovir in the rat were 3.5 (HZV) and 0.8 (CMV) times human concentrations. In additional studies in which rats were given three SC doses of 100mg/kg aciclovir on gestation day 10, foetal abnormalities, such as head and tail anomalies, were reported. Plasma concentrations of aciclovir in the rat were 19 (HZV) and 4.3 (CMV) times human concentrations.

Use in pregnancy (Category B3)

There are no adequate and well-controlled studies of valaciclovir or aciclovir in pregnant women. A prospective epidemiologic registry of aciclovir use during pregnancy has been ongoing since June 1984. Pregnancy registries have documented the pregnancy outcomes in women exposed to valaciclovir or to any formulation of aciclovir (the active metabolite of valaciclovir); 111 and 1,246 outcomes (29 and 756 exposed during the first trimester of pregnancy), respectively, were obtained from women prospectively registered. Registry findings do not indicate an increased risk of major birth defects after aciclovir exposure, i.e. in comparison with the general population. The accumulated case histories represent an insufficient sample for reaching reliable and definitive conclusions regarding the risk associated with aciclovir exposure during pregnancy. The daily aciclovir AUCs (area under plasma concentration-time curve) following valaciclovir 1000mg and 8000mg daily would be approximately 2 and 9 times greater than that expected with oral aciclovir 1000mg daily, respectively. There are limited data on the use of valaciclovir in pregnancy. Valaciclovir tablets should only be used in pregnancy if the potential benefit outweighs the potential risk.

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

Use in lactation

Lactating rats given a 25mg/kg PO dose of 14C-valaciclovir showed peak milk radioactivity levels of 26mg/eq/g, 2 hours post dose. The milk radioactivity levels declined slower than in plasma, and were undetectable at 12 hours. Suckling pups had radioactivity in the stomach and intestinal contents up to 7 hours post dose, but not in tissues. Limited data show that aciclovir does pass into human breast milk. In a study conducted on 5 women, following oral administration of a 500mg dose of valaciclovir, peak aciclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 (median 1.4) times the corresponding maternal aciclovir serum concentrations. The aciclovir AUC was 2.2 times (range 1.4 to 2.6) higher in breast milk compared to maternal serum. In other studies conducted with oral aciclovir administration, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding aciclovir plasma concentrations. Caution is therefore advised if valaciclovir is to be administered to a breast-feeding mother. Valaciclovir should only be administered to breast-feeding mothers if the benefits to the mother outweigh the potential risks to the baby.

Use in children

Use in the elderly

Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Elderly patients 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 ADVERSE EFFECTS). Reversible neurological reactions including dizziness, confusion, hallucinations, rarely decreased consciousness and very rarely tremor, ataxia, dysarthria, convulsions, encephalopathy and coma have been reported. These events are usually seen in patients with renal impairment or with other predisposing factors. In organ transplant patients receiving high doses (8g daily) of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.

Carcinogenicity

The data presented below include references to the steady-state aciclovir AUC observed in humans treated with 1g valaciclovir given orally three times a day to treat herpes zoster (HZV) or with 2g valaciclovir given orally four times a day to treat cytomegalovirus (CMV). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to aciclovir. Valaciclovir was noncarcinogenic in lifetime carcinogenicity bioassays at oral doses of up to 120mg/kg/day for mice and 100mg/kg/day for rats. There was no significant difference in the incidence of tumours between treated and control animals, nor did valaciclovir shorten the latency of tumours. Plasma concentrations (AUC) of aciclovir were equivalent to 1.1 (HZV) and 0.1 times (CMV) human levels in the mouse bioassay and 1.3 (HZV) and 0.1 (CMV) times human concentrations in the rat bioassay.

Genotoxicity

Valaciclovir was not mutagenic in bacterial cells nor did it demonstrate any clastogenic potential in vitro in human lymphocytes or in vivo in the rat bone marrow assay. The mouse micronucleus assay was negative at 250mg/kg but weakly positive at 500mg/kg. Valaciclovir, at concentrations >= 2000mg/mL in the presence of S9 metabolic activation was mutagenic in the mouse lymphoma assay. The active metabolite, aciclovir, was clastogenic in Chinese hamster cells in vivo, at exposure levels also causing nephrotoxicity (500 & 1000mg/kg parenteral dose). There was also an increase, though not statistically significant, in chromosomal damage at maximum tolerated doses (100mg/kg) of aciclovir in rats. No activity was found in a dominant lethal study in mice or in 4 microbial assays. Positive results were obtained in 2 of 7 genetic toxicity assays using mammalian cells in vitro (positive in human lymphocytes in vitro and one locus in mouse lymphoma cells, negative at 2 other loci in mouse lymphoma cells and 3 loci in a Chinese hamster ovary cell line). The results of these mutagenicity tests in vitro and in vivo suggest that valaciclovir and aciclovir are unlikely to pose a genetic threat to man at therapeutic dose levels.

Interactions with other medicines

No clinically significant interactions have been identified. 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 following valaciclovir administration. Following 1g valaciclovir, cimetidine and probenecid increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. These effects are not considered to be of clinical significance in subjects with normal renal function. Therefore, no dosage adjustment is recommended when valaciclovir is co-administered with cimetidine, or probenecid in subjects with normal renal function. In patients receiving high-dose valaciclovir (8g/day) for CMV prophylaxis, caution is required during concurrent administration with drugs which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both drugs or their metabolites. 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 co administered. Care is also required (with monitoring for changes in renal function) if administering high-dose valaciclovir with drugs which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).

ADVERSE EFFECTS

Valaciclovir was well tolerated when used for the treatment of herpes zoster and genital herpes in clinical trials. The most commonly reported adverse experiences were headache and nausea and these were reported in a similar proportion of patients on valaciclovir, aciclovir and placebo.

Herpes Zoster Infections

The Table 3 lists all adverse events reported during a six month observation period in immunocompetent patients receiving short-term treatment (7 or 14 days) with valaciclovir and reference products in controlled clinical trials.

HSV Infections

Initial and recurrent genital herpes (short term treatment)

The adverse events reported by greater than 2% of a given treatment group in the initial and recurrent genital herpes clinical trials with valaciclovir and reference products used in the trials are listed in Table 4.

CMV Infections

Prophylaxis of cytomegalovirus (CMV) infection and disease, following organ transplantation Valaciclovir was well tolerated in the clinical studies of renal and heart transplant patients. The nature and frequency of adverse events were similar between placebo, aciclovir and valaciclovir treated patients, with the exception of adverse events relating to the CNS (hallucinations, confusion and thinking abnormality). These were reported more frequently in valaciclovir than placebo in renal transplant patients. The most common adverse events reported in the renal transplant patients were anaemia, hypertension and headache. Headache and myalgia were the most common adverse events reported in the heart transplant patients. All the clinical adverse events occurring at an incidence of >= 5% or >= 20% in a given treatment group, in clinical trials for CMV prophylaxis following renal and heart transplants respectively are listed in Table 5 and Table 6.

Table 3: All adverse events reported during a six month observation period in immunocompetent patients receiving short-term treatment (7 or 14 days) for Herpes Zoster with valaciclovir, acicilovir and placebo in controlled clinical trials

Patient age group % Incidence of adverse events >= 50 years 18 to 50 years

	valaciclovir 1 g 3 x daily (n=765) 14 days n=381 7 days n=384	aciclovir 800 mg 5 x daily 7 days (n=376)	valaciclovir 1 g 3 x daily 7 days (n=202)	placebo 7 days (n=197)
Nausea	16.5	19.1	9.9	7.6
Headache	12.9	12.8	16.8	11.7
Vomiting	6.8	7.7	4.5	2.5
Diarrhoea	5.5	7.4	4.5	6.1
Constipation	5.1	5.3	1.5	2.5
Asthenia	4.4	5.3	3.0	3.6
Dizziness	3.7	5.9	2.0	2.0
Abdominal Pain	3.3	2.7	2.5	1.5
Anorexia	3.0	2.7	0.5	2.0
Dyspepsia	2.5	1.9	-	-
Dry mouth	1.8	0.5	-	-
Flatulence	1.8	1.6	-	-
Fever	1.4	2.4	-	-
Insomnia	1.6	0.5	-	-
Rhinitis	1.3	1.6	1.5	1.5
Chills	1.0	1.6	-	-
Back Pain	1.0	0.5	-	-
Nervousness	1.0	0.0	-	-
Somnolence	0.9	2.1	-	-
Pain	0.8	1.6	-	-
Rash	0.7	1.9	-	-
Myalgia	-	-	0.5	2.5
Infection	-	-	2.0	1.0

Table 4: Adverse Events reported by > 2% of a given treatment group in the initial and recurrent genital herpes clinical trials with valaciclovir, acicilovir, and placebo

% Incidence of adverse events (patient age group: 17 - 79 years)
Adverse Event	Valaciclovir 1 g 2 x daily (n=1203) 10 days n=323 5 days n=880 500 mg 2 x daily 5 days (n=738)	Aciclovir 200 mg 5 x daily 5 days (n=1187)	Placebo (n=441)
Headache	16 %	11 %	14 %
Nausea	6 %	7 %	7 %
Diarrhoea	4 %	3 %	6 %
Dizziness	3 %	2 %	2 %
Abdominal pain	2 %	3 %	2 %
Asthenia	2 %	2 %	4 %
Rhinitis	2 %	2 %	2 %
Pharyngitis	1 %	2 %	1 %
Pain	1 %	1 %	2 %
Dyspepsia	1 %	1 %	2 %
Vomiting	1 %	2 %	0 %
Back pain	1 %	1 %	2 %

Table 5: Summary of all adverse events reported at an incidence >= 5 % by renal transplant recipients in clincial trials for CMV prophylaxis

Adverse Event	Valaciclovir * (n = 306)	Placebo (n = 310)
Anaemia	12 %	12 %
Hypertension	11 %	8 %
Headache	9 %	11 %
Diarrhoea	9 %	12 %
Abdominal Pain	8 %	11 %
Leukopenia	8 %	8 %
Hallucination	8 %	1 %
Fever	8 %	11 %
Nausea	8 %	7 %
Vomiting	8 %	7 %
Peripheral Oedema	8 %	9 %
Confusion	7 %	2 %
Dyspnoea	7 %	5 %
Pain	7 %	7 %
Constipation	7 %	5 %
Insomnia	6 %	3 %
ALT * * increase	5 %	6 %
Thrombocytopenia	5 %	5 %
Pruritus	5 %	2 %
Arthralgia	5 %	6 %
Tremor	4 %	6 %
Oedema	4 %	5 %
AST * * * increase	4 %	6 %

* The dosage adjustment of valaciclovir (and aciclovir) in the renal and heart transplant clinical studies differed;

* * ALT = alanine aminotransferase;

* * * AST = aspartate aminotransferase

Table 6: Summary of all adverse events reported at an incidence >= 20 % by heart transplant recipients in clincial trials for CMV prophylaxis

Adverse Event	Valaciclovir * (n = 14)	Aciclovir (n = 13)
Headache	57 %	62 %
Myalgia	57 %	46 %
Cough increase	57 %	46 %
Peripheral Oedema	50 %	62 %
Asthenia	43 %	15 %
Effus Pericard	43 %	46 %
Pain	43 %	31 %
Dyspnoea	36 %	38 %
Back Pain	29 %	15 %
Nausea	21 %	23 %
Insomnia	21 %	15 %
General Oedema	21 %	54 %
Hypertension	21 %	38 %
Somnolence	21 %	23 %
Constipation	21 %	15 %
Depression	21 %	15 %
Sleep Disorder	21 %	15 %
Chest Pain	21 %	-
Dizziness	21 %	31 %
Diarrhoea	7 %	23 %
Mouth Ulcer	-	23 %

* The dosage adjustment of valaciclovir (and aciclovir) in the renal and heart transplant clinical studies differed

Other Adverse Effects

The following adverse events have been observed in clinical practice with valaciclovir:

Gastrointestinal tract:
Common:	Nausea, abdominal discomfort, vomiting and diarrhoea
Haematological:
Rare:	Thrombocytopenia
Very rare:	Leukopenia , thrombotic microangiopathy (TMA) (see PRECAUTIONS). Leukopenia is mainly reported in immunocompromised patients
Hypersensitivity, skin and subcutaneous tissue disorders:
Uncommon:	Rashes including photosensitivity
Rare:	Pruritus, dyspnoea and anaphylaxis
Very rare:	Urticaria, angioedema
Immune system disorders:
Very rare:	Anaphylaxis
Kidney:
Rare:	Renal impairment
Very rare:	Reports of acute renal failure , renal pain Renal pain may be associated with renal failure
Liver:
Rare:	Reversible increases in liver function tests, occasionally described as hepatitis
Neurological/psychiatry:
Common:	Headache
Uncommon:	Dizziness , confusion and hallucinations *
Rare:	Decreased consciousness *
Very rare:	Coma , agitation , tremor , ataxia , dysarthria , psychotic symptoms , convulsions , encephalopathy
* Usually in patients with renal impairment or with other predisposing factors.
In organ transplant patients receiving high doses of valaciclovir for CMV prophylaxis, neurological reactions occurred more frequently compared with lower doses.
Respiratory, thoracic and mediastinal disorders:
Uncommon:	Dyspnoea

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

DOSAGE AND ADMINISTRATION

Herpes Zoster:

Genital Herpes:

First clinical presentation, 500mg of valaciclovir twice a day for 5 to 10 days. For recurrent episodes of genital herpes, 500 mg twice daily for 5 days. Dosing should begin as early as possible. For recurrent episodes of genital herpes, this should ideally be during the prodromal period or immediately following the appearance of the first signs or symptoms.

For the prophylaxis of cytomegalovirus infection (CMV) and disease:

The dosage in adults and adolescents (from 12 years of age) is 2g four times a day for 90 days, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance (see DOSAGE AND ADMINISTRATION, Use in patients with renal impairment).

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see DOSAGE AND ADMINISTRATION, Use in patients with renal impairment). Adequate hydration should be maintained.

Caution is advised when administering valaciclovir tablets to patients with impaired renal function. Adequate hydration should be maintained.

Herpes zoster treatment and herpes simplex treatment:

The dose of valaciclovir should be modified as in Table 7 for patients with significantly impaired renal function.

CMV prophylaxis:

The dosage of valaciclovir tablets should be adjusted in patients with impaired renal function as shown in Table 8. The creatinine clearance should be monitored frequently, especially during periods when renal function is changing rapidly e.g. immediately after transplantation or engraftment. The valaciclovir dosage should be adjusted accordingly.

Table 7: Valaciclovir dosage recommendations in renal impairment for the treatment of Herpes Zoster and Herpes Simplex

Creatinine clearance
(mL/min)
Valaciclovir dosage in
Herpes Zoster Herpes Simplex
< 15 *	1000 mg once a day	500 mg once daily
15-30	1000 mg twice a day	No modification
		required

clearance of less than 15mL/min should be used, but the dose should be administered after the haemodialysis has been performed.

Table 8: Valaciclovir dosage recommendations in renal impairment for CMV

Studies with a 1 g unit dose of valaciclovir show that dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment; however clinical experience is limited. For higher doses recommended for CMV prophylaxis see PRECAUTIONS.

OVERDOSAGE

Contact the Poisons Information Centre on 13 11 26 for advice on management of overdose.

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.

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.

PRESENTATION AND STORAGE CONDITIONS

Valvala 500 mg tablets - White to off-white capsule-shaped, film coated tablets with ,,500" debossed on one side and plain on other side. Blister packs of 2 (physician starter pack ), 10, 20 (not currently marketed), 30, 42 and 100 film-coated tablets. Valvala 1000 mg tablets - White to off-white, capsule-shaped film-coated tablets with "1000" debossed on one side and plain on other side. Blister packs of 21 and 50 film coated tablets.

NAME AND ADDRESS OF THE SPONSOR

Novartis Pharmaceuticals Australia Pty Limited 54 Waterloo Road North Ryde NSW 2113

POISON SCHEDULE OF THE MEDICINE

DATE OF APPROVAL

Approved by the Therapeutic Goods Administration: 20 December 2010 Date of most recent amendment: 13 April 2011

Endpoints		Renal [D+ R-]			Renal [R+]			Heart
	Hazard Ratio	95% CI	p-value	Hazard Ratio	95% CI	p-value	Hazard Ratio	95% CI	p-value
CMV disease	0.22	0.12, 0.40	< 0.0001	0.18	0.04, 0.83	< 0.027	0.19	0.02, 1.70	0.09
CMV antigenaemia		Not done			Not done		0.42	0.18, 0.99	0.049
CMV infection		Not done			Not done		0.46	0.20, 1.06	0.075
CMV viraemia	0.25	0.14, 0.44	< 0.0001	0.28	0.18, 0.45	< 0.0001		Not done
CMV viruria	0.49	0.32, 0.76	0.001	0.32	0.24, 0.44	< 0.0001		Not done
Acute graft rejection
- biopsy proven	0.43	0.27, 0.70	0.001	0.86	0.60, 1.22	0.40	0.51	0.22, 1.19	0.09
- clinical	0.55	0.37, 0.83	0.004	0.75	0.55, 1.03	0.073		Not done
Opportunistic infections	0.52	0.36, 0.76	0.001	0.90	0.70, 1.16	0.41	(0.42) *	Not protocolled
HSV disease	0.33	0.15, 0.74	0.007	0.16	0.09, 0.30	< 0.0001		Not done
VZV disease		Did not develop			Did not develop			Did not develop

Creatinine clearance (mL/min)	Valaciclovir dosage in CMV
75 or greater 50 to less than 75 25 to less than 50 10 to less than 25 less than 10 or dialysis *	2 g for times daily 1.5 g four times a day 1.5 g three times a day 1.5 g twice a day 1.5 g once a day

NAME OF THE MEDICINE