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VALTREX 250MG FILM COATED TABLETS

Active substance(s): VALACICLOVIR HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Valtrex 250 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains valaciclovir hydrochloride equivalent to 250 mg valaciclovir
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet
250 mg tablet
White, biconvex, elongated tablet with a white to off-white core, engraved “GX CE7” on one
side.

4.1

Therapeutic indications

Varicella zoster virus (VZV) infections – herpes zoster
Valtrex is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster
in immunocompetent adults (see sections 4.4).
Valtrex is indicated for the treatment of herpes zoster in adult patients with mild or
moderate immunosuppression (see section 4.4).
Herpes simplex virus (HSV) infections
Valtrex is indicated


for the treatment and suppression of HSV infections of the skin and mucous
membranes including:
and

treatment of first-episode of genital herpes in immunocompetent adults
adolescents and in immunocompromised adults

and

treatment of recurrences of genital herpes in immunocompetent adults
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
(see section 4.4)

Clinical studies have not been conducted in HSV-infected patients
immunocompromised for other causes than HIV-infection (see section 5.1).
Cytomegalovirus (CMV) infections:
Valtrex is indicated for the prophylaxis of CMV infection and disease following solid
organ transplantation in adults and adolescents (see section 4.4)

4.2 Posology and method of administration
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 Valtrex 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. Valtrex 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 Valtrex 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 Valtrex 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 Valtrex 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 Valtrex 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 Valtrex to patients with impaired renal
function. Adequate hydration should be maintained. The dose of Valtrex should be
reduced in patients with impaired renal function as shown in Table 1 below.
In patients on intermittent haemodialysis, the Valtrex 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 Valtrex
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). Pharmacokinetic data in adult patients with advanced
cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic
shunting) do not indicate the need for dose adjustment; however, clinical experience is
limited. For higher doses (4000 mg or more per day), see section 4.4.

Table 1:

DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT
Creatinine
Clearance
(mL/min)

Valaciclovir
Dosage a

≥ 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

- 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

≥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

- 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

Therapeutic Indication
Varicella-Zoster Virus (VZV) Infections
Treatment of herpes zoster (shingles)
in immunocompetent and
immunocompromised adults
Herpes Simplex Virus (HSV) Infections
Treatment of HSV infections

Treatment of herpes labialis (cold
sores) in immunocompetent adults and
adolescents
(alternative 1-day regimen)
Suppression of HSV infections

Cytomegalovirus (CMV) Infections
2000 mg four times daily
≥75
1500 mg four times daily
50 to <75
1500 mg three times daily
25 to <50
1500 mg twice daily
10 to <25
1500 mg once daily
<10 or on dialysis
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.
CMV prophylaxis in solid organ
transplant recipients in adults and
adolescents

4.3

Contraindications

Hypersensitivity to valaciclovir or aciclovir or any of the excipients listed in section
6.1. ( see section 6.1).
4.4

Special warnings and precautions for use

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 (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).
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 antithymocyte 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).

4.5

Interaction with other medicinal products and other forms of interaction

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.

4.6

Fertility, pregnancy and lactation

Pregnancy
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.
Breastfeeding
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.
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.

4.7 Effects on ability to drive and use machines
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
Valtrex 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.
4.8

Undesirable effects

The most common adverse reactions (ARs) reported in at least one indication by
patients treated with Valtrex 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
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 (see section 4.4). In organ transplant patients receiving high
doses (8000 mg daily) of Valtrex 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:
Rare:

Urticaria
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 (see section 4.4).
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.

4.9 Overdose
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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
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
Valtrex 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. Valtrex 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.
Valaciclovir 500 mg twice daily was superior to 1000 mg once daily for suppression
of symptomatic recurrences Valaciclovir 1000 mg twice daily for treatment of
recurrences was comparable to oral aciclovir 200 mg five times daily on herpes
episode duration. Valaciclovir has not been studied in patients with severe immune
deficiency.
The efficacy of valaciclovir for the treatment of other HSV skin infections has been
documented. Valaciclovir has shown efficacy in the treatment of herpes labialis (cold
sores), mucositis due to chemotherapy or radiotherapy, HSV reactivation from facial
resurfacing, and herpes gladiatorum. Based on historical aciclovir experience,
valaciclovir appears to be as effective as aciclovir for the treatment of erythema
multiforme, eczema herpeticum and herpetic whitlow.
Valaciclovir has been proven to reduce the risk of transmission of genital herpes in
immunocompetent adults when taken as suppressive therapy and combined with safer
sex practices. A double blind, placebo controlled study was conducted in 1,484
heterosexual, immunocompetent adult couples discordant for HSV-2 infection.
Results showed significant reductions in risk of transmission: 75 % (symptomatic
HSV-2 acquisition), 50 % (HSV-2 seroconversion), and 48 % (overall HSV-2
acquisition) for valaciclovir compared to placebo. Among subjects participating in a
viral shedding sub-study, valaciclovir significantly reduced shedding by 73 %
compared to placebo (see section 4.4 for additional information on transmission
reduction).
Cytomegalovirus Infection (see section 4.4)
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.

5.2

Pharmacokinetic properties

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
500 mg
1000 mg
2000 mg
(N=15)
(N=15)
(N=15)
(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–
1.0 (0.75–
2.0 (0.75–
2.0 (1.5–
1.5)
2.5)
3.0)
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
(see section 4.2).
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.

5.3 Preclinical safety data
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).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core
Microcrystalline cellulose
Crospovidone
Povidone
Magnesium stearate
Silica colloidal anhydrous
Film coat
Hypromellose
Titanium dioxide
Macrogol 400
Carnauba wax

6.2 Incompatibilities
Not applicable.
6.3

Shelf life
250 mg tablets
Two years

6.4

Special Precautions for Storage
Store below 30°C

6.5

Nature and contents of container
Polyvinyl chloride / aluminium foil blister packs.

250 mg tablets
Packs of 20 or 60 tablets
Not all pack sizes may be marketed

6.6

Special precautions for disposal

No special requirements for disposal
7.

MARKETING AUTHORISATION HOLDER
The Wellcome Foundation Ltd
Glaxo Wellcome House
Berkeley Avenue
Greenford
Middlesex
UB6 ONN

8.

MARKETING AUTHORISATION NUMBER
PL 00003/0371

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/12/2011

10

DATE OF REVISION OF THE TEXT
25/07/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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