Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Varicella zoster virus (VZV) infections – herpes zoster

Valtrex is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults.

Valtrex is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression.

Herpes simplex virus (HSV) infections

Valtrex 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

Clinical studies have not been conducted in HSV-infected patients immunocompromised for other causes than HIV-infection.

Cytomegalovirus (CMV) infections:

Valtrex is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents

Adult Dosage

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).

Table 1: DOSAGE ADJUSTMENT FOR RENAL IMPAIRMENT 

^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.

Child Dosage

Elderly Dosage

Contra Indications

Hypersensitivity to valaciclovir or aciclovir or any of the excipients

Special Precautions

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 Valtrex 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 high dose Valtrex in hepatic impairment:

There are no data available on the use of higher doses of Valtrex (for CMV prophylaxis) in patients with liver disease. However, following a 1g unit dose of Valtrex, aciclovir AUCs were elevated in patients with moderate or severe cirrhosis. Therefore, caution should be exercised when administering higher doses of Valtrex to patients with hepatic impairment.

Use in genital herpes: Suppressive therapy with Valtrex 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 Valtrex, it is recommended that patients use safer sex practices (particularly the use of condoms).

Interactions

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 coadministered. 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.

Adverse Reactions

Adverse reactions are listed below by MedDRA body system organ class and by frequency.

The frequency categories used are:

Very common 1 in 10,

Common 1 in 100 and < 1 in 10,

Uncommon 1 in 1,000 and < 1 in 100,

Rare 1 in 10,000 and < 1 in 1,000,

Very rare < 1 in 10,000.

Blood and lymphatic system disorders

Very rare: Leukopenia / Neutropenia, thrombocytopenia.

Leukopenia / Neutropenia is mainly reported in immunocompromised patients.

Immune system disorders

Very rare: Anaphylaxis.

Psychiatric and nervous system disorders

Common: *Headache

Rare: Dizziness, confusion, hallucinations, decreased consciousness.

Very rare: Agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma.

The above events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors. In renal transplant patients receiving high doses (8 g daily) of Valtrex for CMV prophylaxis, psychiatric reactions (confusion, hallucinations and thinking disorders) occurred more frequently compared with lower doses for other indications. They were mainly mild to moderate in nature, reversible upon dose adjustment, and occurred mainly in the immediate post-transplant period. Therefore, it is important to monitor creatinine clearance frequently in these patients, and to adjust the dose accordingly. The cause of these events appears to be multi-factorial, including the over-exposure to aciclovir, renal impairment, dialysis, administration of psychotropic agents, and other underlying medical conditions.

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea.

Gastrointestinal disorders

Common: *Nausea

Rare: Abdominal discomfort, vomiting, diarrhoea.

Hepato-biliary disorders

Very rare: Reversible increases in liver function tests.

These are occasionally described as hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: Rashes including photosensitivity.

Rare: Pruritus.

Very rare: Urticaria, angioedema.

Renal and urinary disorders

Rare: Renal impairment.

Very rare: Acute renal failure, renal pain.

Renal pain may be associated with renal failure.

Other: 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 doses (8 g 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.

* Clinical trial data have been used to assign frequency categories to these adverse reactions. For all other adverse events, spontaneous post-marketing data has been used as a basis for allocating frequency.

Manufacturer

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