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Drug Details

VALTREX Tablets 250mg

• Drug Class Description
  Nucleosides and nucleotides excluding reverse transcriptase inhibitors - ATC code: J05AB11.
• Generic Name
  Valaciclovir hydrochloride
• Presentation
  Film-coated tablet
  
  250 mg tablet
  
  White, biconvex, elongated tablet with a white to off-white core, engraved “GX CE7” on one side.
• Description
  Each tablet contains valaciclovir hydrochloride equivalent to 250 mg valaciclovir
• 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

  - 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), see section Precautions.

  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.

• Child Dosage
  No data is available.
• Elderly Dosage
  Dosage modification is not required unless renal function is significantly impaired (see Dosage in renal impairment, below). Adequate hydration should be maintained.
• 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 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.

• 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 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.

• Adverse Drug Reactions
  

  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. 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:	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.