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Drug Details

Valtrex Tablets 500mg

• Drug Class Description
  Nucleosides and nucleotides excluding reverse transcriptase inhibitors, ATC code: J05AB11.
• Generic Name
  valaciclovir hydrochloride
• Presentation
  Film-coated tablet 500 mg tablet White, biconvex, elongated tablet with a white to off-white core, engraved “GX CF1” on one side.
• Description
  Each tablet contains valaciclovir hydrochloride equivalent to 500 mg valaciclovir
• Indications
  Valtrex is indicated for the treatment of herpes zoster (shingles). Valtrex is indicated for the treatment of herpes simplex infections of the skin and mucous membranes, including initial and recurrent genital herpes. Valtrex is indicated for the suppression (prevention) of recurrent herpes simplex infections of the skin and mucous membranes, including genital herpes. Valtrex can reduce transmission of genital herpes when taken as suppressive therapy and combined with safer sex practices (particularly the use of condoms). Valtrex is indicated for the prophylaxis of cytomegalovirus (CMV) infection and disease, following renal transplantation.
• 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.

   

  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 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
  

  The efficacy of Valtrex in children below the age of 12 years has not been evaluated.

• Elderly Dosage
  

  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.

• Contra Indications
  

  Valtrex is contra-indicated in patients known to be hypersensitive to valaciclovir, aciclovir or any components of formulations of Valtrex.

• 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 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).

  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
  

  No clinically significant interactions have been identified.

  Aciclovir is eliminated primarily unchanged in the urine via active tubular secretion. Any drugs administered concurrently that compete with this mechanism for elimination may increase aciclovir plasma concentrations following Valtrex administration.

  In patients receiving high dose Valtrex (4g/day) for CMV prophylaxis, caution is required during concurrent administration with drugs which compete with aciclovir elimination, because of the potential for increased plasma levels of one or both drugs or their metabolites. Following 1g Valtrex, cimetidine and probenecid increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. However, no dosage adjustment is necessary at this dose of 1g because of the wide therapeutic index of aciclovir. Alternative agents, which do not interact with other agents excreted primarily via the kidney, may be considered for the management of excess gastric acid production and urate-lowering therapy when administering high dose valaciclovir.

  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 coadministered; there is limited clinical experience with the use of this combination.

  Care is also required, with monitoring for changes in renal function, if administering high-doses of Valtrex (4g or more/day) with drugs which affect other aspects of renal physiology (e.g.ciclosporin, tacrolimus).

• 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, delerium.
  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.