Alaclov Tablet

Valacyclovir

Indications

Varicella zoster virus (VZV) infections: Alaclov is indicated for the treatment of herpes zoster (shingles) and ophthalmic zoster in immunocompetent adults. It also is indicated for the treatment of herpes zoster in adult patients with mild or moderate immunosuppression. Herpes simplex virus (HSV) infections

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.
• Cytomegalovirus (CMV) infections Alaclov is indicated for the prophylaxis of CMV infection and disease following solid organ transplantation in adults and adolescents.

Pharmacology

Valacyclovir is the hydrochloride salt of L-valyl ester of the antiviral drug acyclovir. Valacyclovir is an antiviral drug. It slows the growth and spread of the herpes virus so that the body can fight off the infection. Valacyclovir lessens the symptoms of infections and shortens the length of time of sickness. Valacyclovir is used in the treatment and suppression of genital herpes, shingles and cold sores.

Dosage & Administration

Varicella zoster virus (VZV) infections- herpes 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 Valacyclovir 1000mg (1 Valacyclovir 1000mg tablet) three times daily for 7 days (3000mg total daily dose).

Immunocompromised Adults: The dose in immunocompromised patients is Valacyclovir 1000mg (1 Valacyclovir 1000mg tablet) 3 times daily for at least 7 days (3000mg total daily dose) and for 2 days following crusting of lesions. 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 (³12 years): The dose is Valacyclovir 500mg (1 Valacyclovir 500mg tablet) to be taken twice daily (1000mg total daily dose). This dose should be reduced according to creatinine clearance. For recurrent episodes, treatment should be for 3 to 5 days. For initial episodes, which can be more severe, treatment may have to be extended to 10 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. Valacyclovir can prevent lesion development when taken at the first signs and symptoms of an HSV recurrence.

Herpes labialis: For herpes labialis (cold sores), Valacyclovir 2000mg (2 Valacyclovir 1000mg tablet) 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. 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: The dosage is Valacyclovir 1000mg (1 Valacyclovir 1000mg tablet) 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. 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 Valacyclovir 500mg (1 Valacyclovir 500mg tablet) 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 Valacyclovir 500mg (1 Valacyclovir 500mg tablet) being taken as a divided dose (250mg twice daily). Treatment should be re-evaluated after 6 to 12 months of therapy.

Immunocompromised Adults: The dose is Valacyclovir 500mg (1 Valacyclovir 500mg tablet) twice daily. 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 Valacyclovir is 2000mg (2 Valacyclovir 1000 mg tablet) four times a day, to be initiated as early as possible post-transplant. This dose should be reduced according to creatinine clearance.The duration of treatment will usually be 90 days, but may need to be extended in high-risk patients.

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Interaction

The combination of Alaclov 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 1000mg Alaclov, 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 Alaclov 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, Alaclov administration may increase plasma concentrations of the concurrently administered substance. In patients receiving higher aciclovir exposures from Alaclov, 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 mycophenolatemotefil have been shown when the drugs are co-administered. No changes in peak concentrations or AUCs are observed with co-administration of Alaclov and mycophenolatemofetil in healthy volunteers. There is limited clinical experience with the use of Alaclov.

Contraindications

Hypersensitivity to Valacyclovir or aciclovir or any of the excipients.

Side Effects

The most common side effects reported in at least one indication by patients treated with Alaclov in clinical trials were headache and nausea. Other side effects include: Blood and lymphatic system disorders: leucopenia, thrombocytopenia, Leucopenia is mainly reported in immunocompromised patients. Immune system disorders: Anaphylaxis. Psychiatric and nervous system disorders: Dizziness, confusion, hallucinations, decreased concentrations, tremor, agitation, ataxia, dysarthria, convulsions, encephalopathy, coma, psychotic symptoms. Respiratory disorders: Dyspnea. Gastrointestinal disorders: Vomiting, diarrhea, abdominal discomfort. Hepato-biliary disorders: Reversible increases in liver function tests. Skin and subcutaneous tissue disorders: Rashes including photosensitivity, pruritus, urticaria. Renal system disorders: Renal pain, renal impairment (especially in elderly patients or in patients with renal impairment receiving higher than the recommended doses). Renal pain may be associated with renal failure.

Pregnancy & Lactation

A limited amount of data on the use of Valacyclovir and a moderate amount of data on the use of aciclovir in pregnancy is available from pregnancy registries and postmarketing experience indicate no malformative or foeto/neonatal toxicity. Animal studies do not show reproductive toxicity for Valacyclovir. Valacyclovir should only be used in pregnancy if the potential benefits of treatment outweigh the potential risk. Use in lactation: Aciclovir, the principle metabolite of Valacyclovir, is excreted in breast milk. However, at therapeutic doses of Valacyclovir, 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. Valacyclovir should be used with caution during breast feeding and only when clinically indicated.

Precautions & Warnings

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 Alaclov 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 dose of Alaclov in hepatic impairment and liver transplantation: There are no data available on the use of higher doses of Alaclov (4000mg or more per day) in patients with liver disease. Specific studies of Alaclov have not been conducted in liver transplantation, and hence caution should be exercised when administering daily doses greater than 4000mg 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, immunocom-promised 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.

Use of 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 Alaclov from transplant patients at high risk of CMV disease indicate that Alaclov should only be used in these patients when safety concerns preclude the use of valganciclovir or ganciclovir. High dose Alaclov as required for CMV prophylaxis may result in more frequent adverse events than observed with lower doses administered for other indications. Patients should be closely monitored for changes in renal function, and doses adjusted accordingly.

Overdose Effects

Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma have been reported in patients receiving overdoses of Alaclov. 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. Hemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

Therapeutic Class

Herpes simplex & Varicella-zoster virus infections

Storage Conditions

Store in cool & dry place, away from children.