Valacyclovir

Valacyclovir is an Antiviral Agent belonging to the Pharmacology class of Guanosine analog

Valacyclovir is used in the treatment of Bell palsy, new onset, Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients, Herpes simplex virus, central nervous system infection; Herpes simplex virus, mucocutaneous infection; Herpes simplex virus, prevention in immunocompromised patients; Herpes zoster, treatment ;Herpes zoster ophthalmicus Varicella, treatment Varicella zoster virus, acute retinal necrosis ;Varicella zoster virus, encephalitis ;Varicella zoster virus, prevention in immunocompromised patients

Valacyclovir is rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 54% (aciclovir) and widely distributed into body organs, muscle, uterus, vagina and CSF and get entersin breast milk (aciclovir). Plasma protein binding: Approx 14-18% which gets converted to aciclovir and L-valine via first-pass intestinal and/or hepatic metabolism. Aciclovir is converted to a small extent by aldehyde oxidase and by alcohol and aldehyde dehydroxegenase to its inactive metabolites and gets excreted mainly via urine (89% as aciclovir; <1% as unchanged drug); faeces (46% as non-absorbed drug). With elimination half-life of approx 30 minutes (valaciclovir); 2.5-3.3 hours (aciclovir)

Valacyclovir is available in the form of dosage forms as Tablets.

Valacyclovir is available in India, France, Japan, and the USA.

Valacyclovir is rapidly and nearly completely converted to Valacyclovir by intestinal and hepatic metabolism. Valacyclovir is converted to Valacyclovir monophosphate by virus-specific thymidine kinase then further converted to Valacyclovir triphosphate by other cellular enzymes. Valacyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

Valacyclovir is available in the form of Tablets.

Valacyclovir is used in the treatment of Bell palsy, Cytomegalovirus, prevention in low-risk allogeneic hematopoietic cell transplant recipients, Herpes simplex virus, central nervous system infection; Herpes simplex virus, mucocutaneous infection; Herpes simplex virus, prevention in immunocompromised patients; Herpes zoster, treatment ;Herpes zoster ophthalmicus Varicella, treatment Varicella zoster virus, acute retinal necrosis ;Varicella zoster virus, encephalitis ;Varicella zoster virus, prevention in immunocompromised patients.

Valacyclovir is rapidly and nearly completely converted to Valacyclovir by intestinal and hepatic metabolism. Valacyclovir is converted to Valacyclovir monophosphate by virus-specific thymidine kinase then further converted to Valacyclovir triphosphate by other cellular enzymes. Valacyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

Valacyclovir is approved for use in the following clinical indications:

Treatment of herpes zoster (shingles) in patients who are immunocompetent; treatment of first-episode and recurrent genital herpes in patients who are immunocompetent; suppression of recurrent genital herpes and reduction of transmission of genital herpes in patients who are immunocompetent; suppression of genital herpes in patients with HIV; treatment of herpes labialis (cold sores); treatment of chickenpox in children who are immunocompetent.

Although not approved there have been certain off labelled uses documented for Valacyclovir which includes:

Bell palsy, new onset; Cytomegalovirus, prevention in allogeneic hematopoietic cell transplant recipients; Herpes simplex virus, meningitis; Herpes simplex virus, prevention in patients who are immunocompromised; Herpes zoster ophthalmicus; Varicella zoster virus, acute retinal necrosis; Varicella zoster virus, prevention in patients who are immunocompromised.

Bell palsy, new onset (adjunctive therapy) (off-label use): Oral: 1 g three times daily for 7 days in combination with corticosteroids; begin within 3 days of symptom onset Note: Antiviral therapy alone is not recommended ; some experts only recommend addition of an antiviral to steroid therapy in patients with severe Bell palsy

Cytomegalovirus, prevention in allogeneic hematopoietic cell transplant recipients (alternative agent) (off-label use): Oral: 2 g three to four times daily, beginning at engraftment and continued to day 100 or 2 g three times daily, started after initial therapy with IV ganciclovir from day −8 to day −2 prior to transplant, and continued until engraftment or longer in patients on glucocorticoids . Note: Combine with screening for CMV reactivation (due to weak activity)

Herpes simplex virus, meningitis (off-label use): Oral: 1 g three times daily, to complete a 10- to 14-day course following clinical improvement with IV Valacyclovir. Note: Not recommended for herpes simplex virus encephalitis, which requires treatment with IV Valacyclovir

Herpes simplex virus, mucocutaneous infection:

Genital:

Patients who are immunocompetent:

Treatment, initial episode: Oral: 1 g twice daily for 7 to 10 days; extend duration if lesion has not healed completely after 10 days.

Treatment, recurrent episode: Oral: 500 mg twice daily for 3 days or 1 g once daily for 5 days. Note: Treatment is most effective when initiated during the prodrome or within 1 day of lesion onset

Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 500 mg or 1 g once daily. Note: Reassess need periodically (eg, annually). The 500 mg daily dose may be less effective in patients who experience very frequent (≥10) recurrences per year

Patients who are immunocompromised (including patients with HIV):

Treatment, initial or recurrent episode: Oral: 1 g twice daily for 5 to 10 days (7 to 10 days for initial episode in patients with HIV); extend treatment duration if lesions have not healed completely after 10 days. Note: Treat severe disease initially with IV Valacyclovir; may switch to Valacyclovir when lesions begin to regress and continue for >10 days total and until lesions have resolved completely

Suppressive therapy (e.g., for severe and/or frequent recurrences): Oral: 500 mg twice daily. Note: Reassess need periodically (e.g., annually).

Pregnant patients:

Treatment, initial episode (alternative agent): Oral: 1 g twice daily for 7 to 10 days; extend duration if lesion has not healed completely after 10 days.

Treatment, recurrent episode (symptomatic) (alternative agent): Oral: 500 mg twice daily for 3 days or 1 g once daily for 5 days. Note: Some experts reserve treatment of recurrent episodes for patients with severe and/or frequent symptoms.

Suppressive therapy, for patients with a genital herpes simplex virus lesion anytime during pregnancy (alternative agent): Oral: 500 mg twice daily, beginning at 36 weeks' gestation and continued until delivery; some experts recommend discontinuing suppressive therapy at the onset of labor. Note: For patients with a primary infection during the third trimester, may consider suppressive therapy earlier than 36 weeks’ gestation .

Orolabial: Note: Initiate therapy at earliest symptom.

Patients who are immunocompetent:

Treatment, initial infection (eg, gingivostomatitis): Oral: 1 g twice daily for 7 to 10 days.

Treatment, recurrent infection (eg, cold sores): Oral: 2 g twice daily for 1 day.

Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 500 mg or 1 g once daily.

Patients who are immunocompromised (including patients with HIV):

Treatment, initial or recurrent infection: Oral: 1 g twice daily for 5 to 10 days and until complete lesion resolution.

Suppressive therapy (eg, for severe and/or frequent recurrences): Oral: 500 mg twice daily. Note: Reassess need periodically (eg, annually)

Herpes simplex virus, prevention in patients who are immunocompromised (off-label use):

Seropositive HCT recipients (allogeneic or autologous) or seropositive patients undergoing leukemia induction chemotherapy: Oral: 500 mg twice daily . Note: Initiate with the chemotherapeutic or conditioning regimen and continue until recovery of WBC count and resolution of mucositis; duration may be extended in patients with frequent recurrences or graft-vs-host disease (GVHD)

Solid organ transplant recipients (patients who are HSV-seropositive who do not require CMV prophylaxis): Oral: 500 mg twice daily for ≥1 mo6nth; some experts recommend continuing for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection.

Herpes zoster (shingles), treatment:

Note: Initiate at earliest sign or symptom. Antiviral treatment is most effective ≤72 hours after rash onset but may be initiated >72 hours in certain situations (eg, new lesions continue to appear); for patients who are immunocompromised, initiate treatment even if >72 hours after symptom onset unless all lesions have crusted.

Acute localized dermatomal lesion(s): Oral: 1 g three times daily for 7 to 10 days; for slowly improving lesions, may extend therapy until resolution. For select patients who are immunocompromised at high risk of dissemination (eg, recent transplant, graft-versus-host disease), some experts suggest regimens used for disseminated zoster

Disseminated zoster (extensive cutaneous lesions or visceral involvement): Oral: Initial therapy with Valacyclovir IV may be switched to Valacyclovir 1 g three times daily to complete a 10- to 14-day course when formation of new lesions has ceased and signs/symptoms of visceral infection are improving

Herpes zoster ophthalmicus (off-label use): Oral: 1 g three times daily for 7 days.

Varicella (chickenpox), uncomplicated, treatment: Oral: 1 g three times daily.

Note: Ideally initiate therapy within 24 hours of symptom onset, but may start later if patient still has active skin lesions; continue treatment for at least 5 to 7 days and until all lesions have crusted . In patients who are immunocompromised (eg, solid organ transplant recipients), some experts recommend a minimum duration of 7 days. Patients who are immunocompromised generally require IV Valacyclovir; however, for patients with uncomplicated or mild disease (<50 lesions), some experts treat with Valacyclovir

Varicella zoster virus, acute retinal necrosis (off-label use): Oral: 1 g three times daily following initial treatment with IV Valacyclovir ; in patients with HIV, duration is ≥14 weeks and intravitreal ganciclovir may be considered.

Varicella zoster virus, prevention in patients who are immunocompromised (off-label use):

HCT recipients (allogeneic and autologous):

Postexposure prophylaxis: Oral: 1 g three times daily; initiate within 96 hours (preferably within 48 hours) of exposure and continue until 22 days after exposure. Note: Indicated following exposure if varicella-zoster immune globulin is unavailable in seronegative HCT recipients who are <24 months after HCT or >24 months after HCT and on immunosuppressive therapy or have chronic GVHD.

Prevention of VZV reactivation in seropositive patients: Oral: 500 mg twice daily for 1 year following transplantation; may extend duration in patients requiring ongoing immunosuppression (some experts continue prophylaxis in these patients until 6 months after discontinuation of all systemic immunosuppression).

Solid organ transplant recipients (patients who are VZV-seropositive who do not require CMV prophylaxis): Oral: 500 mg twice daily for 3 to 6 months after transplantation and during periods of lymphodepletion associated with treatment of rejection.

Valacyclovir is available in various dosage strengths as 200 mg, 50 mg/ml, 200 mg/ 5ml, 400 mg, 800 mg.

Valacyclovir is available in the form of Capsule, Solution, suspension, Tablet, Ointment and Injection.

Dose Adjustment in Kidney patient:

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m²):

Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post-trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients.

Use the indication-specific maximum allowable dose along with therapeutic drug monitoring of Valacyclovir to support Valacyclovir dosing when available

Hemodialysis, intermittent (thrice weekly): Dialyzable (33% removed during 4-hour session).

500 mg every 24 hours; give after dialysis when given on dialysis day.

Peritoneal dialysis: 500 mg every 24 hours.

CRRT:

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.

Usual recommended dose: 500 mg to 1 g every 12 to 24 hours along with therapeutic drug monitoring of Valacyclovir to support Valacyclovir dosing when available; for less severe infections, a maximum daily dose of 1.5 g/day is recommended

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection). Close monitoring of response and adverse reactions (eg, neurotoxicity) due to drug accumulation is important.

Usual recommended dose: 500 mg to 1 g every 12 to 24 hours along with therapeutic drug monitoring of Valacyclovir to support Valacyclovir dosing when available; for less severe infections, a maximum daily dose of 1.5 g/day is recommended

Dose Adjustment in the Pediatric patient:

Herpes simplex virus (HSV), orolabial infection: Note: Initiate at earliest symptom onset.

Patients without HIV: Treatment:

Weight-directed dosing: Limited data available: Infants ≥3 months, Children, and Adolescents: Oral: 20 mg/kg/dose every 12 hours; maximum dose: 1,000 mg/dose. In immunocompetent patients, treat for 5 to 7 days; immunocompromised patients may require 10 to 14 days of therapy.

Fixed dosing: Children ≥12 years and Adolescents: Oral: 2,000 mg every 12 hours for 1 day (2 doses).

Patients with HIV: Limited data available:

Treatment: Adolescents: Oral: 1,000 mg every 12 hours for 5 to 10 days.

Suppressive therapy (eg, for severe or frequent recurrences): Adolescents: Oral: 500 mg every 12 hours; reassess continued need annually

Herpes simplex virus (HSV), genital infection: Limited data available:

First episode; treatment: Children and Adolescents: Oral: 20 mg/kg/dose every 12 hours; maximum dose: 1,000 mg/dose. Treat for 7 to 10 days; some patients may need a longer duration if lesions are incompletely healed.

Recurrent episode; treatment: Note: Most effective if started during prodrome or within 1 day lesion appearance.

Children and Adolescents: Oral: 20 mg/kg/dose every 12 hours; maximum dose: 1,000 mg/dose. Treat for 5 to 10 days. Alternatively, adolescents who are not HIV infected may receive 500 mg every 12 hours for 3 days.

Suppressive therapy:

Patients without HIV: Adolescents: Oral: 20 mg/kg/dose once daily; maximum dose: 500 mg/dose. In adolescents with frequent recurrences (ie, ≥10 per year), doses of 1,000 mg/day may be more effective.

Patients with HIV: Adolescents: Oral: 500 mg every 12 hours; reassess continued need annually

Herpes simplex virus (HSV), prophylaxis in immunocompromised patients (alternative agent): Limited data available:

Hematopoietic cell transplant (HCT) recipients, seropositive:

Children and Adolescents: Note: To prevent early reactivation, begin at initiation of conditioning and continue until engraftment or resolution of mucositis; to prevent late reactivation, continue throughout the first year following HCT

<40 kg: Oral: 250 mg twice daily.

≥40 kg: Oral: 500 mg once or twice daily; use twice-daily dosing in highly suppressed patients (eg, high-dose steroids, T cell depletion).

Solid organ transplant recipients, seropositive: Note: Administer for ≥1 month after transplant and during treatment of rejection episodes.

Children and Adolescents: Oral: 20 mg/kg/dose twice daily; maximum dose: 500 mg/dose

Herpes zoster (shingles; caused by varicella zoster virus [VZV]), treatment:

Note: In immunocompromised patients with extensive lesions, visceral involvement, disseminated disease, or who are <2 years of age, initial parenteral treatment is recommended.

Children ≥2 years and Adolescents: Oral: 20 mg/kg/dose every 8 hours; maximum dose: 1,000 mg/dose. Treat for at least 7 to 10 days and until lesions have crusted over; lesions resolving more slowly may require longer treatment.

Varicella zoster virus (VZV) (chickenpox), prophylaxis in HCT recipients (alternative agent): Limited data available:

Postexposure prophylaxis:

Children and Adolescents: Note: Begin within 48 hours if possible; continue for 22 days postexposure.

<40 kg: Oral: 500 mg every 8 hours.

≥40 kg: Oral: 1,000 mg every 8 hours.

Prevention of VZV reactivation in seropositive patients:

Children and Adolescents:

<40 kg: Oral: 250 or 500 mg every 12 hours .

≥40 kg: Oral: 500 mg every 12 hours

Varicella zoster virus (VZV) (chickenpox), treatment:

Note: Treatment not routinely recommended in otherwise healthy younger children; consider treatment in individuals at high risk for moderate to severe disease (eg, unvaccinated adolescents, patients with chronic cutaneous or pulmonary conditions, patients on long-term salicylate therapy or receiving corticosteroids). Parenteral Valacyclovir is generally recommended for immunocompromised patients; oral therapy may be considered in select cases when outcome is expected t.o be good or as oral step-down therapy.

Infants ≥3 months, Children, and Adolescents <18 years: Limited data available in patients <2 years of age: Oral: 20 mg/kg/dose every 8 hours for 5 days; maximum dose: 1,000 mg/dose; initiate as soon as possible and within 24 hours of rash onset. In immunocompromised patients, treat for 7 to 14 days, dependent upon clinical response; patients with HIV may need 4 to 6 weeks of treatment

Varicella zoster virus, acute retinal necrosis; step-down therapy:

Limited data available: HIV-infected: Adolescents: 1,000 mg every 8 hours for ≥14 weeks (following initial treatment with IV Valacyclovir)

May be taken with meals to reduce GI discomfort.

Valacyclovir may be contraindicated in the following:

Hypersensitivity to Valacyclovir, Valacyclovir, or any component of the formulation.

Disease-related concerns:

• Renal impairment: Use caution in patients with renal impairment; dosage adjustments may be required.

Other warnings/precautions:

• Appropriate use: For genital herpes, treatment should begin as soon as possible after the first signs and symptoms (within 72 hours of onset of first diagnosis or within 24 hours of onset of recurrent episodes).

Valacyclovir is rapidly metabolized to Valacyclovir. Following administration of Valacyclovir, Valacyclovir is present in breast milk; unchanged Valacyclovir has not been detected in breast milk.

Peak Valacyclovir milk concentrations (1.1 to 6.4 mcg/mL) occurred 4 hours (range: 2 to 4 hours) following maternal administration of a single oral dose of Valacyclovir 500 mg to 5 postpartum females; the half-life of Valacyclovir in breast milk was ~2 hours (range: 1.3 to 12.2 hours). Peak breast milk concentrations were 0.5 to 2.3 times the concentration of Valacyclovir in the maternal serum. Valacyclovir was detected in the urine of breastfeeding infants following 5 days of maternal treatment with Valacyclovir 500 mg twice daily.

Some products may contain sodium.

The adverse reactions related to molecule Valacyclovir can be categorized as

• Common Adverse effects:

Acute renal failure, CNS effects (e.g. agitation, hallucination, confusion, delirium, seizures, encephalopathy). Blood and lymphatic system disorders: Thrombocytopenia, leucopenia. Gastrointestinal disorders: Nausea, abdominal pain, vomiting, diarrhoea.

• Less Common adverse effect:

Increased liver enzymes (reversible), BUN and creatinine. Nervous system disorders: Headache, dizziness. Skin and subcutaneous tissue disorders: Pruritus, rash, photosensitivity, urticaria, accelerated diffuse hair loss. Vascular disorders: Phlebitis (IV).

• Rare adverse effects:

Fatigue, ataxia, fever. Immune system disorders: Urticaria. Rarely, anaphylaxis, angioedema.

The clinically relevant drug interactions of Valacyclovir are briefly summarized here:

• Increased risk of renal impairment with nephrotoxic drugs (e.g. aminoglycosides, organo platinum compounds, iodinated contrast media, methotrexate, pentamidine, foscarnet, ciclosporin, tacrolimus).
• Probenecid and cimetidine may reduce renal clearance of aciclovir.

The common side of Valacyclovir include the following

Contact sensitization (topical). Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain.

The use of Valacyclovir should be prudent in the following group of special populations:

Teratogenic Effects:

Pregnancy Category B.

Valacyclovir was not teratogenic in rats or rabbits given 400 mg/kg (which results in exposures of 10 and 7 times human plasma levels, respectively) during the period of major organogenesis. There are no adequate and well-controlled studies of Valacyclovir in pregnant women. A prospective epidemiologic registry of Valacyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic Valacyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of Valacyclovir in pregnant women and their developing fetuses. Valacyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

There is no experience with Valacyclovir. However, Valacyclovir concentrations have been documented in breast milk in 2 women following oral administration of Valacyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of Valacyclovir as high as 0.3 mg/kg per day. Valacyclovir should be administered to a nursing mother with caution and only when indicated.

Pediatric Use:

Safety and effectiveness of Valacyclovir in pre-pubertal paediatric patients have not been established.

Geriatric Use:

Of the total number of subjects in clinical studies of Valacyclovir, 852 were 65 and over, and 346 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults.

Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, agitation, hallucinations, confusion, delirium, and encephalopathy were reported more frequently in elderly patients Dosage reduction may be required in geriatric patients with underlying renal impairment.

Symptoms:

Acute renal failure, nausea, vomiting, confusion, agitation, hallucinations, decreased consciousness, and coma.

Management:

May consider haemodialysis to enhance removal of acyclovir from the blood.

Pharmacodynamics:

Valacyclovir is rapidly and nearly completely converted to Valacyclovir by intestinal and hepatic metabolism. Valacyclovir is converted to Valacyclovir monophosphate by virus-specific thymidine kinase then further converted to Valacyclovir triphosphate by other cellular enzymes. Valacyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

Pharmacokinetics:

Absorption:

Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 54% (acyclovir).

Distribution:

Widely distributed into body organs, muscle, uterus, vagina and CSF. Enters breast milk (acyclovir). Plasma protein binding: Approx 14-18%.

Metabolism:

Converted to acyclovir and L-valine via first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent by aldehyde oxidase and by alcohol and aldehyde de hydrogenase to its inactive metabolites.

Excretion:

Mainly via urine (89% as acyclovir; <1% as unchanged drug); faeces (46% as non-absorbed drug). Elimination half-life: Approx 30 minutes (valacyclovir); 2.5-3.3 hours (acyclovir). End-stage renal disease: 14-20 hours (acyclovir); During haemodialysis: 4 hours.

• https://www.pfizer.com/products/product-detail/altace
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022021s008lbl.pdf
• https://go.drugbank.com/drugs/DB00178