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ValACYclovir

Pronunciation

Pronunciation

(val ay SYE kloe veer)

Index Terms

  • Valacyclovir HCl
  • Valacyclovir Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Valtrex: 500 mg [contains fd&c blue #2 aluminum lake]

Valtrex: 1 g [scored; contains fd&c blue #2 aluminum lake]

Generic: 500 mg, 1 g

Brand Names: U.S.

  • Valtrex

Pharmacologic Category

  • Antiviral Agent
  • Antiviral Agent, Oral

Pharmacology

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

Absorption

Rapid

Distribution

Acyclovir is widely distributed throughout the body including brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, and CSF

Metabolism

Hepatic; valacyclovir is rapidly and nearly completely converted to acyclovir and L-valine by first-pass effect; acyclovir is hepatically metabolized to a very small extent by aldehyde oxidase and by alcohol and aldehyde dehydrogenase (inactive metabolites)

Excretion

Urine, primarily as acyclovir (89%); Note: Following oral administration of radiolabeled valacyclovir, 46% of the label is eliminated in the feces (corresponding to nonabsorbed drug), while 47% of the radiolabel is eliminated in the urine.

Time to Peak

Children: 1.4 to 2.6 hours; Adults: 1.5 hours

Half-Life Elimination

Normal renal function: Children: 1.3 to 2.5 hours, slower clearance with increased age; Adults: 2.5 to 3.3 hours (acyclovir), ~30 minutes (valacyclovir); End-stage renal disease: 14 to 20 hours (acyclovir); During hemodialysis: 4 hours

Protein Binding

~14% to 18%

Special Populations: Children

Cmax ~4.2 mcg/mL in children 1 month to <12 years of age.

Use: Labeled Indications

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

Use: Unlabeled

Prophylaxis of cancer-related HSV, VZV, and CMV infections; treatment of cancer-related HSV, VZV infection; CMV prophylaxis in allogeneic HSCT recipients

Contraindications

Hypersensitivity to valacyclovir, acyclovir, or any component of the formulation

Dosing: Adult

CMV prophylaxis in allogeneic HSCT recipients (off-label use): 2 g 4 times daily

Herpes labialis (cold sores): Oral: 2 g twice daily for 1 day (separate doses by ~12 hours)

Herpes labialis (cold sores) in HIV-infected patients (off-label use): Oral: 1 g twice daily for 5 to 10 days (HHS [OI adult 2015])

Herpes zoster (shingles): Oral:

Immunocompetent patients: 1 g 3 times daily for 7 days

HIV-infected patients (off-label use): 1 g 3 times daily for 7 to 10 days; consider longer duration if lesions resolve slowly.

HSV, VZV in cancer patients (off-label use):

Prophylaxis: 500 mg 2-3 times daily

Treatment: 1 g 3 times daily

Herpes simplex virus, genital infection: Oral:

Manufacturer’s labeling:

Initial episode: Immunocompetent patients: 1 g twice daily for 10 days

Recurrent episode: Immunocompetent patients: 500 mg twice daily for 3 days

Reduction of transmission: 500 mg once daily (source partner)

Suppressive therapy:

Immunocompetent patients: 1 g once daily (500 mg once daily in patients with ≤9 recurrences per year)

HIV-infected patients (CD4 ≥100 cells/mm3): 500 mg twice daily

Alternate dosing: HIV-infected patients:

Initial or recurrent episodes (off-label use): 1 g twice daily for 5 to 14 days (HHS [OI adult 2015])

Chronic suppressive therapy: 500 mg twice daily; continue indefinitely regardless of CD4 count in patients with severe recurrences or in patients who want to minimize frequency of recurrences (HHS [OI adult 2015])

Varicella (chickenpox) in HIV-infected patients (off-label use): 1 g 3 times daily for 5 to 7 days in uncomplicated cases (HHS [OI adult 2015])

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Herpes labialis (cold sores): Oral: Children ≥12 years and Adolescents: Refer to adult dosing.

Herpes labialis (cold sores) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Herpes simplex virus, genital infection in HIV-infected patients: Adolescents (off-label population): Oral:

Initial or recurrent episodes (off-label use): 1 g twice daily for 5 to 14 days (HHS [OI adult 2015])

Chronic suppressive therapy (off-label dose): 500 mg twice daily; continue indefinitely regardless of CD4 count in patients with severe recurrences or in patients who want to minimize frequency of recurrences (HHS [OI adult 2015])

Herpes zoster (shingles) in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Varicella (chickenpox): Oral:

Immunocompetent patients: Children ≥2 years and Adolescents: 20 mg/kg/dose 3 times daily for 5 days (maximum: 1 g 3 times daily)

HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

Herpes zoster: Adults:

CrCl 30 to 49 mL/minute: 1 g every 12 hours

CrCl 10 to 29 mL/minute: 1 g every 24 hours

CrCl <10 mL/minute: 500 mg every 24 hours

Genital herpes: Adults:

U.S. labeling:

Initial episode:

CrCl 10 to 29 mL/minute: 1 g every 24 hours

CrCl <10 mL/minute: 500 mg every 24 hours

Recurrent episode: CrCl <29 mL/minute: 500 mg every 24 hours

Suppressive therapy: CrCl <29 mL/minute:

For usual dose of 1 g every 24 hours, decrease dose to 500 mg every 24 hours

For usual dose of 500 mg every 24 hours, decrease dose to 500 mg every 48 hours

HIV-infected patients: 500 mg every 24 hours

Canadian labeling:

Initial episode:

CrCl 10 to 29 mL/minute: 1 g every 24 hours

CrCl <10 mL/minute: 500 mg every 24 hours

Recurrent episode:

CrCl 10 to 29 mL/minute: 500 mg every 24 hours

CrCl <10 mL/minute: 500 mg every 24 hours

Suppressive therapy:

CrCl 10 to 29 mL/minute:

Immunocompetent or HIV-infected patients: 500 mg every 24 hours

Immunocompetent patients with ≤9 recurrences/year: 500 mg every 48 hours

CrCl <10 mL/minute:

Immunocompetent or HIV-infected patients: 500 mg every 24 hours

Immunocompetent patients with ≤9 recurrences/year: 500 mg every 48 hours

Herpes labialis: Adolescents and Adults (U.S. labeling) or Adults (Canadian labeling):

CrCl 30 to 49 mL/minute: 1 g every 12 hours for 2 doses

CrCl 10 to 29 mL/minute: 500 mg every 12 hours for 2 doses

CrCl <10 mL/minute: 500 mg as a single dose

Hemodialysis: Dialyzable (~33% removed during 4-hour session); administer dose postdialysis

Chronic ambulatory peritoneal dialysis/continuous arteriovenous hemofiltration dialysis: Pharmacokinetic parameters are similar to those in patients with ESRD; supplemental dose not needed following dialysis

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Extemporaneously Prepared

A 50 mg/mL oral suspension may be made with caplets and either Ora-Sweet® or Ora-Sweet SF®. Crush eighteen 500 mg caplets in a mortar and reduce to a fine powder. Add 5 mL portions of chosen vehicle (40 mL total) and mix to a uniform paste; transfer to a 180 mL calibrated amber glass bottle, rinse mortar with 10 mL of vehicle 5 times, and add quantity of vehicle sufficient to make 180 mL. Label "shake well" and "refrigerate". Stable for 21 days refrigerated.

Fish DN, Vidaurri VA, and Deeter RG, "Stability of Valacyclovir Hydrochloride in Extemporaneously Prepared Oral Liquids," Am J Health Syst Pharm, 1999, 56(19):1957-60.10554914

Administration

If GI upset occurs, administer with meals.

Dietary Considerations

May be taken with or without food.

Storage

Store at 15°C to 25°C (59°F to 77°F).

Drug Interactions

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Acyclovir-Valacyclovir. Avoid combination

Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Talimogene Laherparepvec: Antiherpetic Antivirals may diminish the therapeutic effect of Talimogene Laherparepvec. Monitor therapy

Tenofovir Products: Acyclovir-Valacyclovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Varicella Virus Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Varicella Virus Vaccine. Management: When possible, avoid use of acyclovir or valacyclovir within the 24 hours prior to administration of the varicella vaccine, and avoid use of these antiviral agents for 14 days after vaccination. Avoid combination

Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Monitor therapy

Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (13% to 38%)

Gastrointestinal: Nausea (5% to 15%), abdominal pain (1% to 11%)

Hepatic: Increased serum AST (2% to 16%), increased serum ALT (≤14%)

Respiratory: Nasopharyngitis (≤16%)

1% to 10%:

Central nervous system: Fatigue (≤8%), depression (≤7%), dizziness (2% to 4%)

Dermatologic: Skin rash (≤8%)

Endocrine & metabolic: Dehydration (children: 2%)

Gastrointestinal: Vomiting (≤6%), diarrhea (children: 5%; adults: <1%)

Genitourinary: Dysmenorrhea (≤8%)

Hematologic & oncologic: Thrombocytopenia (≤3%), leukopenia (≤1%; mild)

Hepatic: Increased serum alkaline phosphatase (≤4%)

Infection: Herpes simplex infection (children: 2%)

Neuromuscular & skeletal: Arthralgia (≤6%)

Respiratory: Rhinorrhea (children: 2%)

Miscellaneous: Fever (children: 4%)

<1% (Limited to important or life-threatening): Aggressive behavior, agitation, alopecia, anemia, aplastic anemia, ataxia, brain disease, coma, confusion, delirium, dysarthria, erythema multiforme, facial edema, hallucination (auditory and visual), hemolytic-uremic syndrome, hepatitis, hypersensitivity reaction (acute; includes anaphylaxis, angioedema, dyspnea, pruritus, skin rash, urticaria), hypertension, hypersensitivity angiitis, increased serum creatinine, loss of consciousness, mania, psychosis, renal failure, renal pain, seizure, skin photosensitivity, tachycardia, thrombotic thrombocytopenic purpura, tremor, urinary urgency, visual disturbance

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: CNS adverse effects (including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy) have been reported in both adult and pediatric patients with or without renal dysfunction. Elderly patients are more likely to experience CNS adverse effects.

• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: Has occurred in immunocompromised patients (at doses of 8 g/day).

Disease-related concerns:

• Renal impairment: Use caution in patients with renal impairment, the elderly, and/or those receiving nephrotoxic agents. Acute renal failure and CNS effects have been observed in patients with renal dysfunction; dose adjustment may be required. Precipitation in renal tubules may occur; maintain adequate hydration.

Special populations:

• Elderly: Use with caution in the elderly; CNS effects have been reported.

• Immunocompromised patients: Advanced HIV (CD4 <100 cells/mm3): Safety and efficacy have not been established for treatment/suppression of recurrent genital herpes or disseminated herpes in patients with profound immunosuppression.

Other warnings/precautions:

• Appropriate use: For cold sores, treatment should begin with earliest symptom (tingling, itching, burning). 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). For herpes zoster, treatment should begin within 72 hours of onset of rash. For chickenpox, treatment should begin with earliest sign or symptom.

Monitoring Parameters

Urinalysis, BUN, serum creatinine, liver enzymes, and CBC

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Valacyclovir is metabolized to acyclovir. In a pharmacokinetic study, maternal acyclovir serum concentrations were higher in pregnant women receiving valacyclovir than those given acyclovir for the suppression of recurrent herpes simplex virus (HSV) infection late in pregnancy. Amniotic fluid concentrations were also higher; however, there was no evidence that fetal exposure differed between the groups (Kimberlin, 1998). Data from an acyclovir pregnancy registry has shown no increased rate of birth defects than that of the general population; however, the registry is small and the manufacturer notes that use during pregnancy is only warranted if the potential benefit to the mother justifies the risk of the fetus. Because more data is available for acyclovir, that agent is preferred for the treatment of genital herpes in pregnant women (ACOG 2000; CDC 2010); however, valacyclovir may be considered for use due to its simplified dosing schedule (DHHS 2013). Pregnant women who have a history of genital herpes recurrence, suppressive therapy is recommended starting at 36 weeks gestation (ACOG 2000; DHHS 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, vomiting, dizziness, fatigue, or abdominal pain. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), confusion, behavioral changes, mood changes, hallucinations, tremors, difficulty moving, rigidity, or signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; feeling very tired or weak; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; vision changes; change in strength on one side is greater than the other, trouble speaking or thinking, change in balance; or fever) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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