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Acyclovir


Acyclovir

is used to treat infections caused by certain types of viruses. It treats

cold sores

around the mouth (caused by herpes simplex), shingles (caused by herpes zoster), and chickenpox.

Acyclovir

is also used to treat outbreaks of genital herpes.
Dosing
Adult dosing:
Important Note:
Orphan drug designation: Treatment of acute herpetic keratitis caused by Herpes Simplex Virus type 1 and 2

Bell’s palsy:
400 mg orally 5 times daily for 10 days plus prednisone 1 mg/kg (minimum dose, 30 mg) orally twice daily for the first 5 days, followed by a gradual taper down to 5 mg twice daily over the next 5 days (off-label dosage)

Eczema herpeticum:
200 mg orally 5 times daily for 5 days

Genital herpes simplex:
Oral:
Initial episode: 200 mg orally every 4 hours 5 times per day for 10 days (FDA dosage)

Oral:
Initial episode: 400 mg orally 3 times per day for 7 to 10 days
200 mg orally 5 times daily for 7 to 10 days; may extend duration of therapy if healing is not complete after 10 days (guideline dosage)

Oral:
Episodic therapy: 200 mg orally every 4 hours, 5 times daily for 5 days
Initiate therapy at the earliest sign or symptom of recurrence (FDA dosage)

Oral:
Episodic therapy: 400 mg orally 3 times daily for 5 days
800 mg orally twice daily for 5 days
800 mg orally 3 times daily for 2 days; initiate treatment preferably within 1 day of lesion onset or during preceding prodrome (guideline dosage)

Oral:
Suppressive therapy: 400 mg orally twice daily for up to 12 months

Topical:
Initial therapy: Apply ointment topically every 3 hours (6 times per day) for 7 days in sufficient quantities to adequately cover lesion

Genital herpes simplex – HIV infection:
Initial or recurrent:
400 mg orally 3 times daily for 5 to 14 days (guideline dosage)

Chronic suppressive therapy:
400 mg orally twice daily (guideline dosage)

Herpes labialis – HIV infection:
400 mg orally 3 times daily for 5 to 10 days (guideline dosage)

Chronic suppressive therapy:
400 mg orally twice daily (guideline dosage)

Herpes simplex, Non-Life Threatening Mucocutaneous Infections – Patient immunocompromised:
Apply ointment topically (using a finger cot or glove) every 3 hours (6 times per day) for 7 days in sufficient quantities to adequately cover lesions (manufacturer dosing). The CDC discourages the use of topical therapy.

Herpes zoster, Shingles:
800 mg orally every 4 hours (5 times a day) for 7 to 10 days

Herpes zoster, Shingles – HIV infection:
Acute localized dermatome:
800 mg orally 5 times daily for 7 to 10 days (guideline dosage)

HIV infection – Varicella:
Uncomplicated cases:
20 mg/kg (Maximum, 800 mg per dose) orally 5 times daily for 5 to 7 days (guideline dosage)

Ophthalmic herpes simplex:
Topical:
3% ophthalmic ointment applied 5 times daily for 7 to 10 days (off-label dosage)

Oral:
400 mg orally 5 times daily (off-label dosage)

Recurrent herpes simplex labialis:
Buccal tablet:
Place one 50-mg tablet buccally in upper gum above incisor tooth (canine fossa) and hold with slight pressure for 30 seconds

Cream:
Apply cream topically 5 times per day for 4 days

Varicella:
800 mg orally 4 times a day for 5 days

Varicella-zoster virus infection; Prophylaxis:
(Infection as a result of vaccination and post-exposure prophylaxis) 800 mg orally 5 times a day for 5 to 7 days; for post-exposure prophylaxis, begin treatment 7 to 10 days after exposure (guideline dosage)

Pediatric dosing:
Important Note:
Orphan drug designation: Treatment of acute herpetic keratitis caused by Herpes Simplex Virus type 1 and 2

General Dosage Information:
Buccal tablet:
Safety and effectiveness not established in pediatric patients

Capsule, tablet, suspension:
Safety and effectiveness of oral acyclovir formulations not established in pediatric patients younger than 2 years

Topical cream:
Safety and effectiveness not established in pediatric patients younger than 12 years

Topical ointment:
Safety and effectiveness not established in pediatric patients

Eczema herpeticum:
25 to 30 mg/kg/day orally in 5 divided doses (study dose)

Genital herpes simplex – HIV infection:
Less than 45 kg:
20 mg/kg orally 3 times daily for 5 to 14 days
Maximum 400 mg/dose (guideline dose)

Adolescents:
400 mg orally twice daily for 5 to 14 days (guideline dose)

Herpes labialis – HIV infection:
Mild symptomatic gingivostomatitis:
20 mg/kg orally 3 times daily for 5 to 10 days
Maximum 400 mg/dose (guideline dosage)

HIV infection – Varicella:
Mild disease with no or moderate immune suppression, CDC immunologic categories 1 and 2:
20 mg/kg (Maximum, 800 mg per dose) orally 4 times daily for 7 to 10 days or until no new lesions appear for 48 hours (guideline dose)

Recurrent herpes simplex labialis:
12 years or older:
Apply cream topically 5 times per day for 4 days

Varicella:
2 years or older, 40 kg or less:
20 mg/kg orally 4 times a day for 5 days

2 years or older, more than 40 kg:
800 mg orally 4 times a day for 5 days

Indications
FDA-Labeled Indications:
Genital herpes simplex
Herpes simplex, Non-Life Threatening Mucocutaneous Infections – Patient immunocompromised
Herpes zoster, Shingles
Recurrent herpes simplex labialis
Varicella

Non-FDA Labeled Indications:
Acute retinal necrosis
Bell’s palsy
Chickenpox pneumonia
Eczema herpeticum
Genital herpes simplex – HIV infection
Herpes labialis – HIV infection
Herpes zoster, Shingles – HIV infection
Herpes zoster; Prophylaxis – Patient immunocompromised
Herpes zoster auricularis
HIV infection – Varicella
Ophthalmic herpes simplex
Varicella-zoster virus infection; Prophylaxis
Mechanism of Action

Acyclovir

is a synthetic purine nucleoside analog with inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).

Acyclovir

triphosphate, a converted form of

acyclovir

, stops replication of herpes viral DNA by competitive inhibition of viral DNA polymerase, incorporation into and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.
Adverse Effect
Common:
Dermatologic:
Contact dermatitis (topical cream, 2%)

Gastrointestinal:
Diarrhea (2.4% to 3.2%)
Nausea (2.7% to 4.8%)
Vomiting

Neurologic:
Headache (2.2%)

Other:
Malaise (11.5%)

Serious:
Hematologic:
Thrombotic thrombocytopenic purpura
Hemolytic Uremic Syndrome

Renal:
Renal failure

Contraindication
Hypersensitivity to acyclovir, milk protein concentrate, or any other component of the product with the buccal tablet
Hypersensitivity to acyclovir or valacyclovir with oral capsule, tablet, or suspension, or any component of the product with the topical cream
Hypersensitivity to any component of the product with the topical ointment
Interaction
Major:
Foscarnet (theoretical)
Tolvaptan (theoretical)

Moderate:
Fosphenytoin (probable)
Phenytoin (probable)
Valproic Acid (probable)

Phamacokinetics
Absorption:
Time for Maximum Plasma Concentration (Tmax):
Oral: 1.7 hours
Buccal: 8 hours (salivary)

Bioavailability:
Oral: 10% to 20%, decreases with increasing dose
Topical: minimal
Buccal: minimal

Effect of food: No effect on absorption

Distribution:
Plasma Protein binding: 9% to 33%

Volume of Distribution (Vd):
Adults: 48 L/m(2) (range, 37 to 57 L/m(2))
Children and adolescents: 45 L/m(2)
Neonates: 28 L/m(2) (range, 24 to 30 L/m(2))

Metabolism:
Metabolite:
9-(carboxy methoxy) methyl guanine (inactive)
8-hydroxy-acyclovir (inactive)

Excretion:
Fecal:
Oral: 2%

Renal:
Oral: extensive
Topical, cream: 0.04% of daily-applied dose
Topical, ointment: less than 0.02% to 9.4% of daily applied dose

Dialyzable:
Hemodialysis: Yes, 60% decrease in plasma concentrations following 6-hour dialysis period; Peritoneal dialysis: No, less than 10% is removed

Other extracorporeal:
Plasmapheresis: No
Exchange transfusion: No
Hemofiltration: No

Elimination:
2.5 to 3.3 hours
Neonates 0 to 3 months: 4 hours

Precaution
Dermatologic:
Contact sensitization or irritation has been reported with topical cream
Cutaneous use only; avoid contact with eyes when using topical ointment or cream, the inside of the mouth, or nose with topical cream

Hematologic:
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), resulting in fatalities, has been reported in immunocompromised patients with oral capsule, tablet, and suspension

Renal:
Renal failure, with some fatal cases, has been reported with oral capsule, tablet, and suspension
Renal impairment; dose adjustment recommended, and maintain adequate hydration when using oral capsule, tablet, or suspension

Pregnancy Category
B (FDA)
B3 (AUS)
Breast Feeding
AAP: Maternal medication usually compatible with breastfeeding.
Monitoring
Genital herpes:
Reduction in the duration of acute genital herpes infection, lesion healing, pain, and viral shedding is indicative of efficacy; long-term therapy effectiveness is measured by the prevention or reduction in the frequency or severity of genital herpes recurrence

Need for continued treatment; after one year of therapy

Herpes labialis (cold sores):
Reduction in mean duration of recurrent episode and prevention of cold sore lesion progression are indicative of efficacy

Herpes zoster (shingles):
Reduced duration of viral shedding and new lesion formation, shortened time to complete cessation of pain, lesion scabbing and healing, and decreased incidence of shingles-related neurologic symptoms (i.e., paresthesia, dysesthesia, hyperesthesia) are indicative of efficacy

Varicella (chickenpox):
Shortened time to rash healing, reduction in number of lesions, vesicles, and residual lesions, and alleviation of fever, anorexia, and lethargy are indicative of efficacy

How to Take or Administration
Buccal:
Do not crush, chew, suck, or swallow buccal tablet

Apply within 1 hour after onset of prodromal symptoms and before signs of lesions appear

Place with dry finger immediately after removing from blister; place on upper gum just above incisor tooth (canine fossa) on the same side of mouth as symptoms; face rounded side of tablet towards gum for comfort, but either side of tablet can be applied; hold with slight pressure for 30 seconds for adhesion

If tablet does not adhere or falls off within first 6 hours, reapply the same tablet immediately; if repositioning fails, place a new tablet

If tablet is swallowed within first 6 hours, drink a glass of water and apply a new tablet; if tablet falls off or is swallowed after the first 6 hours, reapplication is not needed

Oral:
Take with or without food
(Suspension) shake well before measuring each dose

Topical:
Ointment:
Apply sufficient quantity with finger cot or rubber glove to adequately cover lesions; dose size per application should approximate a one-half inch ribbon per 4 square inches of surface area

Dosage Form
Oral Capsule:
200 MG

Oral Suspension:
200 MG/5 ML

Oral Tablet:
400 MG
800 MG

Topical Ointment:
5 %
Topical Cream:
5 %

Treatment
Management of Mild to Moderate Toxicity:
Patients generally do well with supportive care. Nausea and vomiting should be treated with antiemetics. Rashes should be treated with supportive care, discontinuation of the offending agent, and consideration of antihistamines and corticosteroids. With massive overdose, hydrate patients and monitor renal function.

Management of Severe Toxicity:
Supportive care remains the mainstay of care in severe toxicity. Seizures should be treated with benzodiazepines as first line therapy, followed by barbiturates or propofol, if seizures persist. Hydrate patients and monitor urine output and renal function. Airway protection should be employed as need for patients with coma.

Toxicology
A toxic dose has not been established for these agents.
Acyclovir:
Adult: Overdose ingestions up to 20 grams have been reported associated with the development of lethargy, agitation, seizures, and coma.

Pediatric:
A 2-year-old received 800 mg acyclovir IV and developed transient neurotoxicity, but recovered. Two neonates, who received 65 mg/kg and 100 mg/kg acyclovir IV, had no evidence of toxicity. Transient nephrotoxicity developed in a neonate who received acyclovir 100 mg/kg IV three times daily for 4 days, and another who received 750 mg/kg IV.

Patient Counselling or Clinical Teaching
Advise patient to maintain adequate hydration with oral therapy to prevent renal toxicity.
Counsel patient that acyclovir does not prevent reinfection or disease transmission with genital herpes.
Instruct patient to abstain from sex during acute outbreaks of genital herpes and to always use condoms, as the disease can also be transmitted in the absence of symptoms.
The oral form may cause diarrhea, nausea, vomiting, malaise, or renal failure.
The buccal form may cause headache and application site pain.
The topical form may cause local application reactions such as a burning sensation, dryness (cream), pruritus, or stinging.
Elderly patients may experience more neurological adverse effects such as confusion, dizziness, somnolence, or hallucinations with oral therapy.
Advise patient to initiate treatment as soon as possible after diagnosis, at earliest sign or symptom of a breakout, or within 1 hour after the first symptom but before a cold sore appears.
Instruct patient to apply the buccal mucosa tablet to the area of the upper gum above the incisor tooth (not to the inside of the lip or cheek) and on the same side of the mouth as the herpes labialis symptoms.
Advise patient that if the buccal mucosa table does not stick or falls off of the upper gum within the first 6 hours of applying it, the same tablet should be placed back onto the upper gum right away. If this tablet does not stay in place, another tablet should be applied to the upper gum.
Inform patient that if the buccal mucosa tablet is swallowed with the first 6 hours of applying it, the patient should drink a glass of water and apply a new tablet to the upper gum. However, if the tablet falls out or is swallowed after the first 6 hours or more of it being in place, it should not be reapplied.
Instruct patient that topical ointment or cream should only be used on the affected external aspects of the lips and face and is not to be used in the eye, or inside the mouth or nose.
Advice patient ointment application should be performed with a finger cot or rubber glove to prevent transmission of virus.
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