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standards of non-Merck sources.
Medication Safety Issues
Sound-alike/look-alike issues:
Zovirax® may be confused with Zostrix®, Zyvox®
International issues:
Opthavir® [Mexico] may be confused with Optivar® which is a brand name for azelastine in the U.S.
Pronunciation
(ay SYE kloe veer)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes cream, ointment
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use
Treatment of genital herpes simplex virus (HSV), herpes labialis (cold sores), herpes zoster (shingles), HSV encephalitis, neonatal HSV, mucocutaneous HSV in immunocompromised patients, varicella-zoster (chickenpox)
Use: Dental
Treatment of initial and prophylaxis of recurrent mucosal and cutaneous herpes simplex (HSV-1 and HSV-2) infections in immunocompromised patients
Use: Unlabeled/Investigational
Prevention of HSV reactivation in HIV-positive patients; prevention of HSV reactivation in hematopoietic stem-cell transplant (HSCT); prevention of HSV reactivation during periods of neutropenia in patients with acute leukemia
Pregnancy Risk Factor
B
Pregnancy Implications
Teratogenic effects were not observed in animal studies. Acyclovir has been shown to cross the human placenta. There are no adequate and well-controlled studies in pregnant women. Results from a pregnancy registry, established in 1984 and closed in 1999, did not find an increase in the number of birth defects with exposure to acyclovir when compared to those expected in the general population. However, due to the small size of the registry and lack of long-term data, the manufacturer recommends using during pregnancy with caution and only when clearly needed. Data from the pregnancy registry may be obtained from GlaxoSmithKline.
Lactation
Enters breast milk/use with caution (AAP rates “compatible”)
Breast-Feeding Considerations
Nursing mothers with herpetic lesions near or on the breast should avoid breast-feeding. Limited data suggest exposure to the nursing infant of ?0.3 mg/kg/day following oral administration of acyclovir to the mother.
Contraindications
Hypersensitivity to acyclovir, valacyclovir, or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Renal effects: Renal failure (sometimes fatal) has been reported. Dehydration, pre-existing renal disease and nephrotoxic drugs increase risk; infuse over at least 1 hour to reduce risk of renal tubular damage.
• Thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has been reported.
Disease-related concerns:
• Chickenpox: Appropriate use: Treatment should begin within 24 hours of appearance of rash; oral route not recommended for routine use in otherwise healthy children with varicella, but may be effective in patients at increased risk of moderate to severe infection (>12 years of age, chronic cutaneous or pulmonary disorders, long-term salicylate therapy, corticosteroid therapy).
• Genital herpes: Appropriate use: Physical contact should be avoided when lesions are present; transmission may also occur in the absence of symptoms. Treatment should begin with the first signs or symptoms.
• Herpes labialis: Appropriate use: For external use only to the lips and face; do not apply to eye or inside the mouth or nose. Treatment should begin with the first signs or symptoms.
• Herpes zoster: Appropriate use: Therapy should be started within 72 hours of appearance of rash to be effective.
• Renal impairment: Use with caution in patients with pre-existing renal impairment; dosage adjustments recommended.
Concurrent drug therapy issues:
• Nephrotoxic drugs: Use with caution in patients receiving other nephrotoxic drugs.
Special populations:
• Elderly: Use with caution in the elderly; higher risk for CNS and renal adverse events.
• Immunocompromised patients: Use with caution in immunocompromised patients.
• Pediatrics: Safety and efficacy of oral formulations have not been established in children <2 years of age.
Dosage form specific issues:
• Injection: Use I.V. preparation with caution in patients with underlying neurologic abnormalities, serious hepatic or electrolyte abnormalities, or substantial hypoxia.
Other warnings/precautions:
• Adequate hydration: Maintain adequate hydration during oral or intravenous therapy.
Adverse Reactions
Systemic: Oral:
>10%: Central nervous system: Malaise (12%)
1% to 10%:
Central nervous system: Headache (2%)
Gastrointestinal: Nausea (2% to 5%), vomiting (3%), diarrhea (2% to 3%)
Systemic: Parenteral:
1% to 10%:
Dermatologic: Hives (2%), itching (2%), rash (2%)
Gastrointestinal: Nausea/vomiting (7%)
Hepatic: Liver function tests increased (1% to 2%)
Local: Inflammation at injection site or phlebitis (9%)
Renal: BUN increased (5% to 10%), creatinine increased (5% to 10%), acute renal failure
Topical:
>10%: Dermatologic: Mild pain, burning, or stinging (ointment 30%)
1% to 10%: Dermatologic: Pruritus (ointment 4%), itching
All forms: <1%, postmarketing, and/or case reports: Abdominal pain, aggression, agitation, alopecia, anaphylaxis, anemia, angioedema, anorexia, ataxia, coma, confusion, consciousness decreased, delirium, desquamation, diarrhea, disseminated intravascular coagulopathy (DIC), dizziness, dry lips, dysarthria, encephalopathy, erythema multiforme, fatigue, fever, gastrointestinal distress, hallucinations, hematuria, hemolysis, hepatitis, hyperbilirubinemia, hypotension, insomnia, jaundice, leukocytoclastic vasculitis, leukocytosis, leukopenia, local tissue necrosis (following extravasation), lymphadenopathy, mental depression, myalgia, neutrophilia, paresthesia, peripheral edema, photosensitization, pruritus, psychosis, renal failure, seizure, somnolence, sore throat, Stevens-Johnson syndrome, thrombocytopenia, thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), thrombocytosis, toxic epidermal necrolysis, tremor, urticaria, visual disturbances
Ethanol/Nutrition/Herb Interactions
Food: Does not affect absorption of oral acyclovir.
Storage
Capsule, tablet: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F); protect from moisture.
Cream, suspension: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F).
Ointment: Store at controlled room temperature of 15°C to 25°C (59°F to 77°F) in a dry place.
Injection: Store powder at controlled room temperature of 15°C to 25°C (59°F to 77°F). Reconstituted solutions remain stable for 12 hours at room temperature. Do not refrigerate reconstituted solutions as they may precipitate. Once diluted for infusion, use within 24 hours.
Reconstitution
Powder for injection: Reconstitute acyclovir 500 mg with SWFI 10 mL; do not use bacteriostatic water containing benzyl alcohol or parabens. For intravenous infusion, dilute to a final concentration ?7 mg/mL. Concentrations >10 mg/mL increase the risk of phlebitis.
Compatibility
Stable in D5W, D5NS, D51/4NS, D51/2NS, LR, NS.
Incompatible with blood products and protein-containing solutions.
Y-site administration: Compatible: Allopurinol, amikacin, amphotericin B cholesteryl sulfate complex, ampicillin, cefamandole, cefazolin, cefoperazone, cefotaxime, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, clindamycin, co-trimoxazole, dexamethasone, dimenhydrinate, diphenhydramine, docetaxel, doxorubicin liposome, doxycycline, erythromycin lactobionate, etoposide, famotidine, filgrastim, fluconazole, gatifloxacin, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, linezolid, lorazepam, magnesium sulfate, melphalan, methylprednisolone sodium succinate, metoclopramide, metronidazole, multivitamins, nafcillin, oxacillin, paclitaxel, penicillin G potassium, pentobarbital, perphenazine, piperacillin, potassium chloride, propofol, ranitidine, remifentanil, sodium bicarbonate, tacrolimus, teniposide, theophylline, thiotepa, ticarcillin, tobramycin, vancomycin, zidovudine. Incompatible: Amifostine, amsacrine, aztreonam, cefepime, dobutamine, dopamine, fludarabine, foscarnet, gemcitabine, idarubicin, levofloxacin, ondansetron, piperacillin/tazobactam, sargramostim, vinorelbine. Variable (consult detailed reference): Cisatracurium, diltiazem, meperidine, meropenem, morphine, TPN.
Compatibility when admixed: Compatible: Fluconazole. Incompatible: Dobutamine, dopamine. Variable (consult detailed reference): Meropenem.
Mechanism of Action
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.
Pharmacodynamics/Kinetics
Absorption: Oral: 15% to 30%
Distribution: Vd: 0.8 L/kg (63.6 L): Widely (eg, brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, CSF)
Protein binding: 9% to 33%
Metabolism: Converted by viral enzymes to acyclovir monophosphate, and further converted to diphosphate then triphosphate (active form) by cellular enzymes
Bioavailability: Oral: 10% to 20% with normal renal function (bioavailability decreases with increased dose)
Half-life elimination: Terminal: Neonates: 4 hours; Children 1-12 years: 2-3 hours; Adults: 3 hours
Time to peak, serum: Oral: Within 1.5-2 hours
Excretion: Urine (62% to 90% as unchanged drug and metabolite)
Dosage
Note: Obese patients should be dosed using ideal body weight
Genital HSV:
I.V.: Children ?12 years and Adults (immunocompetent): Initial episode, severe: 5 mg/kg every 8 hours for 5-7 days
Oral:
Children:
Initial episode (unlabeled use): 40-80 mg/kg/day divided into 3-4 doses for 5-10 days (maximum: 1 g/day)
Chronic suppression (unlabeled use; limited data): 80 mg/kg/day in 3 divided doses (maximum: 1 g/day), re-evaluate after 12 months of treatment
Adults:
Initial episode: 200 mg every 4 hours while awake (5 times/day) for 10 days (per manufacturer's labeling); 400 mg 3 times/day for 5-10 days has also been reported
Recurrence: 200 mg every 4 hours while awake (5 times/day) for 5 days (per manufacturer's labeling; begin at earliest signs of disease); 400 mg 3 times/day for 5 days has also been reported
Chronic suppression: 400 mg twice daily or 200 mg 3-5 times/day, for up to 12 months followed by re-evaluation (per manufacturer's labeling); 400-1200 mg/day in 2-3 divided doses has also been reported
Topical: Adults (immunocompromised): Ointment: Initial episode: 1/2” ribbon of ointment for a 4” square surface area every 3 hours (6 times/day) for 7 days
Herpes labialis (cold sores): Topical: Children ?12 years and Adults: Cream: Apply 5 times/day for 4 days
Herpes zoster (shingles):
Oral: Adults (immunocompetent): 800 mg every 4 hours (5 times/day) for 7-10 days
I.V.:
Children <12 years (immunocompromised): 20 mg/kg/dose every 8 hours for 7 days
Children ?12 years and Adults (immunocompromised): 10 mg/kg/dose or 500 mg/m2/dose every 8 hours for 7 days
HSV encephalitis: I.V.:
Children 3 months to 12 years: 20 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); dosing for 14-21 days also reported
Children ?12 years and Adults: 10 mg/kg/dose every 8 hours for 10 days (per manufacturer's labeling); 10-15 mg/kg/dose every 8 hours for 14-21 days also reported
Mucocutaneous HSV:
I.V.:
Children <12 years (immunocompromised): 10 mg/kg/dose every 8 hours for 7 days
Children ?12 years and Adults (immunocompromised): 5 mg/kg/dose every 8 hours for 7 days (per manufacturer's labeling); dosing for up to 14 days also reported
Oral: Adults (immunocompromised, unlabeled use): 400 mg 5 times a day for 7-14 days
Topical: Ointment: Adults (nonlife-threatening, immunocompromised): 1/2” ribbon of ointment for a 4” square surface area every 3 hours (6 times/day) for 7 days
Neonatal HSV: I.V.: Neonate: Birth to 3 months: 10 mg/kg/dose every 8 hours for 10 days (manufacturer's labeling); 15 mg/kg/dose or 20 mg/kg/dose every 8 hours for 14-21 days has also been reported
Varicella-zoster (chickenpox): Begin treatment within the first 24 hours of rash onset:
Oral:
Children ?2 years and ?40 kg (immunocompetent): 20 mg/kg/dose (up to 800 mg/dose) 4 times/day for 5 days
Children >40 kg and Adults (immunocompetent): 800 mg/dose 4 times a day for 5 days
I.V.:
Children <1 year (immunocompromised, unlabeled use): 10 mg/kg/dose every 8 hours for 7-10 days
Children ?1 year and Adults (immunocompromised, unlabeled use): 1500 mg/m2/day divided every 8 hours or 10 mg/kg/dose every 8 hours for 7-10 days
Prevention of HSV reactivation in HIV-positive patients, for use only when recurrences are frequent or severe (unlabeled use): Oral:
Children: 80 mg/kg/day in 3-4 divided doses
Adults: 200 mg 3 times/day or 400 mg 2 times/day
Prevention of HSV reactivation in HSCT (unlabeled use): Note: Start at the beginning of conditioning therapy and continue until engraftment or until mucositis resolves (?30 days)
Oral: Adults: 200 mg 3 times/day
I.V.:
Children: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 hours
Adults: 250 mg/m2/dose every 12 hours
Bone marrow transplant recipients (unlabeled use): I.V.: Children and Adults: Allogeneic patients who are HSV and CMV seropositive: 500 mg/m2/dose (10 mg/kg) every 8 hours; for clinically-symptomatic CMV infection, consider replacing acyclovir with ganciclovir
Dosing adjustment in renal impairment:
Oral:
Clcr 10-25 mL/minute/1.73 m2: Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 8 hours
Clcr <10 mL/minute/1.73 m2:
Normal dosing regimen 200 mg every 4 hours, 200 mg every 8 hours, or 400 mg every 12 hours: Administer 200 mg every 12 hours
Normal dosing regimen 800 mg every 4 hours: Administer 800 mg every 12 hours
I.V.:
Clcr 25-50 mL/minute/1.73 m2: Administer recommended dose every 12 hours
Clcr 10-25 mL/minute/1.73 m2: Administer recommended dose every 24 hours
Clcr <10 mL/minute/1.73 m2: Administer 50% of recommended dose every 24 hours
Hemodialysis: Administer dose after dialysis
Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of normal dose once daily; no supplemental dose needed
Continuous renal replacement therapy (CRRT): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug levels in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 L/hour) and should not supersede clinical judgment:
CVVH or CVVHD/CVVHDF: 5-7.5 mg/kg every 24 hours
Note: The higher dose of 7.5 mg/kg is recommended for infections with CNS involvement (Trotman, 2005).
Dental Usual Dosing
Herpes labialis (cold sores): Children ?12 years and Adults: Topical: Cream: Apply 5 times/day for 4 days
Mucocutaneous HSV: Adults:
Immunocompromised (unlabeled use): Oral: 400 mg 5 times a day for 7-14 days
Nonlife-threatening, immunocompromised: Topical: Ointment: 1/2” ribbon of ointment for a 4” square surface area every 3 hours (6 times/day) for 7 days
Administration: Oral
May be administered with or without food.
Administration: I.V.
For I.V. infusion only. Avoid rapid infusion. Infuse over 1 hour to prevent renal damage. Maintain adequate hydration of patient. Check for phlebitis and rotate infusion sites.
Administration: Topical
Not for use in the eye. Apply using a finger cot or rubber glove to avoid transmission to other parts of the body or to other persons.
Administration: I.V. Detail
pH: 10.5-11.6 (reconstituted solution)
Monitoring Parameters
Urinalysis, BUN, serum creatinine, liver enzymes, CBC
Dietary Considerations
May be taken with or without food. Acyclovir 500 mg injection contains sodium ?50 mg (?2 mEq).
Patient Education
Do not take any new medication during therapy (including creams, lotions, or ointments) unless approved by prescriber. This is not a cure for herpes (recurrences tend to continually reappear every 3-6 months after original infection), nor will this medication reduce the risk of transmission to others when lesions are present; avoid sexual intercourse when visible lesions are present. Use as directed for full course of therapy; do not discontinue even if feeling better. Oral doses may be taken with food. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); lightheadedness or dizziness (use caution when driving or engaging in tasks that require alertness until response to drug is known); or headache, fever, muscle pain (consult prescriber for approved analgesic). Report any change in urination (difficulty urinating, dark colored or concentrated urine); persistent lethargy; acute headache; severe nausea or vomiting; confusion or hallucinations; rash; or respiratory difficulty.
Topical: Apply as directed. Use gloves or finger cot when applying.
Geriatric Considerations
For herpes zoster, acyclovir should be started within 72 hours of the appearance of the rash to be effective. Dose adjustment may be necessary depending on creatinine clearance.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Topical (Zovirax® cream): Dry/cracked lips and dry/flaky skin were reported in fewer than 1 in 100 patients in clinical studies.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May see lethargy, confusion, or agitation; rarely may see depression or insomnia
Mental Health: Effects on Psychiatric Treatment
Usually not a problem, may see additive sedation with sedating psychotropics
Nursing: Physical Assessment/Monitoring
Assess carefully for use cautions. Assess potential for interactions with other prescriptions, OTC, or herbal medications patient may be taking. Patient should be adequately hydrated during I.V. therapy and monitored closely during intravenous administration. Assess results of laboratory tests, therapeutic effects, and adverse responses according to purpose for use and formulation. Teach patient proper use (if self-administered), possible side effects/appropriate interventions, and adverse symptoms to report.
Oncology: Emetic Potential
Very low (<10%)
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 200 mg
Zovirax®: 200 mg
Cream, topical:
Zovirax®: 5% (2 g, 5 g)
Injection, powder for reconstitution, as sodium: 500 mg, 1000 mg
Injection, solution, as sodium [preservative free]: 50 mg/mL (10 mL, 20 mL)
Ointment, topical:
Zovirax®: 5% (15 g)
Suspension, oral: 200 mg/5 mL (480 mL)
Zovirax®: 200 mg/5 mL (480 mL) [banana flavor]
Tablet: 400 mg, 800 mg
Zovirax®: 400 mg, 800 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Acyclovir)
200 mg (30): $12.99
Capsules (Zovirax)
200 mg (30): $79.65
Cream (Zovirax)
5% (2): $55.98
5% (5): $126.43
Ointment (Zovirax)
5% (15): $141.68
Suspension (Acyclovir)
200 mg/5 mL (473): $123.97
Suspension (Zovirax)
200 mg/5 mL (473): $219.95
Tablets (Acyclovir)
400 mg (60): $28.99
800 mg (30): $24.99
Tablets (Zovirax)
400 mg (60): $290.80
800 mg (30): $282.81
References
American Academy of Pediatrics Committee on Infectious Diseases, “The Use of Oral Acyclovir in Otherwise Healthy Children With Varicella,” Pediatrics, 1993, 91(3):674-6.
American Academy of Pediatrics Committee on Drugs, “The Transfer of Drugs and Other Chemicals Into Human Breast Milk,” Pediatrics, 2001, 108:776-89.
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007.
Centers for Disease Control and Prevention, “Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents: Recommendations From CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America,” MMWR Recomm Rep, 2004, 53(RR-15):1-112. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5315a1.htm. Accessed January 9, 2006.
Centers for Disease Control and Prevention, "Treating Opportunistic Infections Among HIV-Exposed and Infected Children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America," MMWR Recomm Rep, 2004, 53(RR-14):1-63. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5314a1.htm. Accessed January 9, 2006.
Centers for Disease Control and Prevention, “Guidelines for Preventing Opportunistic Infections Among HIV-Infected Persons. 2002 Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America,” MMWR Recomm Rep, 2002, 51(RR-8):1-46. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5108a1.htm. Accessed January 26, 2004.
Centers for Disease Control and Prevention, “Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients: Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation,” MMWR Recomm Rep, 2000, 49(RR-10):1-112. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm. Accessed January 26, 2004.
Dunkle LM, Arvin AM, Whitley RJ, et al, “A Controlled Trial of Acyclovir for Chickenpox in Normal Children,” N Engl J Med, 1991, 325(22):1539-44.
Eck P, Silver SM, and Clark EC, “Acute Renal Failure and Coma After a High Dose of Oral Acyclovir,” N Engl J Med, 1991, 325(16):1178-9.
Eisen D, Essell J, Broun ER, et al, “Clinical Utility of Oral Valacyclovir Compared With Oral Acyclovir for the Prevention of Herpes Simplex Virus Mucositis Following Autologous Bone Marrow Transplantation or Stem Cell Rescue Therapy,” Bone Marrow Transplant, 2003, 31(1):51-5.
Englund JA, Fletcher CV, and Balfour HH Jr, “Acyclovir Therapy in Neonates,” J Pediatr, 1991, 119(1 Pt 1):129-35.
National Comprehensive Cancer Network (NCCN), “Clinical Practice Guidelines in Oncology™: Prevention and Treatment of Cancer-Related Infections,” Version 2, 2007. Available at http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf.
Novelli VM, Marshall WC, Yeo J, et al, “High-Dose Oral Acyclovir for Children at Risk of Disseminated Herpesvirus Infections,” J Infect Dis, 1985, 151(2):372.
Rayani SA, Nimmo CJ, Frighetto L, et al, “Implementation and Evaluation of a Standardized Herpes Simplex Virus Prophylaxis Protocol on a Leukemia/Bone Marrow Transplant Unit,” Ann Pharmacother, 1994, 28(7-8):852-6.
Trotman RL, Williamson JC, Shoemaker DM, et al, "Antibiotic Dosing in Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy," Clin Infect Dis, 2005, 41(8):1159-66.
Wade JC, Newton B, Flournoy N, et al, “Oral Acyclovir for Prevention of Herpes Simplex Virus Reactivation After Marrow Transplantation,” Ann Intern Med, 1984, 100(6):823-8.
Wood MJ, Johnson RW, McKendrick MW, et al, “A Randomized Trial of Acyclovir for 7 Days or 21 Days With and Without Prednisolone for Treatment of Acute Herpes Zoster,” N Engl J Med, 1994, 330(13):896-900.
International Brand Names
Lexi-Comp.com
Last full review/revision April 2008
Content last modified April 2008
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