Professional Drug Information > Zovirax Wellstat Pac

Acyclovir (Systemic)

INN:
Aciclovir

VA CLASSIFICATION
Primary: AM820

Commonly used brand name(s): Alti-Acyclovir; Avirax; Zovirax; Zovirax Wellstat Pac; Zovirax Zostab Pac.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Acyclovir is a synthetic purine analog that has antiviral activity against herpes simplex virus (HSV-1 and HSV-2) and varicella-zoster virus (VZV). Resistance of HSV and VZV to acyclovir has been reported to develop with prolonged treatment or repeated therapy with acyclovir in severely immunocompromised patients. Resistance may occasionally develop as quickly as within a few weeks of beginning treatment. If lesions due to herpes simplex virus fail to respond to acyclovir therapy, especially with continued viral shedding, viral isolates should be tested for susceptibility to acyclovir. ^{{02} {10} {41}}

This resistance of HSV and VZV to antiviral nucleoside analogs can result from qualitative or quantitative changes in the viral thymidine kinase (TK) or deoxyribonucleic acid (DNA) polymerase. Most of the acyclovir-resistant mutants isolated from immunocompromised patients, such as those from patients with advanced human immunodeficiency virus (HIV) infections, have been found to be TK-deficient mutants; however, other mutants involving the viral TK gene (TK-partial and TK-altered) and DNA polymerase also have been isolated. TK-negative mutants of HSV and VZV may cause severe disease in infants and immunocompromised adults. ^{{58} {59}}

Accepted

Herpes genitalis, initial episode (treatment)— Oral acyclovir is indicated in the treatment of initial episodes of genital herpes infection ^{{59} {61}} in immunocompetent and immunocompromised patients ^{{02} {03}}. Parenteral acyclovir is indicated in the treatment of severe initial episodes of genital herpes infection in immunocompetent patients and in patients who are unable to take (or absorb) oral acyclovir ^{{01} {07} {41} {58}}.

Herpes genitalis, recurrent episodes (treatment)—Oral acyclovir is indicated in the treatment of frequently recurrent (³ 6 episodes per year) or intermittent episodes of genital herpes infection in immunocompetent and immunocompromised patients ^{{02} {03} {59} {61}}.

Herpes simplex (treatment)—Parenteral [ and oral]¹ acyclovir are indicated in the treatment of initial and recurrent mucocutaneous herpes simplex (HSV-1 and HSV-2) infections in immunocompromised patients. ^{{01} {07} {42} {47} {50} {58} {60}}

Herpes simplex, neonatal infection (treatment) ¹—Parenteral acyclovir is indicated in the treatment of neonatal herpes simplex virus infections. ^{58}

Herpes simplex encephalitis (treatment)¹—Parenteral acyclovir is indicated in the treatment of herpes simplex encephalitis in immunocompetent patients. ^{{01} {17} {18} {44} {46} {58}}

Herpes zoster (treatment)—Oral acyclovir is indicated in the treatment of herpes zoster infections (shingles) caused by varicella-zoster virus (VZV) in any adult patient with herpes zoster. ^{{59} {61}} Therapy is most effective when started within 48 hours of the onset of rash. ^{{02} {03} {39} {44} {45} {50} {59}} Parenteral acyclovir is indicated in the treatment of herpes zoster infections (shingles) caused by VZV in immunocompromised patients ^{{01} {07} {58} {60}} [and disseminated herpes zoster in immunocompetent patients]. ^{{15} {22}}

Varicella (treatment)—Oral acyclovir is indicated in the treatment of varicella infections (chickenpox) in immunocompetent patients when started within 24 hours of the onset of a typical chickenpox rash ^{{02} {03} {12} {13} {33} {59} {61}}. [ Parenteral acyclovir is used in the treatment of varicella infections (chickenpox) caused by VZV in immunocompromised patients ^{{21} {58}} ].¹
—Although acyclovir is indicated for the treatment of varicella infections in immunocompetent patients, the American Academy of Pediatrics does not recommend its use for the treatment of uncomplicated chickenpox in healthy children. It is recommended for certain groups at increased risk of severe varicella or its complications, such as otherwise healthy, nonpregnant persons 13 years of age or older; children older than 12 months of age with a chronic cutaneous or pulmonary disorder; and children receiving short, intermittent, or aerosolized courses of corticosteroids. If possible, steroids should be discontinued after known exposure to varicella. ^{06}

[Herpes simplex (prophylaxis)]¹—Parenteral and oral acyclovir are used in the prophylaxis of herpes simplex virus (HSV) infections in patients who are immunocompromised, including transplant patients receiving immunosuppressant therapy, human immunodeficiency virus (HIV)-infected patients, and patients receiving chemotherapy ^{{08} {14} {23} {24} {25} {40} {50}}.

[Herpes zoster (prophylaxis)]¹—Oral acyclovir is used in the prophylaxis of herpes zoster infections (shingles) caused by VZV, after an initial period of treatment with parenteral acyclovir, in any immunocompromised patient, including transplant patients receiving immunosuppressant therapy, HIV-infected patients, and patients receiving chemotherapy ^{{50} {55}}.

[Herpes zoster ophthalmicus (treatment) ]¹—Oral and parenteral acyclovir are indicated in the treatment of herpes zoster ophthalmicus ^{{04} {30} {31} {32}}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Acyclovir: 225.21^{05}
    Acyclovir sodium: 247.19^{05}


pH
    Reconstituted acyclovir (50 mg per mL): Approximately 11^{01}.

Mechanism of action/Effect:

Acyclovir is a synthetic purine nucleoside analog that possesses in vitro and in vivo inhibitory^{59} activity against herpes virus types HSV-1, HSV-2, and VZV. The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase encoded by HSV and VZV. In vitro, acyclovir exhibits stronger antiviral activity against HSV-1, followed by HSV-2 and VZV in decreasing order of potency. The reason for greater antiviral activity against HSV compared to that against VZV is more efficient phosphorylation of acyclovir by HSV thymidine kinase.^{58}{59}

Acyclovir is converted to the nucleotide analog acyclovir monophosphate by the viral thymidine kinases of herpes simplex virus (HSV-1 and HSV-2) and varicella-zoster virus (VZV). Acyclovir monophosphate is converted to the diphosphate by cellular guanylate kinase and to the triphosphate by a number of cellular enzymes.^{02}The antiviral activity of acyclovir is achieved by the prevention of viral DNA replication by acyclovir triphosphate. Viral DNA replication is prevented through three mechanisms: competitive inhibition of viral DNA polymerase, incorporation into and termination of the growing viral DNA chain, and inactivation of viral DNA polymerase.^{58}{59}

Absorption:

Oral—Bioavailability 10 to 20%^{59} ; the bioavailability decreases with increasing dose^{02}. Poorly absorbed from the gastrointestinal tract^{02}{44}. Not significantly affected by food^{02}.

Distribution:

Widely distributed into tissues and body fluids, including brain, kidneys, lungs, liver, aqueous humor, tears, intestines, muscle, spleen, breast milk, uterus, vaginal mucosa, vaginal secretions, semen, amniotic fluid, cerebrospinal fluid (CSF), and herpetic vesicular fluid. Highest concentrations are found in kidneys, liver, and intestines. CSF concentrations are approximately 50% of plasma concentrations. Crosses the placenta, also.^{01}{29}{50}


Vol _D (steady state):

Adults: Approximately 48 liters (L) per square meter of body surface area (m²) (range, 37 to 57 L per m ²)^{11}{53}.

Children and adolescents (1 to 18 years old): Approximately 45 L per m ^{2 {11}}.

Neonates (0 to 28 days^{69}old): Approximately 28 L per m ² (range, 24 to 30 L per m ²)^{11}{52}.

End-stage renal disease: Approximately 41 L per m ^2{11}.


Protein binding:

Low (9 to 33%)^{01}{04}.

Biotransformation:

Hepatic; the only major urinary metabolite that has been detected is 9-carboxymethoxymethylguanine, which accounts for up to 14.1% of the acyclovir dose in patients who have normal renal function.^{58} This metabolite has no known antiviral activity.^{01}{07}

Half-life:


Elimination of parenteral acyclovir:

Adults with normal renal function: Approximately 2.5 hours^{54}.

Children ( 29 days to 12 years old): Approximately 2.3 hours^{54}{65}.

Neonates (0 to 28 days^{69}old): Approximately 3.8 hours^{50}{65}.

Adults with renal function impairment^{01}{50}:

Creatinine clearance (mL/min)/(mL/sec)	Half-life (hr)
> 80/1.33	2.5
50–80/0.83–1.33	3
15–50/0.25–0.83	3.5
Anuric	19.5
During hemodialysis	5.7
Continuous ambulatory peritoneal dialysis	14–18

Oral acyclovir:

2.5 to 3.3 hours^{02}{54}.


Time to peak serum concentration

Intravenous—End of infusion (approximately 1 hour)^{01}.

Oral—1.7 hours^{48}.

Mean peak serum concentration (steady-state)


Oral:


Adults—

200 mg every 4 hours—0.83 mcg/mL (3.68 micromoles/L)^{02}.

400 mg every 4 hours—1.2 mcg/mL (5.3 micromoles/L)^{02}.

800 mg every 4 hours—1.6 mcg/mL (6.9 micromoles/L)^{02}{14}.




Intravenous:


Adults—

5 mg per kg (over 1 hour) every 8 hours—9.8 mcg/mL (43.5 micromoles/L)^{01}{53}.

10 mg per kg (over 1 hour) every 8 hours—22.9 mcg/mL (101.7 micromoles/L)^{53}.



Children (1 to 18 years old)—

250 mg per m² (over 1 hour) every 8 hours—10.3 mcg/mL (45.8 micromoles/L)^{{01} {53}}.

500 mg per m² (over 1 hour) every 8 hours—20.7 mcg/mL (91.9 micromoles/L)^{53}.



Neonates (0 to 28 days^{69} old)—

5 mg per kg (over 1 hour) every 8 hours—6.8 mcg/mL (30 micromoles/L)^{52}.

10 mg per kg (over 1 hour) every 8 hours—13.8 mcg/mL (61.2 micromoles/L)^{52}.



Elimination:


Renal—
        Excreted by both glomerular filtration and tubular secretion.^{01}
        Oral: Approximately 14% of total dose excreted unchanged in urine^{04}.
        Intravenous: Approximately 62 to 91% excreted unchanged in urine.^{58}



Fecal—
        Insignificant amounts (< 2%)^{01}{11}.



Lungs—
        Trace amounts in exhaled CO ₂^{01}{11}.



Dialysis—
        Hemodialysis: A single 6-hour period of hemodialysis reduces plasma acyclovir concentrations by approximately 60%^{01}.
        Peritoneal dialysis: Peritoneal dialysis does not substantially alter acyclovir clearance^{51}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to valacyclovir may also be allergic to acyclovir .^{70}

Tumorigenicity

Lifetime bioassays in rats and mice given daily doses of up to 450 mg per kg of body weight (mg/kg) by gavage did not increase the incidence of tumors or shorten the latency of tumor formation. Maximum plasma concentrations were three to six times the human plasma concentration in the mouse bioassay and one to two times the human plasma concentration in the rat bioassay. However, one of two in vitro cell transformation assays resulted in morphologically transformed cells that formed tumors when inoculated into immunosuppressed, syngeneic, weanling mice.^{59}

Mutagenicity

Acyclovir has been shown to be mutagenic in some in vitro cytogenetic assay systems (human lymphocytes and one mouse lymphoma cell line). However, acyclovir was not mutagenic in other in vitro cytogenetic assay systems (three Chinese hamster ovary cell lines and two mouse lymphoma cell lines) or in four microbial assays. Acyclovir was clastogenic in Chinese hamster cells at 380 to 760 times the human plasma concentration. No mutagenicity was reported in a dominant lethal study in mice (36 to 73 times the human plasma concentration).^{59}

Pregnancy/Reproduction
Fertility—
Impairment of spermatogenesis, sperm motility, or morphology has not been documented in humans given the recommended doses of acyclovir^{03}{28}.

High doses of parenteral acyclovir have caused testicular atrophy in rats and dogs. However, no testicular abnormalities were observed in dogs given intravenous acyclovir at doses of 50 mg/kg per day for 1 month (resulting in plasma concentrations one to three times the human plasma concentration^{58}) or in dogs given oral acyclovir at doses of 60 mg/kg per day for 1 year (resulting in plasma concentrations 6 to 12 times the human plasma concentration). Studies in mice given oral doses of 450 mg/kg per day or rats given subcutaneous doses of 25 mg/kg per day have shown that acyclovir does not impair fertility or reproduction. Studies in female rats^{69} and rabbits given acyclovir subcutaneously subsequent to mating have shown a significant decrease in implantation efficiency, but no decrease in litter size, at doses of 50 mg/kg per day.^{01}

Pregnancy—
Acyclovir crosses the placenta.^{01} Acyclovir has been used in all stages of pregnancy, and no adverse fetal effects have been reported^{36}. One small, controlled study found that pre-partum treatment of women with recurrent genital herpes helped prevent symptomatic recurrences and viral shedding at the time of delivery, reducing the risk of the infant being exposed to the virus^{20}. Also, a prospective epidemiological registry of acyclovir was established in 1984 and completed in 1999.^{64} The registry had 756 outcomes in 749 women exposed to systemic acyclovir during the first trimester of pregnancy.^{64} The occurrence rate of birth defects approximates the rate found in the general population^{02}{58}{64}. However, the small size of the registry is insufficient to evaluate the risk of less common defects or to permit reliable and definitive conclusions regarding the safety of acyclovir use in pregnant women and their developing fetuses^{02}{58}{59}. Adequate and well-controlled studies in humans have not been done. During pregnancy, acyclovir should be used only if the potential benefit to the mother outweighs the potential risk to the fetus^{02}.

Acyclovir was not teratogenic in mice given oral doses of 450 mg/kg per day (resulting in plasma concentrations 9 to 18 times the human plasma concentration), rabbits given subcutaneous or intravenous doses of 50 mg/kg per day (resulting in plasma concentrations 16 to 106 times the human plasma concentration), or rats given subcutaneous doses of 50 mg/kg per day (resulting in plasma concentrations 11 to 22 times the human plasma concentration).^{59}

FDA Pregnancy Category B^{02}{58}{59}.

Breast-feeding

Acyclovir was distributed into the breast milk of two patients at concentrations from 0.6 to 4.1 times the corresponding plasma concentration ^{69}. These concentrations would potentially expose the nursing infant to a dose as high as 0.3 mg/kg per day ^{02}. A very small amount of acyclovir has been measured in one nursing infant's urine; no toxicity was observed^{48}{49}.

Pediatrics

Limited data are available about the use of oral acyclovir in children younger than 2 years of age. However, no unusual toxicity or pediatrics-specific problems have been observed in studies done in children using doses of up to 3000 mg per square meter of body surface area (mg/m ²) per day and 80 mg/kg per day ^{{33} {34} {35} {37} {38} {55}}. Intravenous acyclovir should be used with greater caution in neonates due to their age-related decrease in clearance ^{51}. The half-life and clearance of intravenous acyclovir in children older than 1 year of age is similar to that seen in adults with normal renal function ^{01}.


Geriatrics


Geriatric patients may be more sensitive to the central nervous system effects of acyclovir.^{70} In addition, acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function impairment.^{69} Dosage adjustment may be required in geriatric patients with underlying renal function impairment.^{69}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Nephrotoxic medications, other (see Appendix II)^{{01}{02}{58}{59}}    (concurrent use with oral or parenteral acyclovir may increase the potential for nephrotoxicity, especially in the presence of renal function impairment )


Probenecid^{{01}{26}{54}{58}{59}}    (may decrease renal tubular secretion of intravenous acyclovir when used concurrently, resulting in increased acyclovir serum and cerebrospinal fluid [CSF] concentrations, prolonged elimination half-life in the serum and CSF, and, potentially, increased toxicity)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
» Blood urea nitrogen (BUN) and
» Creatinine, serum    (concentrations may be increased because of renal tubular obstruction caused by intravenous acyclovir; no increase generally occurs with proper dosage and adequate hydration^{01})


Liver function tests^{58}{59}    (serum values may be increased with either oral or parenteral acyclovir )


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Dehydration or
» Renal function impairment, pre-existing ^{01}    ( the potential for nephrotoxicity may be increased^{70}; it is recommended that acyclovir be administered in a reduced dosage to patients with impaired renal function)


Hypersensitivity to acyclovir or valacyclovir ^{58}
Neurological abnormalities or
Prior neurologic reactions to cytotoxic medications^{01}    ( the potential for neurologic side effects may be increased^{70})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood urea nitrogen (BUN) and
» Creatinine, serum^{01}    (concentrations required prior to and during therapy since intravenous acyclovir may be nephrotoxic; if acyclovir is given by rapid intravenous injection or its urine solubility is exceeded, precipitation of acyclovir crystals may occur in renal tubules; renal tubular damage may occur and may progress to acute renal failure)




Side/Adverse Effects

Note: Acute renal insufficiency may occur due to precipitation of acyclovir in the renal tubules. It is most likely to occur if acyclovir is given by rapid intravenous injection, concurrently with known nephrotoxic medications, to patients who are inadequately hydrated, or to patients with renal function impairment without appropriate dosage reduction. However, acute renal failure has also been reported in patients receiving oral acyclovir.^{16}{19}{50}
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has occurred in immunocompromised patients with high exposures to parenteral acyclovir and has resulted in death.^{58}
Neuropsychiatric toxicity has been associated with high plasma acyclovir concentrations—which may occur when high doses are used, or when patients with renal function impairment are not given an appropriately lowered dose. Neuropsychiatric toxicity may also be more likely to occur in immunocompromised patients and geriatric patients.^{50}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent^{02}{50}
    
Phlebitis or inflammation at the injection site (pain, swelling, or redness at site of injection )—with parenteral acyclovir ^{69}


Incidence less frequent ^{{02} {50}}
    
Acute renal failure ( abdominal pain; decreased frequency of urination or amount of urine; increased thirst; loss of appetite; nausea; vomiting ; unusual tiredness or weakness)


Incidence rare
    
Encephalopathic changes ( coma; confusion; hallucinations; seizures; tremors)
    
hematologic abnormalities, such as anemia ^{58} (unusual tiredness or weakness), leukocytosis, neutropenia or neutrophilia^{58} (chills, fever, or sore throat), or thrombocytopenia or thrombocytosis^{58} (black, tarry stools; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising)— usually asymptomatic
    
hematuria^{58} (blood in urine)
    
urticaria^{58} (hives)


Incidence not determined
—Observed during clinical practice; estimates of frequency cannot be determined^{58}{59}    
Delirium ^{70}
    
disseminated intravascular coagulation (DIC)^{58} (cyanosis [bluish coloring], especially of the hands and feet; bruising at the injection site; persistent bleeding or oozing from puncture sites or mucous membranes [bowel, mouth, nose, or urinary bladder])
    
hemolysis
    
hypotension^{58} (faintness or lightheadedness)
    
mental obtundation ^{70}(mental changes)
    
psychosis ^{70}(mood or mental changes, severe)

Note:  Delirium, mental obtundation, and psychosis may be marked, particularly in older adults.^{58}{59}{70}


    
Anaphylaxis^{58}{59} (changes in facial skin color; coughing; difficulty in breathing or swallowing; dizziness or feeling faint, severe; fast heartbeat; rash, itching, or hives; sense of agitation or uneasiness; swelling of eyelids, face, or lips)
    
anemia ( pale skin; unusual tiredness or weakness)^{64}
    
angioedema (large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs )^{64}
    
ataxia (shakiness and unsteady walk; clumsiness, unsteadiness, or other problems with muscle control or coordination)^{64}
    
confusion ^{{58} {59}}
    
consciousnesss, decreased ^{64}
    
elevated liver function tests ^{{58} {59}} —asymptomatic
    
encephalopathy (blurred vision; confusion; dizziness ; mood or mental changes; seizures; unusual tiredness or weakness)^{64}
    
fever^{{58} {59}}
    
hallucinations^{{58} {59}} (seeing, hearing, or feeling things that are not there)
    
hyperbilirubinemia (yellow eyes or skin)^{64}
    
leukopenia^{58}{59} (chills, fever, or sore throat)— usually asymptomatic
    
lymphadenopathy^{58}{59} (swollen, painful, or tender lymph nodes [glands] in neck, armpit, or groin)
    
peripheral edema^{{58} {59}} (swelling of hands, feet, or lower legs)
    
seizures^{58}{59}
    
skin reactions, such as erythema multiforme, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, or urticaria^{58}{59} (blistering, peeling, or loosening of skin; muscle cramps, pain, or weakness; red or irritated eyes; skin rash, itching, or hives; sore throat, fever, or chills; sores, ulcers, or white spots in mouth or on lips )
    
tremors (shakiness)^{64}
    
visual abnormalities^{58}{59} (changes in vision )




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—especially with high doses    
Gastrointestinal disturbances (nausea or vomiting)—incidence approximately 7% with parenteral acyclovir^{71}
    
malaise ^{59}(general feeling of discomfort or illness)—incidence 11%


Incidence less frequent
—with long-term use or high doses    
Gastrointestinal disturbances (diarrhea; nausea or vomiting)— with oral acyclovir^{70}
    
headache
    
lightheadedness


Incidence not determined
—Observed during clinical practice; estimates of frequency cannot be determined^{58}{59}    
Agitation^{58}{59}
    
alopecia^{{58} {59}} (loss of hair)
    
dizziness^{59}
    
myalgia^{58}{59} (muscle pain)
    
paresthesia^{59} (burning, prickling, or tingling sensations)
    
somnolence^{{58} {59}} (drowsiness)

Note: Agitation, dizziness , paresthesia, and somnolence may be marked, particularly in older adults. ^{{58} {59}}






Overdose
In general, acyclovir has a broad therapeutic index and excessive doses of acyclovir are well-tolerated.^{73} There are limited data in the medical literature regarding acyclovir intoxication, and there are no reports in peer-reviewed literature on serious toxic effects following an overdose of acyclovir.^{73} The inadvertent infusion of acyclovir at a dose ten times higher than the normal dose to two neonates (65 and 100 mg per kg of body weight, respectively) did not produce any adverse renal or neurological effects.^{74}

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Nephrotoxicity (crystallization of acyclovir within renal tubules; elevation of serum creatinine, transient)^{75}{76}
    
neurotoxicity (coma; hallucinations; lethargy; seizures; tremors)^{75}{76}

Note: Nephrotoxicity and neurotoxicity usually resolve after cessation of acyclovir therapy.^{77} However, there is no well-defined relationship between acyclovir concentrations in the blood and these adverse effects.^{77} Therefore, additional factors other than elevated acyclovir concentrations may account for these effects.^{77}



Treatment of overdose
There are no clinical data to guide management of acyclovir overdose.^{73} Treatment is supportive.^{73} Adequate urine flow should be maintained to prevent precipitation of acyclovir in the renal tubules.^{73} Hemodialysis is generally not recommended because even very large overdoses do not usually result in major toxicity.^{78}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Acyclovir (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to acyclovir or valacyclovir

Pregnancy—Acyclovir crosses the placenta; acyclovir should be used only if the potential benefit to the mother outweighs the potential risk to the fetus





Breast-feeding—Acyclovir is distributed into breast milk





Use in children—Neonates have an age-related decrease in acyclovir clearance






Use in the elderly—Elderly patients may be more sensitive to the central nervous system effects of acyclovir
Other medications, especially nephrotoxic medications
Other medical problems, especially dehydration or pre-existing renal function impairment

Proper use of this medication
Supplying patient information about herpes simplex or varicella-zoster infections

» For treatment of herpes zoster (shingles) or recurrent herpes simplex infections, initiating use of the medication as soon as possible after symptoms of recurrence begin to appear

» For treatment of chickenpox (varicella), initiating use of oral acyclovir at the earliest sign or symptom; it is most effective when started within 24 hours of the onset of a typical chickenpox rash

Capsules, tablets, and oral suspension may be taken with meals or on an empty stomach

Taking with full glass of water

Proper administration technique for oral liquids

» Compliance with full course of therapy; not using more often or for longer than prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days

Keeping affected areas as clean and dry as possible; wearing loose-fitting clothing to avoid irritation of lesions

» Use of acyclovir has not been shown to prevent the transmission of herpes simplex virus to sexual partners

» Herpes genitalis may be sexually transmitted even if partner is asymptomatic; sexual activity should be avoided if either partner has signs and symptoms of herpes genitalis; use of a condom may help prevent transmission of herpes; however, spermicidal jellies or diaphragms probably will not be adequately protective


Side/adverse effects
Signs of potential side effects, especially phlebitis or inflammation at site of injection; acute renal failure; encephalopathic changes; hematologic abnormalities, such as anemia, leukocytosis, neutropenia or neutrophilia, thrombocytopenia or thrombocytosis; hematuria; and urticaria

Signs of potential side effects observed during clinical practice, especially delirium; disseminated intravascular coagulation (DIC); hemolysis; hypotension; mental obtundation; psychosis; anaphylaxis; anemia; angioedema; ataxia; confusion; decreased consciousness; encephalopathy; fever; hallucinations; hyperbilirubinemia; leukopenia; lymphadenopathy; peripheral edema; seizures; skin reactions, such as erythema multiforme, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, or urticaria; tremors; and visual abnormalities


General Dosing Information
Therapy should be initiated as soon as possible following the onset of signs and symptoms of herpes simplex or varicella zoster infections.

Because it may take longer for lesions to heal in immunocompromised patients (an average of 2 weeks of therapy for herpes simplex infections), the duration of therapy may need to be prolonged beyond the recommended number of days until the lesions are crusted over or epithelialized.^{50}

The frequency and severity of episodes of untreated genital herpes may change over time.^{59} It is recommended by the manufacturer that the frequency and severity of the patient's genital herpes infection be re-evaluated following 1 year of treatment with acyclovir, to assess the need for continued acyclovir treatment.^{59}

For oral dosage forms only
Acyclovir capsules, tablets, and oral suspension may be taken with meals since absorption has not been shown to be significantly affected by food; however, they may be taken on an empty stomach^{02}.

Intermittent short-term treatment of recurrent herpes genitalis infections may be effective for some patients, especially when treatment is patient-initiated during the prodrome or first sign of lesion formation^{02}.

For parenteral dosage forms only
Acyclovir for injection should be administered by intravenous infusion only. It should not be administered topically, intramuscularly, orally, subcutaneously, or ophthalmically.^{01}

Intravenous infusions of acyclovir should be administered at a constant rate over at least a 1-hour period to avoid renal tubular damage. Rapid or bolus injection must be avoided since precipitation of acyclovir crystals in the renal tubules may occur and may result in acute renal failure. Also, precipitation of acyclovir crystals in renal tubules and resulting renal damage may occur if the maximum water solubility of free acyclovir (2.5 mg/mL at 37 °C) is exceeded.^{58}

Obese patients should be dosed based on ideal body weight.^{01}

Patients receiving parenteral acyclovir should be adequately hydrated to reduce the risk of renal damage.^{58} Since maximum urinary concentrations of acyclovir are achieved within 2 hours, patients receiving intravenous infusions and high oral doses must be adequately hydrated during this period to prevent precipitation of acyclovir in renal tubules.^{01}

Abnormal renal function (decreased creatinine clearance) can occur as a result of acyclovir administration and depends on the patient's state of hydration, other treatments and the rate of drug administration. Concomitant use of other nephrotoxic drugs, pre-existing renal disease, and dehydration make further renal impairment more likely.^{65}

The dose of acyclovir should be adjusted so that a dose is repeated after hemodialysis, since each 6-hour hemodialysis period results in approximately a 60% reduction in acyclovir plasma concentrations.^{01}

Bioequivalence information
Bioequivalence informationThe capsule, oral suspension, and tablet dosage forms are bioequivalent^{02}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ACYCLOVIR CAPSULES USP

Usual adult and adolescent dose
Genital herpes infection
Initial episode: Oral, 200 mg every four hours while awake, five times a day, for ten days^{02}{59}{61}.

Recurrent infections, intermittent therapy (< 6 episodes per year): Oral, 200 mg every four hours while awake, five times a day, for five days^{02}{59}{61}.

Recurrent infections, chronic suppressive therapy (³ 6 episodes per year): Oral, 400 mg twice a day, or 200 mg three to five times a day, for up to twelve months^{02}{59}{61}.

[Herpes simplex, mucocutaneous (treatment)]¹
Oral, 200 to 400 mg five times a day for seven^{72} to ten days in immunocompromised patients^{42}{50}.

[Herpes simplex, mucocutaneous (prophylaxis)]¹
Oral, 400 mg every twelve^{08} or twenty-four^{72} hours.

Herpes zoster (shingles)
Oral, 800 mg every four hours while awake, five times a day, for seven to ten days^{02}{59}{61}.

Varicella (chickenpox)
Oral, 800 mg four times a day for five days. Treatment should be initiated at the earliest sign or symptom of chickenpox.^{02}{59}


Note: Adults with acute or chronic renal impairment may require a reduction in dose as follows^{02}{59}:

Normal dosing regimen	Creatinine clearance (mL/min)/(mL/sec)	Adjusted dosing regimen
200 mg every 4 hours, 5 times daily while awake	> 10/0.17	200 mg every 4 hours, 5 times daily while awake
	0–10/0–0.17	200 mg every 12 hours
400 mg every 12 hours	> 10/0.17	400 mg every 12 hours
	0–10/0–0.17	200 mg every 12 hours
800 mg every 4 hours, 5 times daily while awake	> 25/0.42	800 mg every 4 hours, 5 times daily while awake
	10–25/0.17–0.42	800 mg every 8 hours
	0–10/0–0.17	800 mg every 12 hours

Hemodialysis patients: A dose should be administered after each dialysis session ^{02}{59}.


Usual pediatric dose
Varicella (chickenpox)
Children up to 2 years of age: Safety and efficacy have not been established^{02}{59}. However, no unusual toxicity or pediatrics-specific problems have been observed in studies done in children given 3000 mg per square meter of body surface area per day or 80 mg per kg of body weight per day^{{33}{34}{35}{37}{38}{55}}.

Children 2 to 12 years of age, up to 40 kg of body weight: Oral, 20 mg per kg of body weight, up to 800 mg per dose, four times a day for five days^{02}{59}{61}. Treatment should be initiated at the earliest sign or symptom of chickenpox^{02}{59}{61}.

Children 2 to 12 years of age, 40 kg of body weight and over: See Usual adult and adolescent dose^{02}{59}.


Strength(s) usually available
U.S.—


200 mg (Rx) [Zovirax (lactose) (may contain one or more parabens)]^{02}{64}{70}

Canada—
Not commercially available.^{68}

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), in a tight container. Protect from light and moisture.^{02}

Auxiliary labeling:
   • Continue medicine for full time of treatment.


ACYCLOVIR ORAL SUSPENSION USP

Usual adult and adolescent dose
See Acyclovir Capsules USP.

Usual pediatric dose
See Acyclovir Capsules USP.

Strength(s) usually available
U.S.—


200 mg per 5 mL (Rx) [Zovirax (methylparaben 0.1%) (propylparaben 0.02%) (sorbitol)]^{02}{64}{70}

Canada—


200 mg per 5 mL (Rx) [Zovirax (sodium)]^{68}

Note: The acyclovir suspension products are banana-flavored.^{59}{61}


Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), in a tight container. Protect from light.^{02}

Stability:
Suspension retains its potency for 24 months from date of manufacture. Does not require reconstitution or refrigeration.^{27}

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Shake well.
   • Take with water.
   • Beyond-use date.

Note: When dispensing, include a calibrated liquid-measuring device.



ACYCLOVIR TABLETS USP

Usual adult and adolescent dose
See Acyclovir Capsules USP.

Usual pediatric dose
See Acyclovir Capsules USP.

Strength(s) usually available
U.S.—


400 mg (Rx) [Zovirax]^{02}{64}{70}


800 mg (Rx) [Zovirax]^{02}{64}{70}

Canada—


200 mg (Rx) [Alti-Acyclovir^{63} (lactose)] [Avirax^{62} (scored) ( lactose)]^{09} [Zovirax^{61} (lactose)]^{03}


400 mg (Rx) [Alti-Acyclovir^{63} (scored)] [Avirax^{62} (scored)]^{09} [Zovirax Wellstat Pac^{61}]^{03}


800 mg (Rx) [Alti-Acyclovir^{63} (scored)] [Avirax^{62} (scored)]^{09} [Zovirax Zostab Pac^{61}]^{03}

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), in a tight container. Protect from light.^{02}{03}

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

The dosing and strength of the dosage forms available are expressed in terms of acyclovir base.

ACYCLOVIR FOR INJECTION USP

Usual adult and adolescent dose
Genital herpes infections, severe, initial episode
Intravenous infusion, 5 mg (base) per kg of body weight every eight hours for five days. Administer at a constant rate over at least a one-hour period.^{01}{07}{58}

Herpes simplex (HSV-1 and HSV-2) infections, mucocutaneous, in immunocompromised patients
Intravenous infusion, 5 mg (base) per kg of body weight every eight hours for seven days. Administer at a constant rate over at least a one-hour period.^{58}

Herpes simplex encephalitis ¹
Intravenous infusion, 10 mg (base) per kg of body weight every eight hours for ten days. Administer at a constant rate over at least a one-hour period.^{01}{58}

Herpes zoster, caused by varicella zoster virus, in immunocompromised patients
Intravenous infusion, 10 mg (base) per kg of body weight every eight hours for seven days. Administer at a constant rate over at least a one-hour period.^{01}{07}{58}


Note: Adults with acute or chronic renal impairment require a reduction in dose and/or dosing interval as follows^{01}{07}{58}:

Creatinine clearance (mL/min)/(mL/sec)	Dose (base)	Dosing interval (hr)
> 50/0.83	100%	8
25–50/0.42–0.83	100%	12
10–25/0.17–0.42	100%	24
0–10/0–0.17	50%	24

Hemodialysis patients require administration of an additional dose following each hemodialysis session^{01}{58}.
No additional dosing is required for peritoneal dialysis patients^{01}{58}.
Obese patients should be dosed at the recommended adult dosing using Ideal Body Weight.^{65}{67}


Usual adult prescribing limits
20 mg per kg of body weight, every 8 hours.^{65}

Usual pediatric dose
Genital herpes infections, severe, initial episode
[Infants and children up to 12 years of age: Intravenous infusion, 250 mg (base) per square meter of body surface area every eight hours for five days. Administer at a constant rate over at least a one-hour period. ^{{01} {07} {43} {60}{65}}] Children 12 years of age and over: See Usual adult and adolescent dose.

Herpes simplex (HSV-1 and HSV-2) infections, mucocutaneous, in immunocompromised patients
Infants and children up to 12 years of age: Intravenous infusion, 10 mg (base) per kg of body weight every eight hours for seven days. Administer at a constant rate over at least a one-hour period.^{58}

Children 12 years of age and over: See Usual adult and adolescent dose.

Herpes simplex infections , neonatal¹
Infants from birth to 3 months of age: Intravenous infusion, 10 mg (base) per kg of body weight every eight hours for ten days. Administer at a constant rate over at least a one-hour period.^{58}
Note: Intravenous doses of 15 or 20 mg (base) per kg of body weight every eight hours, administered at a constant rate over at least a one-hour period, have been used; however, the safety and efficacy of these doses have not been established.^{58}



Herpes simplex encephalitis ¹
Infants 3 months and older and children up to 12 years of age: Intravenous infusion, 20 mg (base) per kg of body weight every eight hours for ten days. Administer at a constant rate over at least a one-hour period.^{58}

Children 12 years of age and older: See Usual adult and adolescent dose .

Herpes zoster, caused by varicella zoster virus, in immunocompromised patients
Children up to 12 years of age: Intravenous infusion, 20 mg (base) per kg of body weight every eight hours for seven days. Administer at a constant rate over at least a one-hour period.^{58}

Children 12 years of age and older: See Usual adult and adolescent dose .


Note: Patients with acute or chronic renal impairment require a reduction in dose and/or dosing interval as follows^{58}:

Creatinine clearance (mL/min)/(mL/sec)	Dose (base)	Dosing interval (hr)
> 50/0.83	100%	8
25–50/0.42–0.83	100%	12
10–25/0.17–0.42	100%	24
0–10/0–0.17	50%	24

Hemodialysis patients require administration of an additional dose following each hemodialysis session^{58}.
No additional dosing is required for peritoneal dialysis patients^{58}.


Usual pediatric prescribing limits
20 mg per kg of body weight every eight hours.^{65}

Strength(s) usually available
U.S.—


500 mg (base) (Rx) [Zovirax^{58} (49 mg sodium)]^{01}{58}{64}


1 gram (base) (Rx) [Zovirax^{58} (98 mg sodium)]^{01}{58}{64}

Canada—


500 mg (base) (Rx) [Zovirax^{60} (sodium hydroxide)]^{07}{68}


1 gram (base) (Rx) [Zovirax^{60} (sodium hydroxide)^{68}]

Packaging and storage:
Prior to reconstitution, store between 15 and 25 °C (59 and 77 °F).^{01}

Preparation of dosage form:
To prepare initial dilution for intravenous infusion, add 10 or 20 mL of sterile water for injection to each 500-mg or 1-gram vial, respectively, to provide a concentration of 50 mg per mL. Do not use bacteriostatic water for injection containing benzyl alcohol or parabens. To ensure complete dissolution, shake vial well until solution is clear. The resulting solution should be further diluted with a suitable diluent (standard electrolyte- and glucose-containing solutions [see manufacturer's package insert]) to at least 100 mL. Final concentrations of 7 mg per mL or less are recommended. Higher concentrations (e.g., 10 mg per mL) may cause phlebitis or inflammation at the injection site upon inadvertent extravasation.^{58}

Stability:
After reconstitution with sterile water for injection, solutions at concentrations of 50 mg per mL retain their potency for 12 hours at controlled room temperature (15 to 25 °C [59 to 77 °F]).^{01}

After further dilution with standard electrolyte- and dextrose-containing solutions for intravenous infusion, solutions retain their potency for 24 hours at controlled room temperature (15 to 25 °C [59 to 77 °F]). ^{01}

Refrigeration of reconstituted solutions may result in the formation of a precipitate, which will redissolve when warmed to room temperature.^{01}

Incompatibilities:
Acyclovir for injection is incompatible with biological or colloidal solutions (e.g., blood products, protein-containing solutions).

Parabens are incompatible with acyclovir for injection and may cause precipitation.^{01}

Revised: 01/15/2002

References

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46. Panel comments, 4/17/89.
    

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73. Expert committee comment, 10/10/2001.
    

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