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ACYCLOVIR AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Available Forms Sources

    A) FORMS
    1) ACYCLOVIR
    a) 5% cream in 2 g and 5 g tubes (Prod Info ZOVIRAX(R) topical cream, 2009).
    b) 5% ointment in 15 g tubes (Prod Info ZOVIRAX(R) topical ointment, 2009)
    c) Acyclovir for injection, containing 500 mg acyclovir/10 mL vial (Prod Info acyclovir IV injection, 2008)
    d) 200 mg capsules, 400 mg and 800 mg tablets, and 200 mg/5 mL oral suspension (Prod Info ZOVIRAX(R) oral capsule, oral tablet, oral suspension, 2005)
    2) FAMCICLOVIR
    a) Famciclovir tablets: 125 mg, 250 mg, and 500 mg (Prod Info FAMVIR(R) oral tablets, 2011)
    3) PENCICLOVIR
    a) Penciclovir cream: 1% white cream (10 mg/g) in a 1.5 g tube (Prod Info Denavir(R) topical cream, 2002)
    B) USES
    1) ACYCLOVIR
    a) Acyclovir is indicated for the acute treatment of herpes infections, including herpes simplex and herpes zoster (shingles), initial episodes and management of recurrent episodes of genital herpes, treatment of chickenpox (varicella), and management of recurrent herpes labialis (cold sores) (Prod Info ZOVIRAX(R) topical cream, 2009; Prod Info ZOVIRAX(R) topical ointment, 2009; Prod Info acyclovir IV injection, 2008; Prod Info ZOVIRAX(R) oral capsule, oral tablet, oral suspension, 2005).
    2) FAMCICLOVIR
    a) Famciclovir is indicated for the acute treatment of herpes zoster (shingles) and the treatment of recurrent episodes of genital herpes and herpes labialis (cold sores) (Prod Info FAMVIR(R) oral tablets, 2011).
    3) PENCICLOVIR
    a) Penciclovir cream is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children ages 12 years and older (Prod Info Denavir(R) topical cream, 2002).

Therapeutic Toxic Class

    A) These drugs are synthetic acyclic guanine derivatives used as antiviral agents active against herpes viruses. Famciclovir is the prodrug of penciclovir. Drugs of this group inhibit viral reverse transcriptase which then terminates viral DNA synthesis. Ganciclovir, valganciclovir, and valacyclovir have their own managements. Refer to GANCICLOVIR AND RELATED AGENTS and VALACYCLOVIR for further information.

Specific Substances

    A) ACYCLOVIR
    1) 2-Amino-1,9-dihydro-9-(2-hydroxyethoxymethyl)
    2) purin-6-one
    3) 9-(2-Hydroxyethoxymethyl)guanine
    4) Aciclovir
    5) Acycloguanosine
    6) Acyclovir
    7) BW248U
    8) Wellcome 248U
    9) Molecular formula: C8-H11-N5-O3
    10) CAS 59277-89-3
    FAMCICLOVIR
    1) 2-(2-(2-Amino-9H-purin-9 yl)ethyl)-1,
    2) 3-propanediol diacetate
    3) 2(2-(2-Amino-9H-purin-9-yl)ethyl)
    4) trimethylene diacetate
    5) BRL-42810
    6) Famciclovir
    7) Molecular formula: C14-H19-N5-O4
    8) CAS 104227-87-4
    PENCICLOVIR
    1) 9-(4-Hydroxy-3-(hydroxymethyl)butyl)guanine
    2) BRL-39123
    3) Penciclovir
    4) Molecular formula: C10-H15-N5-O3
    5) CAS 39809-25-1

    1.2.1) MOLECULAR FORMULA
    1) Acyclovir: C8H11N5O3
    2) Acyclovir sodium: C8H10N5NaO3
    3) Famciclovir: C14H19N5O4
    4) Penciclovir: C10H15N5O3

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Substances include acyclovir, famciclovir, and penciclovir. Famciclovir is a prodrug of penciclovir. Ganciclovir, valganciclovir, and valacyclovir are covered in separate managements. Acyclovir and related medications are used for prophylaxis and treatment of herpes virus infections, including varicella infection.
    B) PHARMACOLOGY: These drugs are acyclic analogues of the natural nucleoside guanosine. They are activated via monophosphorylation by virus-induced thymidine kinase and then will undergo 2 additional phosphorylations. The triphosphate forms inhibit herpes viral DNA synthesis but do not inhibit DNA synthesis in uninfected cells because the initial phosphorylation only occurs in herpes-infected cells.
    C) TOXICOLOGY: At high concentrations, acyclovir precipitates as crystals in the urine, causing nephropathy. The mechanism for neurologic toxicity is not understood.
    D) EPIDEMIOLOGY: Overdose is uncommon; most reported toxicity is from high therapeutic doses. Severe toxicity is very rare, and there are no reported deaths from overdose.
    E) WITH THERAPEUTIC USE
    1) ORAL: Nausea, vomiting, and headaches are common.
    2) IV: Adverse effects include neurotoxicity which resembles an extension of viral infection into the central nervous system. Most commonly, mental status changes and involuntary movements occur. Lethargy, fatigue, irritability, depression, agitation, occasional myoclonus with muscle fasciculations, hyperactive tendon reflexes, tremor, stupor and coma have been reported following intravenous acyclovir, particularly rapid infusions. Psychosis and neuropsychiatric symptoms have also been described with IV acyclovir administration. Neurotoxicity is generally reversible. Local inflammation at injection site or phlebitis, renal injury and acute renal failure, agitation, coma, seizures, and lethargy may occur with acute or repeated administration to patients with renal insufficiency. Obstructive nephropathy as a result of acyclovir crystalluria may develop following high-dose therapy. Leukopenia has occasionally been reported as an adverse effect following therapeutic doses.
    3) TOPICAL: Mild pain, burning, stinging, and itching.
    4) OCULAR: Mild irritation.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients who ingest these agents in overdose experience only mild or moderate effects. The primary manifestations are nausea, vomiting, and headache. Renal injury has been reported.
    2) SEVERE TOXICITY: Most toxicity from these agents is from therapeutic or high therapeutic doses (particularly in patients with renal insufficiency) rather than inadvertent or intentional oral overdose. Neurotoxicity predominates and may include lethargy, confusion, ataxia, nystagmus, dysarthria, hallucinations, myoclonus, agitation, and in severe cases, seizures or coma. Renal failure can also develop and is usually transient.
    0.2.20) REPRODUCTIVE
    A) Acyclovir, acyclovir/hydrocortisone (topical), famciclovir, and penciclovir are classified as pregnancy category B. A large population-based cohort study showed no increased risk of major birth defects following first-trimester acyclovir or valacyclovir use. Head and tail abnormalities developed in embryos of pregnant rats when they received acyclovir. Testicular toxicity has been reported in animal studies following the use of famciclovir or penciclovir.

Laboratory Monitoring

    A) Monitor renal function and urine output in patients receiving IV acyclovir with suspected toxicity or after massive oral overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) 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.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) 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.
    C) DECONTAMINATION
    1) PREHOSPITAL: No pre-hospital decontamination is indicated.
    2) HOSPITAL: Activated charcoal should be considered for patients that present early after large overdose if they are awake, alert, and willing to drink the charcoal. Gastric lavage has no role, as toxicity is not life threatening.
    D) AIRWAY MANAGEMENT
    1) Central respiratory failure is not expected with oral overdose of acyclovir. Patients with profound CNS depression or recurrent seizures require airway management, but this is exceedingly rare.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Acyclovir and famciclovir have low protein binding and volumes of distribution, and can be removed by hemodialysis. Hemodialysis has been used to reduce serum acyclovir concentrations in patients with toxicity, but is rarely indicated as patients do well with supportive care.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent ingestion of these products may be observed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose and symptomatic patients should be sent to a healthcare facility for evaluation and treatment. Patients should be observed for 6 hours, primarily monitoring signs of co-ingestant toxicity or development of significant CNS depression. Follow-up renal function tests should be obtained in patients with massive overdose.
    3) ADMISSION CRITERIA: Admit patients with severe toxicity characterized by CNS effects or renal injury.
    4) CONSULT CRITERIA: Consider consultation with nephrology for patients with renal injury.
    H) PITFALLS
    1) Failure to consider polypharmacy ingestion. Failure to adjust the dose of acyclovir for renal insufficiency.
    I) PHARMACOKINETICS
    1) ACYCLOVIR: Poorly absorbed; bioavailability 10% to 20%, decreases with increasing dose. Volume of distribution 0.8 L/kg. Protein binding 9% to 33%. Half-life is 2 to 3 hours and increases to nearly 20 hours in patients with renal failure. FAMCICLOVIR: Prodrug of penciclovir, the active agent. Pharmacokinetics pertain to penciclovir: Bioavailability approximately 77%. Protein binding less than 20%. Volume of distribution 1.1 L/kg. Extensive hepatic metabolism of famciclovir to penciclovir with subsequent renal elimination. Half-life 2 to 2.3 hours. PENCICLOVIR (TOPICAL): Not detectable in plasma or urine following topical application.
    J) DIFFERENTIAL DIAGNOSIS
    1) Patients with suspected CNS effects following IV overdose or toxicity from drug accumulation due to renal insufficiency should be evaluated for metabolic, infectious, vascular, or traumatic causes of altered mental status.

Range Of Toxicity

    A) TOXICITY: 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.
    B) THERAPEUTIC DOSE: Varies with indication. ACYCLOVIR: ADULT: Oral dose is 200 to 800 mg 3 to 5 times daily. The IV dose is 5 to 10 mg/kg every 8 hours. PEDIATRIC: ORAL: 2 yrs and older, less than 40 kg: 20 mg/kg 4 times daily; greater than 40 kg: 800 mg 4 times daily. IV (birth to 12 yrs of age): 10 to 20 mg/kg every 8 hours. FAMCICLOVIR: ADULT: 500 mg to 2 g daily divided in 2 or 3 doses. PENCICLOVIR: ADULT: Apply topically every 2 hours while awake.

Clinical Effects

Summary Of Exposure

    A) USES: Substances include acyclovir, famciclovir, and penciclovir. Famciclovir is a prodrug of penciclovir. Ganciclovir, valganciclovir, and valacyclovir are covered in separate managements. Acyclovir and related medications are used for prophylaxis and treatment of herpes virus infections, including varicella infection.
    B) PHARMACOLOGY: These drugs are acyclic analogues of the natural nucleoside guanosine. They are activated via monophosphorylation by virus-induced thymidine kinase and then will undergo 2 additional phosphorylations. The triphosphate forms inhibit herpes viral DNA synthesis but do not inhibit DNA synthesis in uninfected cells because the initial phosphorylation only occurs in herpes-infected cells.
    C) TOXICOLOGY: At high concentrations, acyclovir precipitates as crystals in the urine, causing nephropathy. The mechanism for neurologic toxicity is not understood.
    D) EPIDEMIOLOGY: Overdose is uncommon; most reported toxicity is from high therapeutic doses. Severe toxicity is very rare, and there are no reported deaths from overdose.
    E) WITH THERAPEUTIC USE
    1) ORAL: Nausea, vomiting, and headaches are common.
    2) IV: Adverse effects include neurotoxicity which resembles an extension of viral infection into the central nervous system. Most commonly, mental status changes and involuntary movements occur. Lethargy, fatigue, irritability, depression, agitation, occasional myoclonus with muscle fasciculations, hyperactive tendon reflexes, tremor, stupor and coma have been reported following intravenous acyclovir, particularly rapid infusions. Psychosis and neuropsychiatric symptoms have also been described with IV acyclovir administration. Neurotoxicity is generally reversible. Local inflammation at injection site or phlebitis, renal injury and acute renal failure, agitation, coma, seizures, and lethargy may occur with acute or repeated administration to patients with renal insufficiency. Obstructive nephropathy as a result of acyclovir crystalluria may develop following high-dose therapy. Leukopenia has occasionally been reported as an adverse effect following therapeutic doses.
    3) TOPICAL: Mild pain, burning, stinging, and itching.
    4) OCULAR: Mild irritation.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients who ingest these agents in overdose experience only mild or moderate effects. The primary manifestations are nausea, vomiting, and headache. Renal injury has been reported.
    2) SEVERE TOXICITY: Most toxicity from these agents is from therapeutic or high therapeutic doses (particularly in patients with renal insufficiency) rather than inadvertent or intentional oral overdose. Neurotoxicity predominates and may include lethargy, confusion, ataxia, nystagmus, dysarthria, hallucinations, myoclonus, agitation, and in severe cases, seizures or coma. Renal failure can also develop and is usually transient.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER was reported after an acyclovir dose of 250 mg/m(2) (Vartian & Shlaes, 1983).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) IRRITATION: Only mild local irritation is reported after ocular use of ointments containing up to 6% acyclovir (Morgan, 1980; (Tucker et al, 1983b). Ointments containing 1% to 3% were not irritating when applied to rabbits' eyes (Tucker et al, 1983b; Grant & Schuman, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) A 6-month-old girl was treated with cyclosporine, ticarcillin-clavulanic acid, fluconazole and acyclovir after liver transplant. On post transplant day 5 she suddenly became comatose and agitated with choreoathetoid limb movements and random eye movements. Cranial CT was normal, EEG showed no signs of seizures, CSF was normal, and cyclosporine trough levels was below the therapeutic range. Acyclovir level was 4.5 mg/L above the recommended target range of 2.3 +/- 1.4 mg/L. Neurologic status returned to baseline with acyclovir withdrawal (Chevret et al, 2006).
    2) Stupor and progressive somnolence leading to coma have been associated with intravenous infusion of acyclovir (Wade & Meyers, 1983; Spiegal & Lau, 1986; Cohen et al, 1984) and high oral doses (Eck et al, 1991; Bradley et al, 1997).
    3) CASE REPORT: Following a one week course of oral acyclovir, 600 mg 4 times daily, a 68-year-old man was admitted to the hospital with watery diarrhea, fever, unsteady gait, and progressive lethargy, which lead to coma. Brain CT revealed diffuse cortical atrophy. Neurologic and renal function improved following 3 days of hemodialysis (Bradley et al, 1997).
    B) ALTERED MENTAL STATUS
    1) Mental status changes, including lethargy, disorientation, fatigue, and depression have been reported as adverse effects of acyclovir (Adair et al, 1994).
    2) INCIDENCE: Confusion and lethargy have been reported in 9 out of 30 (30%) patients with acyclovir neurotoxicity (Adair et al, 1994).
    3) CASE REPORT: Neurotoxicity, including lethargy, fatigue, irritability, and depression, was described in a 57-year-old man with normal renal function following oral acyclovir therapy. Symptoms were reproducible upon re-challenge (Krigel, 1986).
    4) CASE REPORT: Signs of neurotoxicity, including somnolence, confusion, and weakness, developed in a 76-year-old woman with end-stage renal disease after receiving oral acyclovir 200 mg five times daily for 4 days. Adjustments in dosing are necessary in patients with kidney disease (Swan & Bennett, 1989).
    5) CASE REPORT: A 48-year-old man developed neurotoxicity consisting of lethargy, dysarthria, nystagmus, ataxia, slurred speech and dizziness following 2 days of high dose intravenous acyclovir (Krieble et al, 1993).
    C) NEUROTOXICITY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 59-year-old woman developed acute renal failure and neurotoxicity 2 days after receiving intravenous acyclovir 250 mg every 8 hours for herpes zoster involving the first branch of trigeminal nerve and eye. She experienced drowsiness, lethargy, with incoherent speech and hallucinations. Neurological examination showed that muscle strength of the extremities was more than grade 4 symmetrically, and the deep tendon reflex was grade 2 to 3 with negative Babinski reflex bilaterally. EEG revealed mild diffuse cortical dysfunction with more emphasis in the right hemisphere and regional epileptiform activities in the bilateral frontal and the right parietal region. The plasma acyclovir trough level was 18 mg/L (in adults after receiving 5 mg/kg, the therapeutic peak and trough levels are from 5.5 to 13.8 mg/L and 0.2 to 1 mg/L, respectively). Following 2 sessions of 4-hour hemodialysis, her plasma acyclovir level decreased to 3 mg/L and her mental status improved (Hsu et al, 2005).
    D) HALLUCINATIONS
    1) Hallucinations have been associated with intravenous infusion of acyclovir (Wade & Meyers, 1963; (Hsu et al, 2005; Spiegal & Lau, 1986; Cohen et al, 1984; Jones & Beier-Hanratty, 1986; Feldman et al, 1988).
    2) INCIDENCE: Hallucinations have been reported in 6 out of 30 (20%) patients with acyclovir neurotoxicity (Adair et al, 1994).
    E) MYOCLONUS
    1) Muscle fasciculations and myoclonic jerks have been described in patients with high acyclovir serum levels (Adair et al, 1994; Feldman et al, 1988).
    2) INCIDENCE: Myoclonus has been reported in 9 out of 30 (30%) patients with acyclovir neurotoxicity; tremor has been reported in 9 out of 30 (30%) (Adair et al, 1994).
    3) CASE REPORT: Impaired consciousness, dysarthria, myoclonus, hyperactive tendon reflexes, and a left-sided Babinski's sign developed in a previously healthy 77-year-old woman after being given a total IV dose of 6 grams acyclovir over 2 days. EEG revealed moderate generalized disturbances without focal abnormalities. Serum levels were reported to peak at 51.8 mg/L, but signs of CNS toxicity were delayed for 24 to 48 hours. Neurologic symptoms resolved 6 days after discontinuation of acyclovir (Haefeli et al, 1993).
    F) PSYCHOMOTOR AGITATION
    1) Agitation is a common adverse effect of these drugs, particularly following higher doses (Adair et al, 1994).
    2) INCIDENCE: Agitation was reported in 8 out of 30 (26.7%) patients with acyclovir neurotoxicity (Adair et al, 1994).
    3) CASE REPORT: Agitation and confusion, as well as renal insufficiency, were reported following an inadvertent IV overdose of 800 mg acyclovir in a 2-year-old child. Following fluid therapy and frequent neurologic exams, the child recovered (Sigg et al, 2001).
    4) CASE REPORT: Tremor, agitation, and lethargy have been reported (Wade et al, 1983). Tremor, lethargy, agitation, disorientation, and abnormal EEG occurred 2 to 18 days after treatment with intravenous acyclovir 750 to 3,000 mg/m(2) (Wade & Meyers, 1983).
    a) These symptoms resolved in 4 to 14 days after discontinuation of therapy. Neurologic symptoms occurred in approximately 4% of patients during phase 2 trials (Brigden & Whiteman, 1983).
    G) SEIZURE
    1) ACYCLOVIR: Seizures have been infrequently reported following massive acyclovir overdoses (Prod Info acyclovir IV injection, 2008).
    H) HEADACHE
    1) FAMCICLOVIR: Headache is one of the most commonly reported adverse effects of famciclovir in clinical trials (Prod Info FAMVIR(R) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting were present in patients after acyclovir doses of 500 mg/m(2) every 8 hours intravenously (Brigden & Whiteman, 1983).
    2) CASE REPORT: Nausea and vomiting occurred after 2 intravenous 1 gram acyclovir doses in a 48-year-old male (Krieble et al, 1993).
    3) FAMCICLOVIR: Nausea and headache were the most frequent adverse effects reported with famciclovir in clinical trials (Prod Info FAMVIR(R) oral tablets, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Several studies have reported no adverse effects of acyclovir on liver function during IV administration (O'Meara & Hillary, 1981; Saral et al, 1981; Selby et al, 1979). However, in a study by Van der Meer & Versteeg (1982), one patient on intravenous acyclovir experienced a transient elevation in transaminases (Van der Meer & Versteeg, 1982).
    2) Elevated hepatic enzymes have been reported after intravenous acyclovir use, but have yet to be directly attributed to the drug (Gnann et al, 1983).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) SUMMARY: The risk of nephrotoxicity is primarily related to high serum levels following bolus IV injections or overdose and is usually reversible. Adequate hydration and high urine output should be maintained throughout treatment to minimize nephrotoxicity (Rauber-Luthy et al, 2001). Empiric therapy with as little as 3 doses of IV acyclovir has resulted in elevated serum creatinine levels (Erdman et al, 2001).
    2) Increased plasma urea or creatinine was seen in 10% of patients given IV bolus injections (Brigden & Whiteman, 1983). Wade et al (1983) reported increased serum creatinine after a 2,000 mg/m(2) bolus dose.
    3) CASE REPORT: Following a 10-fold overdose (100 mg/kg instead of 10 mg/kg 3 times daily for 4 days) of IV acyclovir, acute renal failure was reported in a newborn. A serum creatinine level of 211 micromoles/liter was reported on day 5, which decreased to normal within 2.5 days after discontinuation of acyclovir (Rauber-Luthy et al, 2001).
    4) CASE REPORT: An 11-day-old infant inadvertently received intravenous acyclovir 750 mg (220 mg/kg/dose) after having received 5 doses at 10 mg/kg/dose every 8 hours. At 24 hours post-exposure, the error was discovered. No clinical manifestations of toxicity (tremor, myoclonus, or seizures) occurred; only a minor transient rise in serum creatinine from 0.5 to 0.7 mg/dL, which returned to baseline level within 66 hours, was noted (Baker et al, 2002).
    5) CASE REPORT: Following an inadvertent acyclovir IV overdose of 800 mg in a 2-year-old child, serial serum creatinine levels were obtained, with the highest level reported as 1.3 mg/dL at 24 hours post-exposure. Levels returned to normal by 48 hours (Sigg et al, 2001).
    6) CASE REPORT: Acute nonoliguric renal failure was reported in a 48-year-old woman who received acyclovir 5 mg/kg three times a day by slow IV infusion. She recovered completely in 8 days with reinstitution of acyclovir at a slower rate and dose (Spiegal & Lau, 1986).
    7) CASE SERIES: Acute oliguric renal failure developed in 4 patients, with no pre-existing renal dysfunction, who were treated with high-dose intravenous acyclovir. Peak serum Cr ranged from 3.4 mg/dL to 7 mg/dL. Renal function returned to normal in 3 of the 4 patients within 4 to 7 days of discontinuation (Lopez et al, 1995).
    8) CASE REPORT: A 70-year-old woman developed reversible acute renal failure and coma associated with oral acyclovir therapy (800 mg five times daily for 7 days) for herpes zoster (Eck et al, 1991).
    9) CASE REPORT: A 59-year-old woman developed acute renal failure (BUN 45.1 mg/dL [4.5-24 mg/dL]; serum creatinine 5 mg/dL [0.6-1.3 mg/dL]) and neurotoxicity 2 days after receiving intravenous acyclovir 250 mg every 8 hours for herpes zoster involving the first branch of trigeminal nerve and eye. The plasma acyclovir trough level was 18 mg/L (in adults after receiving 5 mg/kg, the therapeutic peak and trough levels are from 5.5 to 13.8 mg/L and 0.2 to 1 mg/L, respectively). Following 2 sessions of 4-hour hemodialysis, her plasma acyclovir level decreased to 3 mg/L (Hsu et al, 2005).
    B) CRYSTALLURIA
    1) Precipitation of acyclovir crystals in the tubular lumen, leading to obstructive nephropathy, may be one cause of acyclovir-induced renal failure.
    a) CASE REPORT: Crystals of acyclovir were found in the urine, accompanied by renal tubular impairment in a 28-year-old woman who received acyclovir 10 mg/kg intravenously every 8 hours (Peterslund et al, 1988).
    b) CASE REPORT: Krieble et al (1993) report a case of a 48-year-old male who developed acyclovir crystalluria following 5 grams of acyclovir over 2 days. His BUN and serum Cr had increased during this time (Krieble et al, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) CASE SERIES: Winston et al (1995) report 26 of 126 (21%) of liver-transplant patients being treated with IV acyclovir for long-term CMV prophylaxis developed leukopenia (WBC count < 3.0 x 10(9)/L). Severe leukopenia developed in 4 of these patients. There was no increased incidence of infections in these patients (Winston et al, 1995).
    2) CASE REPORT: Neutropenia (WBC 1500 cells/microliter) and thrombocytopenia (133,000 cells/microliter) were reported in an 8-year-old boy following prolonged acyclovir (200 mg twice daily for 5 months) therapy. Following discontinuation of acyclovir, ANC and platelet count normalized within a few days (Grella et al, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rashes have been seen after therapeutic administration (Gould et al, 1982).
    b) CASE REPORT: A 19-year-old woman developed diffuse urticaria following each of 2 doses of intravenous acyclovir 250 mg, given 8 hours apart, after sensitization to topical 5% acyclovir cream (Gola et al, 1989).
    B) INJECTION SITE REACTION
    1) Reactions at the acyclovir injection site have also been seen (possibly due to the high pH of injected solution) (Leitman, 1982).
    C) CONTACT DERMATITIS
    1) CASE REPORT: Erythema, edema, and vesicles developed in a 52-year-old woman after 10 days of topical application of 5% acyclovir cream (Valsecchi et al, 1990).
    2) CASE REPORT: Baes & Van Hecke (1990) reported 2 cases of contact dermatitis to Zovirax(R) cream (5% acyclovir). Both patients had negative patch tests to the constituents of Zovirax(R) cream and to Zovirax(R) ointment (5% acyclovir), while both had positive patch tests to the Zovirax(R) cream (5% acyclovir) (Baes & Van Hecke, 1990).

Reproductive

    3.20.1) SUMMARY
    A) Acyclovir, acyclovir/hydrocortisone (topical), famciclovir, and penciclovir are classified as pregnancy category B. A large population-based cohort study showed no increased risk of major birth defects following first-trimester acyclovir or valacyclovir use. Head and tail abnormalities developed in embryos of pregnant rats when they received acyclovir. Testicular toxicity has been reported in animal studies following the use of famciclovir or penciclovir.
    3.20.2) TERATOGENICITY
    A) CNS ABNORMALITIES
    1) An oral TDLo of acyclovir for women is reported to be 60 mg/kg for 5 to 6 weeks in early pregnancy, which may result in CNS abnormalities to the fetus (RTECS , 2002).
    B) LACK OF EFFECT
    1) A population-based cohort study of 837,795 live births in Denmark showed no increased risk of major birth defects following first-trimester acyclovir or valacyclovir use. Birth records dated between 1996 and 2008 were cross-referenced with mothers’ antiviral prescriptions (acyclovir, valacyclovir, or famciclovir) dated from 4 weeks before conception to birth. Forty infants (2.2%) of 1804 pregnancies exposed to acyclovir or valacyclovir in the first trimester were diagnosed with a major birth defect, compared with 19920 (2.4%) of unexposed infants (adjusted prevalence odds ratio (POR), 0.89; 95% confidence interval (CI), 0.65 to 1.22). Major birth defects were found in 32 (2%) of the 1561 infants with first-trimester exposure to acyclovir (adjusted POR, 0.82; 95% CI, 0.57 to 1.17) and 7 (3.1%) of the 229 infants with valacyclovir exposure in the first trimester (adjusted POR, 1.21; 95% CI, 0.56 to 2.62). Exposure to famciclovir was rare, with 1 case of major birth defects among 26 exposed pregnancies (adjusted POR, 1.63; 95% CI, 0.2 to 13.05). Exploratory analysis revealed an increased risk for heart defects (1.3% exposed compared with 0.8% of unexposed) among infants with mothers using antivirals within the 4 weeks before conception (adjusted POR, 1.71; 95% CI, 1.05 to 2.79) (Pasternak & Hviid, 2010).
    2) In a prospective registry of acyclovir use during pregnancies between 1984 and 1999, where systemic acyclovir exposure occurred during the first trimester of pregnancy (n=749), the rate of birth defects seen in the 756 outcomes was approximately the same as the rate found in the general population. However, registry size was not sufficient in assessing risk for less common adverse events or in drawing conclusions regarding the safety of acyclovir use during pregnancy (Prod Info XERESE(TM) topical cream 5%/1%, 2010; Prod Info SITAVIG buccal tablets, 2013; Prod Info acyclovir oral suspension, 2010; Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir 5% topical ointment, 2012; Prod Info ZOVIRAX(R) topical cream, 2011).
    C) ANIMAL STUDIES
    1) MICE, RABBITS, RATS: There was no evidence of teratogenicity in mice, rabbits, or rats at substantially greater acyclovir exposure than in humans (Prod Info XERESE(TM) topical cream 5%/1%, 2010; Prod Info acyclovir 5% topical ointment, 2012; Prod Info ZOVIRAX(R) topical cream, 2011). Acyclovir administration during organogenesis to the mouse at an oral dose of 450 mg/kg/day (approximately 9 to 18 times the human plasma levels based on exposure), to the rabbit at subQ and IV doses of 50 mg/kg/day (approximately 16 to 106 times the human levels), and to the rat at a subQ dose of 50 mg/kg/day (approximately 11 to 22 times the human levels) resulted in no teratogenic effects (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    2) RABBITS/MICE: No teratogenic effects were seen in rabbit or mouse models in acyclovir studies (Brigden & Whiteman, 1983).
    3) RATS: Head and tail abnormalities developed in embryos of pregnant rats when they received acyclovir doses leading to plasma concentrations well above the therapeutic range (Stahlmann et al, 1988).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturers have classified acyclovir, famciclovir, and penciclovir as FDA pregnancy category B (Prod Info SITAVIG buccal tablets, 2013; Prod Info acyclovir 5% topical ointment, 2012; Prod Info ZOVIRAX(R) topical cream, 2011; Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010; Prod Info FAMVIR(R) oral tablets, 2009; Prod Info DENAVIR(R) cream, 2002). The manufacturer has also classified topical acyclovir/hydrocortisone cream as FDA pregnancy category B (Prod Info XERESE(TM) topical cream 5%/1%, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) ACYCLOVIR
    a) The concentration of acyclovir in breast milk exceeded maternal serum levels (milk to plasma ratio, 0.6 to 4.1) following ingestion of 200 mg every 3 hours. It was estimated that the infant ingested 0.2 mg/kg/day or 1.6% of the adult dose (Lau et al, 1987; Briggs et al, 1998). The milk-plasma ratio was 3.24 in another study with an estimated ingestion of 1 mg/day by the nursing infant (Meyer et al, 1988; Briggs et al, 1998).
    2) FAMCICLOVIR
    a) After administration of famciclovir (prodrug of penciclovir), penciclovir was excreted in breast milk of lactating rats at concentrations greater than those seen in plasma (Prod Info Denavir(R), penciclovir, 2001).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Acyclovir administration in mice at an oral dose of 450 mg/kg/day (9 to 18 times the plasma levels of humans) and in rats at a subQ dose of 25 mg/kg/day (8 to 15 times the human levels) did not result in fertility or reproduction impairment. Higher doses of 50 mg/kg/day administered subQ to rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) decreased implantation efficacy, but not litter size. A statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses resulted from 50 mg/kg/day administered to rats subQ in a perinatal and postnatal study. Dogs given 50 mg/kg/day IV for 1 month (21 to 41 times human levels) or 60 mg/kg/day orally for 1 years (6 to 12 times human levels) resulted in no testicular abnormalities. However, rats and dogs given higher doses had testicular atrophy and aspermatogenesis (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    2) Testicular toxicity has been reported in animal studies following the use of famciclovir or penciclovir. Decreased fertility resulted after 10 weeks of dosing at 500 mg/kg/day (Prod Info Famvir(R), famciclovir, 1998).
    3) Famciclovir was reported to have no effects on general reproductive performance or fertility in female rats with doses up to 1000 mg/kg/day (Prod Info Famvir(R), famciclovir, 1998).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) BREAST CARCINOMA
    1) Famciclovir, the oral prodrug of penciclovir, was reported to result in an increase in mammary adenocarcinoma in female rats receiving doses of 600 mg/kg/day (Prod Info Famvir(R), famciclovir, 1998).

Genotoxicity

    A) MUTAGENICITY has been demonstrated in IN VITRO studies on mouse lymphoma cells and human lymphocytes with high doses, at concentrations of 250 mcg/mL and greater (Clive et al, 1983).
    B) Chromosome aberrations in the absence of metabolic activation (250 mcg/mL) were seen in the L5178Y mouse lymphoma assay for penciclovir (Prod Info Famvir(R), famciclovir, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor renal function and urine output in patients receiving IV acyclovir with suspected toxicity or after massive oral overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function in patients receiving IV acyclovir with suspected toxicity or after massive oral overdose.
    4.1.3) URINE
    A) MONITORING
    1) Monitor urine output in patients receiving IV acyclovir with suspected toxicity or after massive oral overdose.
    B) URINALYSIS
    1) Crystals of acyclovir (fine elongated rectangular crystals) have been noted rarely in patients with acyclovir-induced nephropathy (Peterslund et al, 1988).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Acyclovir plasma levels can be measured with accuracy and sensitivity using radioimmunoassay, high-performance liquid chromatography or bioassay (Lietman, 1982).
    2) Haefeli et al (1993) report measuring acyclovir serum levels with a double antibody radioimmunoassay with a monoclonal antibody to acyclovir (detection limit less than 0.03 micromoles/liter) (Haefeli et al, 1993).
    3) Boulieu et al (1997) described a reversed-phase high-performance liquid chromatography method for the measurement of plasma concentrations of acyclovir. A quantification limit of 0.1 mg/L for a volume of 500 microliters is reported (Boulieu et al, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit patients with severe toxicity characterized by CNS effects or renal injury.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent ingestion of these products may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consider consultation with nephrology for patients with renal injury.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose and symptomatic patients should be sent to a healthcare facility for evaluation and treatment. Patients should be observed for 6 hours, primarily monitoring signs of co-ingestant toxicity or development of significant CNS depression. Follow-up renal function tests should be obtained in patients with massive overdose.
    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Admit patients with severe toxicity characterized by CNS effects or renal injury.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consider consultation with nephrology for patients with renal injury.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with deliberate overdose and symptomatic patients should be sent to a healthcare facility for evaluation and treatment. Patients should be observed for 6 hours, primarily monitoring signs of co-ingestant toxicity or development of significant CNS depression. Follow-up renal function tests should be obtained in patients with massive overdose.

Monitoring

    A) Monitor renal function and urine output in patients receiving IV acyclovir with suspected toxicity or after massive oral overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No pre-hospital decontamination is indicated.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Activated charcoal should be considered for patients that present early after large overdose if they are awake, alert, and willing to drink the charcoal.
    2) Based on animal studies, large amounts of an oral product may be needed to cause significant toxicity (Brigden & Whiteman, 1983).
    B) ACTIVATED CHARCOAL
    1) In an in vitro test, activated charcoal adsorbed more than 10 percent of its weight with acyclovir (McDonald et al, 1989).
    2) When activated charcoal 1 gram/kilogram was administered every 4 hours for 4 doses to an 8-day-old neonate who received approximately 65 milligrams/kilogram of acyclovir intravenously, no change was noted in the elimination half-life (McDonald et al, 1989).
    3) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    4) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment following overdoses of these agents is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor renal function and urine output in patients receiving IV acyclovir with suspected toxicity or after massive oral overdose.
    2) Oral overdoses are unusual, and few serious toxic effects have been seen with therapeutic use. The primary systems to monitor include the CNS (agitation, tremors, lethargy) and kidney (increased serum creatinine). When large amounts of acyclovir were given as a bolus, crystals were deposited in renal tubules and collecting ducts. This may cause a transient increase in creatinine and blood urea nitrogen.
    a) Intravenous fluid hydration may aid in solubilizing crystals and therefore prevent or minimize crystal deposits in renal tubules and collecting ducts (McDonald et al, 1989).
    b) Fluid and electrolytes should be monitored during intravenous hydration to prevent fluid overload and electrolyte abnormalities.
    c) The incidence of renal toxicity may be greatly decreased by administering acyclovir slowly in a concentration less than 7 milligrams/milliliter (Gnann et al, 1983; Prod Info acyclovir IV injection, 2008). These renal symptoms cleared without treatment.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Acyclovir may be dialyzed, approximately 60 percent of the body's burden being removed by this treatment (Lietman, 1982). Due to the low molecular weight, water solubility, and low protein binding of acyclovir, it is anticipated that continuous hemodialysis would be effective in removal of acyclovir from plasma (Boulieu et al, 1997). Hemodialysis may benefit the patient with acyclovir-induced acute renal failure (Prod Info ZOVIRAX(R) oral capsule, oral tablet, oral suspension, 2005). Famciclovir and penciclovir are removed by hemodialysis (Prod Info FAMVIR(R) oral tablets, 2011).
    a) CASE REPORT: Krieble et al (1993) report a case of neurotoxicity and nephrotoxicity following high-dose IV acyclovir(Krieble et al, 1993). The patient underwent 4 hours of hemodialysis with subjective improvement during treatment. Following one hemodialysis session, his speech, ataxia, and nystagmus significantly improved. Pre-hemodialysis acyclovir serum levels were 9.6 mcg/mL and post-hemodialysis acyclovir levels were 5.6 mcg/mL.
    b) CASE SERIES: Boulieu et al (1997) report on the pharmacokinetics of acyclovir (intravenous infusions) in 3 patients undergoing continuous venovenous hemodialysis (CVVHD)(Boulieu et al, 1993). Elimination half-life ranged from 8.8 to 11.2 hours in these patients. Clearance of acyclovir from the plasma by CVVHD (35% of the total clearance) was effective. Clearance from CVVHD is about twice that from continuous arteriovenous hemodialysis (CAVHD).
    c) CASE REPORT: A 59-year-old woman developed acute renal failure and neurotoxicity 2 days after receiving intravenous acyclovir 250 mg every 8 hours for herpes zoster involving the first branch of trigeminal nerve and eye. The plasma acyclovir trough level was 18 mg/L (in adults after receiving 5 mg/kg, the therapeutic peak and trough levels are from 5.5 to 13.8 mg/L and 0.2 to 1 mg/L, respectively). Following 2 sessions of 4-hour hemodialysis, her plasma acyclovir level decreased to 3 mg/L (Hsu et al, 2005).
    B) EXCHANGE TRANSFUSION
    1) Exchange transfusion is not effective in increasing acyclovir elimination after overdose.
    2) A 5-day-old neonate was given a 2-volume exchange transfusion (410 milliliters) beginning approximately 8.5 hours after the last of 3 doses of intravenous acyclovir 250 milligrams (100 milligrams/kilogram) administered over 1 hour for neonatal HSV infection. The pretransfusion concentration of acyclovir was 25 milligrams/liter. At completion of the transfusion the concentration of acyclovir was 10 milligrams/liter. The estimated elimination half-life associated with 6 serum concentrations over a 24-hour period was 3.6 hours (McDonald et al, 1989).

Abstracts

Case Reports

    A) INFANT
    1) Two neonates, a 5-day-old 2560 gram female and an 8-day-old 3235 gram female, received a 10-fold overdose of intravenous acyclovir (100 mg/kg and 65 mg/kg, respectively).
    a) The first neonate was treated with IV fluid hydration and a 2-volume exchange transfusion. The second neonate received 4 doses of activated charcoal 1 g/kg orally every 4 hours and IV fluid hydration. Neither treatment enhanced elimination.
    b) Neither neonate developed any discernible neurologic or renal dysfunction (McDonald et al, 1989).

Range Of Toxicity

Summary

    A) TOXICITY: 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.
    B) THERAPEUTIC DOSE: Varies with indication. ACYCLOVIR: ADULT: Oral dose is 200 to 800 mg 3 to 5 times daily. The IV dose is 5 to 10 mg/kg every 8 hours. PEDIATRIC: ORAL: 2 yrs and older, less than 40 kg: 20 mg/kg 4 times daily; greater than 40 kg: 800 mg 4 times daily. IV (birth to 12 yrs of age): 10 to 20 mg/kg every 8 hours. FAMCICLOVIR: ADULT: 500 mg to 2 g daily divided in 2 or 3 doses. PENCICLOVIR: ADULT: Apply topically every 2 hours while awake.

Therapeutic Dose

    7.2.1) ADULT
    A) ACYCLOVIR
    1) INTRAVENOUS
    a) MUCOSAL AND CUTANEOUS HERPES SIMPLEX INFECTIONS: 5 mg/kg IV infused over 1 hour every 8 hours for 7 days in immunocompromised patients (Prod Info acyclovir IV injection, 2008).
    b) HERPES GENITALIS: 5 mg/kg IV infused over 1 hour every 8 hours for 5 days (Prod Info acyclovir IV injection, 2008).
    c) HERPES SIMPLEX ENCEPHALITIS: 10 mg/kg IV infused over 1 hour every 8 hours for 10 days (Prod Info acyclovir IV injection, 2008).
    d) VARICELLA ZOSTER: Immunocompromised patients: 10 mg/kg IV infused over 1 hour every 8 hours for 7 days (Prod Info acyclovir IV injection, 2008).
    e) MAXIMUM DOSE: The maximum recommended dose in any patient should not exceed 20 mg/kg IV every 8 hours (Prod Info acyclovir IV injection, 2008).
    f) The dose and/or dosing interval should be adjusted in patients with renal impairment (Prod Info acyclovir IV injection, 2008).
    2) ORAL
    a) GENITAL HERPES: 200 mg orally every 4 hours, 5 times daily, for 10 days (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    b) HERPES LABIALIS (COLD SORES): 50 mg applied to upper gum as single dose (buccal tablet) (Prod Info SITAVIG buccal tablets, 2013).
    c) HERPES ZOSTER (SHINGLES): 800 mg orally every 4 hours, 5 times daily, for 7 to 10 days (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    d) VARICELLA ZOSTER (CHICKENPOX): 800 mg orally 4 times daily for 5 days (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    3) TOPICAL
    a) GENITAL HERPES: Apply every 3 hours, 6 times daily, for 7 days (Prod Info acyclovir 5% topical ointment, 2012).
    b) HERPES LABIALIS (COLD SORES): Apply 5 times daily for 4 days (Prod Info ZOVIRAX(R) topical cream, 2011).
    B) FAMCICLOVIR
    1) GENITAL HERPES: 1000 mg orally twice daily for 1 day (Prod Info FAMVIR(R) oral tablets, 2011).
    2) HERPES LABIALIS: 1500 mg orally as a single dose (Prod Info FAMVIR(R) oral tablets, 2011).
    3) HERPES ZOSTER: 500 mg orally every 8 hours for 7 days (Prod Info FAMVIR(R) oral tablets, 2011).
    C) PENCICLOVIR
    1) HERPES LABIALIS: Apply topically every 2 hours during waking hours for 4 days (Prod Info Denavir(R) topical cream, 2002).
    7.2.2) PEDIATRIC
    A) ACYCLOVIR
    1) INTRAVENOUS
    a) MUCOSAL AND CUTANEOUS HERPES SIMPLEX INFECTIONS: Immunocompromised patients: 29 days to 12 years of age , 10 mg/kg IV every 8 hours for 7 to 14 days (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009; Prod Info acyclovir IV injection, 2008). 12 years and older: 5 mg/kg IV every 8 hours for 7 to 14 days (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009; Prod Info acyclovir IV injection, 2008). HIV-Infection: 5 to 10 mg/kg IV every 8 hours until lesions begin to regress, then change to oral acyclovir (20 mg/kg (maximum 400 mg/dose) orally 3 times daily until lesions completely heal) (Centers for Disease Control and Prevention et al, 2009).
    b) GENITAL HERPES: 12 years of age and older, 5 to 10 mg/kg IV every 8 hours for 2 to 7 days, followed by oral therapy to complete 10 days of total treatment (Workowski et al, 2010; Prod Info acyclovir IV injection, 2008).
    c) HERPES SIMPLEX ENCEPHALITIS: 29 days to 12 years of age, 20 mg/kg IV every 8 hours for 21 days (Elbers et al, 2007; Prod Info acyclovir IV injection, 2008). 12 years of age and older, 10 mg/kg IV every 8 hours for 21 days (Elbers et al, 2007; Whitley & Kimberlin, 2005; Prod Info acyclovir IV injection, 2008).
    d) HERPES SIMPLEX ENCEPHALITIS-HIV-INFECTION: 10 mg/kg IV every 8 hours for 21 days (Centers for Disease Control and Prevention et al, 2009).
    e) HERPES SIMPLEX VIRUS (HSV-SEROPOSITIVE), PROPHYLAXIS- HEMATOPOIETIC CELL TRANSPLANT: Less than 40 kg-250 mg/m(2) IV every 8 hours or 125 mg/m(2) IV every 6 hours; maximum 80 mg/kg/day (Tomblyn et al, 2009; Selby et al, 1989). 40 kg or greater- 250 mg/m(2) IV every 12 hours (Tomblyn et al, 2009; Shepp et al, 1987).
    f) NEONATAL HERPES SIMPLEX VIRUS INFECTION, TREATMENT: Birth to 2 months of age- 20 mg/kg IV every 8 hours for 21 days for CNS and disseminated disease or 14 days for disease of the skin and mucous membranes (Workowski et al, 2010; Centers for Disease Control and Prevention et al, 2009; Kimberlin et al, 2001).
    g) HERPES ZOSTER (SHINGLES), IMMUNOCOMPROMISED PATIENTS: 29 days to 1 year of age- 10 mg/kg IV every 8 hours for 7 to 10 days or until no new lesions for 48 hours (Centers for Disease Control and Prevention et al, 2009; Arvin, 2002). 1 year or older: 500 mg/m(2) IV every 8 hours or 10 mg IV every 8 hours until cutaneous lesions and visceral disease are resolving, then switch to oral therapy to complete 10 to 14 days of treatment (Centers for Disease Control and Prevention et al, 2009; Arvin, 2002). For acute retinal necrosis, treat with IV acyclovir for 10 to 14 days, followed by oral acyclovir 20 mg/kg (maximum 800 mg/dose) four times daily for 4 to 6 weeks (or oral valacyclovir 1 g orally three times daily for 4 to 6 weeks in children old enough to receive adult dose) (Centers for Disease Control and Prevention et al, 2009).
    h) VARICELLA ZOSTER VIRUS (VZV SEROPOSITIVE), PROPHYLAXIS - HEMATOPOIETIC CELL TRANSPLANT: 250 mg/m(2) IV every 12 hours starting at day minus 7 and continued until day 30 following transplantation or resolution of mucositis (Erard et al, 2007; Boeckh et al, 2006).
    i) VARICELLA (CHICKENPOX), IMMUNOCOMPROMISED PATIENTS: Less than 1 year of age- 10 mg/kg IV every 8 hours for 7 to 10 days or until no new lesions for 48 hours (Centers for Disease Control and Prevention et al, 2009; Arvin, 2002). 1 year or older- 500 mg/m(2) IV every 8 hours or 10 mg/kg IV every 8 hours for 7 to 10 days or until no new lesions for 48 hours (Centers for Disease Control and Prevention et al, 2009; Arvin, 2002; Carcao et al, 1998; Shepp et al, 1986; Balfour, 1984).
    j) VARICELLA ZOSTER (CHICKENPOX): Immunocompromised patients: 12 years of age or older, 10 mg/kg IV, infused over 1 hour, every 8 hours for 7 days; less than 12 years of age, 20 mg/kg IV, infused over 1 hour, every 8 hours for 7 days (Prod Info acyclovir IV injection, 2008).
    k) MAXIMUM DOSE: The maximum recommended dose in any patient should not exceed 20 mg/kg IV every 8 hours (Prod Info acyclovir IV injection, 2008).
    2) ORAL
    a) GENITAL HERPES SIMPLEX: Less than 12 years of age- 40 to 80 mg/kg/day orally in 3 to 4 divided doses for 5 to 10 days; maximum 1 g/day (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009). 12 years and older- initial episode: 400 mg orally three times daily or 200 mg orally five times daily for 7 to 10 days (Workowski et al, 2010). Chronic suppressive therapy for recurrent episodes- 400 mg orally twice daily; reevaluate therapy at 12 months; safety and efficacy established for as long as 6 years with acyclovir chronic therapy (Workowski et al, 2010). Episodic therapy for recurrent episodes- 400 mg orally three times daily or 800 mg orally twice daily for 5 days or 800 mg orally three times daily for 2 days (Workowski et al, 2010).
    b) GENITAL HERPES SIMPLEX - HIV-INFECTION: Less than 12 years of age- 20 mg/kg orally three times daily for 5 to 14 days. Maximum 400 mg/dose (Centers for Disease Control and Prevention et al, 2009). 12 years and older: 400 mg orally twice daily for 5 to 14 days (Centers for Disease Control and Prevention et al, 2009). Chronic suppressive therapy for recurrent episodes: 20 mg/kg orally 2 times daily. Maximum 400 mg/dose (Centers for Disease Control and Prevention et al, 2009).
    c) HERPES SIMPLEX VIRUS, MUCOCUTANEOUS: 20 mg/kg (maximum 800 mg/dose) orally 4 times daily (Committee on Infectious Diseases, American Academy of Pediatrics et al, 2009). HIV-infected patient: 20 mg/kg (maximum 400 mg/dose) orally three times daily for 5 to 10 days (Centers for Disease Control and Prevention et al, 2009).
    d) HERPES SIMPLEX VIRUS, PROPHYLAXIS- HIV-INFECTION: Chronic suppressive therapy for recurrent episodes: 20 mg/kg (maximum 400 mg/dose) orally twice daily (Centers for Disease Control and Prevention et al, 2009).
    e) HERPES SIMPLEX VIRUS (HSV-SEROPOSITIVE), PROPHYLAXIS-HEMATOPOIETIC CELL TRANSPLANT: Less than 40 kg- 60 to 90 mg/kg/day orally in 2 or 3 divided doses; maximum 800 mg twice daily (Tomblyn et al, 2009). 40 kg and greater- 400 to 800 mg orally twice daily (Tomblyn et al, 2009).
    f) HERPES ZOSTER (SHINGLES), IMMUNOCOMPETENT PATIENT: 12 years and older- 800 mg orally every 4 hours, 5 times daily for 7 to 10 days (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    g) HERPES ZOSTER (SHINGLES) - HIV-INFECTION: Following initial therapy with IV acyclovir- 20 mg/kg (maximum 800 mg/dose) orally four times daily to complete a 10 to 14 day course for trigeminal nerve involvement or multidermatomal zoster, and 4 to 6 weeks for acute retinal necrosis (Centers for Disease Control and Prevention et al, 2009).
    h) NEONATAL HERPES SIMPLEX VIRUS INFECTION, CHRONIC SUPPRESSION: Following initial therapy with IV acyclovir - 300 mg/m(2)/dose orally 3 times a day (Kimberlin, 2010; Kimberlin et al, 1996).
    i) VARICELLA ZOSTER VIRUS (VZV- SEROPOSITIVE), PROPHYLAXIS- HEMATOPOIETIC CELL TRANSPLANT: Less than 40 kg- 60 to 80 mg/kg/day orally in 2 or 3 divided doses; maximum 800 mg twice daily (Tomblyn et al, 2009). 40 kg or greater- 800 mg orally every 12 hours (Tomblyn et al, 2009; Erard et al, 2007; Boeckh et al, 2006).
    j) VARICELLA (CHICKENPOX), IMMUNOCOMPETENT PATIENT: 2 years and older- 20 mg/kg orally 4 times daily for 5 days; administer within 24 hours of rash. MAXIMUM 800 mg/dose (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010; Balfour et al, 2001; Balfour et al, 1992; Dunkle et al, 1991).
    k) VARICELLA (CHICKENPOX) - HIV-INFECTION: No or moderate immune suppression and mild varicella disease: 20 mg/kg orally four times daily for 7 to 10 days or until no new lesions for 48 hours; maximum 800 mg/dose (Centers for Disease Control and Prevention et al, 2009).
    l) VARICELLA ZOSTER (CHICKENPOX): 2 years of age and older and less than 40 kg, 20 mg/kg orally 4 times daily for 5 days; greater than 40 kg, 800 mg orally 4 times daily for 5 days; administer within 24 hours of rash (Prod Info acyclovir oral capsules, oral tablets, 2012; Prod Info acyclovir oral suspension, 2010).
    3) TOPICAL
    a) HERPES LABIALIS (COLD SORES): 12 years and older, apply 5 times daily for 4 days (Prod Info ZOVIRAX(R) topical cream, 2011).
    B) FAMCICLOVIR
    1) Efficacy and safety have not been established in pediatric patients (Prod Info FAMVIR(R) oral tablets, 2011).
    C) PENCICLOVIR
    1) HERPES LABIALIS: 12 years and older, apply every 2 hours during waking hours for 4 days (Prod Info Denavir(R) topical cream, 2002).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) INFANT
    a) Two neonates, less than 10 days old, received 100 and 65 milligrams/kilogram of intravenous acyclovir.
    1) One neonate was treated with intravenous fluid hydration and a 2-volume exchange transfusion, and the other with intravenous fluid hydration and multiple dose oral activated charcoal (1 gram/kilogram orally every 4 hours for 4 doses).
    2) Neither treatment appeared to enhance acyclovir elimination. Neither neonate showed signs of discernible neurologic or renal dysfunction (McDonald et al, 1989).
    b) A newborn was inadvertently given acyclovir 100 milligrams/kilogram intravenously 3 times daily for 4 days instead of 10 milligrams/kilogram. Serum creatinine reached a maximum level of 211 micromols/liter on day 5, then gradually returned to normal (Rauber-Luthy et al, 2001).
    c) An 11-day-old infant inadvertently received intravenous acyclovir 750 milligrams (220 milligrams/kilogram/dose) after having received 5 doses at 10 milligrams/kilogram/dose every 8 hours. No clinical manifestations of toxicity were noted. A minor transient rise in serum creatinine from 0.5 to 0.7 milligram/deciliter, which returned to baseline level within 66 hours, was reported (Baker et al, 2002).
    2) PEDIATRIC
    a) A 2-year-old child was inadvertently given acyclovir 800 milligrams intravenously instead of oxacillin. The child became increasingly agitated and confused over the next several hours. Serum creatinine levels increased, but gradually returned to normal over the next 2 days (Sigg et al, 2001).
    3) ADULT
    a) A total of 6 grams acyclovir was given intravenously over 2 days to a previously healthy 77-year-old woman with resulting peak serum levels of 229.9 micromoles/liter (51.8 milligrams/liter). Delayed neurotoxicity occurred 24 to 48 hours after peak levels (Haefeli et al, 1993).
    b) A 68-year-old man developed progressive somnolence leading to coma following a one week course of oral acyclovir 600 milligrams 4 times daily. His history included chronic renal failure. Neurologic and renal function improved after a 3 day course of hemodialysis (Bradley et al, 1997).
    c) The manufacturer has reported acyclovir overdose ingestions up to 20 grams, associated with the development of lethargy, agitation, seizures, and coma (Prod Info ZOVIRAX(R) oral capsule, oral tablet, oral suspension, 2005).
    B) ANIMAL DATA
    1) Acyclovir oral doses of 45 milligrams/kilogram/day produced vomiting and weight loss after a week's treatment.
    a) Greater than 20 milligrams/kilogram/day of acyclovir intravenously caused obstructive crystal nephropathy.
    b) Chronic (1 year) doses of 450 milligrams/kilogram/day orally of acyclovir showed no symptoms in rats or mice, 30 milligrams/kilogram/day produced nail and foot pad damage in dogs (Brigden & Whiteman, 1983).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Plasma acyclovir levels are dose dependent. Doses of 750 mg/m(2)/day have produced a plasma level of 10.3 mcg/mL while doses of 2,700 to 3,000 mg/m(2)/day peaked at 36.3 mcg/mL (Wade & Meyers, 1983).
    a) Steady-state peak and trough concentrations ranging from 5.5 to 13.8 mcg/mL and 0.2 to 1 mcg/mL, respectively, were achieved in adults who received 5 mg/kg over 1 hour by constant rate of intravenous infusion every 8 hours (Prod Info acyclovir IV injection, 2008).
    b) Comparable plasma concentrations were achieved in children ranging from 3 months to 16 years of age, with normal renal function, when given doses of 10 mg/kg every 8 hours by 1 hour intravenous infusion (Prod Info acyclovir IV injection, 2008).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) Patients with normal renal function receiving 500 milligrams/square meter every 8 hours of acyclovir have peak serum levels of 90 to 100 micromoles/liter (Blum et al, 1982).
    b) Neurotoxicity: Manifested by slurred speech, disorientation, myoclonic jerks, tremors, hallucinations, and muscle fasciculations.
    1) Neurotoxicity was associated with serum acyclovir levels of 190 micromoles/liter in a 17-year-old girl receiving 16.8 milligrams/kilogram every 8 hours (Feldman et al, 1988). The estimated peak level was 470 micromoles/liter.
    2) Elevated peak levels, 4 hours after initiation of infusion, of 130 to 268 micromoles/liter were found in 4 of 6 patients with neurotoxicity (Wade & Meyers, 1983).
    3) Peak serum level of 229.9 micromoles/liter was reported for a 77-year-old woman with mild renal impairment following 6 grams of intravenous acyclovir over 2 days. Delayed neurotoxicity occurred 24 to 48 hours after peak levels (Haefeli et al, 1993).
    c) NEWBORN: Serum acyclovir reached a maximum level of 277 micrograms/milliliter (20-fold increase over maximal therapeutic level) on day 5 following an inadvertent overdose of 100 milligrams/kilogram 3 times daily IV for 4 days, then gradually returned to normal (Rauber-Luthy et al, 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ACYCLOVIR
    1) LD50- (ORAL)MOUSE:
    a) > 10 g/kg (Gnann et al, 1983a)
    2) LD50- (ORAL)RAT:
    a) > 20 g/kg (Tucker et al, 1983)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Acyclovir, a synthetic purine nucleoside analogue, is phosphorylated (activated) by virus-specific thymidine kinase, an event which does not occur to any extent with noninfected cells. It stops replication of herpes viral DNA via: (1) competitive inhibition of viral DNA polymerase; (2) incorporation into and termination of the growing viral DNA chain; and (3) inactivation of the viral DNA polymerase (Prod Info acyclovir IV injection, 2008).
    1) Acyclovir phosphate inhibits viral cells by acting as a substrate for an inhibitor of viral DNA polymerase, therefore blocking DNA synthesis (Gnann et al, 1983).
    B) Famciclovir is an oral prodrug of penciclovir, which has inhibitory action in vitro against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Within infected cells, viral thymidine kinase phosphorylates penciclovir to a monophosphate form which then is converted to penciclovir triphosphate by cellular kinases. The triphosphate salt form inhibits HSV polymerase competitively with deoxyguanosine triphosphate, thus selectively inhibiting herpes viral DNA synthesis and replication (Prod Info FAMVIR(R) oral tablets, 2011).

Toxicologic Mechanism

    A) Renal injury has been shown in animals to be due to precipitation of crystals in renal tissue, causing an obstructive nephropathy (Tucker et al, 1983a).
    1) CRYSTALLURIA has been noted in human patients with acyclovir nephropathy (Peterslund et al, 1988).

Physicochemical

Physical Characteristics

    A) Acyclovir is a white crystalline powder that has a maximum solubility in water at 37 degrees C of 2.5 mg/mL (Prod Info ZOVIRAX(R) oral capsule, oral tablet, oral suspension, 2005).
    B) Acyclovir sodium is a white crystalline powder that has a maximum solubility in water at 25 degrees C of greater than 100 mg/mL (Prod Info ZOVIRAX(R) IV injection, 2003).
    C) Famciclovir is a white to pale yellow solid that is freely soluble in acetone and methanol, sparingly soluble in ethanol and isopropanol, and initially freely soluble (greater than 25% w/v) in water at 25 degrees C (but rapidly precipitates as the sparingly soluble (2% to 3% w/v) monohydrate) (Prod Info FAMVIR(R) oral tablets, 2009).
    D) Penciclovir is a white to pale yellow solid with a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water at 20 degrees C. Solubility is 10 mg/mL in aqueous buffer (pH 2) (Prod Info Denavir(R) topical cream, 2002).

Ph

    A) Acyclovir sodium: 10.85 to 11.5 (Prod Info acyclovir sodium IV injection, 2004)

Molecular Weight

    A) Acyclovir: 225 (Prod Info ZOVIRAX(R) oral capsule, oral tablet, oral suspension, 2005)
    B) Acyclovir sodium: 247.19 (Prod Info acyclovir sodium IV injection, 2004; Prod Info ZOVIRAX(R) IV injection, 2003)
    C) Famciclovir: 321.3 (Prod Info FAMVIR(R) oral tablets, 2009)
    D) Penciclovir: 253.26 (Prod Info Denavir(R) topical cream, 2002)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Dogs receiving 150 mg/kg/day developed vomiting, diarrhea, anorexia, and weight loss. After 13 weeks, sore paws due to erosion and cracking of footpads and nails were noted in some dogs (Tucker et al, 1983).
    B) In a review of 105 reports of accidental acyclovir ingestions in dogs, 10 cases were considered toxicosis. The most common signs were vomiting, diarrhea, anorexia, and lethargy with doses ranging from 40 to 2195 mg/kg body weight. In 60% of cases, signs developed within 3 hours of ingestion (Richardson, 2000).

Treatment

    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOG
    a) Following large acyclovir doses, thorough decontamination is recommended. Emesis is considered more efficient than gastric lavage and may be performed in the asymptomatic animal assuming no contraindication exists. Activated charcoal adsorbs acyclovir in vitro. Recommended doses include 1 to 2 grams/kilogram body weight. A cathartic (2 grams of 70% sorbitol/kilogram body weight) may be administered with the activated charcoal if no dehydration or diarrhea is present.
    1) In a review of 10 dogs with acyclovir toxicosis, treatment in all cases included standard decontamination procedures including induction of emesis and administration of activated charcoal (Richardson, 2000).

Continuing Care

    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) DOG
    a) Following large acyclovir doses, thorough decontamination is recommended. Emesis is considered more efficient than gastric lavage and may be performed in the asymptomatic animal assuming no contraindication exists. Activated charcoal adsorbs acyclovir in vitro. Recommended doses include 1 to 2 grams/kilogram body weight. A cathartic (2 grams of 70% sorbitol/kilogram body weight) may be administered with the activated charcoal if no dehydration or diarrhea is present.
    1) In a review of 10 dogs with acyclovir toxicosis, treatment in all cases included standard decontamination procedures including induction of emesis and administration of activated charcoal (Richardson, 2000).
    11.4.3) TREATMENT
    11.4.3.3) LABORATORY SCHEDULE
    A) DOG
    1) Following an acyclovir exposure, the patient should be monitored for signs/symptoms of renal failure. Monitor BUN, serum creatinine, phosphorus, urine specific gravity, and urinary output in all severe exposures (Richardson, 2000).
    11.4.3.4) PHARMACOLOGIC INTERVENTION
    A) DOG
    1) Therapy for renal failure in dogs includes fluid therapy, correction of electrolyte imbalances, and diuresis. If anuric, peritoneal dialysis should be considered. If the tubular basement membrane remains intact and enough viable epithelial cells are present, acute renal failure can be reversed. Other therapies are symptomatic and supportive. Continue therapies until all clinical signs have resolved. Prognosis is good if treatment is begun early (Richardson, 2000).
    11.4.3.5) SUPPORTIVE CARE
    A) DOG
    1) The goal in therapy of acyclovir exposures is prevention of crystalluria-induced nephropathy. Diuresis may aid in solubilizing crystals and may prevent or minimize crystal deposits in renal tubules and collecting ducts.
    a) In 10 cases of acyclovir toxicosis, following decontamination, all dogs were treated with diuresis to prevent crystal deposits in renal tubules and collecting ducts and were given symptomatic and supportive care (Richardson, 2000).

Kinetics

    11.5.1) ABSORPTION
    A) DOG
    1) Following an oral acyclovir dose, bioavailability is 10% to 20% and considered poor. Peak plasma level occurs at 2 hours (Richardson, 2000).
    11.5.2) DISTRIBUTION
    A) DOG
    1) Following an acyclovir dose, approximately 35% is bound to plasma proteins. Extensive distribution occurs, with highest concentrations in the kidneys, liver, intestines and CSF. Acyclovir crosses the placenta and can pass into maternal milk (Richardson, 2000).
    11.5.4) ELIMINATION
    A) DOG
    1) Acyclovir: 62% to 91% is eliminated as unchanged drug via renal elimination (glomerular filtration and tubular secretion). Plasma terminal half-life is 2.2 to 3.6 hours (Richardson, 2000).

References

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