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VALACYCLOVIR

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Valacyclovir hydrochloride is the hydrochloride salt of L-valyl ester of the antiviral drug acyclovir. This prodrug undergoes rapid and extensive first-pass intestinal and/or hepatic metabolism to yield acyclovir and L-valine (an essential amino acid).

Specific Substances

    1) Valacyclovir hydrochloride
    2) 256 U 87
    3) 256U87
    4) BW256U87
    5) 256U
    6) CAS 124832-26-4

Available Forms Sources

    A) FORMS
    1) Valacyclovir is available as 500 mg and 1 g tablets (Prod Info VALTREX(R) oral caplets, 2010).
    B) USES
    1) Valacyclovir hydrochloride is indicated for the treatment of genital herpes simplex (initial and recurrent episodes), herpes labialis, herpes zoster (shingles), suppression of recurrent genital herpes simplex associated with HIV infection, recurrent genital herpes simplex (suppression and transmission reduction), and varicella (uncomplicated chickenpox in adults and adolescents with HIV) (Prod Info VALTREX(R) oral caplets, 2010).(Centers for Disease Control and Prevention et al, 2009).

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: Valacyclovir, an antiviral agent, is used in the treatment of genital herpes simplex, herpes labialis (cold sores) and herpes zoster. It is also used to treat chickenpox in pediatric patients.
    B) PHARMACOLOGY: Valacyclovir hydrochloride, a L-valyl ester prodrug of acyclovir, is rapidly converted to acyclovir. Acyclovir is than converted to acyclovir monophosphate by viral thymidine kinase, to acyclovir diphosphate by cellular guanylate kinase, and to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits replication of herpes viral DNA by competitive inhibition of viral DNA polymerase, incorporation and termination of the growing viral DNA chain, and by inactivation of viral DNA polymerase.
    C) TOXICOLOGY: As a prodrug of acyclovir, it exhibits similar toxic effects. No ingestions resulting in death have been reported in immunocompetent patients.
    D) EPIDEMIOLOGY: Exposure may occur. Immunocompromised patients may develop more acute effects following exposure.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The following adverse events have occurred in greater than 10% of patients: headache, nausea, and abdominal pain. OTHER: CNS adverse reactions (eg, agitation, hallucinations, seizures, delirium, confusion, and encephalopathy) may develop in both adult and pediatric patients or in patients with renal disease who received higher than recommended doses of valacyclovir. The elderly are the most likely to develop CNS and/or acute renal failure with therapy. RARE: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) (sometimes fatal) has developed in patients with advanced HIV and in allogenic bone marrow transplant and renal transplant patients.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. As a prodrug of acyclovir, similar toxicity is expected in overdose. Manifestations of acyclovir toxicity include acute renal insufficiency, lethargy, coma, agitation, myoclonus and in severe cases seizures.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea and constipation may develop. Headache, dizziness, and asthenia may also occur.
    3) SEVERE TOXICITY: Renal insufficiency, crystalluria of acyclovir when solubility in the renal tubules is exceeded, lethargy, myoclonus, agitation, tremor, seizure, and coma may develop. In rare cases, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and neutropenia can develop in patients with pre-existing advanced HIV and other immune suppressed states.
    0.2.20) REPRODUCTIVE
    A) Valacyclovir is 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. Teratogenicity and fertility studies were negative in rats or rabbits.

Laboratory Monitoring

    A) Monitor renal and CNS function as indicated following a significant exposure.
    B) Monitor CBC, platelet count and renal and liver function tests in patients with suspected hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Rehydration (oral or IV fluids) may prevent crystalluria and nephrotoxicity reported with acyclovir. Treat significant vomiting and diarrhea with fluids as tolerated; treat with antiemetics for persistent vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Rehydration (oral or IV fluids) may prevent crystalluria and nephrotoxicity reported with acyclovir. Support respiratory and cardiovascular function as needed. Benzodiazepines should be the first line agent for agitation or seizures.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in a patient with a potentially toxic ingestion who is awake and able to protect their airway. Activated charcoal should be avoided in patients with any signs or symptoms of an altered mental status or inability to protect their airway.
    2) HOSPITAL: Activated charcoal should be considered for patients that present early after a large overdose if they are awake, alert, and able to ingest the charcoal.
    D) AIRWAY MANAGEMENT
    1) Airway management is not expected to be necessary following a mild to moderate exposure to oral valacyclovir. Patients with profound CNS depression or recurrent seizures require airway management, but this is exceedingly rare.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis may be beneficial in patients that develop acute renal failure or anuria.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with an inadvertent ingestion (1 or 2 extra doses) of valacyclovir may be observed at home.
    2) OBSERVATION CRITERIA: Patients with a 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 for signs of coingestant toxicity or development of significant CNS depression. Follow-up renal function tests should be obtained in patients following a massive overdose.
    3) ADMISSION CRITERIA: Admit patients with severe toxicity characterized by persistent CNS depression, acute renal failure or other major toxic effects.
    4) CONSULT CRITERIA: Consider consultation with a medical toxicologist or poison center if the diagnosis is unclear. Consult a nephrologist for patients with renal injury or acute renal failure.
    H) PITFALLS
    1) Failure to consider a polypharmacy ingestion. Failure to identify other nephrotoxic agents the patient may be receiving. Failure to obtain repeated renal function tests in patients with a significant exposure.
    I) PHARMACOKINETICS
    1) Valacyclovir hydrochloride is rapidly absorbed from the GI and is almost completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Plasma protein binding of valacyclovir ranges from 13.5% to 17.9%. The plasma elimination half-life of acyclovir averages 2.5 to 3.3 hours in volunteers with normal renal function.

Range Of Toxicity

    A) TOXIC DOSE: A toxic dose has not been established. Persistent diarrhea has been reported in patients receiving 2 g of valacyclovir 4 times daily. ANIMAL DATA: Single doses of 2 to 5 g/kg caused lethal nephrotoxicity in rats.
    B) THERAPEUTIC DOSE: ADULT: Varies by indication. Doses up to 2 g every 12 hours have been used. PEDIATRIC: CHICKENPOX: 20 mg/kg 3 times daily for 5 days; not to exceed 1 g 3 times daily.

Clinical Effects

Summary Of Exposure

    A) USES: Valacyclovir, an antiviral agent, is used in the treatment of genital herpes simplex, herpes labialis (cold sores) and herpes zoster. It is also used to treat chickenpox in pediatric patients.
    B) PHARMACOLOGY: Valacyclovir hydrochloride, a L-valyl ester prodrug of acyclovir, is rapidly converted to acyclovir. Acyclovir is than converted to acyclovir monophosphate by viral thymidine kinase, to acyclovir diphosphate by cellular guanylate kinase, and to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits replication of herpes viral DNA by competitive inhibition of viral DNA polymerase, incorporation and termination of the growing viral DNA chain, and by inactivation of viral DNA polymerase.
    C) TOXICOLOGY: As a prodrug of acyclovir, it exhibits similar toxic effects. No ingestions resulting in death have been reported in immunocompetent patients.
    D) EPIDEMIOLOGY: Exposure may occur. Immunocompromised patients may develop more acute effects following exposure.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: The following adverse events have occurred in greater than 10% of patients: headache, nausea, and abdominal pain. OTHER: CNS adverse reactions (eg, agitation, hallucinations, seizures, delirium, confusion, and encephalopathy) may develop in both adult and pediatric patients or in patients with renal disease who received higher than recommended doses of valacyclovir. The elderly are the most likely to develop CNS and/or acute renal failure with therapy. RARE: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) (sometimes fatal) has developed in patients with advanced HIV and in allogenic bone marrow transplant and renal transplant patients.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. As a prodrug of acyclovir, similar toxicity is expected in overdose. Manifestations of acyclovir toxicity include acute renal insufficiency, lethargy, coma, agitation, myoclonus and in severe cases seizures.
    2) MILD TO MODERATE TOXICITY: Nausea, vomiting, diarrhea and constipation may develop. Headache, dizziness, and asthenia may also occur.
    3) SEVERE TOXICITY: Renal insufficiency, crystalluria of acyclovir when solubility in the renal tubules is exceeded, lethargy, myoclonus, agitation, tremor, seizure, and coma may develop. In rare cases, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and neutropenia can develop in patients with pre-existing advanced HIV and other immune suppressed states.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported during postmarketing use with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported during postmarketing use with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in greater than 10% of patients treated with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness is a common adverse event with therapeutic use, but the effect is usually mild (Prod Info VALTREX(R) oral caplets, 2010).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) CNS adverse reactions (eg, agitation, hallucinations, delirium, confusion, seizures, and encephalopathy) may occur in both adults and children receiving valacyclovir (with or without reduced renal function) and in patients with underlying renal insufficiency or renal disease who receive higher than recommended doses of valacyclovir. Elderly patients appear to be at highest risk to develop CNS adverse events (Prod Info VALTREX(R) oral caplets, 2010).
    b) Other CNS events reported in postmarketing experience include: ataxia, coma, decreased consciousness, mania, and psychosis (Prod Info VALTREX(R) oral caplets, 2010).
    c) Disorientation and slurred speech were reported in a 58-year-old man with a history of chronic renal failure (on hemodialysis twice weekly) after receiving a total dose of 4000 mg valacyclovir over a 2-day period (Linssen Schuurmans et al, 1998). The patient required 6 hours of hemodialysis before neurological symptoms disappeared. Dysarthria occurred on the next day requiring repeat hemodialysis; no further symptoms were reported.
    d) Aseptic meningitis, related to valacyclovir therapy, has been reported (Fobelo et al, 2001).
    D) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures and tremors have been reported during postmarketing use with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).
    b) CASE REPORT: A 68-year-old male with a history of end-stage renal disease and hemodialysis developed altered mental status, agitation, confusion, tremulousness and irrational behavior following 3 doses of 1000 mg valacyclovir. Shortly after arrival to the ED he had 2 seizure episodes that were attributed to accumulation of acyclovir. EEG showed no epileptiform abnormalities and head CT was normal. The acyclovir level prior to hemodialysis was 11.2 mcg/mL. Valacyclovir was discontinued and his mental status returned to normal after 2 weeks (Rivkin, 2003).
    E) FEELING AGITATED
    1) WITH THERAPEUTIC USE
    a) Agitation and aggressive behavior have been reported during postmarketing use with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are reported in greater than 10% of patients treated with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).
    b) An uncontrolled study in immunocompromised patients with advanced HIV disease, reported that the incidence of nausea and vomiting may be greater in this patient population compared with immunocompetent patients (Jacobson, 1994).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported in greater than 10% of patients treated with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).
    C) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported with therapeutic use of valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Liver enzyme abnormalities and hepatitis have been reported during postmarketing use with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure may develop with therapy. It is more likely to develop in elderly patients with or without reduced renal function; patients with a history of renal insufficiency or disease who receive higher than recommended doses; and patients receiving other nephrotoxic agents. Patients should be adequately hydrated while receiving valacyclovir. Precipitation of acyclovir can occur in renal tubules when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid (Prod Info VALTREX(R) oral caplets, 2010).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) Single doses of 2 to 5 g/kg in rats caused lethal nephrotoxicity (Jacobson, 1993).
    b) Multiple doses of 150 to 300 mg/kg in rats and 400 to 600 mg/kg doses in monkeys caused reversible obstructive nephropathy and mild anemia (Jacobson, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC PURPURA
    1) WITH THERAPEUTIC USE
    a) Deaths associated with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have been reported in patients with advanced HIV disease and bone marrow and renal transplant recipients during clinical trials with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010). The incidence of this occurrence is not known.
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) IMMUNOCOMPETENT POPULATION: Beutner et al (1995) reported NO adverse events or changes in baseline hematologic parameters.
    b) IMMUNOCOMPROMISED POPULATION: Four patients with advanced HIV disease (clinically stable) with a baseline absolute neutrophil count (ANC) greater than or equal to 750 cells developed grade 3 or 4 neutropenia (ANC, <750 or <500 cells per microliter) after valacyclovir administration; all patients had an increased ANC following cessation of the drug (Jacobson et al, 1994).
    1) Studies are ongoing to determine if the neutropenia observed during this Phase I trial was due to an effect of high doses of valacyclovir or acyclovir exposure, concomitant medications or factors related to HIV disease (Jacobson et al, 1994).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Acute hypersensitivity reactions (ie, includes anaphylaxis, angioedema, dyspnea, pruritus, rash and urticaria) have been reported during postmarketing use with valacyclovir (Prod Info VALTREX(R) oral caplets, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Valacyclovir is 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. Teratogenicity and fertility studies were negative in rats or rabbits.
    3.20.2) TERATOGENICITY
    A) 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. However, an increased risk for heart defects was seen following antiviral exposure within the 4 weeks before conception. Birth records dated between 1996 and 2008 were cross-referenced with mothers’ antiviral prescriptions, including acyclovir and valacyclovir, 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). An adjusted analysis showed 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, 1.83; 95% CI, 1.14 to 2.95) (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 VALTREX(R) oral caplets, 2010).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: Teratogenicity studies were negative in rats or rabbits given doses that achieved up to 10 and 7 times, respectively, the human plasma levels during the period of major organogenesis (Prod Info VALTREX(R) oral caplets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturers have classified valacyclovir as FDA pregnancy category B. Based on prospective registry data from 749 pregnancies, infants exposed to acyclovir in-utero and unexposed infants have similar rates of birth defects (Prod Info VALTREX(R) oral caplets, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) When administered to nursing women, valacyclovir converts to acyclovir in breast milk. An oral dose of valacyclovir 500 mg in 5 nursing mothers led to breast milk acyclovir Cmax concentrations between 0.5 and 2.3 (median, 1.4) times the maternal acyclovir serum concentrations. Maternal doses of valacyclovir 500 mg twice daily would expose a nursing infant to an oral acyclovir dosage of 0.6 mg/kg/day, which would be less than 2% of a standard neonatal dose of acyclovir 30 mg/kg/day given intravenously (Prod Info VALTREX(R) oral caplets, 2010).
    2) When valacyclovir 500 mg twice daily was administered for 7 days, peak serum acyclovir concentration occurred 3 hours before the peak breast milk concentration (2.7 mcg/mL at 1 hour vs 4.2 mcg/mL at 4 hours). The ratio of breast milk to serum acyclovir concentration was 3.4 at 4 hours after the initial dose, and 1.85 at steady state. The amount of acyclovir in breast milk, after valacyclovir administration, is substantially less (2%) than that used in neonatal therapeutic dosing (Sheffield et al, 2002).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Fertility studies showed no impairments in fertility or reproduction at valacyclovir doses 6 times human plasma levels (Prod Info VALTREX(R) oral caplets, 2010).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of up to 120 mg/kg/day for mice and 100 mg/kg/day for rats (Prod Info Valtrex(R), valacyclovir hydrochloride, 1996).
    2) Five genetic toxicity assays were conducted and all were reported to be negative, except for a mouse lymphoma assay (in the presence of metabolic activation; 76% to 88% conversion to acyclovir), valacyclovir was weakly mutagenic (Prod Info Valtrex(R), valacyclovir hydrochloride, 1996).
    3) A mouse micronucleus assay was negative at 250 mg/kg, but weakly positive at 500 mg/kg (26 to 51 times human plasma levels, respectively) (Prod Info Valtrex(R), valacyclovir hydrochloride, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor renal and CNS function as indicated following a significant exposure.
    B) Monitor CBC, platelet count and renal and liver function tests in patients with suspected hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function after significant overdose.
    2) Monitor renal and liver function tests in patients with suspected hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
    B) HEMATOLOGIC
    1) Monitor CBC and platelet count in patients with suspected hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
    4.1.3) URINE
    A) URINALYSIS
    1) Obtain urinalysis and monitor urine output after significant overdose.

Methods

    A) CHROMATOGRAPHY
    1) Linssen-Schuurmans et al (1998) described the use of high-pressure liquid chromatography to determine blood concentrations of acyclovir in a patient following neurotoxic effects. Levels were drawn before dialysis and one hour after dialysis (Linssen-Schuurmans et al, 1998).

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 persistent CNS depression, acute renal failure or other major toxic effects.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with an inadvertent ingestion (1 or 2 extra doses) of valacyclovir may be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consider consultation with a medical toxicologist or poison center if the diagnosis is unclear. Consult a nephrologist for patients with renal injury or acute renal failure.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a 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 for signs of coingestant toxicity or development of significant CNS depression. Follow-up renal function tests should be obtained in patients following a massive overdose.

Monitoring

    A) Monitor renal and CNS function as indicated following a significant exposure.
    B) Monitor CBC, platelet count and renal and liver function tests in patients with suspected hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) 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).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) 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.
    2) 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) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Rehydration (oral or IV fluids) may prevent crystalluria and nephrotoxicity reported with acyclovir. Treat significant vomiting and diarrhea with fluids as tolerated; treat with antiemetics for persistent vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Rehydration (oral or IV fluids) may prevent crystalluria and nephrotoxicity reported with acyclovir. Support respiratory and cardiovascular function as needed. Benzodiazepines should be the first line agent for agitation or seizures.
    B) MONITORING OF PATIENT
    1) SUMMARY
    a) Monitor renal function. Acute renal failure has been reported in the elderly; patients with underlying renal disease who receive higher than recommended doses; patients receiving concomitant nephrotoxic drugs; and patients inadequately hydrated during therapeutic use of valacyclovir. Precipitation of acyclovir in renal tubules may develop when the solubility (2.5 mg/m) is exceeded in the intratubular fluid. Following a significant exposure, hemodialysis may be needed until renal function can be restored (Prod Info VALTREX(R) oral caplets, 2010).
    b) Monitor CBC, platelet count and renal and liver function tests in patients with suspected hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
    2) HYDRATION
    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).
    3) FLUID/ELECTROLYTE
    a) Fluid and electrolytes should be monitored during intravenous hydration to prevent fluid overload and electrolyte abnormalities. Patients may require fluid replacement following significant vomiting and/or diarrhea.
    C) SEIZURE
    1) CNS adverse events, including seizures, have been reported in both adults and children with or without reduced renal function and in patients with underlying rental disease when given valacyclovir in higher than recommended doses for their level of renal function (Prod Info VALTREX(R) oral caplets, 2010). The incidence of this event is unknown following overdose.
    2) 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).
    3) 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 .
    4) 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).
    5) 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).
    6) 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).
    7) 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).
    8) 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) Following an overdose, hemodialysis may be beneficial in patients that develop acute renal failure or anuria until renal function can be restored (Prod Info VALTREX(R) oral caplets, 2010).
    2) CASE REPORT: Hemodialysis successfully lowered acyclovir serum levels in a patient on chronic dialysis (twice weekly) that developed neurotoxic effects from therapeutic use of valacyclovir. Acyclovir concentration prior to dialysis was 21 mg/L (normal range 0.8 to 1.6 mg/L) and 5 mg/L one hour after dialysis; clinical symptoms markedly improved. An additional course of dialysis was required the next day for dysarthria; no further symptoms were reported (Linssen-Schuurmans et al, 1998).

Range Of Toxicity

Summary

    A) TOXIC DOSE: A toxic dose has not been established. Persistent diarrhea has been reported in patients receiving 2 g of valacyclovir 4 times daily. ANIMAL DATA: Single doses of 2 to 5 g/kg caused lethal nephrotoxicity in rats.
    B) THERAPEUTIC DOSE: ADULT: Varies by indication. Doses up to 2 g every 12 hours have been used. PEDIATRIC: CHICKENPOX: 20 mg/kg 3 times daily for 5 days; not to exceed 1 g 3 times daily.

Therapeutic Dose

    7.2.1) ADULT
    A) GENITAL HERPES
    1) INITIAL EPISODE: Recommended dose is 1 g orally twice daily for 10 days (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    2) RECURRENT EPISODE: Recommended dose is 500 mg orally twice daily for 3 days (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    3) SUPPRESSIVE THERAPY: Recommended dose is 500 mg to 1 g/day orally (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    4) REDUCTION OF TRANSMISSION: Recommended dose is 500 mg/day orally (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    B) HERPES LABIALIS
    1) Recommended dose is 2 g twice daily (12 hours apart) orally for 1 day (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    C) HERPES ZOSTER
    1) Recommended dose is 1 g orally 3 times daily for 7 days (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    7.2.2) PEDIATRIC
    A) CHICKENPOX
    1) CAPLETS: CHILDREN 2 TO LESS THAN 18 YEARS OF AGE: The recommended dosage is 20 mg/kgorally 3 times daily for 5 days in immunocompetent patients. MAXIMUM DOSE: 1 g 3 times daily (Prod Info VALTREX(R) oral caplets, 2010).
    2) ORAL SOLUTION: CHILDREN 2 TO LESS THAN 18 YEARS OF AGE: The recommended dose range is 25 mg/mL to 50 mg/mL orally. The oral solution is extemporaneously prepared from 5 or 10 valacyclovir caplets, respectively (Prod Info VALTREX(R) oral caplets, 2010).
    3) TABLETS: CHILDREN 2 TO LESS THAN 18 YEARS OF AGE: The recommended dose is 20 mg/kg orally 3 times daily for 5 days; maximum dose 1 g 3 times daily (Prod Info valacyclovir HCl oral tablets, 2014).
    4) CHILDREN LESS THAN 2 YEARS OF AGE: Safety and efficacy have not been established (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    B) GENITAL HERPES
    1) Safety and efficacy have not been established in pediatric patients younger than 18 years of age (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    C) HERPES LABIALIS
    1) CAPLETS: CHILDREN 12 YEARS OF AGE OR OLDER: The recommended dosage is 2 g taken twice daily for 1 day (12 hours apart) (Prod Info VALTREX(R) oral caplets, 2010).
    2) ORAL SOLUTION: CHILDREN 12 YEARS OF AGE OR OLDER: The recommended dose range is 25 mg/mL to 50 mg/mL. The oral solution is extemporaneously prepared from 5 or 10 valacyclovir caplets, respectively (Prod Info VALTREX(R) oral caplets, 2010).
    3) TABLETS: CHILDREN UP TO 12 YEARS OF AGE: The recommended dose is 2 g orally every 12 hours for 1 day (Prod Info valacyclovir HCl oral tablets, 2014).
    4) CHILDREN LESS THAN 12 YEARS OF AGE: Safety and efficacy have not been established (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).
    D) HERPES ZOSTER
    1) Safety and efficacy have not been established in pediatric patients younger than 18 years of age (Prod Info valacyclovir HCl oral tablets, 2014; Prod Info VALTREX(R) oral caplets, 2010).

Minimum Lethal Exposure

    A) SUMMARY
    1) The development of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has resulted in some deaths in patients with advanced HIV disease and allogenic bone marrow transplant and renal transplant patients receiving valacyclovir doses of 8 g/day during clinical trials (Prod Info VALTREX(R) oral caplets, 2010).
    B) ANIMAL DATA
    1) Single doses of 2 to 5 g/kg caused lethal nephrotoxicity in rats (Jacobson, 1993).

Maximum Tolerated Exposure

    A) SUMMARY
    1) The largest dose administered during clinical trials was 2 g 4 times daily for 11 days. Multiple episodes of diarrhea and nausea were reported at this dose. Time to Cmax increased to approximately 2 hours at this dose. (Weller et al, 1993).
    B) CASE REPORT
    1) A 64-year-old man with end-stage renal failure receiving dialysis presented to the ED with mental status changes, agitation, irrational behavior and subsequently had 2 seizures after taking valacyclovir 3000 mg (1000 mg 3 times daily). Plasma acyclovir concentration before hemodialysis was 11.2 mcg/mL (the institutional reference range was 0.83 to 9.8 mcg/mL) (Rivkin, 2003).

Physicochemical

Physical Characteristics

    A) Valacyclovir hydrochloride is a white to off-white powder (Prod Info Valtrex(R), valacyclovir hydrochloride, 1996)

Molecular Weight

    A) 360.80 (Prod Info Valtrex(R), valacyclovir hydrochloride, 1996)

References

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