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GANCICLOVIR AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ganciclovir is a synthetic guanine derivative and acts as an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses (sensitive viruses include cytomegalovirus (CMV)).
    B) Valganciclovir is the l-valyl ester of ganciclovir. It is a prodrug, being rapidly hydrolyzed to ganciclovir in plasma following oral administration; it was developed to improve the bioavailability of oral ganciclovir.

Specific Substances

    A) GANCICLOVIR
    1) 9-((2-hydroxy-1-(hydroxymethyl)-ethoxy)methyl)
    2) guanine
    3) Biolf 62
    4) BW-759
    5) BW-759U
    6) Bwb759U
    7) DHPG
    8) RS-21592
    9) Molecular Formula: C9-H13-N5-O4
    10) CAS 82410-32-0 (ganciclovir)
    11) CAS 107910-75-8 (ganciclovir sodium)
    VALGANCICLOVIR
    1) Valganciclovir hydrochloride
    2) Ganciclovir valine hydrochloride
    3) RS-79070-194
    4) Ro-107-9070/194
    5) L-valine, ester with 9-[2-hydroxy-1-
    6) (hydroxymethyl-ethoxymethyl)]-guanine
    7) Molecular Formula: C14-H22-N6-O5
    8) CAS 175865-60-8 (valganciclovir)
    9) CAS 175865-59-5 (valganciclovir hydrochloride)

Available Forms Sources

    A) FORMS
    1) Ganciclovir is available as 250 and 500 mg capsules and 0.15% ophthalmic gel/jelly (Prod Info ZIRGAN(R) ophthalmic gel, 2014; Prod Info ganciclovir oral capsules, 2009)
    2) Ganciclovir hydrochloride is available as 50 mg intravenous powder for solution (Prod Info ganciclovir sodium intravenous injection, 2014).
    3) Ganciclovir is also available as an intravitreal implant (for CMV retinitis) which contains a minimum of 4.5 mg of ganciclovir and is designed for drug release over a 5 to 8 month period (Prod Info VITRASERT(R) intravitreal implant, 2005).
    4) Valganciclovir is available as 450 mg and 50 mg/mL oral powder for solution (Prod Info VALCYTE oral tablets, oral powder, 2015).
    B) USES
    1) Ganciclovir is used to prevent CMV disease in patients with advanced HIV infection and solid transplant recipients at risk for CMV disease, and to treat CMV retinitis in immunocompromised patients (Prod Info ganciclovir sodium intravenous injection, 2014; Prod Info ZIRGAN(R) ophthalmic gel, 2014; Prod Info ganciclovir oral capsules, 2009).
    2) Valganciclovir is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and prevention of CMV disease in kidney, heart, and kidney, heart, and kideny-pancreas transplant patients at high risk (Prod Info VALCYTE oral tablets, oral powder, 2015).

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: Ganciclovir is used to prevent CMV disease in patients with advanced HIV infection and solid transplant recipients at risk for CMV disease, and to treat CMV retinitis in immunocompromised patients. Valganciclovir, a prodrug of ganciclovir, (a l-valyl ester of ganciclovir) is rapidly hydrolyzed to ganciclovir in the plasma and was developed to improve the bioavailability of oral ganciclovir.
    B) PHARMACOLOGY: Ganciclovir, an acyclic nucleoside analogue of 2'-deoxyguanosine, inhibits replication of the herpes virus.
    C) EPIDEMIOLOGY: Overdose may occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Since ganciclovir has been almost exclusively evaluated in immunocompromised patients with infections, the adverse events reported may be confounded by underlying disease processes and concomitant drug therapies. Adverse effects at therapeutic doses have included: neutropenia, anemia, thrombocytopenia, hepatitis, hematuria, elevated creatinine, seizures, torsades de pointes, cardiac arrest, cardiac conduction abnormalities, ventricular tachycardia, gastrointestinal perforation, multiple organ failure, pancreatitis, and sepsis.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose data are limited. Clinical effects are anticipated to be similar to adverse effects and have included the following: irreversible pancytopenia, persistent bone marrow suppression, hepatitis, hematuria, elevated creatinine, seizures, neutropenia, anemia, leukopenia, and thrombocytopenia have been reported after intravenous overdose. Retinal damage and permanent visual loss have been reported after overdose by intravitreal injection.
    0.2.3) VITAL SIGNS
    A) Fever has occurred with ganciclovir therapy.
    0.2.4) HEENT
    A) Vitreous disorders including retinal detachment and vitreous hemorrhage have been reported with intravitreal ganciclovir. Ocular abnormalities including blindness, glaucoma, amblyopia, retinitis, conjunctivitis, eye pain, and photophobia have occurred with intravenous or oral ganciclovir.
    0.2.5) CARDIOVASCULAR
    A) Dysrhythmias, deep thrombophlebitis, hypertension, hypotension, vasodilation, and phlebitis have occurred as probably or possibly related to ganciclovir use in immunocompromised patients.
    0.2.6) RESPIRATORY
    A) Pneumonia, dyspnea, and cough have been reported with ganciclovir.
    0.2.7) NEUROLOGIC
    A) Neuropathy and paresthesia have occurred during clinical trials with immunocompromised patients. Seizures associated with ganciclovir use have also occurred.
    0.2.8) GASTROINTESTINAL
    A) Vomiting, diarrhea, and anorexia have been reported in clinical trials.
    B) Upper gastrointestinal bleeding has occurred following ganciclovir therapy.
    0.2.9) HEPATIC
    A) Hepatitis has been reported after intravenous overdose.
    B) Adverse events reported with intravenous or oral ganciclovir included hepatitis and abnormal liver function studies.
    0.2.10) GENITOURINARY
    A) Increased serum creatinine and worsening hematuria have been reported after intravenous overdose.
    B) Elevations in serum creatinine have been reported in clinical trials.
    0.2.13) HEMATOLOGIC
    A) Irreversible pancytopenia and bone marrow suppression and reversible neutropenia and thrombocytopenia have been reported after intravenous overdose.
    B) Neutropenia, anemia, and thrombocytopenia have been observed in patients treated with intravenous and oral ganciclovir; the frequency and degree of severity reported were dependent on the patient population.
    0.2.14) DERMATOLOGIC
    A) Pruritus, rash, and sweating were the most frequent dermatologic complaints associated with intravenous or oral ganciclovir.
    0.2.15) MUSCULOSKELETAL
    A) Myalgias, arthralgias, asthenia, and leg cramps have been reported with ganciclovir.
    0.2.18) PSYCHIATRIC
    A) Nightmares and hallucinations have been associated with ganciclovir therapy.
    0.2.20) REPRODUCTIVE
    A) Ganciclovir is classified by the manufacturer as FDA pregnancy category C. In an ex vivo human placental cotyledon model, ganciclovir was shown to cross the human placenta. Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. In animal studies, fetal resorptions, fetal growth retardation, embryolethality, maternal toxicity, cleft palate, anophthalmia/microphthalmia, aplastic organs, hydrocephaly, and brachygnathia were reported. Valganciclovir is a prodrug that is converted to ganciclovir, an active drug, after oral administration. Therefore, valganciclovir is expected to have reproductive toxicity effects similar to ganciclovir.

Laboratory Monitoring

    A) Monitor renal function with significant ingestion or symptomatic patients.
    B) Monitor hepatic function as appropriate.
    C) Monitor CBC with differential and platelet count with significant ingestion or symptomatic patients.
    D) Obtain baseline ECG to evaluate rhythm; monitor as appropriate.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUMMARY
    1) Ganciclovir is currently intended ONLY for patients with CMV retinitis (immunocompromised) and prevention of CMV disease in transplant recipients, therefore, the adverse events reported are based on individuals with underlying disease processes and possible concomitant drug therapy. Due to limited overdose information, overall treatment is based on symptomatic care.
    B) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose information. Clinical events are anticipated to be similar to adverse events reported.Of the limited cases of overdose, hematologic toxicity (ie, neutropenia, anemia and thrombocytopenia) was the most common event reported with ganciclovir therapy. Monitor CBC with differential daily until cell count recovery occurs (usually begins 3 to 7 days after the discontinuation of ganciclovir). Monitor vital signs. Fever is frequently reported with therapy. Treat with antipyretics, cool compresses and cooling blankets as needed. Assess for potential infection or sepsis. Alteration in fluid status may develop secondary to diarrhea (common) and vomiting. Treat diarrhea with antidiarrheals and replace fluids and electrolytes as indicated.
    C) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Initially treat seizures with IV benzodiazepines, barbiturates.
    D) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination may be contraindicated following a significant ingestion because of the potential for seizures, cardiovascular instability and CNS depression.
    2) HOSPITAL: ORAL: Consider activated charcoal after a potentially toxic ingestion, if the patient is able to maintain their airway or if the airway is protected. DERMAL or EYE EXPOSURE: Direct contact with the skin or mucous membranes either with the powder (capsules should not be crushed or opened) or intravenous solution should be avoided.
    E) ANTIDOTE
    1) There is no known antidote.
    F) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor exposure. Endotracheal intubation may be necessary in patients that develop cardiac dysrhythmias, seizures or CNS depression.
    G) CONDUCTION DISORDER OF THE HEART
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Consider lidocaine and amiodarone.
    H) MYELOSUPPRESSION
    1) Hematologic toxicity (ie, neutropenia, anemia and thrombocytopenia) was the most common event reported with ganciclovir therapy. Administer colony stimulating factors following a significant overdose as these patients are at risk for neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred (cell counts usually begin to recover within 3 to 7 days of drug discontinuation. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    I) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    J) PHARMACOKINETICS
    1) GANCICLOVIR
    a) The oral bioavailability of ganciclovir is poor. Ganciclovir is not metabolized and is approximately 100% renally excreted as unchanged drug. Half-life has been reported as 3.5 hours following IV administration and 4.8 hours following oral administration. No metabolite has been detected. Ganciclovir clearance is dependent upon renal elimination. The steady-state volume of distribution of ganciclovir after IV administration was 0.74 L/kg. Urinary recovery averages greater than 90% in 24 hours.
    2) VALGANCICLOVIR
    a) Valganciclovir, a prodrug that is rapidly hydrolyzed to ganciclovir in plasma following oral administration. It is well absorbed from the gastrointestinal tract. Absorbed valganciclovir is rapidly hydrolyzed to ganciclovir. The short elimination half-life of valganciclovir is about 30 minutes and ganciclovir plasma levels are detectable about 15 minutes following an oral valganciclovir dose. Following oral administration of valganciclovir, the terminal half-life of ganciclovir was 4.08 +/- 0.76 hours.
    K) ENHANCED ELIMINATION
    1) Ganciclovir is removed by hemodialysis; dialysis may be useful in reducing serum concentrations.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with a minor exposure (1 to 2 capsules) can be monitored at home.
    2) ADMISSION CRITERIA: Patients with an inadvertent intravenous exposure should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved (cell count recovery usually begins 3 to 7 days after ganciclovir discontinuation).
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking ganciclovir are likely to be immune suppressed and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity, cytotoxicity).
    0.4.4) EYE EXPOSURE
    A) Manufacturer recommendations include caution in handling ganciclovir formulations (intravenous {alkaline pH 11} or oral) and to avoid direct contact with skin or mucous membranes.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Caution should be used in handling and preparation of ganciclovir; intravenous solutions are alkaline (pH 11) (Prod Info CYTOVENE(R) IV injection, 2006).
    2) Direct contact with the skin or mucous membranes either with the powder (capsules should not be crushed or opened) or intravenous solution should be avoided (Prod Info Vitrasert(R), ganciclovir implant, 1999).
    3) Ganciclovir shares some of the properties of antitumor agents (i.e., mutagenicity and carcinogenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs (Prod Info Vitrasert(R), ganciclovir implant, 1999).

Range Of Toxicity

    A) GANCICLOVIR: Overdose data are limited. An adult developed no toxicity following a total dose of 8.25 grams of ganciclovir given over a 36 hour period. Persistent bone marrow suppression developed after a single 6 gram dose.
    B) VALGANCICLOVIR: Fatal bone marrow depression (medullary aplasia) has been reported in an adult with renal impairment after several days of dosing that was at least 10-fold greater than recommended.
    C) THERAPEUTIC DOSE: GANCICLOVIR: ADULT: ORAL: 1 g orally 3 times a day; IV: Up to 5 mg/kg IV every 12 hours. INTRAVITREAL: 4.5 mg/implant every 6 to 9 months. Renal dosing may be necessary. PEDIATRIC: Ganciclovir is not FDA-approved for pediatric patients. VALGANCICLOVIR: ADULT: ORAL: Up to 900 mg orally twice daily. Renal dosing may be necessary. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Ganciclovir is used to prevent CMV disease in patients with advanced HIV infection and solid transplant recipients at risk for CMV disease, and to treat CMV retinitis in immunocompromised patients. Valganciclovir, a prodrug of ganciclovir, (a l-valyl ester of ganciclovir) is rapidly hydrolyzed to ganciclovir in the plasma and was developed to improve the bioavailability of oral ganciclovir.
    B) PHARMACOLOGY: Ganciclovir, an acyclic nucleoside analogue of 2'-deoxyguanosine, inhibits replication of the herpes virus.
    C) EPIDEMIOLOGY: Overdose may occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Since ganciclovir has been almost exclusively evaluated in immunocompromised patients with infections, the adverse events reported may be confounded by underlying disease processes and concomitant drug therapies. Adverse effects at therapeutic doses have included: neutropenia, anemia, thrombocytopenia, hepatitis, hematuria, elevated creatinine, seizures, torsades de pointes, cardiac arrest, cardiac conduction abnormalities, ventricular tachycardia, gastrointestinal perforation, multiple organ failure, pancreatitis, and sepsis.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose data are limited. Clinical effects are anticipated to be similar to adverse effects and have included the following: irreversible pancytopenia, persistent bone marrow suppression, hepatitis, hematuria, elevated creatinine, seizures, neutropenia, anemia, leukopenia, and thrombocytopenia have been reported after intravenous overdose. Retinal damage and permanent visual loss have been reported after overdose by intravitreal injection.

Vital Signs

    3.3.1) SUMMARY
    A) Fever has occurred with ganciclovir therapy.
    3.3.3) TEMPERATURE
    A) FEVER (38% to 48%) occurred in AIDS patients during clinical trials as an adverse effect (Prod Info ganciclovir sodium intravenous injection, 2014).

Heent

    3.4.1) SUMMARY
    A) Vitreous disorders including retinal detachment and vitreous hemorrhage have been reported with intravitreal ganciclovir. Ocular abnormalities including blindness, glaucoma, amblyopia, retinitis, conjunctivitis, eye pain, and photophobia have occurred with intravenous or oral ganciclovir.
    3.4.3) EYES
    A) OVERDOSE effects have included RETINAL DAMAGE as follows:
    1) CASE REPORT: Loss of vision and central retinal artery occlusion secondary to increased intraocular pressure were reported in one adult following an overdose; 0.4 mL intravenous ganciclovir by intravitreal injection was given instead of 0.1 mL (Prod Info ganciclovir sodium intravenous injection, 2014).
    2) CASE REPORT: A 44-year-old received an intravitreous injection of high dose (40 mg/0.1 ml) ganciclovir for CMV retinitis which resulted in permanent retinal damage and vision loss despite immediate intervention. Although the etiology of the retinal toxicity is unclear, clinically the case resembled necrotizing vasculitis (similar to aminoglycoside toxicity). Precipitation of the ganciclovir within the retinal substance was also observed. The authors suggested that the retinal toxicity may have resulted from the high alkalinity (pH 10 or 11) of the solution, osmotic damage or a direct factor of the concentrated dose (Saran & Maguire, 1994; Saran & Maguire, 1994).
    B) ADVERSE EFFECTS have included the following:
    1) ENDOPHTHALMITIS
    a) CASE REPORT: One case of endophthalmitis occurred following intravitreal ganciclovir in a 35-year-old man with AIDS. The patient had failed maintenance parenteral ganciclovir treatment due to neutropenia (Harris & Mathalone, 1989).
    2) RETINAL DETACHMENT
    a) Retinal detachment has developed in patients with CMV retinitis both before and after treatment with ganciclovir. The relationship between this condition and to ganciclovir therapy is unknown (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) CASE REPORT: Retinal detachment and a retinal tear occurred in 2 individuals following 500 to 1000 mg oral ganciclovir (every 3 hours) (Spector et al, 1995).
    3) OTHER INTRAVITREAL EFFECTS
    a) Additional intravitreal adverse events have included: local foreign body sensation, conjunctival hemorrhage or mild scarring, scleral induration, and bacterial endophthalmitis (Faulds & Heel, 1990).
    4) OTHER IV/ORAL EFFECTS
    a) Abnormal vision and vitreous disorder have been reported infrequently with intravenous or oral ganciclovir therapy (Prod Info ganciclovir sodium intravenous injection, 2014; Prod Info ganciclovir oral capsules, 2009).

Cardiovascular

    3.5.1) SUMMARY
    A) Dysrhythmias, deep thrombophlebitis, hypertension, hypotension, vasodilation, and phlebitis have occurred as probably or possibly related to ganciclovir use in immunocompromised patients.
    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Two AIDS patients developed ventricular tachycardia, with both responding to lidocaine, initially, and mexiletine therapy. One patient had a 27 second run of ventricular fibrillation followed by 30 seconds of VT and brief asystole; the other patient had symptomatic VT Despite underlying disease and multiple drug therapies, VT was reproducible in one patient when rechallenged with ganciclovir and the other had no further arrhythmias with cessation of therapy. Arrhythmic episodes in either patient were NOT marked by abnormalities in serum electrolytes, arterial blood gases or cardiac enzymes. A temporal relationship between ganciclovir administration and VT suggests that ganciclovir may potentiate the arrhythmogenicity of clinically undetected myocarditis (which has been frequently reported in postmortem exam of AIDS patients), or that ganciclovir is itself arrhythmogenic .(Cohen et al, 1990).
    B) VENOUS THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Catheter related events (vein thrombosis, IV site phlebitis) with intravenous ganciclovir have been reported (Anon, 1995; Duncan et al, 1994; Faulds & Heel, 1990).
    C) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) The following events have been reported during postmarketing surveillance, although no data on the occurrence is available: cardiac arrest, cardiac conduction abnormalities, torsades de pointes, and ventricular tachycardia (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) In clinical trials with AIDS patients and transplant recipients the following were reported in 1% or fewer of patients: phlebitis, hypertension and vasodilation (Prod Info ganciclovir sodium intravenous injection, 2014).

Respiratory

    3.6.1) SUMMARY
    A) Pneumonia, dyspnea, and cough have been reported with ganciclovir.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Pneumonia has been reported infrequently in patients receiving ganciclovir therapy (Prod Info ganciclovir sodium intravenous injection, 2014).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Increased cough and dyspnea have been reported infrequently in AIDS patients or transplant recipients receiving intravenous or oral ganciclovir (Prod Info ganciclovir sodium intravenous injection, 2014).
    C) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm and pulmonary fibrosis have been reported in postmarketing use, however, the occurrence of these events is unknown (Prod Info ganciclovir sodium intravenous injection, 2014).

Neurologic

    3.7.1) SUMMARY
    A) Neuropathy and paresthesia have occurred during clinical trials with immunocompromised patients. Seizures associated with ganciclovir use have also occurred.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures and tremors have occurred infrequently in AIDS patients or transplant recipients receiving oral or IV ganciclovir during clinical trials (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) CASE REPORT: Seizures were reported in a 32-year-old man with AIDS and disseminated cytomegalovirus infection. Following 1 month of therapy the patient began to complain of seizure-like activity (initial dose was 270 mg intravenously), after the dose was increased to 320 mg daily (due to progression of CMV retinitis) the patient had a witnessed generalized seizure with intravenous administration. Despite anticonvulsant therapy with phenytoin (500 mg/day orally) the patient continued to have seizures; only after ganciclovir was discontinued did the seizure activity cease (a rechallenge infusion produced seizure activity). Although multiple disease factors were present, the authors believed that the seizure activity was due to ganciclovir administration (Barton et al, 1992).
    2) WITH POISONING/EXPOSURE
    a) One adult with an underlying seizure disorder had a seizure after receiving 9 mg/kg IV for 3 days (Prod Info ganciclovir sodium intravenous injection, 2014).
    B) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Neuropathy has been reported in patients receiving either oral or intravenous ganciclovir therapy (Prod Info ganciclovir sodium intravenous injection, 2014).
    C) MENTAL STATE FINDING
    1) WITH THERAPEUTIC USE
    a) Confusion, abnormal thinking, abnormal dreams and anxiety have occurred infrequently in AIDS patients or transplant recipients receiving oral or IV ganciclovir during clinical trials (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) CASE REPORT: Confusion, aphasia, and meningitis-like symptoms occurred in a 73-year-old, with chronic interstitial nephritis and on hemodialysis, following 5 days of ganciclovir (1.25 mg/kg IV every 24 hrs.) for active Hepatitis B. Increase in ganciclovir half-life and clearance were determined by lumbar puncture 3 days following withdrawal of ganciclovir and measured 0.75 mg/L which was higher than patients with normal renal function 3 to 6 hours after administration. Neurological symptoms resolved with termination of the drug therapy (Combarnous et al, 1994).
    c) CASE REPORT: Agitation, delirium, and mild confusion were observed in a kidney transplant recipient receiving intravenous ganciclovir (5 mg/kg every 12 hrs) for CMV hepatitis. Reduction of the dose to 2.5 mg/kg every 12 hours resulted in improvement of the symptoms (Davis et al, 1990).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has occurred infrequently with ganciclovir therapy (Prod Info ganciclovir sodium intravenous injection, 2014).
    E) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Asthenia has occurred infrequently with ganciclovir therapy (Prod Info ganciclovir sodium intravenous injection, 2014).
    F) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Somnolence, dizziness, and insomnia have been reported infrequent in AIDS patients or transplant recipients receiving ganciclovir during clinical trials (Prod Info ganciclovir sodium intravenous injection, 2014).
    G) DISORDER OF BRAIN
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Encephalopathy occurred in a bone marrow transplant recipient following the escalation of the ganciclovir dose to 5 milligrams/kilogram twice daily to treat CMV antigenemia. The encephalopathy completely resolved shortly after ganciclovir was discontinued and replaced by foscarnet (Sharathkumar & Shaw, 1999).

Gastrointestinal

    3.8.1) SUMMARY
    A) Vomiting, diarrhea, and anorexia have been reported in clinical trials.
    B) Upper gastrointestinal bleeding has occurred following ganciclovir therapy.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea (41% to 44%), vomiting (13%), and anorexia (15% to 14%) were the most frequent gastrointestinal adverse events reported by AIDS subjects in randomized trials with oral or intravenous maintenance therapy (Prod Info ganciclovir sodium intravenous injection, 2014).
    B) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Upper GI bleeding was reported in a patient with CMV retinitis who developed thrombocytopenia (platelet count went from 337,000 to 1000/ul) following 6 days of therapy (2.5 mg/kg three times daily) (Faulds & Heel, 1990a).
    C) GASTROINTESTINAL IRRITATION
    1) WITH THERAPEUTIC USE
    a) Symptoms that are likely related to ganciclovir therapy include: constipation, stomatitis, dysphagia, dyspepsia, and eructation (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) The following adverse events may be potentially fatal in patients receiving ganciclovir: gastrointestinal perforation and pancreatitis (Prod Info ganciclovir sodium intravenous injection, 2014).

Hepatic

    3.9.1) SUMMARY
    A) Hepatitis has been reported after intravenous overdose.
    B) Adverse events reported with intravenous or oral ganciclovir included hepatitis and abnormal liver function studies.
    3.9.2) CLINICAL EFFECTS
    A) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) Hepatitis and hepatic failure have occurred in postmarketing reporting; no incidence rate was reported (Prod Info ganciclovir sodium intravenous injection, 2014).
    2) WITH POISONING/EXPOSURE
    a) Hepatitis following overdose (1 adult receiving 10 mg/kg daily, and one 2 kilogram infant after a single 40 mg dose) have occurred (Prod Info ganciclovir sodium intravenous injection, 2014).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hepatotoxicity occurred in a 33-year-old man with AIDS and presumed retinitis (no other known toxic or infectious processes were present) receiving 2.5 mg/kg/day (Shea et al, 1987). Although baseline liver function tests were abnormal, marked elevations of transaminases and alkaline phosphatase occurred and again with rechallenge.
    b) CASE SERIES: Similarly, four AIDS patients developed mild to marked liver function abnormalities (increased AST, ALP and GGT). Despite evidence of hepatotoxicity with ganciclovir, the authors could not rule out the influence of concurrent administration of hepatotoxic drugs and/or underlying disease with liver function test abnormalities (Figge et al, 1992).
    c) Abnormal liver function tests (eg, SGOT and SGPT increased) have been reported infrequently in AIDS patients or transplant recipients (Prod Info ganciclovir sodium intravenous injection, 2014).

Genitourinary

    3.10.1) SUMMARY
    A) Increased serum creatinine and worsening hematuria have been reported after intravenous overdose.
    B) Elevations in serum creatinine have been reported in clinical trials.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Elevations in serum creatinine (creatinine exceeding 2.5 mg/dL) have been reported more frequently with intravenous ganciclovir, 18% compared to 4% in placebo group of heart transplant recipients (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) In clinical trials the following events occurred infrequent in AIDS patients or transplant recipients: kidney failure, kidney function abnormal, decreased creatinine clearance, and urinary frequency (Prod Info CYTOVENE(R) IV injection, 2006).
    2) WITH POISONING/EXPOSURE
    a) OVERDOSAGE
    1) CASE REPORTS: Renal toxicity occurred in one adult with transient worsening of hematuria after a single 500 mg dose and in another adult with an elevated creatinine (5.2 mg/dL) after a single 5000 to 7000 mg overdose of ganciclovir (Prod Info ganciclovir sodium intravenous injection, 2014).

Hematologic

    3.13.1) SUMMARY
    A) Irreversible pancytopenia and bone marrow suppression and reversible neutropenia and thrombocytopenia have been reported after intravenous overdose.
    B) Neutropenia, anemia, and thrombocytopenia have been observed in patients treated with intravenous and oral ganciclovir; the frequency and degree of severity reported were dependent on the patient population.
    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia is the most frequent adverse event associated with ganciclovir therapy (Faulds & Heel, 1990).
    b) INCIDENCE has been reported to be 13% to 67% and averages 30% to 40% (Fletcher & Balfour, 1989; Faulds & Heel, 1990). Of note, in open-label compassionate-use programs with ganciclovir, neutropenia rates were lower in NON-AIDS patients; ganciclovir therapy was also shorter for these individuals (DeArmond, 1991).
    1) Neutropenia (ANC 750 to less than 1000/microliter (19% to 26%)), and leukopenia (29% to 41%) were reported in AIDS patients receiving oral or intravenous ganciclovir, respectively (Prod Info ganciclovir sodium intravenous injection, 2014).
    2) Neutropenia occurred in 7% to 41% of heart or bone marrow transplant recipients receiving intravenous therapy, respectively (Prod Info ganciclovir sodium intravenous injection, 2014).
    c) Neutropenia appears to be associated with total dose of ganciclovir administered (prior to a total cumulative dose of 200 milligrams/kilogram), but can occur at any phase of treatment (Faulds & Heel, 1990). Neutropenia appears to be reversible.
    d) Most hematological events appear to be rapidly reversible following treatment withdrawal (within 3 to 7 days) (Faulds & Heel, 1990).
    B) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Pancytopenia was reported infrequently in AIDS patients or transplant recipients receiving ganciclovir during clinical trials (Prod Info ganciclovir sodium intravenous injection, 2014).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Irreversible pancytopenia following overdose developed in one adult with AIDS and CMV colitis after receiving 3000 milligrams of intravenous ganciclovir on 2 consecutive days. Worsening gastrointestinal symptoms and acute renal failure with short-term dialysis occurred. Pancytopenia developed and continued until the patient's death several months later from a malignancy (Prod Info ganciclovir sodium intravenous injection, 2014).
    C) BONE MARROW DEPRESSION
    1) WITH POISONING/EXPOSURE
    a) GANCICLOVIR: Persistent bone marrow suppression (1 adult with neutropenia and thrombocytopenia after a single dose of 6000 mg), and reversible neutropenia or granulocytopenia (4 adults, overdose ranging from 8 mg/kg daily for 4 days to a single dose of 25 mg/kg) have inadvertently occurred following overdose (Prod Info ganciclovir sodium intravenous injection, 2014).
    b) VALGANCICLOVIR/CASE REPORT: Fatal bone marrow depression (medullary aplasia) has been reported in an adult with renal impairment after several days of dosing that was at least 10-fold greater than recommended (Prod Info VALCYTE oral tablets, oral powder, 2015).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Thrombocytopenia (6% to 20%) (platelet count less than 50,000/microliter) occurred in ganciclovir recipients with AIDS (Faulds & Heel, 1990).
    b) In transplant recipients (heart or bone marrow), thrombocytopenia occurred in 8% to 57% of patients receiving intravenous ganciclovir therapy, respectively (Prod Info ganciclovir sodium intravenous injection, 2014).
    E) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia can develop with oral or intravenous therapy (Prod Info ganciclovir sodium intravenous injection, 2014).

Dermatologic

    3.14.1) SUMMARY
    A) Pruritus, rash, and sweating were the most frequent dermatologic complaints associated with intravenous or oral ganciclovir.
    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus (5% to 6%) was reported by AIDS patients receiving intravenous or oral ganciclovir, respectively (Prod Info ganciclovir sodium intravenous injection, 2014).
    B) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating was reported by 11% to 12% of AIDS patients receiving oral or intravenous ganciclovir, respectively, during clinical trials (Prod Info ganciclovir sodium intravenous injection, 2014).
    C) VITILIGO
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Vitiligo was reported after ganciclovir treatment of cutaneous chronic graft-versus-host disease in a 44-year-old man who had received donor T lymphocytes expressing herpes simplex virus thymidine kinase at the time of transplantation (Aubin et al, 2000).
    D) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) Adverse events that were reported in AIDS patients that were probably related to therapy included alopecia and dry skin (Prod Info ganciclovir sodium intravenous injection, 2014).

Musculoskeletal

    3.15.1) SUMMARY
    A) Myalgias, arthralgias, asthenia, and leg cramps have been reported with ganciclovir.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgias, arthralgias, myasthenia, and leg cramps have been reported infrequently in AIDS patients or transplant recipients receiving intravenous or oral ganciclovir (Prod Info ganciclovir sodium intravenous injection, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Ganciclovir is classified by the manufacturer as FDA pregnancy category C. In an ex vivo human placental cotyledon model, ganciclovir was shown to cross the human placenta. Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. In animal studies, fetal resorptions, fetal growth retardation, embryolethality, maternal toxicity, cleft palate, anophthalmia/microphthalmia, aplastic organs, hydrocephaly, and brachygnathia were reported. Valganciclovir is a prodrug that is converted to ganciclovir, an active drug, after oral administration. Therefore, valganciclovir is expected to have reproductive toxicity effects similar to ganciclovir.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There are no adequate or well-controlled studies of ganciclovir or valganciclovir use in pregnant women (Prod Info VALCYTE oral tablets, oral powder, 2015; Prod Info CYTOVENE-IV(R) IV injection, 2008).
    B) ANIMAL STUDIES
    1) EMBRYO/FETAL RISK
    a) GANCICLOVIR
    1) RABBITS: Cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia were reported in rabbits administered doses that produced 2 times the human exposure (based on AUC comparisons) following administration of a single 5-mg/kg infusion of IV ganciclovir (Prod Info VALCYTE(R) oral solution, oral tablets, 2009; Prod Info CYTOVENE-IV(R) IV injection, 2008). Maternal and fetal toxicities were also observed. Doses approximately 1.7 times the human exposure resulted in hypoplasia of the testes and seminal vesicles in male offspring and pathological changes to the nonglandular stomach region (Prod Info VALCYTE oral tablets, oral powder, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate or well-controlled studies of ganciclovir or valganciclovir use during pregnancy (Prod Info VALCYTE oral tablets, oral powder, 2015; Prod Info CYTOVENE-IV(R) IV injection, 2008).
    B) PREGNANCY CATEGORY
    1) Ganciclovir has been classified by the manufacturer as FDA pregnancy category C (Prod Info CYTOVENE-IV(R) IV injection, 2008).
    C) RISK SUMMARY
    1) VALGANCICLOVIR
    a) Avoid use during pregnancy (Prod Info VALCYTE oral tablets, oral powder, 2015).
    D) PLACENTAL BARRIER
    1) GANCICLOVIR: In an ex vivo human placental cotyledon model, ganciclovir was shown to cross the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL (Prod Info VALCYTE(R) oral solution, oral tablets, 2009; Prod Info CYTOVENE-IV(R) IV injection, 2008). Fetal ganciclovir levels were 17.2% of the 1 mcg/mL maternal concentration, 19.2% of the 10 mcg/mL maternal concentration, and 17.3% of the 100 mcg/mL maternal concentration. These results were reported after 1 hour (Gilstrap et al, 1994).
    E) EMBRYOTOXICITY
    1) Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use (Prod Info CYTOVENE-IV(R) IV injection, 2008).
    F) ANIMAL STUDIES
    1) GANCICLOVIR
    a) Fetal resorptions were reported in at least 85% of rabbits and mice administered doses that produced 2 times the human exposure (based on AUC comparisons) following administration of a single 5-mg/kg infusion of IV ganciclovir. In the same study, fetal growth retardation, embryolethality, and maternal toxicity were also reported in rabbits, and embryolethality also occurred in the presence of maternal/fetal toxicity in mice (Prod Info VALCYTE(R) oral solution, oral tablets, 2009; Prod Info CYTOVENE-IV(R) IV injection, 2008)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known whether valganciclovir or ganciclovir is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug is unknown. Because valganciclovir use has resulted in granulocytopenia, anemia, and thrombocytopenia in clinical trials, and ganciclovir was mutagenic and carcinogenic in animal studies, there is the potential for serious adverse effects in the nursing infant (Prod Info VALCYTE(R) oral solution, oral tablets, 2009; Prod Info CYTOVENE-IV(R) IV injection, 2008).
    B) RISK SUMMARY
    1) VALGANCICLOVIR
    a) Breastfeeding is not recommended (Prod Info VALCYTE oral tablets, oral powder, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) GANCICLOVIR
    a) DOGS, MICE, RATS: Administration of daily oral or IV doses of ganciclovir ranging from 0.2 to 10 mg/kg led to decreased fertility in male mice and hypospermatogenesis in mice and dogs. Systemic drug exposure (AUC) at the lowest dose exhibiting toxicity in each species ranged from 0.03 to 0.1 times the AUC of the recommended human IV dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs (Prod Info CYTOVENE-IV(R) IV injection, 2008).
    b) MICE: Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg per day (approximately 1.7 times the mean drug exposure in humans following a dose of 5 mg/kg, based on AUC comparisons) given prior to mating, during gestation, and during lactation. Hypoplasia of the testes and seminal vesicles in month-old male offspring were also reported (Prod Info CYTOVENE-IV(R) IV injection, 2008).
    2) VALGANCICLOVIR
    a) Based on animal studies, suppression of fertility in females and inhibition of spermatogenesis (temporary or permanent) may occur with the use of valganciclovir at recommended doses (Prod Info VALCYTE oral tablets, oral powder, 2015).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1 and 1.4 times, respectively of human exposure with the recommended 5mg/kg intravenous dose) (Prod Info Cytovene(R) intravenous, ganciclovir, 1999).
    2) Tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues and liver in females were seen significantly at 1000 mg/kg/day of ganciclovir (Prod Info Cytovene(R) intravenous, ganciclovir, 1999).
    3) Ganciclovir induced tumors were generally of epithelial or vascular origin (histiocytic sarcoma of the liver has been reported) and should be considered a potential carcinogen in humans (Prod Info Cytovene(R) intravenous, ganciclovir, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor renal function with significant ingestion or symptomatic patients.
    B) Monitor hepatic function as appropriate.
    C) Monitor CBC with differential and platelet count with significant ingestion or symptomatic patients.
    D) Obtain baseline ECG to evaluate rhythm; monitor as appropriate.

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) Patients with an inadvertent intravenous exposure should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved (cell count recovery usually begins 3 to 7 days after ganciclovir discontinuation).
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with a minor exposure (1 to 2 capsules) can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor renal function with significant ingestion or symptomatic patients.
    B) Monitor hepatic function as appropriate.
    C) Monitor CBC with differential and platelet count with significant ingestion or symptomatic patients.
    D) Obtain baseline ECG to evaluate rhythm; monitor as appropriate.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Gastrointestinal decontamination may be contraindicated following a significant ingestion because of the potential for seizures, cardiovascular instability and CNS depression.
    B) 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) SUMMARY
    1) Gastrointestinal decontamination may be contraindicated following a significant ingestion because of the potential for seizures, cardiovascular instability and CNS depression.
    B) 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) SUMMARY
    a) Ganciclovir is currently intended ONLY for patients with CMV retinitis (immunocompromised) and prevention of CMV disease in transplant recipients, therefore, the adverse events reported are based on individuals with underlying disease processes and possible concomitant drug therapy. Due to limited overdose information, overall treatment is based on symptomatic care.
    2) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Limited overdose information. Clinical events are anticipated to be similar to adverse events reported.Of the limited cases of overdose, hematologic toxicity (ie, neutropenia, anemia and thrombocytopenia) was the most common event reported with ganciclovir therapy. Monitor CBC with differential daily until cell count recovery occurs (usually begins 3 to 7 days after the discontinuation of ganciclovir). Monitor vital signs. Fever is frequently reported with therapy. Treat with antipyretics, cool compresses and cooling blankets as needed. Assess for potential infection or sepsis. Alteration in fluid status may develop secondary to diarrhea (common) and vomiting. Treat diarrhea with antidiarrheals and replace fluids and electrolytes as indicated.
    3) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Initially treat seizures with IV benzodiazepines, barbiturates.
    B) MONITORING OF PATIENT
    1) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery (cell count recovery usually begins 3 to 7 days after ganciclovir discontinuation). Monitor vital signs.
    2) Liver enzyme levels should be monitored for possible hepatotoxicity.
    3) Monitor renal function tests and urinalysis for patients with significant exposure.
    4) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    5) Evaluate patients for signs and symptoms of stomatitis.
    C) MYELOSUPPRESSION
    1) Severe myelosuppression should be expected after overdose. Cell count recovery usually begins 3 to 7 days after ganciclovir discontinuation (Prod Info ganciclovir sodium intravenous injection, 2014).
    2) Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) has been used to stimulate hematopoiesis, for individuals with ongoing neutropenia who required continuation of ganciclovir therapy (due to progression of CMV disease) (Sulecki et al, 1991; Holland, 1991).
    a) Resolution of neutropenia (ANC 1,036/uL prior to therapy) was reported 2 days following rhGM-CSF 250 micrograms/square meter (subcutaneously twice a day) in a 47-year-old man with myelocytic leukemia who developed CMV interstitial pneumonitis following an allogeneic bone marrow transplant (Sulecki et al, 1991).
    3) Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    4) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997).
    5) Patients with severe neutropenia should be in protective isolation.
    D) NEUTROPENIA
    1) COLONY STIMULATING FACTORS
    a) DOSING
    1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or continuous IV infusion (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
    2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period OR 250 mcg/m(2)/day SubQ once daily (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013). Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013; Smith et al, 2006).
    2) HIGH-DOSE THERAPY
    a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
    b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion no longer than 24 hours. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015):
    1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
    2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
    3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.
    c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
    d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion over a 2-hour period. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013).
    3) SPECIAL CONSIDERATIONS
    a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).
    4) ANTIBIOTIC PROPHYLAXIS
    a) Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).
    E) 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, 2010; 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).
    F) CONDUCTION DISORDER OF THE HEART
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    G) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Cold compresses and cooling blankets should be used in cases of hyperthermia.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) If accidental exposure occurs: rinse eyes thoroughly with plain water (Prod Info CYTOVENE(R) IV injection, 2006).
    1) Patients with underlying disease (CMV retinitis) may require evaluation by an ophthalmologist to determine the extent of injury.
    B) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) Initial treatment for a dermal exposure should include cleansing the area.
    2) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Ganciclovir is excreted entirely by the kidneys through both filtration and tubular secretion (DeArmond, 1991). Ganciclovir is removed by hemodialysis; dialysis may be useful in reducing serum concentrations (DeArmond, 1991; Prod Info CYTOVENE(R) IV injection, 2006).

Range Of Toxicity

Summary

    A) GANCICLOVIR: Overdose data are limited. An adult developed no toxicity following a total dose of 8.25 grams of ganciclovir given over a 36 hour period. Persistent bone marrow suppression developed after a single 6 gram dose.
    B) VALGANCICLOVIR: Fatal bone marrow depression (medullary aplasia) has been reported in an adult with renal impairment after several days of dosing that was at least 10-fold greater than recommended.
    C) THERAPEUTIC DOSE: GANCICLOVIR: ADULT: ORAL: 1 g orally 3 times a day; IV: Up to 5 mg/kg IV every 12 hours. INTRAVITREAL: 4.5 mg/implant every 6 to 9 months. Renal dosing may be necessary. PEDIATRIC: Ganciclovir is not FDA-approved for pediatric patients. VALGANCICLOVIR: ADULT: ORAL: Up to 900 mg orally twice daily. Renal dosing may be necessary. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) GANCICLOVIR
    a) INDUCTION TREATMENT
    1) CYTOMEGALOVIRUS RETINITIS: 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days (Prod Info CYTOVENE(R) IV injection, 2006).
    2) CYTOMEGALOVIRUS DISEASE IN TRANSPLANT RECIPIENTS: 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days (Prod Info CYTOVENE(R) IV injection, 2006).
    a) Followed by 5 mg/kg once daily 7 days per week or 6 mg/kg once daily, 5 days per week (Prod Info CYTOVENE(R) IV injection, 2006).
    3) Cytovene capsules are not recommended for induction treatment (Prod Info Cytovene(R) intravenous, ganciclovir, 1999).
    4) CAUTION: Do not administer intravenous solution by rapid or bolus intravenous injection. Toxicity may be increased as a result of excessive plasma levels (Prod Info CYTOVENE(R) IV injection, 2006).
    a) Intramuscular or subcutaneous injection of reconstituted ganciclovir may result in SEVERE tissue irritation due to high pH (11) (Prod Info CYTOVENE(R) IV injection, 2006).
    b) MAINTENANCE TREATMENT
    1) Following Induction (Intravenous): 5 mg/kg as a constant-rate infusion over 1 hour once daily, 7 days per week, or 6 mg/kg once daily, 5 days per week (Prod Info CYTOVENE(R) IV injection, 2006).
    2) Following Induction (Oral): 1000 milligrams three times daily with food or 500 milligrams 6 times daily every three hours with food, during waking hours (Prod Info ganciclovir oral capsules, 2003). NOTE: Reduction of therapy may be needed for patients experiencing progression of cytomegalovirus retinitis.
    3) NOTE: (cytomegalovirus disease in transplant recipients): the duration of treatment is dependent upon the duration and degree of immunosuppression (Prod Info ganciclovir oral capsules, 2003).
    4) CAUTION: The recommended dose for intravenous or oral administration should NOT be exceeded (Prod Info CYTOVENE(R) IV injection, 2006; Prod Info ganciclovir oral capsules, 2003).
    c) INTRAVITREAL
    1) Each intravitreal implant contains a minimum of 4.5 mg of ganciclovir and is designed for slow release over a 5 to 8 month period (Prod Info VITRASERT(R) intravitreal implant, 2005).
    2) Dosing is based on a return of symptoms, as evidenced by progression of retinitis and the implant may be removed and replaced (Prod Info VITRASERT(R) intravitreal implant, 2005).
    3) Special consideration is indicated in handling the implant (due to possible damage of the polymer which could inadvertently release more drug and its possible shared properties with anti-tumor agents) and it requires surgical implantation with aseptic technique (Prod Info VITRASERT(R) intravitreal implant, 2005).
    2) VALGANCICLOVIR
    a) ORAL
    1) Treatment of cytomegalovirus retinitis: The recommended induction dose in patients with normal renal function is 900 mg twice a day with food for 21 days. The maintenance dose is 900 mg once daily with food (Prod Info VALCYTE oral tablets, oral powder, 2015).
    2) Prevention of cytomegalovirus disease in transplant patients: The recommended dose is 900 mg twice daily starting within 10 days of transplantation until 100 days post-transplantation (heart or kidney-pancreas transplant) or 200 days post-transplantation (kidney transplant) (Prod Info VALCYTE oral tablets, oral powder, 2015).
    7.2.2) PEDIATRIC
    A) GANCICLOVIR
    1) There has been very limited clinical experience using ganciclovir for the treatment of cytomegalovirus retinitis in patients under 12 years of age.
    2) ROUTE OF ADMINISTRATION
    a) INTRAVENOUS
    1) Children under the age of 12 have received induction therapies of 2.5 mg/kg three times daily (Prod Info CYTOVENE(R) IV injection, 2006).
    2) Maintenance therapy in clinical trials with a small number of children was 6 to 6.5 mg/kg once daily, five to seven days per week (Prod Info CYTOVENE(R) IV injection, 2006).
    3) Therapeutic doses at 5 mg/kg (may be increased up to a maximum of 7.5 mg/kg/dose) IV every 12 hours for 14 to 21 days (preferred therapy), or in combination with foscarnet 60 mg/kg IV every 8 hours for 14 to 21 days (alternative therapy) have been used in pediatric patients(Centers for Disease Control and Prevention et al, 2009).
    b) ORAL
    1) 3 YEARS OF AGE OR OLDER: 30 mg/kg orally 3 times daily in combination with 1 sustained-release intravitreal implant (4.5 mg/implant) every 6 to 9 months for CMV Retinitis-HIV Infection (Centers for Disease Control and Prevention et al, 2009)
    c) INTRAVITREAL
    1) 3 YEARS OF AGE OR OLDER: 1 sustained-release intravitreal implant (4.5 mg/implant) every 6 to 9 months in combination with ganciclovir 30 mg/kg orally 3 times daily for CMV Retinitis-HIV Infection (Centers for Disease Control and Prevention et al, 2009).
    d) OPHTHALMIC GEL
    1) 2 YEARS OF AGE OR OLDER: Instill 1 drop in the affected eye 5 times per day (approximately every 3 hours while awake) until corneal ulcer healed, then 1 drop 3 times daily for 7 days Acute Herpetic Keratitis(Prod Info ZIRGAN(TM) ophthalmic gel, 2009).
    B) VALGANCICLOVIR
    1) ORAL
    a) 29 DAYS TO 1 YEAR OF AGE: 16 mg/kg per dose orally every 12 hours. Treat for a minimum of 6 weeks; longer-term treatment may be appropriate for the treatment of CMV disease(Kimberlin et al, 2008; Acosta et al, 2007). Studies have reported continuing prophylaxis for 3 or 6 months (Camacho-Gonzalez et al, 2011; Lapidus-Krol et al, 2010).
    b) Dosages up to 900 mg twice daily have been used in pediatric patients 40 kg or greater for prophylaxis of cytomegalovirus disease after hematopoietic cell transplant (Tomblyn et al, 2009).
    c) The recommended dose of valganciclovir for the prevention of cytomegalovirus (CMV) disease in pediatric heart transplant patients (1 month to 16 years of age) and kidney transplant patients (4 months to 16 years of age) is based on body surface area (BSA) and creatinine clearance (CrCl; derived from a modified Schwartz formula to a maximum calculated value of 150 mL/min/1.73 m(2)). All calculated doses in children should be rounded to the nearest 10-mg increment for the actual deliverable dose up to a maximum dose of 900 mg once daily (Prod Info VALCYTE oral tablets, oral powder, 2015).
    1) CALCULATING DOSAGE: Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula; if calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73 m(2), use the maximum value of 150 mL/min/1.73 m(2) in the equation below), where:
    a) Mosteller BSA (m(2)) = square root (height (cm) X weight (kg)/3600)
    b) Schwartz Creatine Clearance (mL/min/1.73 m(2)) = k x height (cm)/ Serum Creatinine (mg/dL)
    2) where k =
    a) 0.33 for patients less than 1 year old with low birth weight for gestational age
    b) 0.45 for patients less than 1 year old with appropriate birth weight for gestational age
    c) 0.45 for patients ages 1 to less than 2 years old (note k value of 0.45 instead of typical value of 0.55)
    d) 0.55 for boys ages 2 to less than 13 years old and girls ages 2 to 16 years old, and
    e) 0.7 for boys ages 13 to 16 years old
    d) ADOLESCENTS: Adolescents with HIV-infection and old enough to receive an adult dose, have received 900 mg orally once daily to prevent CMV Disease (primary prophylaxis and chronic suppressive therapy)
    1) (Centers for Disease Control and Prevention et al, 2009).

Minimum Lethal Exposure

    A) SUMMARY
    1) GANCICLOVIR: A minimum lethal dose has not been established.
    2) VALGANCICLOVIR: Fatal bone marrow depression (medullary aplasia) has been reported in an adult with renal impairment after several days of dosing that was at least 10-fold greater than recommended (Prod Info VALCYTE oral tablets, oral powder, 2015).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT INTRAVENOUS
    a) OVERDOSE: No toxicity developed in a 44-year-old male cardiac transplant recipient despite receiving a 10-fold overdose of IV ganciclovir (50 mg/kg every 12 hours for 3 doses; total dose of 8.25 g) for suspected CMV infection (Kostis et al, 1999).
    b) Persistent bone marrow suppression developed in an adult who received a 6000-mg dose (Prod Info ganciclovir sodium intravenous injection, 2014).
    c) A dose of 3000 mg daily for 2 days resulted in irreversible pancytopenia in an adult (Prod Info ganciclovir sodium intravenous injection, 2014).
    d) Reversible neutropenia and granulocytopenia were reported after 8 mg/kg/day for 4 days and a single dose of 25 mg/kg (Prod Info ganciclovir sodium intravenous injection, 2014).
    e) Hepatitis was reported after 10 mg/kg/day in an adult and in an infant (2 kilograms) after a single 40 mg dose (Prod Info ganciclovir sodium intravenous injection, 2014).
    f) CASE REPORTS: Renal toxicity occurred in one adult with transient worsening of hematuria after a single 500 mg dose and in another adult with an elevated creatinine (5.2 mg/dL) after a single 5000 to 7000 mg overdose of ganciclovir (Prod Info ganciclovir sodium intravenous injection, 2014).
    2) ADULT INTRAVITREAL
    a) Permanent visual loss occurred after 40 mg in an adult (Prod Info CYTOVENE(R) IV injection, 2006).
    3) PEDIATRIC INTRAVENOUS
    a) Hepatitis occurred after a single 40-mg dose in a 2 kilogram infant (Prod Info CYTOVENE(R) IV injection, 2006).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1 gm/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) >2 gm/kg (RTECS, 2000)

References

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    53) Product Information: CYTOVENE(R) IV injection, ganciclovir sodium IV injection. Roche Pharmaceuticals, Nutley, NJ, 2006.
    54) Product Information: CYTOVENE-IV(R) IV injection, ganciclovir sodium IV injection. Roche Laboratories Inc, Nutley, NJ, 2008.
    55) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    56) Product Information: Cytovene(R) intravenous, ganciclovir. Roche Laboratories, Nutley, NJ, 1999.
    57) Product Information: LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, sargramostim subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution. sanofi-aventis U.S. LLC (per manufacturer), Bridgewater, NJ, 2013.
    58) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    59) Product Information: NEUPOGEN(R) subcutaneous injection, intravenous injection, filgrastim subcutaneous injection, intravenous injection. Amgen Inc. (per FDA), Thousand Oaks, CA, 2015.
    60) Product Information: VALCYTE oral tablets, oral powder, valganciclovir hydrochloride oral tablets, oral powder. Genentech USA, Inc. (per manufacturer), South San Francisco, CA, 2015.
    61) Product Information: VALCYTE(R) oral solution, oral tablets, valganciclovir oral solution, oral tablets. Roche Laboratories Inc., Nutley, NJ, 2009.
    62) Product Information: VITRASERT(R) intravitreal implant, ganciclovir intravitreal implant. Bausch & Lomb Incorporated, Rochester, NY, 2005.
    63) Product Information: Vitrasert(R), ganciclovir implant. Bausch & Lomb, Inc, Claremont, CA, 1999.
    64) Product Information: ZIRGAN(R) ophthalmic gel, ganciclovir 0.15% ophthalmic gel. Bausch & Lomb Incorporated (per DailyMed), Tampa, FL, 2014.
    65) Product Information: ZIRGAN(TM) ophthalmic gel, ganciclovir ophthalmic gel. SIRion Therapeutics, Tampa, FL, 2009.
    66) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
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