Usual Adult Dose for CMV Retinitis

Induction therapy: 90 mg/kg IV (90- to 120-minute infusion) every 12 hours or 60 mg/kg IV (minimum 1-hour infusion) every 8 hours over 2 to 3 weeks depending on clinical response
Maintenance therapy: 90 to 120 mg/kg IV (2-hour infusion) once a day

Comments:

• Maintenance therapy dose should be individualized for renal function.
• Most patients should be started on maintenance therapy at 90 mg/kg/day; escalation to 120 mg/kg/day may be considered should early reinduction be required due to retinitis progression.
• Some patients who show excellent tolerance to this drug may benefit from starting maintenance therapy at 120 mg/kg/day earlier in their treatment.
• Patients who have retinitis progression during foscarnet maintenance therapy may be retreated with the induction and maintenance regimens in combination with ganciclovir; this drug must not be mixed with ganciclovir due to physical incompatibility.

Uses: For the treatment of CMV retinitis in patients with AIDS; in combination with ganciclovir for patients who relapse after monotherapy with either drug

US CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) Recommendations for HIV-infected Patients:
For sight-threatening lesions (adjacent to optic nerve or fovea):

• Intravitreal injections: 2.4 mg as an intravitreal injection for 1 to 4 doses over 7 to 10 days
• Systemic therapy: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 14 to 21 days, then 90 to 120 mg/kg IV every 24 hours

For peripheral lesions: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 14 to 21 days, then 90 to 120 mg/kg IV every 24 hours

Chronic maintenance therapy (secondary prophylaxis): 90 to 120 mg/kg IV once a day

Comments:

• Intravitreal injections plus a systemic antiviral agent should be used for sight-threatening lesions.
• Recommended as alternative systemic therapy

Usual Adult Dose for Herpes Simplex - Mucocutaneous/Immunocompromised Host

Induction therapy: 40 mg/kg IV (minimum 1-hour infusion) every 8 or 12 hours
Duration of therapy: 2 to 3 weeks or until healed

Use: For the treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients

US CDC, NIH, and IDSA recommendations for the treatment of acyclovir-resistant mucocutaneous HSV infections in HIV-infected patients: 80 to 120 mg/kg/day IV in 2 to 3 divided doses
Duration of therapy: Until clinical response

Comments:

• Recommended as preferred therapy

Usual Adult Dose for CMV Gastroenteritis

US CDC, NIH, and IDSA recommendations for the treatment of CMV esophagitis or colitis in HIV-infected patients: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours
Duration of therapy: 21 to 42 days or until signs/symptoms resolve

Comments:

• Recommended as alternative therapy
• Recommended for patients with therapy-limiting toxicities to ganciclovir or with ganciclovir resistance
• Maintenance therapy usually not needed but should be considered after relapses.

Usual Adult Dose for Varicella-Zoster

US CDC, NIH, and IDSA recommendations for progressive outer retinal necrosis in HIV-infected patients:

• Intravitreal: 1.2 mg/0.05 mL intravitreal twice a week
• IV: 90 mg/kg IV every 12 hours

Comments:

• Ganciclovir IV and/or foscarnet IV PLUS ganciclovir intravitreal and/or foscarnet intravitreal recommended.
• An experienced ophthalmologist should be involved.

Usual Pediatric Dose for CMV Retinitis

US CDC, NIH, IDSA, Pediatric Infectious Diseases Society (PIDS), and American Academy of Pediatrics (AAP) Recommendations for HIV-exposed and HIV-infected Children:
Induction therapy: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours
Duration of therapy:

• CNS disease: Until symptomatic improvement
• Disseminated disease and retinitis: 14 to 21 days

Chronic suppressive therapy/secondary prophylaxis: 90 to 120 mg/kg IV once a day

US CDC, NIH, and IDSA Recommendations for HIV-infected Adolescents:
For sight-threatening lesions (adjacent to optic nerve or fovea):

• Intravitreal injections: 2.4 mg as an intravitreal injection for 1 to 4 doses over 7 to 10 days
• Systemic therapy: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 14 to 21 days, then 90 to 120 mg/kg IV every 24 hours

For peripheral lesions: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 14 to 21 days, then 90 to 120 mg/kg IV every 24 hours

Chronic maintenance therapy (secondary prophylaxis): 90 to 120 mg/kg IV once a day

Comments:

• In combination with ganciclovir, recommended as first choice for CNS disease in children
• Recommended as alternative therapy for disseminated disease and retinitis in children
• In combination with ganciclovir, recommended as an alternative for retinitis in children; ganciclovir IV plus foscarnet IV may be considered as induction therapy in children with sight-threatening disease or for treatment after failure/relapse on monotherapy.
• Recommended as a first choice for secondary prophylaxis in children
• Induction therapy should be followed by chronic suppressive therapy in children.
• Intravitreal injections plus a systemic antiviral agent should be used for sight-threatening lesions in adolescents.
• Recommended as alternative systemic therapy in adolescents

Usual Pediatric Dose for Herpes Simplex - Mucocutaneous/Immunocompromised Host

Acyclovir-resistant infection:

• US CDC, NIH, IDSA, PIDS, and AAP recommendations for HIV-exposed and HIV-infected children: 40 mg/kg IV 3 times a day or 60 mg/kg IV twice a day
• US CDC, NIH, and IDSA recommendations for HIV-infected adolescents: 80 to 120 mg/kg/day IV in 2 to 3 divided doses until clinical response

Comments:

• Recommended as preferred therapy for acyclovir-resistant infections
• Should be infused slowly over 2 hours in children

Usual Pediatric Dose for CMV Gastroenteritis

US CDC, NIH, and IDSA recommendations for the treatment of CMV esophagitis or colitis in HIV-infected adolescents: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours
Duration of therapy: 21 to 42 days or until signs/symptoms resolve

Comments:

• Recommended as alternative therapy
• Recommended for patients with therapy-limiting toxicities to ganciclovir or with ganciclovir resistance
• Maintenance therapy usually not needed but should be considered after relapses.

Usual Pediatric Dose for Varicella-Zoster

US CDC, NIH, IDSA, PIDS, and AAP Recommendations for HIV-exposed and HIV-infected Children:
Acyclovir-resistant varicella-zoster virus (VZV): 40 to 60 mg/kg IV every 8 hours
Duration of therapy: 7 days or until no new lesions appear for at least 48 hours

Progressive outer retinal necrosis:

• Intravitreal: 1.2 mg/0.05 mL intravitreal twice a week
• IV: 90 mg/kg IV every 12 hours

US CDC, NIH, and IDSA Recommendations for Progressive Outer Retinal Necrosis in HIV-infected Adolescents:

• Intravitreal: 1.2 mg/0.05 mL intravitreal twice a week
• IV: 90 mg/kg IV every 12 hours

Comments:

• Recommended as treatment of choice for acyclovir-resistant VZV
• Ganciclovir IV PLUS foscarnet IV PLUS ganciclovir intravitreal and/or foscarnet intravitreal recommended as first choice for progressive outer retinal necrosis in children.
• Ganciclovir IV and/or foscarnet IV PLUS ganciclovir intravitreal and/or foscarnet intravitreal recommended for progressive outer retinal necrosis in adolescents.
• An experienced ophthalmologist should be involved.

Renal Dose Adjustments

CrCl greater than 1.4 mL/min/kg:

• CMV retinitis induction: 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours
• CMV retinitis maintenance: 90 or 120 mg/kg IV every 24 hours
• HSV induction: 40 mg/kg IV every 8 or 12 hours

CrCl greater than 1 to 1.4 mL/min/kg:

• CMV retinitis induction: 45 mg/kg IV every 8 hours or 70 mg/kg IV every 12 hours
• CMV retinitis maintenance: 70 or 90 mg/kg IV every 24 hours
• HSV induction: 30 mg/kg IV every 8 or 12 hours

CrCl greater than 0.8 to 1 mL/min/kg:

• CMV retinitis induction: 50 mg/kg IV every 12 hours
• CMV retinitis maintenance: 50 or 65 mg/kg IV every 24 hours
• HSV induction: 20 or 35 mg/kg IV every 12 hours

CrCl greater than 0.6 to 0.8 mL/min/kg:

• CMV retinitis induction: 40 mg/kg IV every 12 hours or 80 mg/kg IV every 24 hours
• CMV retinitis maintenance: 80 or 105 mg/kg IV every 48 hours
• HSV induction: 35 mg/kg IV every 24 hours or 25 mg/kg IV every 12 hours

CrCl greater than 0.5 to 0.6 mL/min/kg:

• CMV retinitis induction: 60 mg/kg IV every 24 hours
• CMV retinitis maintenance: 60 or 80 mg/kg IV every 48 hours
• HSV induction: 25 or 40 mg/kg IV every 24 hours

CrCl greater than 0.4 to 0.5 mL/min/kg:

• CMV retinitis induction: 50 mg/kg IV every 24 hours
• HSV induction: 20 or 35 mg/kg IV every 24 hours

CrCl 0.4 to 0.5 mL/min/kg:

• CMV retinitis maintenance: 50 or 65 mg/kg IV every 48 hours

CrCl less than 0.4 mL/min/kg: Not recommended.

If CrCl falls below 0.4 mL/min/kg during therapy: This drug should be discontinued; patient should be hydrated and monitored daily until ensure that renal impairment resolved.

Comments:

• Renal dose adjustments are based on actual 24-hour CrCl (mL/min) divided by body weight (kg) or the estimated CrCl in mL/min/kg calculated from serum creatinine (mg/dL) according to a modified Cockcroft-Gault formula.
• To minimize risk of nephrotoxicity, CrCl (mL/min/kg) should be determined even if serum creatinine is within the normal range; doses should be adjusted accordingly (at baseline and frequently thereafter).
• This drug should be used with caution in patients with renal dysfunction (reduced plasma clearance will lead to elevated plasma levels); this drug may impair renal function further.
• Safety and efficacy data are limited for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour CrCl less than 50 mL/min.

Liver Dose Adjustments

Data not available

Precautions

US BOXED WARNINGS:

• RENAL IMPAIRMENT: The major toxicity is renal impairment. Serum creatinine should be monitored frequently, adjusting dose accordingly for renal function changes. Adequate hydration with administration is essential.
• SEIZURES: Seizures related to plasma mineral and electrolyte changes reported. Monitoring for such changes (and potential sequelae) is recommended. Mineral and electrolyte supplementation may be needed.
• INDICATIONS: Indicated for use only in immunocompromised patients with CMV retinitis and mucocutaneous acyclovir-resistant HSV infections.

Safety and efficacy have not been established in patients younger than 18 years; this drug should only be used after careful evaluation and only if benefits outweigh risks.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis: Not recommended.

Other Comments

Administration advice:

• Do not exceed recommended dose, frequency, or infusion rates; individualize all doses for patient's renal function.
• Infuse solutions containing this drug into veins with sufficient blood flow (to allow rapid dilution and distribution and avoid local irritation).
• Administer by controlled IV infusion, either by using a central venous line or by using a peripheral vein.
• Do not administer by rapid or bolus IV injection; infusion rate must not exceed 1 mg/kg/min.
• Take care to avoid unintentional overdose by carefully controlling the rate of infusion (excessive plasma levels may increase toxicity); use an infusion pump.
• Before therapy is started, correct clinical dehydration; establish diuresis with adequate hydration, both prior to and during therapy to minimize renal toxicity, provided there are no clinical contraindications.
• Before the first infusion, administer 750 to 1000 mL of normal saline or 5% dextrose solution (to establish diuresis); concurrently with subsequent infusions, administer 750 to 1000 mL hydration fluid with 90 to 120 mg/kg doses and 500 mL with 40 to 60 mg/kg doses; decrease hydration fluid if clinically necessary; may consider oral rehydration with similar regimens in some patients.

Storage requirements:

• Store between 20C and 25C (68F and 77F); protect from excessive heat (above 40C) and from freezing. Precipitation may occur if refrigerated or exposed to temperatures below freezing; precipitate can be brought into solution again by keeping the bottle at room temperature with repeated shaking.
• Should use prepared solutions (diluted or excess quantities removed) within 24 hours of first entry into a sealed bottle

Reconstitution/preparation techniques:

• An individualized dose (at the concentration required for the administration route) should be aseptically prepared before dispensing.
• When using a central venous catheter for infusion: May use the standard 24 mg/mL solution with or without dilution
• When using a peripheral vein catheter for infusion: The 24 mg/mL solution must be diluted to 12 mg/mL with 5% dextrose in water or a normal saline solution prior to administration (to avoid local irritation of peripheral veins).
• Aseptic conditions are recommended for dilutions and/or removals of excess quantities.

IV compatibility:

• This drug should only be administered with normal saline or 5% dextrose solution; no other drug or supplement should be administered concurrently in the same catheter.
• Chemically incompatible: 30% dextrose, amphotericin B, calcium-containing solutions (e.g., Ringer's lactate, TPN)
• Physically incompatible: Acyclovir, ganciclovir, trimetrexate, pentamidine, vancomycin, sulfamethoxazole-trimethoprim, diazepam, midazolam, digoxin, phenytoin, leucovorin, prochlorperazine
• Due to chelating properties of this drug, a precipitate can potentially occur if divalent cations are administered concurrently in the same catheter.

General:

• Current guidelines should be consulted for additional information.
• An individualized dose should be determined based on body weight (mg/kg), renal function, indication, and dosing frequency.
• Despite use of an infusion pump, overdoses have occurred.
• Hydration may reduce risk of nephrotoxicity.
• Safety and efficacy not established for treatment of other CMV infections (e.g., pneumonitis, gastroenteritis), other HSV infections (e.g., retinitis, encephalitis), congenital/neonatal CMV or HSV disease, or non-immunocompromised patients.
• Accidental contact with skin and eyes may cause local irritation and burning; the exposed area should be flushed with water if contact occurs.

Monitoring:

• Metabolic: Serum electrolytes and minerals; serum calcium, phosphorus, magnesium, and potassium (at baseline, 2 to 3 times per week during induction therapy, once a week during maintenance therapy); for symptoms of low ionized calcium
• Ocular: Ophthalmologic examinations with CMV retinitis (regularly)
• Renal: CrCl (mL/min/kg), even if serum creatinine is within normal limits; CrCl, either measured or estimated using modified Cockcroft-Gault formula based on serum creatinine (at baseline, 2 to 3 times per week during induction therapy, once a week during maintenance therapy, or more frequently); 24-hour CrCl (at baseline and periodically thereafter)

Patient advice:

• This drug is not a cure for CMV retinitis or mucocutaneous HSV infections.
• Avoid driving or operating machinery if seizures, dizziness, somnolence, or other side effects that could cause impairment occur.