VA Class:AM800
Foscarnet sodium (phosphonoformic acid), an organic analog of inorganic pyrophosphate, is an antiviral agent active against herpesviruses.1, 2, 3, 4, 85
Treatment of Cytomegalovirus Infection and Disease
Foscarnet sodium is used for initial treatment (induction therapy) and maintenance therapy (secondary prophylaxis) of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection, including those with acquired immunodeficiency syndrome (AIDS).1, 2, 3, 4, 85, 155 The drug also is used for the management of CMV retinitis in HIV-infected adolescents and children†.155, 156 Foscarnet can be used in conjunction with ganciclovir for the management of CMV retinitis that relapsed after monotherapy with either drug.1 Safety and efficacy of foscarnet have not been established for the treatment of CMV retinitis in immunocompetent individuals.1
Like other antivirals, foscarnet, is not a cure for CMV retinitis.1 Although foscarnet can induce stabilization or improvement of ocular manifestations of CMV retinitis, the retinitis may relapse and/or progress during or after discontinuance of the drug.1, 2, 3, 4 The possibility of foscarnet-resistant CMV should be considered in patients who fail to respond to foscarnet or who experience persistent CMV shedding while receiving maintenance therapy with the drug; some strains resistant to foscarnet may be susceptible to ganciclovir.36, 37 In some patients whose retinitis progressed with foscarnet or ganciclovir monotherapy, combined therapy with the drugs stabilized progression of the disease.20, 63, 64
Retinitis is the most common clinical manifestation of CMV end-organ disease in HIV-infected patients and ideally should be managed in consultation with an ophthalmologist familiar with the diagnosis and treatment of retinal diseases.155, 156 Antiviral regimens for initial treatment of CMV retinitis in HIV-infected individuals should be selected based on the location and severity of CMV retinal lesions, severity of underlying immunosuppression, concomitant drug therapy, and the patient's ability to adhere to the treatment regimen.155, 156 The antiviral regimen used for maintenance therapy of CMV retinitis in HIV-infected individuals should be selected with consideration for the location of the CMV retinal lesions, vision in the contralateral eye, the patient's immunologic and virologic status, and the patient's response to antiretroviral therapy.155, 156
For the management of immediate sight-threatening CMV retinal lesions (i.e., within 1.5 mm of the fovea) in HIV-infected adults and adolescents, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) state that the preferred regimen is initial treatment (induction therapy) with intravitreal ganciclovir or intravitreal foscarnet† (1-4 doses given over a period of 7-10 days) in conjunction with oral valganciclovir (twice daily for 14-21 days) followed by maintenance therapy (secondary prophylaxis) with oral valganciclovir (once daily).155 One alternative regimen recommended by these experts for management of sight-threatening CMV retinitis in HIV-infected adults and adolescents is intravitreal ganciclovir or intravitreal foscarnet† (1-4 doses given over a period of 7-10 days) in conjunction with IV foscarnet (2 or 3 times daily for 2-3 weeks) followed by maintenance therapy (secondary prophylaxis) with IV foscarnet (once daily).155 Use of systemic antivirals (without an intravitreal antiviral) usually is adequate for the management of CMV retinitis in patients who have only small peripheral lesions.155
For the management of CMV retinitis in HIV-infected pediatric patients, CDC, NIH, IDSA, and others state that IV ganciclovir is the drug of choice for initial treatment (induction therapy) and is one of several options for maintenance therapy (secondary prophylaxis).156 These experts state that IV foscarnet is a preferred alternative for the management of CMV retinitis in HIV-infected children† and is recommended for infections known or suspected to be caused by ganciclovir-resistant CMV.156 These experts state that a regimen of IV ganciclovir and IV foscarnet can be considered for initial treatment (induction therapy) in HIV-infected children with sight-threatening CMV retinitis or when the infection failed to respond to or relapsed after monotherapy.156 Data are limited regarding use of intravitreal antivirals in children, and intravitreal injections are impractical in most children.156
Because of the risk of relapse, HIV-infected patients who have received adequate initial treatment of CMV retinitis should receive chronic maintenance therapy (secondary prophylaxis) until immune reconstitution occurs as a result of effective antiretroviral therapy.155, 156 CDC, NIH, and IDSA state that consideration can be given to discontinuing maintenance therapy of CMV retinitis in HIV-infected adults and adolescents if CMV lesions have been treated for at least 3-6 months and are inactive and there has been a sustained (i.e., 3-6 months) increase in CD4+ T-cell count to greater than 100/mm3 in response to antiretroviral therapy.155 The safety of discontinuing maintenance therapy of CMV retinitis in HIV-infected pediatric patients has not been well studied; however, CDC, NIH, IDSA, and others state that consideration can be given to discontinuing such maintenance therapy of CMV retinitis in HIV-infected children who are receiving antiretroviral therapy and have a sustained (i.e., greater than 6 months) increase in CD4+ T-cell percentage to greater than 15% (children younger than 6 years of age) or increase in CD4+ T-cell count to greater than 100/mm3 (children 6 years of age and older).156 These experts state that a decision to discontinue maintenance therapy of CMV retinitis should be made in consultation with an ophthalmologist and, if maintenance therapy is discontinued, the patient should continue to receive regular ophthalmologic monitoring (optimally every 3-6 months) for early detection of CMV relapse or immune reconstitution uveitis.155, 156 If CD4+ T-cell count decreases to less than 100/mm3 (adults, adolescents, children 6 years of age or older) or if CD4+ T-cell percentage decreases to less than 15% (children younger than 6 years of age), maintenance therapy of CMV retinitis should be reinitiated.155, 156
For additional information on the management of CMV retinitis and other CMV infections in HIV-infected individuals, the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web] should be consulted.155, 156
Efficacy of IV foscarnet sodium for the treatment of CMV retinitis was evaluated in a prospective, randomized, controlled trial in 24 patients with AIDS.1 Patients received induction treatment with foscarnet sodium (60 mg/kg IV every 8 hours for 3 weeks), followed by maintenance treatment with the drug (90 mg/kg IV once daily until retinitis progression [appearance of a new lesion or advancement of the border of a posterior lesion greater than 750 µm in diameter]).1 All diagnoses and determinations of retinitis progression were made from masked reading of retinal photographs.1 The 13 patients randomized to receive IV foscarnet had a delay in progression of CMV retinitis compared with untreated controls.1 The median time to retinitis progression from study entry was 93 days (range: 21 to greater than 364 days) in those treated with IV foscarnet compared with 22 days (range: 7- 42 days) in untreated controls.1
In another prospective trial in AIDS patients with CMV retinitis, 33 patients received induction treatment with IV foscarnet sodium (60 mg/kg IV 3 times daily for 2-3 weeks) and were randomized to receive maintenance therapy with the drug in a dosage of 90 or 120 mg/kg IV once daily.1 The median time from study entry to retinitis progression was not significantly different between the treatment groups; 96 days (range: 14 to greater than 176 days) in those receiving the lower maintenance dosage and 140 days (range: 16 to greater than 233 days) in those receiving the higher maintenance dosage.1
The comparative efficacy of IV foscarnet and IV ganciclovir for the treatment of newly diagnosed CMV retinitis was evaluated in a study that included 107 patients randomized to receive foscarnet sodium (induction treatment with 60 mg/kg IV 3 times daily for 2 weeks followed by maintenance therapy with 90 mg/kg IV once daily) and 127 patients randomized to receive ganciclovir (induction treatment with 5 mg/kg IV twice daily followed by maintenance therapy with 5 mg/kg IV once daily).1 The median time to retinitis progression was similar with both drugs (59 days in those receiving foscarnet and 56 days in those receiving ganciclovir).1
In a study evaluating efficacy of combination therapy with IV foscarnet and IV ganciclovir versus monotherapy with either drug alone for the treatment of persistently active or relapsed CMV retinitis in patients with AIDS, patients who were randomized to combination therapy while receiving IV foscarnet alone continued to receive the usual maintenance dosage of foscarnet sodium (i.e., 90 mg/kg IV once daily) while IV ganciclovir therapy was initiated using usual ganciclovir induction and maintenance dosages (i.e., 5 mg/kg IV every 12 hours for 14 days followed by 5 mg/kg IV once daily).63 Patients who were randomized to combination therapy while receiving IV ganciclovir alone continued to receive the usual maintenance dosage of ganciclovir (i.e., 5 mg/kg IV once daily) while IV foscarnet therapy was initiated using usual foscarnet sodium induction and maintenance dosages (i.e., 90 mg/kg IV every 12 hours for 14 days followed by 90 mg/kg IV once daily).63 Therapy was then continued using maintenance dosages of both drugs.63 Patients who relapsed while receiving combination therapy were reinduced with both drugs using usual induction dosages (i.e., ganciclovir 5 mg/kg IV every 12 hours and foscarnet sodium 90 mg IV every 12 hours for 14 days) followed by usual maintenance dosages (i.e., ganciclovir 5 mg/kg IV once daily and foscarnet sodium 90 mg/kg IV once daily).63 The median time to retinitis progression in the foscarnet group, ganciclovir group, or combination group was 1.3, 2, or 4.3 months, respectively.63
Extraocular Cytomegalovirus Infections
Although safety and efficacy of foscarnet sodium have not been established for the treatment of extraocular CMV infections (e.g., pneumonitis, gastroenteritis),1 the drug has been used for the management of extraocular CMV infections†.85
CDC, NIH, and IDSA state that IV ganciclovir usually is the preferred antiviral for initial management of CMV GI disease (e.g., colitis, esophagitis) in HIV-infected adults; however, IV foscarnet is a possible alternative for the management of CMV esophagitis† or colitis† in those who cannot receive ganciclovir or have infections caused by ganciclovir-resistant CMV.155
For the management of well-documented CMV pneumonitis† in HIV-infected adults, CDC, NIH, and IDSA state that either IV ganciclovir or IV foscarnet is a reasonable choice.155
A combination regimen of IV ganciclovir and IV foscarnet has been used for the management of CMV neurologic disease† (e.g., CMV encephalitis or myelitis)85 and is recommended by CDC, NIH, IDSA, and others for such infections in HIV-infected individuals.155, 156
Prevention of Cytomegalovirus Infection and Disease
Foscarnet sodium has been used for prophylaxis or preemptive treatment of CMV infection and disease in hematopoietic stem cell transplant (HSCT) recipients†.39, 74, 75, 76, 77, 78, 85 Although safety and efficacy have not been established, IV foscarnet sodium is considered a second-line or alternative antiviral for prophylaxis or preemptive treatment of CMV infection in HSCT recipients and usually is reserved for resistant and refractory CMV infections or when first-line antivirals cannot be used because of intolerance.74, 75, 76, 78 Foscarnet also has been recommended as a second-line or alternative antiviral for treatment of CMV infection in solid organ transplant recipients† when first-line antivirals cannot be used because of resistance or intolerance.82
CMV infection in transplant recipients can occur either as a primary infection in CMV-seronegative recipients of organs and cells from CMV-positive donors or as reactivation of latent CMV infection in CMV-seropositive recipients.74, 75, 76, 77, 78, 81, 82 CMV reactivation commonly occurs in CMV-seropositive transplant recipients and can result in severe CMV disease with substantial morbidity and mortality.74, 75, 76, 82 The risk for CMV infection or reactivation is greatest during the first 3 months after transplantation and depends on several factors, including the serologic status of the recipient and donor and CMV-specific T-cell immunity and immunosuppressive regimens used in the recipient.74, 76, 82 Certain antiviral strategies have been used to prevent severe, life-threatening CMV disease in HSCT or solid organ transplant patients, including antiviral prophylaxis (initiated posttransplant and continued for at least 3 months) and/or preemptive antiviral treatment (i.e., initiated when CMV infection is detected, but before clinical progression to symptomatic CMV disease).74, 75, 76, 77, 78, 81, 82 These strategies each have certain advantages and disadvantages.74, 75, 76, 78, 81, 82
Specialized references should be consulted for specific information regarding management of CMV infections in HSCT or solid organ transplant recipients.74, 75, 76, 78, 81, 82
Mucocutaneous Herpes Simplex Virus Infections
Foscarnet sodium is used for the management of mucocutaneous infections (e.g., orofacial, genital, digital) caused by acyclovir-resistant herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) in immunocompromised patients, including HIV-infected individuals with AIDS.1, 33, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 56, 57, 85, 155, 344 Safety and efficacy of foscarnet have not been established for the treatment of other HSV infections (e.g., retinitis, encephalitis), congenital or neonatal HSV disease, or HSV infections in immunocompetent individuals.1
The drugs of choice for the management of orolabial lesions or initial or recurrent genital lesions caused by HSV are valacyclovir, famciclovir, and acyclovir.155, 156, 344 For the management of mucocutaneous lesions caused by acyclovir-resistant HSV in HIV-infected adults and adolescents†, CDC, NIH, and IDSA recommend IV foscarnet as the drug of choice.155 These experts also recommend IV foscarnet as the drug of choice for the management of acyclovir-resistant HSV infections in HIV-infected children†.156
Like other antivirals, foscarnet is not a cure for mucocutaneous HSV infections.1 While complete healing is possible, relapse occurs in most patients.1 Repeated foscarnet treatment of HSV infections has led to development of resistance that was associated with poor response.1 If there is a poor therapeutic response to foscarnet therapy, in vitro susceptibility testing of the HSV isolate is advised.1
Efficacy of IV foscarnet sodium for the treatment of mucocutaneous acyclovir-resistant HSV infections was evaluated in a study in AIDS patients that included 8 patients randomized to receive IV foscarnet sodium (40 mg/kg IV 3 times daily), 6 patients randomized to receive vidarabine (15 mg/kg daily; not commercially available in the US), and 11 patients nonrandomly assigned to receive treatment with IV foscarnet sodium because of prior intolerance to vidarabine.1 HSV lesions in the 8 patients randomized to foscarnet healed after 11-25 days and HSV lesions in 7 of the 11 patients nonrandomly treated with foscarnet healed in 10-30 days.1 In a second trial, 40 patients with AIDS and 3 bone marrow transplant recipients with mucocutaneous acyclovir-resistant HSV infections were randomized to receive IV foscarnet sodium (40 mg/kg 2 or 3 times daily).1 HSV lesions in 15 of the 43 patients healed in 11-72 days with no difference in response between the 2 groups.1
Foscarnet sodium (40 mg/kg IV every 8 hours until clinical resolution is attained) often is effective in the treatment of acyclovir-resistant genital herpes.344 Limited data have shown that foscarnet may decrease duration of viral shedding and time required for crusting and healing of lesions, and the duration of positive cultures in AIDS patients with HSV infections that did not respond to oral or parenteral acyclovir therapy.40, 41, 42, 43, 46, 49, 50, 51 However, eventual recurrence of HSV has been reported in virtually all such patients following discontinuance of foscarnet therapy; median time to recurrence reportedly was 42.5 days (range: 14-191 days) following discontinuance of the drug.40, 41, 43, 46, 50, 51, 55 Such recurrences may or may not be associated with acyclovir-resistant strains of the virus.40, 41, 43, 50, 51, 55, 56 In some patients who had received foscarnet (repeated or chronic therapy) for management of acyclovir-resistant HSV infection, foscarnet-resistant strains of the virus were reported.48 Patients who developed foscarnet-resistant HSV infections subsequently received oral or parenteral acyclovir or, alternatively, concomitant therapy with acyclovir and foscarnet.41, 43, 48
Varicella-Zoster Virus Infections
Foscarnet sodium is used in the management of acyclovir-resistant varicella-zoster virus (VZV) infections† in immunocompromised patients, including those with AIDS.52, 53, 70, 85, 156
The preferred antivirals for the management of acute, localized herpes zoster (shingles) in HIV-infected adults and adolescents are acyclovir, famciclovir, and valacyclovir.155 For the management of proven or suspected acyclovir-resistant VZV infections† in HIV-infected adults or adolescents, CDC, NIH, and IDSA recommend IV foscarnet.155
In HIV-infected children, acyclovir is the drug of choice for VZV infections and foscarnet is the preferred alternative for the management of acyclovir-resistant VZV infections†.156
Although optimal regimens for the management of progressive outer retinal necrosis caused by VZV† in HIV-infected individuals have not been identified, CDC, NIH, and IDSA recommend treatment with at least one IV antiviral (acyclovir, ganciclovir, foscarnet, cidofovir) used in conjunction with at least one intravitreal antiviral (ganciclovir or foscarnet).155 Some experts recommend a regimen of IV ganciclovir and/or IV foscarnet used in conjunction with intravitreal ganciclovir and/or intravitreal foscarnet†.155 The prognosis for visual preservation in patients with progressive outer retinal necrosis caused by VZV is poor and such infections should be managed in consultation with an ophthalmologist.155
Renal function must be assessed prior to initiation of foscarnet sodium and monitored during therapy with the drug.1 (See Renal Impairment under Dosage and Administration: Special Populations.)
To reduce the risk of foscarnet-associated nephrotoxicity, patients must receive adequate hydration prior to and during foscarnet sodium therapy.1
The recommended dosage of foscarnet sodium and recommended frequency and rate of administration of the drug must not be exceeded.1
Patients must be adequately hydrated before and during administration of foscarnet sodium.1, 2, 7, 9, 21, 22, 23, 24
Patients who are clinically dehydrated should have their hydration status corrected before the drug is initiated.1
Prior to the first dose of foscarnet, patients should receive IV hydration with 750-1000 mL of 0.9% sodium chloride or 5% dextrose injection to establish diuresis.1 With each subsequent dose of foscarnet, 750-1000 mL of IV hydration fluid should be administered concurrently with each foscarnet sodium dose of 90-120 mg/kg or 500 mL of IV hydration fluid should be administered concurrently with each foscarnet sodium dose of 40-60 mg/kg.1 The volume of IV hydration fluid may be decreased if clinically appropriate.1
Oral rehydration using similar regimens may be considered in some patients.1, 37
Foscarnet sodium is administered by slow IV infusion using a controlled-infusion device (e.g., pump).1 The drug should not be administered by rapid IV infusion or direct IV injection since potentially toxic plasma foscarnet concentrations may result.1
Foscarnet has been administered by intravitreal injection†;79, 80, 86, 155, 85 however, a preparation of the drug specifically for intravitreal administration is not commercially available in the US.
IV infusions of foscarnet sodium must be administered using a controlled-infusion device (e.g., pump) and the rate of administration carefully controlled to avoid adverse effects and unintentional overdosage.1
Foscarnet sodium is commercially available as a solution for IV infusion containing 24 mg/mL.1
If a central venous line is used for IV infusion, the commercially available solution of foscarnet sodium can be administered either undiluted or diluted.1
If a peripheral vein is used for IV infusion, the commercially available solution of the drug must be diluted prior to administration with a compatible infusion solution to a concentration of 12 mg/mL.1 In addition, care should be taken to select a vein that will provide adequate blood flow for rapid dilution and distribution of the drug.1
Foscarnet sodium solution should appear clear and colorless and should not be used if it appears discolored or contains particles.1
Commercially available foscarnet sodium solution should be stored at 20-25°C.1 Precipitates may form if the solution is refrigerated or exposed to freezing temperatures, but may be brought into solution again if kept at room temperature with repeated shaking.1
IV solutions of foscarnet sodium should not be admixed or administered through the same catheter with other drugs.1 Foscarnet sodium injection is physically and/or chemically incompatible with certain infusion solutions (e.g., calcium-containing solutions such as Ringer's or lactated Ringer's) and certain drugs (e.g., ganciclovir).1, 300 Specialized references should be consulted for specific information.300
Caution should be exercised when preparing and administering solutions of foscarnet sodium.1 Accidental skin and eye contact with solutions of the drug may cause local irritation and burning sensation.1 If accidental contact occurs, the exposed area should be flushed with water.1
When a diluted solution of foscarnet sodium is indicated for IV infusion (e.g., for infusion via a peripheral vein), the commercially available solution of the drug containing 24 mg/mL must be diluted with a compatible infusion solution (i.e., 0.9% sodium chloride injection or 5% dextrose injection) to a concentration of 12 mg/mL.1
Diluted solutions of foscarnet sodium should be used within 24 hours after first entry into the sealed bottle.1
IV infusions of foscarnet sodium should be administered at a constant rate using a controlled-infusion device (e.g., pump) and usually are given over 1-2 hours depending on dosage.1
The IV infusion rate must not exceed 1 mg/kg per minute.1
Foscarnet is commercially available as the hydrated trisodium salt (i.e., foscarnet sodium);1 dosage is expressed in terms of foscarnet sodium.1
For the treatment of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection and normal renal function, the recommended dosage of IV foscarnet sodium for initial treatment (induction therapy) is 60 mg/kg (by IV infusion over at least 1 hour) every 8 hours for 14-21 days1, 2, 4, 33, 155 or 90 mg/kg (by IV infusion over 1.5-2 hours) every 12 hours for 14-21 days.1, 33, 155 In patients with immediate sight-threatening CMV retinal lesions (i.e., within 1.5 mm of the fovea), the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) recommend that initial treatment also include an appropriate intravitreal antiviral.155 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)
After completion of initial treatment, the recommended dosage of IV foscarnet sodium for maintenance therapy (secondary prophylaxis) of CMV retinitis in adults with normal renal function is 90-120 mg/kg (by IV infusion over 2 hours) once daily.1, 2, 3, 4, 33, 155 Because superiority of the 120-mg/kg daily dosage has not been established in controlled studies and because such dosage is likely to be associated with an increased risk of toxicity,1, 2, 3, 4 the manufacturer recommends that most patients initially receive a maintenance dosage of 90 mg/kg IV once daily.1 However, dosage may be increased up to 120 mg/kg daily in patients in whom early reinduction therapy is required because of progression of CMV retinitis.1 In addition, some patients exhibiting excellent tolerance to the drug may benefit from early initiation of a maintenance dosage of 120 mg/kg daily.1
Patients who experience relapse or progression of CMV retinitis while receiving foscarnet maintenance therapy may be retreated with foscarnet using the usual dosages for initial treatment (induction therapy) and maintenance therapy (secondary prophylaxis) or, alternatively, these patients may receive combination therapy with foscarnet and ganciclovir.1, 63, 155
Decisions regarding discontinuance of maintenance therapy of CMV retinitis in HIV-infected individuals who have been treated for at least 3-6 months, have inactive CMV retinal lesions, and have achieved immune reconstitution as the result of antiretroviral therapy should be made in consultation with an ophthalmologist.155 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)
Cytomegalovirus Esophagitis or Colitis
If IV foscarnet sodium is used as an alternative for the management of CMV esophagitis† or colitis† in HIV-infected adults, CDC, NIH, and IDSA recommend a dosage of 60 mg/kg every 8 hours or 90 mg/kg every 12 hours given for 21-42 days or until signs and symptoms of the infection have resolved.155 Maintenance therapy (secondary prophylaxis) usually is not necessary, but should be considered if relapse occurs.155
If IV foscarnet sodium is used as an alternative for the management of well-documented CMV pneumonitis† in HIV-infected adults, CDC, NIH, and IDSA state that the same dosage recommended for the management of CMV retinitis in HIV-infected adults should be used.155 The optimal duration of treatment in such patients has not been established.155
Cytomegalovirus Neurologic Disease
If IV foscarnet sodium is used in conjunction with IV ganciclovir for the management of CMV neurologic disease† in HIV-infected adults, CDC, NIH, and IDSA state that the same dosage recommended for the management of CMV retinitis in HIV-infected adults should be used.155 The optimal duration of treatment in such patients has not been established.155
Mucocutaneous Herpes Simplex Virus Infections
For the management of mucocutaneous herpes simplex virus (HSV) infections known or suspected to be caused by acyclovir-resistant strains in immunocompromised patients, the manufacturer and some clinicians recommend that IV foscarnet sodium be given in a dosage of 40 mg/kg (by IV infusion over at least 1 hour) every 8 or 12 hours for 2-3 weeks or until clinical resolution.1, 33, 40, 46 For the management of acyclovir-resistant genital herpes, CDC states that foscarnet sodium has been effective when given in a dosage of 40-80 mg/kg IV every 8 hours until clinical resolution.344
For the management of acyclovir-resistant mucocutaneous HSV infections in HIV-infected adults, CDC, NIH, and IDSA recommend that IV foscarnet sodium be given in a dosage of 80-120 mg/kg daily in 2 or 3 divided doses until a clinical response is obtained.155
Varicella-Zoster Virus Infections
For the management of mucocutaneous varicella-zoster virus (VZV) infections† known or suspected to be caused by acyclovir-resistant strains in immunocompromised patients, some clinicians recommend that IV foscarnet sodium be given in a dosage of 40-60 mg/kg IV every 8 hours for 10-21 days.33, 52, 53
For the management of progressive outer retinal necrosis caused by VZV† in HIV-infected adults, CDC, NIH, and IDSA state that a regimen that includes IV foscarnet sodium in a dosage of 90 mg/kg IV every 12 hours (used with or without IV ganciclovir) in conjunction with intravitreal foscarnet† (used with or without intravitreal ganciclovir) can be considered.155
If IV foscarnet sodium is used with or without IV ganciclovir for initial treatment (induction therapy) of CMV retinitis in HIV-infected children†, CDC, NIH, IDSA, and others recommend a dosage of 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 14-21 days or until symptomatic improvement.156
After completion of initial treatment, the recommended dosage of IV foscarnet sodium for maintenance therapy (secondary prophylaxis) of CMV retinitis in HIV-infected children† is 90-120 mg/kg IV once daily.156
Decisions regarding discontinuance of maintenance therapy of CMV retinitis in HIV-infected individuals who have been treated at least 3-6 months, have inactive CMV retinal lesions, and have achieved immune reconstitution as the result of antiretroviral therapy should be made in consultation with an ophthalmologist.156 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)
Disseminated Cytomegalovirus Infections
If IV foscarnet sodium is used with or without IV ganciclovir for initial treatment (induction therapy) of disseminated CMV infections in HIV-infected children†, CDC, NIH, IDSA, and others recommend a dosage of 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours until symptomatic improvement.156
After completion of initial treatment, the recommended dosage of IV foscarnet sodium for maintenance therapy (secondary prophylaxis) of disseminated CMV infection in HIV-infected children† is 90-120 mg/kg IV once daily.156
Mucocutaneous Herpes Simplex Virus Infections
If IV foscarnet sodium is used for the management of mucocutaneous acyclovir-resistant HSV infections in HIV-infected children†, CDC, NIH, IDSA, and others recommend a dosage of 40 mg/kg every 8 hours or 60 mg/kg every 12 hours (by IV infusion over 2 hours).156
Varicella-Zoster Virus Infections
If IV foscarnet sodium is used for the management of VZV infections caused by acyclovir-resistant strains in HIV-infected children†, CDC, NIH, IDSA, and others recommend a dosage of 40-60 mg/kg (by IV infusion over 2 hours) given 3 times daily for 7-10 days or until no new lesions have appeared for at least 48 hours.156
For the management of progressive outer retinal necrosis caused by VZV† in HIV-infected children, CDC, NIH, IDSA, and others state that a regimen that includes IV foscarnet given in a dosage of 90 mg/kg IV every 12 hours (used with or without IV ganciclovir) in conjunction with intravitreal foscarnet† given in a dosage of 1.2 mg/0.05 mL by intravitreal injection twice weekly (with or without intravitreal ganciclovir) can be considered.156
The manufacturer makes no specific dosage recommendations for use of foscarnet sodium in patients with hepatic impairment;1 some clinicians state that dosage of the drug does not need to be adjusted in such patients.85
In patients with impaired renal function, dosage of foscarnet sodium must be modified based on the degree of impairment.1, 4, 66 Dosage adjustment may be required in patients with initially normal renal function since most patients will experience a decrease in renal function during foscarnet therapy.1, 2, 4
Renal function (i.e., measured and estimated creatinine clearance) should be assessed prior to initiating foscarnet sodium, 2 or 3 times weekly during induction therapy, and at least once every 1 or 2 weeks during maintenance therapy with the drug and dosage should be adjusted accordingly.1, 2, 4 (See Table 1 and Table 2.)
Dosage of foscarnet sodium should be based on the patient's measured or estimated creatinine clearance.1, 4 Creatinine clearance (mL/minute per kg) should be calculated even if serum creatinine is within the normal range.1
If creatinine clearance declines to less than 0.4 mL/minute per kg during foscarnet therapy, the drug should be discontinued and the patient should be hydrated and monitored daily until resolution of renal impairment is ensured.1
To determine dosage of foscarnet sodium in patients with renal impairment, the patient's weight-adjusted 24-hour creatinine clearance (Ccr divided by body weight in kg) is used or Ccr (per kg) can be calculated using the following formulas:1
Ccr (per kg) male = [(140 - age)] / [72 × serum creatinine (in mg/dL)]
Ccr (per kg) female = 0.85 × Ccr male
Creatinine Clearance (mL/minute per kg) | Induction Dosage for CMV (in mg/kg) Equivalent to 60 mg/kg Every 8 Hours | Induction Dosage for CMV (in mg/kg) Equivalent to 90 mg/kg Every 12 Hours | Induction Dosage for HSV (in mg/kg) Equivalent to 40 mg/kg Every 12 Hours | Induction Dosage for HSV (in mg/kg) Equivalent to 40 mg/kg Every 8 Hours |
|---|---|---|---|---|
>1.4 | 60 every 8 hours | 90 every 12 hours | 40 every 12 hours | 40 every 8 hours |
>1-1.4 | 45 every 8 hours | 70 every 12 hours | 30 every 12 hours | 30 every 8 hours |
>0.8-1 | 50 every 12 hours | 50 every 12 hours | 20 every 12 hours | 35 every 12 hours |
>0.6-0.8 | 40 every 12 hours | 80 every 24 hours | 35 every 24 hours | 25 every 12 hours |
>0.5-0.6 | 60 every 24 hours | 60 every 24 hours | 25 every 24 hours | 40 every 24 hours |
≥0.4-0.5 | 50 every 24 hours | 50 every 24 hours | 20 every 24 hours | 35 every 24 hours |
<0.4 | Not recommended | Not recommended | Not recommended | Not recommended |
Creatinine Clearance (mL/minute per kg) | Maintenance Dosage for CMV (in mg/kg) Equivalent to 90 mg/kg Once Daily | Maintenance Dosage for CMV (in mg/kg) Equivalent to 120 mg/kg Once Daily |
|---|---|---|
>1.4 | 90 every 24 hours | 120 every 24 hours |
>1-1.4 | 70 every 24 hours | 90 every 24 hours |
>0.8-1 | 50 every 24 hours | 65 every 24 hours |
>0.6-0.8 | 80 every 48 hours | 105 every 48 hours |
>0.5-0.6 | 60 every 48 hours | 80 every 48 hours |
≥0.4-0.5 | 50 every 48 hours | 65 every 48 hours |
<0.4 | Not recommended | Not recommended |
Dosage recommendations are not available for use of foscarnet sodium in patients undergoing hemodialysis.1 Use of the drug is not recommended in patients undergoing hemodialysis1 or peritoneal dialysis.38
Dosage of foscarnet sodium for geriatric patients should be selected with caution because of age-related decreases in renal function.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Foscarnet sodium is contraindicated in patients with clinically important hypersensitivity to the drug.1
Foscarnet appears to be nephrotoxic.1, 2, 4, 21, 22, 23, 24, 25, 26 Renal impairment and/or failure, manifested mainly as an increase in serum creatinine concentration and/or a decrease in creatinine clearance, is the major toxicity of foscarnet and occurs to some degree in most patients receiving the drug.1, 2, 4, 21, 22, 23, 24, 25, 26 Renal impairment may be accompanied by polyuria and associated polydipsia and, less frequently, by oliguria.2, 27, 28 In at least one patient, polyuria and polydipsia were attributed to nephrogenic diabetes insipidus temporally related to foscarnet therapy.27
In initial clinical trials in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) who received foscarnet sodium for the treatment of cytomegalovirus (CMV) retinitis, 27% of patients developed abnormal renal function.1 Approximately 33% of patients who received a dosage of 60 mg/kg 3 times daily without adequate hydration developed renal impairment (serum creatinine concentration of 2 mg/dL or greater).1 In subsequent clinical trials in patients who received 1 L of 0.9% sodium chloride or 5% dextrose injection with each dose of foscarnet, only 12% developed renal impairment.1
Based on measurement of serum creatinine, renal impairment is most likely to become clinically evident during the second week of induction therapy in patients receiving foscarnet sodium in a dosage of 180 mg/kg daily; however, renal impairment may occur at any time during therapy with the drug.1, 21, 22, 25 Foscarnet-induced increases in serum creatinine concentration are usually, but not uniformly, reversible following dosage adjustment or discontinuance of the drug,1, 2, 21, 22 although maximum deterioration in renal function may not be apparent until several weeks after discontinuance of the drug.25 Foscarnet is removed by hemodialysis,85 and some clinicians have suggested that hemodialysis may be useful in the management of foscarnet-induced nephrotoxicity when elevated plasma concentrations of the drug are present and the degree of renal failure is severe.2, 25
The risk of foscarnet-induced renal impairment may be decreased by adequate hydration before and during administration of the drug.1, 2, 7, 9, 21, 22, 23, 24 It is imperative that patients receive adequate hydration to establish diuresis prior to the first dose of foscarnet and also receive a recommended hydration regimen with each subsequent dose of the drug.1 (See Hydration under Dosage and Administration: General.)
The mechanism of foscarnet-induced nephrotoxicity has not been fully determined.21, 22, 23, 24, 26, 85 While underlying disease and concomitant therapy may contribute to the development and degree of acute renal impairment in some patients, foscarnet alone appears to be nephrotoxic.2, 21, 22 Autopsy findings of extensive tubular necrosis have been reported in at least one patient,2, 21, 22 and clinical and laboratory findings in other patients,2, 21, 22 as well as evidence of a potential beneficial prophylactic effect of adequate hydration,2, 21, 22, 23, 24 have been consistent with acute tubulopathy. Biopsy or autopsy findings of tubular interstitial nephritis also have been reported,2, 26 as well as the presence of crystals within glomerular capillary lumen; while positive identification was not made, the physicochemical characteristics of the crystals were suggestive of foscarnet crystals.2, 26, 85
Because renal impairment is the principal toxicity of foscarnet and occurs to some degree in most patients receiving the drug, foscarnet must be used with caution, particularly in patients with a history of renal impairment, and it is imperative that renal function be assessed prior to initiation of foscarnet and continually during therapy with the drug and that dosage be modified as needed based on renal function.1, 2, 21, 22, 23, 24, 25, 26 In patients with impaired renal function, reduced plasma clearance of foscarnet will result in elevated plasma concentrations of the drug; in addition, foscarnet potentially may further impair renal function in these patients.1 Therefore, dosage modification based on renal function (i.e., creatinine clearance) is essential.1, 38
The manufacturer recommends that creatinine clearance (measured or estimated based on serum creatinine) be determined at baseline prior to initiating foscarnet therapy, 2 or 3 times weekly during induction therapy, and at least once every 1 or 2 weeks during maintenance therapy, and dosage should be adjusted accordingly.1 More frequent monitoring may be necessary for some patients.1 It is also recommended that a 24-hour creatinine clearance be determined at baseline and periodically thereafter to ensure appropriate dosing (assuming verification of an adequate urine collection using the creatinine index).1 If creatinine clearance declines to less than 0.4 mL/minute per kg during foscarnet therapy, the drug should be discontinued and the patient should be hydrated and monitored daily until resolution of renal impairment is ensured.1 (See Renal Impairment under Dosage and Administration: Special Populations.)
Electrolyte and Metabolic Effects
Foscarnet therapy has been associated with changes in serum electrolyte concentrations,1, 2, 4, 7, 9, 10 which potentially may contribute to the risk of cardiac disturbances and seizures.1 Hypocalcemia has occurred in 15-30%,1, 7, 10 hypophosphatemia in 8-26%,1, 7, 10 hyperphosphatemia in 6%,1, 2, 28 hypomagnesemia in 15-30%,1, 7, 10 and hypokalemia in 16-48%1, 10 of patients receiving the drug.1 Hyponatremia, hypercalcemia, decreased body weight, acidosis, cachexia, and thirst (including polydipsia) have been reported in 1-5% of patients receiving foscarnet.1, 27, 28 The higher incidences of these electrolyte changes were derived from patients receiving hydration.1 Increased serum creatine kinase (CK; creatine phosphokinase, CPK) concentration, hematuria, and hypoproteinemia have been reported in less than 1% of patients.1 Rarely, nephrogenic diabetes mellitus has been associated with foscarnet therapy.27
Foscarnet has been shown to produce a dose-related decrease in ionized serum calcium concentration that may not be reflected in total serum calcium concentration.1, 2 Decreased serum concentrations of ionized calcium may result in symptoms such as perioral tingling, numbness in the extremities, or paresthesias.1 Foscarnet-induced changes in serum concentrations of calcium or other electrolytes most likely result from the drug's ability to chelate divalent metal ions, such as calcium and magnesium, and form stable coordination compounds.1, 2
Because foscarnet has a propensity to chelate divalent metal ions and alter serum concentrations of calcium and other electrolytes (including magnesium, potassium, or phosphate), which may contribute to the risk of cardiac disturbances and seizures, patients receiving the drug must be monitored carefully and frequently for such changes and their potential sequelae.1, 2, 7, 10 The manufacturer recommends that serum calcium (particularly ionized calcium), magnesium, potassium, and phosphorous concentrations be determined on a schedule similar to that recommended for creatinine clearance.1 Foscarnet should be used with particular caution in patients with altered serum concentrations of calcium or other electrolytes at baseline and especially in those who have neurologic or cardiac abnormalities or are receiving other drugs known to influence electrolytes (especially calcium).1, 7
Patients should be advised about the symptoms of low ionized serum calcium concentration (e.g., perioral tingling, numbness in the extremities, paresthesias) and the importance of reporting such symptoms to a clinician.1 In patients who experience mild (e.g., perioral tingling) or severe (e.g., seizures) symptoms of electrolyte abnormalities, serum electrolyte concentrations should be determined as soon as possible in temporal relation to the symptoms.1 If adverse nervous system manifestations (e.g., perioral tingling) occur during IV infusion of foscarnet, the infusion should be discontinued, appropriate laboratory samples obtained for assessment of serum electrolyte concentrations, and a clinician consulted before resuming treatment; if the infusion is restarted, the rate of IV infusion should not exceed 1 mg/kg per minute.1 Clinicians should be prepared to treat manifestations resulting from electrolyte abnormalities, including severe manifestations such as tetany, seizures, or cardiac disturbances.1, 10 Careful monitoring and appropriate management of serum electrolyte (including calcium and magnesium) concentrations are particularly important in patients with conditions that may predispose to seizures.1 (See Nervous System Effects under Warning/Precautions: Warnings, in Cautions.) Since the rate of infusion of foscarnet may affect the transient decrease in ionized serum calcium concentrations, a controlled-infusion device (e.g., pump) must be used for administration of foscarnet; in addition, slowing the rate of infusion may decrease or prevent symptoms.1
Since foscarnet may decrease serum concentrations of ionized calcium, other drugs known to influence serum calcium concentrations should be administered concomitantly with caution.1 In addition, elimination of foscarnet may be impaired by drugs that inhibit renal tubular secretion, although no studies have been performed to determine whether this occurs.1, 2 Because foscarnet may cause renal impairment, concomitant administration with other potentially nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, IV pentamidine) should be avoided unless potential benefits outweigh possible risks.1, 2 (See Drug Interactions.)
Seizures related to mineral and electrolyte abnormalities have been associated with foscarnet therapy.1 Several cases of seizures were associated with death.1 Cases of status epilepticus have been reported.1 There have been at least 3 reports of seizures associated with overdosage of the drug.1 In initial clinical studies evaluating foscarnet in patients with AIDS, seizures occurred in 10% of patients;1 the rate of seizures did not increase with the duration of treatment.1
Risk factors associated with seizures during foscarnet therapy have included impaired baseline renal function, low total serum calcium concentration, and underlying CNS conditions.1 Close monitoring of plasma electrolytes and minerals and appropriate electrolyte and/or mineral supplementation is particularly important in patients predisposed to seizures.1 (See Electrolyte and Metabolic Effects under Warnings/Precautions: Warnings, in Cautions.)
Foscarnet therapy has been associated with prolongation of the QT interval, which may increase the risk of torsades de pointes.1 There have been postmarketing reports of torsades de pointes in patients receiving foscarnet.1 Some of these patients had confounding risk factors (e.g., underlying cardiac disease, electrolyte abnormalities, concomitant drug therapy).1 Foscarnet-associated transient changes in serum concentrations of calcium or other electrolytes may contribute to the risk of cardiac disturbances.1 (See Electrolyte and Metabolic Effects under Warnings/Precautions: Warnings, in Cautions.)
Foscarnet should be used with caution in patients with a history of QT-interval prolongation and in those receiving other drugs known to prolong the QT interval, those with electrolyte abnormalities, and those with other risk factors for QT-interval prolongation.1 Electrocardiograms (ECGs) and electrolyte concentrations should be assessed prior to and periodically during foscarnet therapy.1
If any cardiovascular adverse effects occur, the foscarnet IV infusion should be stopped, electrolyte concentrations determined, and a clinician consulted before treatment with the drug is resumed.1
Selection and Use of Antivirals
Foscarnet is labeled by the FDA only for the treatment of CMV retinitis in HIV-infected patients and the treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised patients.1
Safety and efficacy of foscarnet have not been established for the treatment of extraocular CMV infections (e.g., pneumonitis, gastroenteritis), congenital or neonatal CMV disease, or CMV disease in individuals not infected with HIV.1
Safety and efficacy of foscarnet have not been established for the treatment of systemic HSV infections (e.g., retinitis, encephalitis), congenital or neonatal HSV disease, or HSV infections in immunocompetent individuals.1
When used for the management of mucocutaneous HSV infections, repeated treatment with foscarnet has led to the development of resistance associated with poor response.1 If there is a poor therapeutic response to foscarnet therapy, in vitro susceptibility testing of the HSV isolate is advised.1
Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported in patients receiving foscarnet.1
If an acute hypersensitivity reaction occurs, foscarnet therapy should be discontinued and appropriate medical therapy should be immediately initiated.1
Other Warnings and Precautions
To avoid local irritation, the commercially available preparation of foscarnet sodium containing 24 mg/mL must be diluted before IV administration via a peripheral vein.1 In addition, particular care must be taken to select a vein with adequate blood flow to permit rapid dilution and distribution of the drug.1 (See Dosage and Administration: Administration.)
Because of the potential for nephrotoxicity, patients must receive adequate hydration prior to the initial dose of foscarnet and also receive a recommended hydration regimen with each subsequent dose of the drug.1 (See Hydration under Dosage and Administration: General.)
To avoid unintentional overdosage, foscarnet must be administered by slow IV infusion using a controlled-infusion device (e.g., pump) to carefully control the infusion rate.1 (See Rate of Administration under Administration: IV Infusion, in Dosage and Administration.)
Local irritation and ulceration of the penile epithelium (resembling fixed drug eruption grossly but not histologically)11, 13, 16, 26 have been reported in male patients1, 2, 4, 11, 12, 13, 14, 15, 16 and vulvovaginal ulceration has been reported in at least one female patient1, 17 receiving foscarnet. The genital lesions are often painful,11, 13 erythematous,11, 15 and erosive13, 15 and may require discontinuance of the drug.12, 13 The lesions usually resolve spontaneously within several weeks after discontinuing foscarnet,11, 12, 13, 14, 17 but may recur when the drug is reinstituted.11, 12, 13, 14, 17 Occasionally, the lesions may resolve despite continued foscarnet therapy.11
The local irritation and ulceration effects may be related to exposure to high concentrations of unchanged foscarnet in the urine;1, 2, 14, 15 it also has been suggested that precipitation of the drug in arterioles and capillaries may contribute to ulceration.26 Adequate hydration and close attention to personal hygiene may minimize the risk of genital irritation and lesions associated with foscarnet therapy.2, 15
Anemia, manifested as decreased hemoglobin concentration and hematocrit, is the most common adverse hematologic effect of foscarnet1, 2, 4, 8, 9, 18, 20 and has been reported in 33% of AIDS patients in controlled clinical trials receiving the drug for the treatment of CMV retinitis.1 The risk of anemia may be increased in patients receiving foscarnet and ganciclovir concomitantly for progressive retinitis.20
Granulocytopenia was reported in 17% of AIDS patients with CMV retinitis receiving foscarnet in controlled clinical trials, but resulted in discontinuance of the drug in only 1% of patients.1 Leukopenia was reported in 5% or more of AIDS patients with CMV retinitis receiving foscarnet, while thrombocytopenia, platelet abnormalities, thrombosis, leukocyte abnormalities, and lymphadenopathy were reported in 1-5% and pancytopenia was reported in less than 1% of patients.1 Foscarnet generally is not myelosuppressive.2, 4, 8, 18, 19, 20, 38 Only 1% of patients did not complete clinical studies because of neutropenia.1
Commercially available foscarnet sodium solution containing 24 mg of the drug per mL contains 5.5 mg (0.24 mEq) of sodium per mL.1
Foscarnet should be avoided in patients who may not tolerate large amounts of sodium or water (e.g., patients with cardiomyopathy) and in patients on a sodium-controlled diet.1
Carcinogenic and Mutagenic Potential
Foscarnet caused genotoxic effects in the BALB/3T3 in vitro transformation assay at concentrations exceeding 0.5 mcg/mL and an increased frequency of chromosomal aberrations in the sister chromatid exchange assay at a concentration of 1 mg/mL.1 A high dose of foscarnet (350 mg/kg) produced an increase in micronucleated polychromatic erythrocytes in vivo in mice at doses that produced exposures (as measured by the area under the plasma concentration-time curve [AUC]) comparable to that anticipated clinically.1
There was no evidence of oncogenicity in studies in rats and mice receiving oral foscarnet dosages of 500 and 250 mg/kg daily, respectively, which resulted in plasma foscarnet concentrations equal to 33 and 20%, respectively, of those in humans (at the maximum recommended human daily dose) as measured by the AUC.1
Foscarnet did not adversely affect fertility and general reproductive performance in rats.1 The results of perinatal and postnatal studies in rats were also negative; however, these studies used exposures that were inadequate to define the potential for impairment of fertility at human foscarnet exposure levels.1
There are no adequate and well-controlled studies to date using foscarnet sodium in pregnant women.1 The drug should be used during pregnancy only when clearly needed.1
Reproduction studies in female rats given subcutaneous foscarnet sodium in doses up to 75 mg/kg daily prior to and during mating, during gestation, and through 21 days postpartum caused a slight increase (less than 5%) in the number of skeletal anomalies compared with the control group.1 Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation also caused an increased frequency of skeletal anomalies and variations.1 On the basis of estimated drug exposure (as measured by AUC), the 150- and 75-mg/kg doses were approximately one-eighth (rats) and one-third (rabbits) the estimated maximal daily human exposure.1 These data were inadequate to define the potential teratogenicity of foscarnet at dosages used in humans.1
It is not known whether foscarnet is distributed into human milk.1 In lactating rats that received a dose of 75 mg/kg, the drug was distributed in maternal milk at concentrations 3 times higher than peak maternal blood concentrations.1
Since there is potential for serious adverse reactions to foscarnet in nursing infants, a decision should be made to discontinue nursing or the drug, taking into consideration the importance of the drug to the woman.1
Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.1
Safety and efficacy of foscarnet sodium have not been established in pediatric patients younger than 18 years of age.1, 5
The manufacturer states that the drug should be used in children† only after careful evaluation and only when potential benefits of the drug outweigh possible risks.1
Some experts recommend foscarnet as the preferred alternative for the management of CMV retinitis, acyclovir-resistant mucocutaneous HSV infections, and acyclovir-resistant varicella-zoster virus (VZV) infections in HIV-infected children†.156
In animals, foscarnet is deposited in teeth and bone and such deposition is greater in those that are young and growing.1 Foscarnet adversely affects tooth enamel development in mice and rats;1 the effects of drug deposition on skeletal development have not been studied.1 There is evidence that foscarnet accumulates in bone in humans, but the extent to which this occurs has not been studied.1 Since foscarnet is deposited in human bone, it is likely that it does so to a greater degree in developing bone in children.1
Safety and efficacy of foscarnet have not been specifically studied in geriatric patients 65 years of age or older.1
Adverse effects reported in patients 65 years of age or older have been similar to those reported in younger adults.
Because geriatric patients frequently have decreased renal function and because foscarnet is substantially excreted by the kidneys, particular attention should be paid to evaluating renal function prior to and during foscarnet therapy in this age group.1 If evidence of renal impairment exists or develops, appropriate dosage adjustments should be made.1 (See Renal Impairment under Dosage and Administration: Special Populations.)
Foscarnet sodium should be used with particular caution in patients with impaired renal function since reduced clearance of the drug will result in increased plasma concentrations and increase the risk of toxicity.1 In addition, foscarnet has the potential to further impair renal function in patients with preexisting renal impairment.1 (See Renal Effects under Warnings/Precautions: Warnings, in Cautions.)
Due to the risk of nephrotoxicity, renal function should be assessed at baseline and monitored carefully during foscarnet therapy.1 Dosage of the drug must be individualized and adjusted as needed based on renal function.1 (See Renal Impairment under Dosage and Administration: Special Populations.)
If creatinine clearance declines to less than 0.4 mL/minute per kg during foscarnet therapy, the drug should be discontinued and the patient should be hydrated and monitored daily until resolution of renal impairment is ensured.1
Only limited safety and efficacy data are available regarding use of foscarnet in patients with baseline serum creatinine concentrations greater than 2.8 mg/dL or measured 24-hour creatinine clearances less than 50 mL/minute.1
Foscarnet is not recommended in patients undergoing hemodialysis1, 38 or peritoneal dialysis.38 Foscarnet is removed by hemodialysis.85
Adverse effects reported in 10% or more of patients receiving foscarnet include fever, nausea, anemia, diarrhea, abnormal renal function, vomiting, headache, seizures, and marrow suppression.1
Because foscarnet sodium can decrease serum concentrations of ionized calcium, possibly because the drug chelates divalent metal ions such as calcium, extreme caution and close monitoring of serum electrolytes is advised if foscarnet is used concomitantly with other drugs known to influence serum calcium concentrations (e.g., IV pentamidine).1
Drugs That Prolong QT Interval
Because foscarnet sodium may increase the risk of QT-interval prolongation and the potential for torsades de pointes, concomitant use of foscarnet with drugs known to prolong the QT interval (e.g., class IA antiarrhythmics [procainamide, quinidine], class III antiarrhythmics [amiodarone, dofetilide, sotalol], other antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, certain fluoroquinolones) should be avoided.1 (See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.)
Concomitant use of foscarnet sodium with potentially nephrotoxic drugs (e.g., acyclovir, aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus) may increase the risk of nephrotoxicity85 and should be avoided unless potential benefits outweigh potential risks.1 If foscarnet is used with another drug known to be nephrotoxic, renal function must be monitored closely.85
There are no clinically important pharmacokinetic interactions between foscarnet and didanosine85 or zidovudine.1, 85
Abnormal renal function has been observed when foscarnet was used concomitantly with ritonavir (with or without saquinavir).1
Because acyclovir and foscarnet have both been associated with renal impairment, concomitant use of the drugs should be avoided unless potential benefits outweigh potential risks.1
There was no in vitro evidence of antagonistic antiviral effects between acyclovir and foscarnet.1
The manufacturer of cidofovir states that concomitant use of cidofovir and foscarnet is contraindicated and foscarnet must be discontinued at least 7 days prior to initiating cidofovir therapy.84
Concomitant use of ganciclovir and foscarnet does not affect the pharmacokinetics of either drug.1, 85 However, ganciclovir and foscarnet are physically incompatible and must not be admixed.1, 85 (See IV Infusion under Dosage and Administration: Administration.)
There was no in vitro evidence of antagonistic antiviral effects between ganciclovir and foscarnet.1 Although the clinical importance is unclear, some in vitro studies indicate that the combination of ganciclovir and foscarnet results in synergistic or additive antiviral effects against cytomegalovirus (CMV).85
In vitro, there was no evidence of antagonistic anti-CMV effects between letermovir and foscarnet.83
Concomitant use of foscarnet and loop diuretics may impair elimination of foscarnet due to inhibition of renal tubular excretion, which may lead to toxicity.1 If concomitant use of foscarnet and a diuretic is required, the manufacturer of foscarnet states that thiazide diuretics are preferred over loop diuretics.1
Concomitant use of IV pentamidine and foscarnet may cause hypocalcemia;1 severe hypocalcemia resulting in death occurred in at least one patient receiving the drugs concomitantly.1 Renal impairment also has been observed when IV pentamidine and foscarnet were used concomitantly.1 Toxicity associated with concomitant use of foscarnet and pentamidine administered by oral inhalation via nebulization (aerosolized pentamidine) has not been reported.1
Concomitant use of IV pentamidine and foscarnet should be avoided unless potential benefits outweigh potential risks.1 If the drugs are used concomitantly, extreme caution is advised1 and renal function should be monitored closely (e.g., daily assessment of renal function).85
There are no clinically important pharmacokinetic interactions between probenecid and foscarnet.1
Foscarnet (phosphonoformic acid), an organic analog of inorganic pyrophosphate, is an antiviral agent.1, 2, 3, 4, 85 The drug is commercially available as the trisodium salt.1 Foscarnet is structurally unrelated to other currently available antiviral agents.5 Unlike nucleoside and nucleotide antivirals (e.g., acyclovir, cidofovir, ganciclovir, valganciclovir),85 foscarnet does not require intracellular enzyme conversion to an active metabolite.1, 85
Foscarnet acts as a viral DNA polymerase inhibitor.85 The mechanism of action of foscarnet against herpesviruses involves selective inhibition of the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases.1, 85
The pharmacokinetics of foscarnet sodium have been evaluated in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) receiving intermittent IV infusions of the drug for the management of cytomegalovirus (CMV) retinitis.1, 85 Considerable interindividual variation in plasma concentrations of the drug has been reported.85 Following a single 90-mg/kg dose of IV foscarnet sodium in one study, plasma concentrations of the drug ranged from 297-1775 mcg/mL.85 Foscarnet is distributed into CSF;1, 85 the CSF-to-plasma ratio has been reported to be 0.2-0.7.1, 85 Postmortem data indicate that foscarnet accumulates in human bones, but the extent to which this occurs has not been determined.1 In vitro studies indicate that foscarnet is 14-17% bound to plasma proteins.1 Foscarnet is not substantially metabolized and is principally excreted unchanged in urine by glomerular filtration.85 Following a single IV infusion of 60 mg/kg of foscarnet sodium, the plasma half-life of the drug was 1.9 hours in adults with normal renal function (creatinine clearance greater than 80 mL/minute) and approximately 3, 13, and 25 hours in those with creatinine clearances of 50-80, 25-49, and 10-24 mL/minute, respectively.1 However, the terminal half-life of foscarnet determined by urinary excretion has been reported to be 87.5 hours,1 most likely because of slow release of the drug from bone.1, 85
Foscarnet is active in vitro against human herpesviruses, including CMV,1, 85 herpes simplex virus types 1 and 2 (HSV-1 and HSV-2),1, 85 and varicella-zoster virus (VZV).85 Although the clinical importance is unclear, foscarnet has some in vitro activity against Epstein-Barr virus (EBV)85 and human herpes viruses types 6 and 8 (HHV-6 and HHV-8).85 Foscarnet also has some in vitro activity against human hepatitis B virus (HBV)85 and human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2),85 but is not used for the treatment of infections caused by these viruses.85
CMV and HSV isolates with reduced susceptibility to foscarnet have been selected in vitro in cell culture.1 In CMV strains, foscarnet resistance-associated substitutions are located in the viral DNA polymerase pUL54;1 in HSV strains, foscarnet resistance-associated substitutions are located in the viral DNA polymerase pUL30.1 Limited data are available on clinical resistance to foscarnet and several pathways to resistance likely exist.1
Certain foscarnet resistance-associated substitutions also result in reduced susceptibility to some other antivirals (e.g., acyclovir, cidofovir, ganciclovir).1 In CMV strains, foscarnet resistance-associated substitutions associated with cross-resistance to ganciclovir and/or cidofovir have been identified.1 In HSV-1 and HSV-2 strains, foscarnet resistance-associated substitutions with cross-resistance to acyclovir have been identified;1 strains marginally cross-resistant to cidofovir also have been identified.1
Advise patients that foscarnet is not a cure for cytomegalovirus (CMV) retinitis; progression and/or recurrence can occur, particularly during periods of continued immunosuppression.1 Regular ophthalmologic examinations are necessary.1
Advise patients that foscarnet is not a cure for herpes simplex virus (HSV) infections.1 Although complete healing of HSV lesions is possible, relapse occurs in most patients.1 Repeated treatment with foscarnet may lead to development of resistance and poor response;1 in vitro susceptibility testing may be necessary if there is a poor therapeutic response or if relapse occurs.1
Inform patients about the major toxicities of foscarnet (e.g., renal impairment, electrolyte disturbances, seizures) and that dosage modifications and possibly discontinuance of the drug may be necessary.1 The importance of close monitoring during foscarnet therapy must be emphasized.1
Advise patients of the importance of adequate hydration to establish and maintain diuresis and minimize the risk of renal impairment during foscarnet therapy.1
Advise patients of the importance of promptly informing clinicians if symptoms of electrolyte imbalance (e.g., perioral tingling, numbness in the extremities, paresthesias) or any cardiac symptoms occur during or after IV infusion of foscarnet.1 If such symptoms occur, the IV infusion should be stopped, electrolyte concentrations determined, and a clinician consulted before treatment with the drug is resumed.1
Advise patients that dizziness and convulsions may occur during foscarnet therapy.1 Patients who experience seizures, dizziness, somnolence, or other adverse reactions that could result in cognitive impairment should avoid driving or operating machinery.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of advising patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Hospira. Foscavir® (foscarnet sodium) injection prescribing information. Lake Forest, IL; 2017 Nov.
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3. Polis MA. Foscarnet and ganciclovir in the treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr . 1992; 5(Suppl 1):S3-10. [PubMed 1318365]
4. Minor JR, Baltz JK. Foscarnet sodium. DICP . 1991; 25:41-7. [PubMed 1848959]
5. Hwang SB (Astra Pharmaceutical, Westborough, MA): Personal communication; 1992 May 5.
7. Palestine AG, Polis MA, De Smet MD et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med . 1991; 115:665-73. [PubMed 1656826]
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13. Feguex S, Salmon D, Picard C et al. Penile ulcerations with foscarnet. Lancet . 1990; 335:547.
14. Moyle G, Nelson M, Barton SE et al. Penile ulcerations with foscarnet. Lancet . 1990; 335:547-8.
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