Class: Antivirals, Miscellaneous
VA Class: AM800
Chemical Name: Dihydroxyphosphinecarboxylic acid oxide trisodium salt
Molecular Formula: CNa3O5P
CAS Number: 63585-09-1
Brands: Foscavir
The major toxicity is renal impairment.1 It is imperative that adequate hydration be maintained, serum creatinine be monitored frequently, and dosage adjusted for changes in renal function.1 (See Hydration under Dosage and Administration.)
Seizures related to alterations in plasma minerals and electrolytes may occur.1 Carefully monitor for such changes and their potential sequelae.1 Mineral and electrolyte supplementation may be required.1
The only FDA-approved indications are treatment of cytomegalovirus (CMV) retinitis in HIV-infected patients or treatment of mucocutaneous acyclovir-resistant HSV infections in immunocompromised patients.1
Introduction
Antiviral; organic analog of inorganic pyrophosphate.1 2 3 4
Uses for Foscarnet Sodium
Cytomegalovirus (CMV) Infection
Treatment of CMV retinitis in HIV-infected patients.1 2 3 4 33 Foscarnet is not curative; stabilization or improvement of ocular manifestations may occur, but progression of retinitis is possible during or following treatment.1 2 3 4
Drugs of choice for initial induction and maintenance therapy of CMV retinitis are IV ganciclovir, IV foscarnet, IV cidofovir, oral valganciclovir, or intravitreal fomivirsen.33 62 A regimen of both ganciclovir and foscarnet is used for treatment of CMV retinitis in patients who have relapsed following monotherapy with either drug.1 63 64
Long-term suppressive or maintenance therapy (secondary prophylaxis) of recurrent CMV disease† in HIV-infected adults, adolescents, or children†.38 USPHS/IDSA recommends IV ganciclovir or IV foscarnet as drugs of choice for such prophylaxis.38
Prophylaxis or preemptive treatment of CMV disease in adult and pediatric allogeneic or autologous hematopoietic stem cell transplant (HSCT) recipients†.39 CDC, IDSA, and ASBMT recommend IV foscarnet as an alternative to IV ganciclovir in HSCT recipients, especially when ganciclovir cannot be tolerated or when ganciclovir-resistant CMV may be involved.39
Safety and efficacy not established for treatment of extraocular CMV infections or for CMV infections in immunocompetent individuals.1
Mucocutaneous Herpes Simplex Virus (HSV) Infections
Treatment of acyclovir-resistant mucocutaneous HSV (HSV-1 and HSV-2) infections (e.g., orofacial, genital, digital) in immunocompromised patients (e.g., those with AIDS).1 33 40 41 42 43 44 45 46 48 49 50 51 56 57 73
Safety and efficacy not established for treatment of other HSV infections, such as retinitis, encephalitis, and congenital neonatal HSV disease, or for HSV infections in immunocompetent individuals.1
Chronic suppressive or maintenance therapy (secondary prophylaxis) against recurrence of HSV infections† in HIV-infected individuals who have frequent or severe recurrences.59
Drugs of choice for secondary prophylaxis are oral acyclovir or oral famciclovir in adults and adolescents and oral acyclovir in infants and children; IV foscarnet and IV cidofovir are alternatives for such prophylaxis if acyclovir-resistant HSV is suspected.59
Varicella-Zoster Infections
Management of acyclovir-resistant varicella-zoster infections† in patients with AIDS.50 52 53 70
Foscarnet Sodium Dosage and Administration
General
Hydration
To minimize risk of nephrotoxicity, patients should be adequately hydrated before and during administration of foscarnet.1 2 6 7 9 21 22 23 24
The manufacturer recommends that diuresis be established before the first dose of foscarnet by administering 750–1000 mL of 0.9% sodium chloride or 5% dextrose solution.1
With subsequent foscarnet doses, 750–1000 mL of fluid should be administered concurrently with each foscarnet dose of 90–120 mg/kg, and 500 mL of fluid should be administered concurrently with each foscarnet dose of 40–60 mg/kg.1
The volume of fluid may be decreased if clinically appropriate.1
Adequate hydration also may be possible orally in some patients.37
Administration
Administer by slow IV infusion via a controlled infusion device (e.g., pump).1 Do not administer by rapid IV infusion or direct IV injection since potentially toxic plasma foscarnet concentrations may result.1
If manifestations of hypocalcemia or adverse nervous system effects (e.g., perioral tingling) develop during administration of the drug, the infusion should be stopped, at least temporarily.1 (See Mineral and Electrolyte Imbalance under Cautions.)
IV Infusion
Can infuse foscarnet solutions via either a peripheral or central vein, but take care in selecting a vein that will provide adequate blood flow for rapid dilution and distribution of the drug.1
Do not admix foscarnet IV solutions or administer through the same catheter as other drugs.1
Dilution
For infusion via a peripheral vein, foscarnet injection containing 24 mg/mL must be diluted with a compatible infusion solution (i.e., 0.9% sodium chloride injection, 5% dextrose injection) to a final concentration of 12 mg/mL to minimize the risk of local irritation.1 4
Foscarnet injection containing 24 mg/mL does not need to be diluted if it is infused via a central vein.1 4
Rate of Administration
IV infusions usually are given over 1–2 hours depending on dosage.1
Dosage
Available as the hydrated trisodium salt (i.e., foscarnet sodium); dosage is expressed in terms of foscarnet sodium.1
Dosage must be carefully individualized according to body weight and renal function.1 Do not exceed recommended doses, frequency of administration, and rates of IV infusion.1
Pediatric Patients
Cytomegalovirus (CMV) Infections
Prevention of Recurrence (Secondary Prophylaxis) of CMV Disease in HIV-infected Children and Adolescents†
IV
90–120 mg/kg once daily.59 Initiate secondary prophylaxis after initial induction treatment.59
HIV-infected children with a history of CMV disease should receive life-long suppressive therapy to prevent recurrence.59 The safety of discontinuing secondary CMV prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.59
Consideration can be given to discontinuing secondary prophylaxis in HIV-infected adolescents according to recommendations in adults.59
Adults
Cytomegalovirus (CMV) Infections
Treatment of CMV Retinitis
IV
Initial induction therapy: 60 mg/kg (infused over ≥1 hour) every 8 hours for 14–21 days1 2 4 33 or 90 mg/kg (infused over 1.5–2 hours) every 12 hours for 14–21 days.1 33
Maintenance treatment: 90–120 mg/kg (infused over 2 hours) once daily.1 2 3 4 33 Most patients should receive an initial IV maintenance dosage of 90 mg/kg daily since the higher dosage may be associated with increased toxicity;1 2 3 4 dosage may be increased up to 120 mg/kg daily in patients in whom early reinduction is required because of further progression of CMV retinitis.1
Some patients exhibiting excellent tolerance to the drug may benefit from early initiation of a maintenance dosage of 120 mg/kg daily.1
Prevention of Recurrence (Secondary Prophylaxis) of CMV Disease in HIV-infected Adults
IV
90–120 mg/kg once daily recommended by USPHS/IDSA.59 Initiate secondary prophylaxis after initial induction treatment.59
Consideration can be given to discontinuing secondary prophylaxis in adults with sustained (e.g., for ≥6 months) increase in CD4+ T-cell counts to >100–150/mm3 in response to potent antiretroviral therapy.59 This decision should be made in consultation with an ophthalmologist and factors such as the magnitude and duration of CD4+ T-cell increase, anatomic location of the retinal lesion, vision in the contralateral eye, and feasibility of regular ophthalmic monitoring should be considered.59
Relapse of CMV retinitis could occur following discontinuance of secondary prophylaxis, especially in those whose CD4+ T-cell count decreases to <50/mm3; relapse has been reported rarely in those with CD4+ T-cell counts >100/mm3.59
Reinitiate secondary CMV prophylaxis if CD4+ T-cell count decreases to <100–150/mm3.59
Mucocutaneous Herpes Simplex Virus (HSV) Infections
Treatment of Acyclovir-resistant Mucocutaneous HSV Infections
IV
40 mg/kg (infused IV over ≥1 hour) every 8 or 12 hours for 2–3 weeks or until clinical resolution is attained.1 33 40 46 73
Varicella-Zoster Infections†
Management of Acyclovir-resistant Varicella-Zoster Infections†
IV
40 mg/kg every 8 hours for 10–21 days33 52 53 or until complete healing occurs.55 Higher dosage (e.g., 60 mg/kg every 8 hours, 100 mg/kg every 12 hours) also has been used.55 70
Special Populations
Renal Impairment
Dosage must be modified according to the degree of renal impairment1 4 66 and is based on the patient’s measured or estimated Clcr.1 4
Consider that dosage adjustment may be required in patients with initially normal renal function since most patients experience a decrease in renal function during foscarnet therapy.1 2 4
Monitor renal function (i.e., measured and estimated Clcr) prior to initiating therapy, 2 or 3 times weekly during induction therapy, and at least once every 1 or 2 weeks during maintenance therapy.1 2 4 Clcr should be calculated even if serum creatinine is within the normal range, and dosage adjusted accordingly.1
If Clcr declines to <0.4 mL/minute per kg during therapy, foscarnet should be discontinued and the patient should be hydrated and monitored daily until resolution of renal impairment is ensured.1
Clcr (mL/min 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 |
Clcr (mL/min per kg) | Maintenance Dosage (mg/kg) Equivalent to 90 mg/kg Once Daily | Maintenance Dosage (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 |
Geriatric Patients
Select dosage with caution because of age-related decreases in renal function.1 (See Renal Impairment under Dosage and Administration.)
Cautions for Foscarnet Sodium
Contraindications
Hypersensitivity to foscarnet.1
Warnings/Precautions
Warnings
Nephrotoxicity
Renal impairment and/or failure, manifested mainly as an increase in serum creatinine concentration and/or a decrease in Clcr, is the major toxicity of foscarnet, occurring to some degree in most patients.1 2 4 6 21 22 23 24 25 26
Based on measurement of serum creatinine, renal impairment is most likely to become clinically evident during the second week of induction therapy at a dosage of 180 mg/kg daily; however, renal impairment may occur at any time during therapy.1 21 22 25
Foscarnet-induced increases in serum creatinine concentrations usually (but not always) are reversible following dosage adjustment or discontinuance of the drug;1 2 21 22 maximum deterioration in renal function may not be apparent until several weeks after discontinuance.1 25 Fatalities have been reported.1
Hemodialysis may be useful in management of foscarnet-induced nephrotoxicity when elevated plasma concentrations are present and the degree of renal failure is severe.1 2 25
Adequate hydration (e.g., inducing diuresis) is imperative before and during foscarnet therapy since it decreases the risk of foscarnet-induced renal impairment.1 2 6 7 9 21 22 23 24 (See Hydration under Dosage and Administration.)
Mineral and Electrolyte Imbalance
Alterations in serum electrolytes reported, including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia.1 2 4 6 7 9 10
Dose-related decreases in ionized serum calcium may occur, which may not be reflected in total serum calcium.1
Decreased serum concentrations of ionized calcium may result in symptoms such as perioral tingling, numbness in the extremities, or paresthesias.1 Clinicians should be prepared to treat these or more severe manifestations such as tetany, seizures, or cardiac disturbances.1
Foscarnet-induced changes in serum concentrations of calcium or other electrolytes most likely result from the drug’s ability to chelate and form stable coordination compounds with divalent metal ions such as calcium and magnesium.1 2 6
The decrease in ionized calcium may be affected by the foscarnet IV infusion rate.1 An infusion pump must be used to prevent rapid IV infusion; slowing the infusion rate may decrease or prevent symptoms.1
Particular caution and careful management of serum electrolytes is advised in patients who have altered baseline calcium or other electrolyte levels prior to initiation of foscarnet, especially those with neurologic or cardiac abnormalities and those receiving other drugs known to influence minerals and electrolytes (especially calcium).1 7
Seizures
Seizures related to mineral and electrolyte abnormalities (see Mineral and Electrolyte Imbalance under Cautions) have occurred; some seizures resulted in death.1
Factors that may increase risk of seizures include renal impairment at baseline, low total serum calcium concentrations, and underlying CNS conditions.1
General Precautions
Local Reactions
To avoid local irritation, care must be taken to infuse only into veins with adequate blood flow to permit rapid dilution and distribution of the drug.1
Genitourinary Effects
Local irritation and ulcerations of penile epithelium (resembling fixed drug eruption grossly but not histologically) reported in male patients1 2 4 6 11 12 13 14 15 16 and vulvovaginal ulcerations reported in at least 1 female.1 17
These effects possibly are related to high concentrations of unchanged drug in urine.1 14 15 Use of adequate hydration with close attention to personal hygiene may minimize risk of these adverse effects.1 15
Hematologic Effects
Although foscarnet usually is not myelosuppressive,2 4 6 8 18 19 20 38 anemia and granulocytopenia may occur.1
Specific Populations
Pregnancy
Category C.1
Lactation
Distributed into milk in rats; not known whether distributed into human milk.1
Pediatric Use
Safety and efficacy not established in children <18 years of age.1 5
Animal studies indicate foscarnet is deposited in teeth and bone in animals (particularly during early growth and development) and adversely affects tooth enamel development.1 Also deposited to an unknown extent in bone in humans.1
Use in children should be undertaken only after careful evaluation and only when potential benefits outweigh possible risks.1
Geriatric Use
Adverse effects reported in adults ≥65 years of age are similar to those reported in younger adults.1
Substantially eliminated by kidneys; risk of toxicity may be greater in patients with impaired renal function.1 Select dosage with caution and assess renal function periodically since geriatric patients are more likely to have renal impairment.1
Renal Impairment
Because renal impairment is the principal toxicity of foscarnet and occurs to some degree in most patients, foscarnet must be used with particular caution in those with a history of renal impairment.1 2 21 22 23 24 25 26
In patients with renal impairment, reduced plasma clearance of foscarnet will result in increased plasma concentrations; in addition, the drug potentially may further impair renal function in these patients.1
Renal function must be assessed prior to and frequently during therapy; adjust dosage for decreased baseline renal function and for changes in renal function that may occur during treatment.1 2 21 22 23 24 25 26 38 (See Renal Impairment under Dosage and Administration.)
In patients with renal impairment, dosage is adjusted based on Clcr (measured or calculated).1 In addition, a 24-hour Clcr should be determined at baseline and periodically thereafter to ensure appropriate dosing (assuming verification of an adequate urine collection using the creatinine index).1
If Clcr declines to <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
Data are limited regarding safety and efficacy in patients with baseline measured Clcr <50 mL/minute or baseline serum creatinine concentrations >2.8 mg/dL1 or in patients undergoing hemodialysis or peritoneal dialysis. Use in such patients is not recommended.38
Common Adverse Effects
Nephrotoxicity; alterations in serum electrolytes; CNS effects (headache, seizures); GI effects (nausea, diarrhea, vomiting); fever.1 2 4 6 7 8 9 21 22 23 24 25 26
Interactions for Foscarnet Sodium
Specific Drugs
Drug | Interaction | Comments |
---|---|---|
Aminoglycosides | Possible increased nephrotoxicity1 | Avoid concomitant use unless potential benefits outweigh risks1 |
Amphotericin B | Possible increased nephrotoxicity1 | Avoid concomitant use unless potential benefits outweigh risks1 |
Drugs affecting calcium | Possible additive effects on serum calcium concentrations; foscarnet decreases calcium1 | Use concomitantly with particular caution1 |
Ganciclovir | No apparent effect on ganciclovir or foscarnet pharmacokinetics with concomitant or alternating therapy with the drugs.1 In vitro evidence of synergistic antiviral activity.1 | |
Pentamidine | Possible hypocalcemia when used with IV pentamidine;1 not reported to date with aerosolized pentamidine1 | Avoid concomitant use unless potential benefits outweigh risks1 |
Ritonavir | Possible abnormal renal function when used with ritonavir (with or without saquinavir)1 |
Foscarnet Sodium Pharmacokinetics
Distribution
Extent
Distrubuted into bone; extent of accumulation unknown.1
Distributed into CSF.1
Plasma Protein Binding
14–17%.1
Elimination
Half-life
Adults with normal renal function: 1.93 hours.1
Special Populations
Clearance is decreased and half-life prolonged in patients with renal impairment.1 Half-life is 3.35 hours in those with Clcr 50–80 mL/minute, 13 hours in those with Clcr 25–49 mL/minute, and 25.3 hours in those with Clcr 10–24 mL/minute.1
Stability
Storage
Parenteral
Injection, for IV Infusion
15–30°C.1 Protect from excessive heat (>40°C); protect from freezing.1 Solution should be used within 24 hours after first entry into a sealed bottle.1
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution CompatibilityHID
Compatible |
---|
Dextrose 5% in water |
Sodium chloride 0.9% |
Drug Compatibility
Compatible |
---|
Potassium chloride |
Compatible |
---|
Aldesleukin |
Amikacin sulfate |
Aminophylline |
Ampicillin sodium |
Aztreonam |
Cefazolin sodium |
Cefoperazone sodium |
Cefoxitin sodium |
Ceftazidime |
Ceftizoxime sodium |
Ceftriaxone sodium |
Cefuroxime sodium |
Chloramphenicol sodium succinate |
Cimetidine HCl |
Clindamycin phosphate |
Dexamethasone sodium phosphate |
Dopamine HCl |
Erythromycin lactobionate |
Fluconazole |
Flucytosine |
Furosemide |
Gentamicin sulfate |
Heparin sodium |
Hydrocortisone sodium succinate |
Hydromorphone HCl |
Hydroxyzine HCl |
Imipenem–cilastatin sodium |
Metoclopramide HCl |
Metronidazole |
Morphine sulfate |
Nafcillin sodium |
Oxacillin sodium |
Penicillin G potassium |
Ranitidine HCl |
Ticarcillin disodium–clavulanate potassium |
Tobramycin sulfate |
Incompatible |
Acyclovir sodium |
Amphotericin B |
Diazepam |
Digoxin |
Diphenhydramine HCl |
Dobutamine HCl |
Droperidol |
Ganciclovir sodium |
Haloperidol lactate |
Leucovorin calcium |
Midazolam HCl |
Pentamidine isethionate |
Prochlorperazine edisylate |
Promethazine HCl |
Trimetrexate glucuronate |
Variable |
Co-trimoxazole |
Lorazepam |
Vancomycin HCl |
Actions and SpectrumActions
Organic analog of inorganic pyrophosphate with antiviral activity.1
Mechanism of antiviral activity appears to involve selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases.1
Active against herpesviruses, including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).1
Some ganciclovir-resistant CMV and some acyclovir-resistant HSV may be susceptible to foscarnet.1
CMV and HSV resistant to foscarnet can be selected in vitro and may occur in vivo in patients who receive the drug.1
Advice to Patients
Advise patients that foscarnet is not a cure for CMV retinitis; they may continue to experience progression of retinitis during or following treatment.1 Regular ophthalmologic examinations are necessary.1
Advise patients that foscarnet is not a cure for HSV infection.1 Complete healing is possible, but relapse occurs in most patients.1 Repeated treatment with foscarnet may lead to resistance associated with poorer response; in vitro susceptibility testing may be necessary.1
The major toxicities of foscarnet are renal impairment, electrolyte disturbances, and seizures; dosage adjustments or discontinuance may be required.1
Importance of maintaining adequate hydration (diuresis should be maintained during dosing) to minimize risk of renal impairment.1
Importance of informing clinician if symptoms of electrolyte imbalance (perioral tingling, numbness in the extremities, paresthesias) occur during or after IV infusion.1 If these occur, the infusion should be stopped, electrolyte concentrations determined, and the clinician consulted before treatment is resumed.1
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.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.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 24 mg/mL* | Foscarnet Sodium Injection | Hospira |
Foscavir | AstraZeneca |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
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37. Reviewers’ comments (personal observations).
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