Foscavir

Generic Name: Foscarnet Sodium
Class: Antivirals, Miscellaneous
VA Class: AM800
Chemical Name: Dihydroxyphosphinecarboxylic acid oxide trisodium salt
Molecular Formula: CNa3O5P
CAS Number: 63585-09-1

Warning(s)

  • 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 Foscavir

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

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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

Foscavir 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

Induction Dosage for CMV Retinitis or HSV Infections in Adults with Renal Impairment1

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

Maintenance Dosage for CMV Retinitis in Adults with Renal Impairment1

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 Foscavir

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 Foscavir

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

Foscavir 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
Admixture CompatibilityHID

Compatible

Potassium chloride

Y-Site CompatibilityHID

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 Spectrum

  • 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

Foscarnet Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion only

24 mg/mL*

Foscarnet Sodium Injection

Hospira

Foscavir

AstraZeneca

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 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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2. Chrisp P, Clissold SP. Foscarnet: a review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs. 1991; 41:104-29. [PubMed 1706982]

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]

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28. Sjövall J, Bergdahl S, Movin G et al. Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1989; 33:1023-31. [IDIS 256767] [PubMed 2528939]

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36. Leport C, Puget S, Pepin JM et al. Cytomegalovirus resistant to foscarnet: clinicovirologic correlation in a patient with human immunodeficiency virus. J Infect Dis. 1993; 168:1329-30. [IDIS 321506] [PubMed 8228376]

37. Reviewers’ comments (personal observations).

38. Astra, Westborough, MA: personal communication.

39. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Morb Mortal Wkly Rep. 2000; 49(No. RR-10):1-125. [IDIS 439515] [PubMed 10993565]

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