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Foscarnet

Pronunciation

(fos KAR net)

Index Terms

  • Foscavir
  • PFA
  • Phosphonoformate
  • Phosphonoformic Acid

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as sodium [preservative free]:

Foscavir: 24 mg/mL (250 mL)

Generic: 12,000 mg/500 mL (500 mL [DSC])

Brand Names: U.S.

  • Foscavir

Pharmacologic Category

  • Antiviral Agent

Pharmacology

Pyrophosphate analogue which acts as a noncompetitive inhibitor of many viral RNA and DNA polymerases as well as HIV reverse transcriptase. Similar to ganciclovir, foscarnet is a virostatic agent. Foscarnet does not require activation by thymidine kinase.

Distribution

Vd: ~0.5 L/kg; up to 28% of cumulative IV dose may be deposited in bone

Metabolism

Biotransformation does not occur

Excretion

Urine (≤28% as unchanged drug)

Half-Life Elimination

Elimination: ~3 to 4 hours; terminal: ~88 hours (due to bone deposition)

Protein Binding

Protein binding: 14% to 17%

Special Populations: Renal Function Impairment

CrCl of 50 to 80 mL/minute has a clearance of about 1.33 mL/minute/kg and a plasma half-life of about 3.35 hours. CrCl of 25 to 49 mL/minute has a clearance of about 0.46 mL/minute/kg and a plasma half-life of about 13 hours. CrCl of 10 to 24 mL/minute has a clearance of 0.43 mL/minute/kg and plasma half-life about 25.3 hours.

Use: Labeled Indications

Cytomegalovirus retinitis: Treatment of cytomegalovirus (CMV) retinitis in persons with AIDS

Herpes simplex virus: Treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised persons (eg, with advanced AIDS)

Use: Unlabeled

Other CMV infections (eg, colitis, esophagitis, neurological disease); CMV prophylaxis for cancer patients receiving alemtuzumab therapy or allogeneic stem cell transplant

Contraindications

Clinically significant hypersensitivity to foscarnet or any component of the formulation.

Dosing: Adult

Cytomegalovirus (CMV) retinitis: IV:

Induction treatment: 60 mg/kg/dose every 8 hours for 14 to 21 days or 90 mg/kg every 12 hours for 14 to 21 days

Maintenance therapy: 90 to 120 mg/kg/day as a single daily infusion; due to lower toxicity, begin with 90 mg/kg once daily, may escalate to 120 mg/kg once daily if lower dose tolerated or for retinitis progression

CMV infection (preemptive therapy) after allogeneic stem cell transplantation (off-label use; second-line therapy): IV:

<100 days posttransplant: Induction: 60 mg/kg every 12 hours for 7 to 14 days, followed by maintenance therapy: 90 mg/kg once daily if CMV is still detectable and declining, continue until indicator test is negative. Minimum total duration (induction and maintenance) is 2 weeks (Tomblyn 2009)

>100 days posttransplant: 60 mg/kg every 12 hours for 14 days, continue treatment with 90 mg/kg once daily for 7 to 14 days or until indicator test is negative (Tomblyn 2009)

CMV infection (prophylaxis) after allogeneic stem cell transplantation (off-label use; second-line therapy): IV: 60 mg/kg every 12 hours for 7 days, followed by 90 to 120 mg/kg once daily until day 100 after transplant (Tomblyn 2009)

CMV esophagitis or colitis in HIV-infected patients (alternative to preferred therapy) (off-label use): IV: 60 mg/kg/dose every 8 hours or 90 mg/kg/dose every 12 hours for 21 to 42 days or until symptom resolution (HHS [OI adult 2015])

CMV neurological disease in HIV-infected patients (off-label use): IV: 60 mg/kg/dose every 8 hours or 90 mg/kg/dose every 12 hours plus ganciclovir until symptoms improve followed by chronic maintenance suppression (secondary prophylaxis) (HHS [OI adult 2015])

Herpes simplex infections (acyclovir-resistant): Induction: IV: 40 mg/kg/dose every 8 to 12 hours for 14 to 21 days

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Cytomegalovirus (CMV) infection (preemptive therapy) after allogeneic stem cell transplantation (off-label use; second-line therapy): IV:

<100 days posttransplant: Induction: 60 mg/kg every 12 hours for 7 to 14 days, followed by maintenance therapy: 90 mg/kg once daily if CMV is still detectable and declining, continue until indicator test is negative. Minimum total duration (induction and maintenance) is 2 weeks (Tomblyn 2009)

>100 days posttransplant: 60 mg/kg every 12 hours for 14 days, continue treatment with 90 mg/kg once daily for 7 to 14 days or until indicator test is negative (Tomblyn 2009)

CMV infection (prophylaxis) after allogeneic stem cell transplantation (off-label use; second-line therapy): IV: 60 mg/kg every 12 hours for 7 days, followed by 90 to 120 mg/kg once daily until day 100 after transplant (Tomblyn 2009)

CMV esophagitis or colitis in HIV-infected patients (alternative to preferred therapy) (off-label use): Adolescents: Refer to adult dosing.

CMV neurological disease in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing

Dosing: Renal Impairment

See tables.

Induction Dosing of Foscarnet in Patients With Abnormal Renal Function

CrCl (mL/min/kg)

HSV

HSV

CMV

CMV

Equivalent to 40 mg/kg every 12 hours

Equivalent to 40 mg/kg every 8 hours

Equivalent to 60 mg/kg every 8 hours

Equivalent to 90 mg/kg every 12 hours

<0.4

Not recommended

Not recommended

Not recommended

Not recommended

≥0.4-0.5

20 mg/kg every 24 hours

35 mg/kg every 24 hours

50 mg/kg every 24 hours

50 mg/kg every 24 hours

>0.5-0.6

25 mg/kg every 24 hours

40 mg/kg every 24 hours

60 mg/kg every 24 hours

60 mg/kg every 24 hours

>0.6-0.8

35 mg/kg every 24 hours

25 mg/kg every 12 hours

40 mg/kg every 12 hours

80 mg/kg every 24 hours

>0.8-1

20 mg/kg every 12 hours

35 mg/kg every 12 hours

50 mg/kg every 12 hours

50 mg/kg every 12 hours

>1-1.4

30 mg/kg every 12 hours

30 mg/kg every 8 hours

45 mg/kg every 8 hours

70 mg/kg every 12 hours

>1.4

40 mg/kg every 12 hours

40 mg/kg every 8 hours

60 mg/kg every 8 hours

90 mg/kg every 12 hours

Table has been converted to the following text.

Induction Dosing of Foscarnet in Patients With Abnormal Renal Function

CrCl <0.4 mL/minute/kg: Not recommended

CrCl ≥0.4 to 0.5 mL/minute/kg:

• HSV: 20 mg/kg every 24 hours (equivalent to 40 mg/kg every 12 hours)

• HSV: 35 mg/kg every 24 hours (equivalent to 40 mg/kg every 8 hours)

• CMV: 50 mg/kg every 24 hours (equivalent to 60 mg/kg every 8 hours)

• CMV: 50 mg/kg every 24 hours (equivalent to 90 mg/kg every 12 hours)

CrCl >0.5 to 0.6 mL/minute/kg:

• HSV: 25 mg/kg every 24 hours (equivalent to 40 mg/kg every 12 hours)

• HSV: 40 mg/kg every 24 hours (equivalent to 40 mg/kg every 8 hours)

• CMV: 60 mg/kg every 24 hours (equivalent to 60 mg/kg every 8 hours)

• CMV: 60 mg/kg every 24 hours (equivalent to 90 mg/kg every 12 hours)

CrCl >0.6 to 0.8 mL/minute/kg:

• HSV: 35 mg/kg every 24 hours (equivalent to 40 mg/kg every 12 hours)

• HSV: 25 mg/kg every 12 hours (equivalent to 40 mg/kg every 8 hours)

• CMV: 40 mg/kg every 12 hours (equivalent to 60 mg/kg every 8 hours)

• CMV: 80 mg/kg every 24 hours (equivalent to 90 mg/kg every 12 hours)

CrCl >0.8 to 1 mL/minute/kg:

• HSV: 20 mg/kg every 12 hours (equivalent to 40 mg/kg every 12 hours)

• HSV: 35 mg/kg every 12 hours (equivalent to 40 mg/kg every 8 hours)

• CMV: 50 mg/kg every 12 hours (equivalent to 60 mg/kg every 8 hours)

• CMV: 50 mg/kg every 12 hours (equivalent to 90 mg/kg every 12 hours)

CrCl >1 to 1.4 mL/minute/kg:

• HSV: 30 mg/kg every 12 hours (equivalent to 40 mg/kg every 12 hours)

• HSV: 30 mg/kg every 8 hours (equivalent to 40 mg/kg every 8 hours)

• CMV: 45 mg/kg every 8 hours (equivalent to 60 mg/kg every 8 hours)

• CMV: 70 mg/kg every 12 hours (equivalent to 90 mg/kg every 12 hours)

CrCl >1.4 mL/minute/kg:

• HSV: 40 mg/kg every 12 hours (equivalent to 40 mg/kg every 12 hours)

• HSV: 40 mg/kg every 8 hours (equivalent to 40 mg/kg every 8 hours)

• CMV: 60 mg/kg every 8 hours (equivalent to 60 mg/kg every 8 hours)

• CMV: 90 mg/kg every 12 hours (equivalent to 90 mg/kg every 12 hours)

Maintenance Dosing of Foscarnet in Patients With Abnormal Renal Function

CrCl (mL/min/kg)

CMV

CMV

Equivalent to 90 mg/kg every 24 hours

Equivalent to 120 mg/kg every 24 hours

<0.4

Not recommended

Not recommended

≥0.4-0.5

50 mg/kg every 48 hours

65 mg/kg every 48 hours

>0.5-0.6

60 mg/kg every 48 hours

80 mg/kg every 48 hours

>0.6-0.8

80 mg/kg every 48 hours

105 mg/kg every 48 hours

>0.8-1

50 mg/kg every 24 hours

65 mg/kg every 24 hours

>1-1.4

70 mg/kg every 24 hours

90 mg/kg every 24 hours

>1.4

90 mg/kg every 24 hours

120 mg/kg every 24 hours

Table has been converted to the following text.

Maintenance Dosing for CMV in Patients With Abnormal Renal Function

CrCl <0.4 mL/minute/kg: Not recommended

CrCl ≥0.4 to 0.5 mL/minute/kg:

• 50 mg/kg every 48 hours (equivalent to 90 mg/kg every 24 hours)

• 65 mg/kg every 48 hours (equivalent to 120 mg/kg every 24 hours)

CrCl >0.5 to 0.6 mL/minute/kg:

• 60 mg/kg every 48 hours (equivalent to 90 mg/kg every 24 hours)

• 80 mg/kg every 48 hours (equivalent to 120 mg/kg every 24 hours)

CrCl >0.6 to 0.8 mL/minute/kg:

• 80 mg/kg every 48 hours (equivalent to 90 mg/kg every 24 hours)

• 105 mg/kg every 48 hours (equivalent to 120 mg/kg every 24 hours)

CrCl >0.8 to 1 mL/minute/kg:

• 50 mg/kg every 24 hours (equivalent to 90 mg/kg every 24 hours)

• 65 mg/kg every 24 hours (equivalent to 120 mg/kg every 24 hours)

CrCl >1 to 1.4 mL/minute/kg:

• 70 mg/kg every 24 hours (equivalent to 90 mg/kg every 24 hours)

• 90 mg/kg every 24 hours (equivalent to 120 mg/kg every 24 hours)

CrCl >1.4 mL/minute/kg:

• 90 mg/kg every 24 hours (equivalent to 90 mg/kg every 24 hours)

• 120 mg/kg every 24 hours (equivalent to 120 mg/kg every 24 hours)

Hemodialysis:

Foscarnet is highly removed by hemodialysis (up to ~38% in 2.5 hours HD with high-flux membrane) (Aweeka 1999)

Doses of 45 to 60 mg/kg/dose posthemodialysis (3 times/week) with the monitoring of weekly plasma concentrations to maintain peak plasma concentrations in the range of 500 to 800 micromolar for the treatment of CMV infection have been recommended (Aweeka 1999; Jayasekara 1999; MacGregor 1991)

Peritoneal dialysis: HSV infection (localized or disseminated): IV: 60 mg/kg/dose every 48 to 72 hours; higher doses may be necessary for herpes encephalitis or herpes zoster infection (Jayasekara 1999)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer’s labeling.

Reconstitution

Foscarnet should be diluted in D5W or NS. For peripheral line administration, foscarnet must be diluted to ≤12 mg/mL with D5W or NS. For central line administration, foscarnet may be administered undiluted.

Administration

Foscarnet is administered by intravenous infusion, using an infusion pump, at a rate not exceeding 1 mg/kg/minute. Undiluted (24 mg/mL) solution can be administered without further dilution when using a central venous catheter for infusion. For peripheral vein administration, the solution must be diluted to a final concentration not to exceed 12 mg/mL. The manufacturer recommends 750 to 1000 mL of NS or D5W be administered prior to first infusion to establish diuresis. With subsequent infusions of 90 to 120 mg/kg, this volume would be repeated. If the dose were 40 to 60 mg/kg, then the volume could be reduced to 500 mL. After the first dose, the hydration fluid should be administered concurrently with foscarnet.

Dietary Considerations

Some products may contain sodium.

Compatibility

Stable in D5W, NS; incompatible with dextrose 30%, LR, TPN, IV solutions containing calcium, magnesium, or vancomycin.

Y-site administration: Incompatible with acyclovir, diazepam, digoxin, diphenhydramine, dobutamine, droperidol, ganciclovir, haloperidol, leucovorin calcium, midazolam, pentamidine, prochlorperazine edisylate, promethazine.

Storage

Store intact bottles at room temperature of 20°C to 25°C (68°F to 77°F) and protect from temperatures >40°C (>104°F) and from freezing. Following dilution in D5W or NS, solutions are stable for 24 hours at room temperature or under refrigeration.

Drug Interactions

Acyclovir-Valacyclovir: Foscarnet may enhance the nephrotoxic effect of Acyclovir-Valacyclovir. Avoid combination

Aminoglycosides: Foscarnet may enhance the nephrotoxic effect of Aminoglycosides. Avoid combination

Amphotericin B: Foscarnet may enhance the nephrotoxic effect of Amphotericin B. Avoid combination

CycloSPORINE (Systemic): Foscarnet may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Loop Diuretics: May increase the serum concentration of Foscarnet. Consider therapy modification

Methotrexate: Foscarnet may enhance the nephrotoxic effect of Methotrexate. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Pentamidine (Systemic): May enhance the adverse/toxic effect of Foscarnet. The specific toxicities may include hypocalcemia, renal failure, and QT-prolongation. Management: Consider alternatives to this combination when possible. If this combination must be used, monitor patients more closely for hypocalcemia, renal dysfunction, and QT interval prolongation. Consider therapy modification

Tacrolimus (Systemic): Foscarnet may enhance the nephrotoxic effect of Tacrolimus (Systemic). Avoid combination

Talimogene Laherparepvec: Antiherpetic Antivirals may diminish the therapeutic effect of Talimogene Laherparepvec. Monitor therapy

ALERT: U.S. Boxed Warning

Renal impairment:

Renal impairment is the major toxicity of foscarnet. Frequent monitoring of serum creatinine, with dose adjustment for changes in renal function, and adequate hydration with administration of foscarnet is imperative.

Seizures:

Seizures, related to alterations in plasma minerals and electrolytes, have been associated with foscarnet treatment. Therefore, patients must be carefully monitored for such changes and their potential sequelae. Mineral and electrolyte supplementation may be required.

Appropriate use:

Foscarnet is indicated for use only in immunocompromised patients with cytomegalovirus (CMV) retinitis and mucocutaneous acyclovir-resistant herpes simplex virus (HSV) infections.

Warnings/Precautions

Concerns related to adverse effects:

• Dental effects: Foscarnet is deposited in teeth and bone of young, growing animals; it has adversely affected tooth enamel development in rats.

• Electrolyte imbalance: Imbalance of serum electrolytes or minerals occurs in at least 15% of patients (hypocalcemia, low ionized calcium, hyper/hypophosphatemia, hypomagnesemia, or hypokalemia); reducing infusion rate may decrease/prevent symptoms. Patients with low ionized calcium may experience perioral tingling, numbness, paresthesias, tetany, and seizures. Correct electrolytes before initiating therapy; use caution in patients who have any underlying electrolyte imbalances, those with neurologic or cardiac abnormalities, and those receiving medications that are influenced by calcium levels. Use caution when administering other medications that cause electrolyte imbalances. Patients who experience signs or symptoms of an electrolyte imbalance should be assessed immediately.

• Hematologic effects: May cause anemia and granulocytopenia.

• Renal impairment: [U.S. Boxed Warning]: Renal impairment occurs to some degree in the majority of patients treated with foscarnet; renal impairment may occur at any time (though typically during second week of induction therapy) and is usually reversible within 1 week following dose adjustment or discontinuation of therapy, however, several patients have died with renal failure within 4 weeks of stopping foscarnet; therefore, renal function should be closely monitored during both induction and maintenance therapy. To reduce the risk of nephrotoxicity and the potential to administer a relative overdose, always calculate the CrCl even if serum creatinine is within the normal range. Dosage adjustments are recommended for renal dysfunction; safety and efficacy in patients with a baseline Scr >2.8 mg/dL or CrCl <50 mL/minute are limited. Use in patients with CrCl <0.4 mL/kg/minute is not recommended. Adequate hydration may reduce the risk of nephrotoxicity; the manufacturer makes specific recommendations regarding this (see Administration).

• Seizures: [U.S. Boxed Warning]: Seizures related to plasma electrolyte/mineral imbalance may occur; incidence has been reported in up to 10% of HIV patients. Risk factors for seizures include impaired baseline renal function, low total serum calcium, and underlying CNS condition. Some patients who have experienced seizures have been able to continue or resume foscarnet treatment after their mineral or electrolyte abnormality has been corrected, their underlying disease state treated, or their dose decreased.

• Vascular irritant: Administer only into vein with adequate blood flow to prevent tissue irritation/ulceration. Genital vascular tissue damage has been reported; adequate hydration recommended.

Disease related concerns:

• Heart failure: Due to sodium content, use with caution in patients with heart failure.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: [U.S. Boxed Warning]: Indicated only for immunocompromised patients with CMV retinitis and mucocutaneous acyclovir-resistant HSV infection.

Monitoring Parameters

24-hour creatinine clearance at baseline and periodically thereafter. During induction therapy: Obtain complete blood counts, and electrolytes (including serum creatinine, calcium, magnesium, potassium, and phosphorus) twice weekly and then one weekly during maintenance therapy. More frequent monitoring may be required in some patients. Check hydration status before and after infusion.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproductions studies. A single case report of use during the third trimester with normal infant outcome was observed. Monitoring of amniotic fluid volumes by ultrasound is recommended weekly after 20 weeks of gestation to detect oligohydramnios (DHHS [adult] 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, headache, hyperhidrosis, anxiety, nausea, vomiting, dizziness, lack of appetite, sweating a lot, or abdominal pain. Have patient report immediately to prescriber signs of infection, signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea, or vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), seizures, burning or numbness feeling, abnormal movements, depression, shortness of breath, loss of strength and energy, muscle rigidity, vision changes, genital irritation, or severe injection site irritation or pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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