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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.

Pronunciation

(fos KAR net)

U.S. Brand Names

• Foscavir®

Index Terms

• PFA
• Phosphonoformate
• Phosphonoformic Acid

Generic Available

Yes

Canadian Brand Names

• Foscavir®

Pharmacologic Category

• Antiviral Agent

Use: Labeled Indications

Treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised persons (eg, with advanced AIDS); treatment of CMV retinitis in persons with HIV

Use: Dental

Treatment of acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infections in immunocompromised persons (eg, with advanced AIDS); treatment of CMV retinitis in persons with HIV

Use: Unlabeled/Investigational

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Associated with an increase in skeletal anomalies in animal studies at approximately the equivalent of 13% to 33% of the maximal daily human dose. There are no adequate and well controlled studies in pregnant women. 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.

Lactation

Excretion in breast milk unknown/contraindicated

Breast-Feeding Considerations

The CDC recommends not to breast-feed if diagnosed with HIV to avoid postnatal transmission of the virus.

Contraindications

Hypersensitivity to foscarnet or any component of the formulation

Warnings/Precautions

Boxed warnings:

• Approved indications: See “Other warnings/precautions” below.

• Renal impairment: See “Concerns related to adverse effects” below.

• Seizures: See “Concerns related to adverse effects” below.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

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 Cl_cr even if serum creatinine is within the normal range. Dosage adjustments are recommended for renal dysfunction; safety and efficacy in patients with a baseline S_cr >2.8 mg/dL or Cl_cr <50 mL/minute are limited. Use in patients with Cl_cr <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.

Other warnings/precautions:

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

Adverse Reactions

>10%:

Central nervous system: Fever (65%), headache (26%)

Endocrine & metabolic: Hypokalemia (16% to 48%), hypocalcemia (15% to 30%), hypomagnesemia (15% to 30%), hypophosphatemia (8% to 26%)

Gastrointestinal: Nausea (47%), diarrhea (30%), vomiting (26%)

Hematologic: Anemia (33%), granulocytopenia (17%)

Renal: Abnormal renal function/decreased creatinine clearance (12%; without adequate hydration 33%)

1% to 10%:

Cardiovascular: Chest pain (1% to 5%), edema (1% to 5%), facial edema (1% to 5%), flushing (1% to 5%), hyper-/hypotension (1% to 5%), palpitation (1% to 5%), ECG changes (1% to 5%)

Central nervous system: Seizure (includes grand mal; 8%), anxiety (?5%), confusion (?5%), depression (?5%), dizziness (?5%), fatigue (?5%), hypoesthesia (?5%), malaise (?5%), pain (?5%), aggressiveness (1% to 5%), agitation (1% to 5%), amnesia (1% to 5%), aphasia (1% to 5%), ataxia (1% to 5%), coordination abnormal (1% to 5%), dementia (1% to 5%), EEG abnormal (1% to 5%), hallucination (1% to 5%), insomnia (1% to 5%), meningitis (1% to 5%), nervousness (1% to 5%), somnolence (1% to 5%), stupor (1% to 5%)

Dermatologic: Rash (?5%), erythematous rash (1% to 5%), maculopapular rash (1% to 5%), pruritus (1% to 5%), seborrhea (1% to 5%), skin discoloration (1% to 5%), skin ulceration (1% to 5%)

Endocrine & metabolic: Hyperphosphatemia (6%), acidosis (1% to 5%), hyponatremia (1% to 5%)

Gastrointestinal: Abdominal pain (?5%), anorexia (?5%), constipation (1% to 5%), dyspepsia (1% to 5%), dysphasia (1% to 5%), flatulence (1% to 5%), melena (1% to 5%), pancreatitis (1% to 5%), rectal hemorrhage (1% to 5%), taste perversion (1% to 5%), ulcerative stomatitis (1% to 5%), weight loss (1% to 5%), xerostomia (1% to 5%)

Genitourinary: Dysuria (1% to 5%), nocturia (1% to 5%), urinary retention (1% to 5%)

Hematologic: Leukopenia (?5%), lymphadenopathy (1% to 5%), thrombocytopenia (1% to 5%), thrombosis (1% to 5%)

Hepatic: Alkaline phosphatase increased (1% to 5%), ALT/AST increased (1% to 5%), hepatic function abnormal (1% to 5%), LDH increased (1% to 5%)

Local: Injection site pain/inflammation (1% to 5%)

Neuromuscular & skeletal: Paresthesia (?5%), involuntary muscle contractions (?5%), rigors (?5%), neuropathy (peripheral; ?5%), weakness (?5%), arthralgia (1% to 5%), back pain (1% to 5%), leg cramps (1% to 5%), myalgia (1% to 5%), tremor (1% to 5%)

Ocular: Vision abnormalities (?5%), conjunctivitis (1% to 5%), eye pain (1% to 5%)

Renal: Acute renal failure (1% to 5%), albuminuria (1% to 5%), BUN increased (1% to 5%), polyuria (1% to 5%), urinary tract infection (1% to 5%)

Respiratory: Cough (?5%), dyspnea (?5%), bronchospasm (1% to 5%), hemoptysis (1% to 5%), pharyngitis (1% to 5%), pneumonia (1% to 5%), pneumothorax (1% to 5%), rhinitis (1% to 5%), sinusitis (1% to 5%), stridor (1% to 5%)

Miscellaneous: Diaphoresis (?5%), sepsis (?5%), infection (includes bacterial and fungal; ?5%), flu-like syndrome (1% to 5%), malignancies (lymphoma/sarcoma 1% to 5%), thirst (1% to 5%)

<1%, postmarketing, and/or case reports: Amylase increased, cardiac arrest, coma, creatinine phosphokinase increased, dehydration, diabetes insipidus (usually nephrogenic), erythema multiforme, GGT increased muscle weakness, hematuria, hypoproteinemia, myopathy, myositis, neutropenia, pancytopenia, QT_c prolongation, renal calculus, rhabdomyolysis, Stevens-Johnson syndrome, syndrome of inappropriate antidiuretic hormone (SIADH), toxic epidermal necrolysis, ventricular arrhythmia, vesiculobullous eruptions

Drug Interactions

Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

Storage

Foscarnet injection is a clear, colorless solution. Store intact bottles at room temperature of 15°C to 30°C (59°F to 86°F) and protect from temperatures >40°C and from freezing. Diluted solution is stable for 24 hours at room temperature or under refrigeration.

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.

Compatibility

Stable in D₅W, NS; incompatible with dextrose 30%, LR, TPN, and I.V. solutions containing calcium, magnesium, vancomycin.

Y-site administration: Compatible: Aldesleukin, amikacin, aminophylline, ampicillin, aztreonam, cefazolin, cefoperazone, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cimetidine, clindamycin, dexamethasone sodium phosphate, dopamine, erythromycin lactobionate, fluconazole, flucytosine, furosemide, gentamicin, heparin, hydrocortisone sodium succinate, hydromorphone, hydroxyzine, imipenem/cilastatin, metoclopramide, metronidazole, morphine, nafcillin, oxacillin, penicillin G potassium, phenytoin, piperacillin, ranitidine, ticarcillin/clavulanate, tobramycin. Incompatible: Acyclovir, amphotericin B, diazepam, digoxin, diphenhydramine, dobutamine, droperidol, ganciclovir, haloperidol, leucovorin, midazolam, pentamidine, prochlorperazine edisylate, promethazine. Variable (consult detailed reference): Co-trimoxazole, lorazepam, vancomycin.

Compatibility when admixed: Compatible: Potassium chloride.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Distribution: V_d: ~0.5 L/kg; up to 28% of cumulative I.V. dose may be deposited in bone

Protein binding: 14% to 17%

Metabolism: Biotransformation does not occur

Half-life elimination: Elimination: ~3-4 hours; terminal: ~88 hours (due to bone deposition)

Excretion: Urine (?28% as unchanged drug)

Dosage

CMV retinitis: I.V.:

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

Maintenance therapy: 90-120 mg/kg/day as a single daily infusion

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

Therapy of CMV infection in cancer patients (unlabeled use): I.V.:

Prophylaxis: 60 mg/kg every 8-12 hours for 7 days, followed by 90-120 mg/kg daily until day 100 after HSCT

Pre-emptive treatment: 60 mg/kg every 12 hours for 14 days; if CMV still detectable, continue with 90 mg/kg daily for 5 days/week for 2 additional weeks

Treatment: 90 mg/kg every 12 hours for 2 weeks, followed by 120 mg/kg daily for ?2 weeks

Dosage adjustment in renal impairment: Induction and maintenance dosing schedules based on creatinine clearance (mL/minute/kg): See tables.

Hemodialysis:

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

Doses of 50 mg/kg/dose posthemodialysis have been found to produce similar serum concentrations as doses of 90 mg/kg twice daily in patients with normal renal function

Doses of 60-90 mg/kg/dose loading dose (posthemodialysis) followed by 45-60 mg/kg/dose posthemodialysis (3 times/week) with the monitoring of weekly plasma concentrations to maintain peak plasma concentrations in the range of 400-800 ?Molar have been recommended by some clinicians

Continuous arteriovenous or venovenous hemodiafiltration effects: Dose as for Cl_cr 10-50 mL/minute

Dental Usual Dosing

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

Administration: I.V.

Use an infusion pump, at a rate not exceeding 1 mg/kg/minute. Adult induction doses of 60 mg/kg are administered over 1 hour. Adult maintenance doses of 90-120 mg/kg are infused over 2 hours. The manufacturer recommends 750-1000 mL of NS or D₅W be administered prior to first infusion to establish diuresis. With subsequent infusions of 90-120 mg/kg, this volume would be repeated. If the dose were 40-60 mg/kg, then the volume could be reduced to 500 mL. After the first dose, the hydration fluid should be administered concurrently with foscarnet.

Administration: I.V. Detail

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 recommended dosage, frequency, and rate of infusion should not be exceeded.

pH: 7.4 (adjusted)

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.

Patient Education

Do not take any new medication during therapy unless approved by prescriber. Foscarnet is not a cure for the disease; progression may occur during or following therapy. While on therapy, it is important to maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake, and nutrition (small, frequent meals may help). Regular dental check-ups are recommended. May cause dizziness or confusion (use caution when driving or engaging in tasks that require alertness until response to drug is known); nausea and vomiting (small, frequent meals, frequent mouth care, chewing gum or sucking lozenges may help); or diarrhea (buttermilk, boiled milk, or yogurt may help). Report any change in sensorium or seizures; unresolved diarrhea or vomiting; unusual fever, chills, sore throat, unhealed sores, swollen lymph glands; or malaise. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Barrier contraceptives are recommended to reduce transmission of disease. Do not breast-feed.

Geriatric Considerations

Information on the use of foscarnet is lacking in the elderly. Dose adjustments and proper monitoring must be performed because of the decreased renal function common in older patients.

Additional Information

CMV retinitis maintenance treatment may be discontinued if immune reconstitution occurs as a result of ART.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), taste perversion, and ulcerative stomatitis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Foscarnet is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, levonordefrin [Neo-Cobefrin®]) be used with caution. See Dental Comment.

Dental Comment

Foscarnet is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”).

Prolongation of the QT interval is thought to result from delayed ventricular repolarization. The repolarization process within the myocardial cell is due to the efflux of intracellular potassium. The channels associated with this current can be blocked by many drugs and predispose the electrical propagation cycle to torsade de pointes.

Foscarnet is considered as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. It is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, levonordefrin [Neo-Cobefrin®]) be used with caution.

Mental Health: Effects on Mental Status

Dizziness, anxiety, confusion, and depression are common; may rarely produce abnormal crying

Mental Health: Effects on Psychiatric Treatment

Leukopenia is common; use caution with clozapine and carbamazepine

Nursing: Physical Assessment/Monitoring

Evaluate electrolytes, renal status, and dental status prior to beginning therapy. Assess potential for interactions with other pharmacological agents patient may be taking (eg, increased risk of seizures, renal failure, electrolyte imbalance). See Administration for infusion specifics. Assess results of laboratory tests (electrolytes) and renal function, therapeutic effectiveness (resolution of viral infection), and adverse response (eg, nephrotoxicity, electrolyte imbalance, seizures). Teach patient possible side effects/appropriate interventions (eg, need for regular dental evaluations) and adverse symptoms to report.

Oncology: Emetic Potential

Moderate (30% to 60%)

Oncology: Vesicant

No

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution, as sodium [preservative-free]: 24 mg/mL (250 mL, 500 mL)

Foscavir®: 24 mg/mL (500 mL)

References

Aweeka FT, Jacobson MA, Martin-Munley S, et al, “Effect of Renal Disease and Hemodialysis on Foscarnet Pharmacokinetics and Dosing Recommendations,” J Acquir Immune Def Syndr Hum Retrovirol, 1999, 20(4):350-7.

Benson CA, Kaplan JE, Masur H, et al, “Treating Opportunistic Infections Among HIV-Exposed and Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health and the HIV Medicine Association/IDSA,” MMWR Recomm Rep 2004, 53(RR-15):1-112.

Butler KM, DeSmet MD, Husson RN, et al, “Treatment of Aggressive Cytomegalovirus Retinitis With Ganciclovir in Combination With Foscarnet in a Child Infected With Human Immunodeficiency Virus,” J Pediatr, 1992, 120(3):483-6.

Calligaro KD, Stern J, and DeLaurentis DA, “Foscarnet: A Possible Cause of Ulnar Artery Thrombosis in a Patient With AIDS,” J Vasc Surg, 1994, 20(6):1007-8.

Chilukuri S and Rosen T, "Management of Acycovir-Resistant Herpes Simplex Virus," Dermatol Clin, 2003, 21(2):311-20.

Chrisp P and Clissold SP, “Foscarnet. A Review of Its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Use in Immunocompromised Patients With Cytomegalovirus Retinitis,” Drugs, 1991, 41(1):104-29.

Deray G, Martinez F, Katlama C, et al, “Foscarnet Nephrotoxicity: Mechanism, Incidence and Prevention,” Am J Nephrol, 1989, 9:316-21.

“Drugs for Non-HIV Viral Infections,” Med Lett Drugs Ther, 1994, 36(919):27.

Jacobson MA, “Review of the Toxicities of Foscarnet,” J Acquir Immune Defic Syndr, 1992, 5(Suppl 1):11-7.

Jayaweera DT, “Minimizing the Dosage-Limiting Toxicities of Foscarnet Induction Therapy,” Drug Saf, 1997, 16(4):258-66.

Keating MR, “Antiviral Agents,” Mayo Clin Proc, 1992, 67(2):160-78.

Mofenson LM, Oleske J, Serchuck L, et al, “Treating Opportunistic Infections Among HIV-Exposed and Infected Children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America,” Clin Infect Dis, 2005, 40 (Suppl 1):1-84.

Morales JM, Munoz MA, Fernandez Zatarain G, et al, “Reversible Acute Renal Failure Caused by the Combined Use of Foscarnet and Cyclosporin in Organ Transplanted Patients,” Nephrol Dial Transplant, 1995, 10(6):882-3.

National Comprehensive Cancer Network (NCCN), “Clinical Practice Guidelines in Oncology™: Prevention and Treatment of Cancer-Related Infections,” Version 1, 2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf.

Polis MA, “Foscarnet and Ganciclovir in the Treatment of Cytomegalovirus Retinitis,” J Acquir Immune Defic Syndr, 1992, 5(Suppl 1):3-10.

Whitley RJ, Jacobson MA, Friedberg DN, et al, “Guidelines for the Treatment of Cytomegalovirus Diseases in Patients With AIDS in the Era of Potent Antiretroviral Therapy: Recommendations of an International Panel. International AIDS Society-USA,” Arch Intern Med, 1998, 158(9):957-69.

International Brand Names

• Foscarnet Elea (AR)
• Foscarnet Filaxis (AR)
• Foscarnet Richmond (AR)
• Foscavir (AR, AT, AU, BE, BR, CH, CZ, DE, ES, FI, FR, GB, GR, HN, HU, IL, IT, JP, LU, NL, NO, PT, SE)
• Terap (AR)
• Triapten (DE, PL)

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Last full review/revision September 2008

Content last modified September 2008