Foscarnet

Mechanism of Action

Foscarnet is an analog of pyrophosphate, a phosphorous oxyanion found in the DNA molecule. This analog acts like the pyrophosphate molecule by binding selectively and reversibly to the binding site on the DNA polymerase enzyme of the virus and inhibiting the DNA chain from elongating further. The DNA polymerase enzyme cleaves the pyrophosphate molecule from the DNA chain to add further nucleotides to the growing chain. Foscarnet binding inhibits this cleaving process. While foscarnet has selectivity for the viral DNA polymerase, it can also inhibit human DNA polymerase in much larger drug concentrations. However, such high concentrations are seldom necessary to treat these viral pathogens.[3] Mutations in the UL54 gene can cause foscarnet resistance.[8]

Pharmacokinetics

Absorption: Foscarnet is administered as an intravenous infusion. At steady state, foscarnet's maximum plasma concentration (Cmax) is 589 ± 192 µM.

Distribution: The volume of distribution for foscarnet ranges from 0.41 to 0.52 L/kg. Approximately 14% to 17% of foscarnet is protein-bound. Additionally, foscarnet exhibits a cerebrospinal fluid (CSF) to plasma ratio of 0.69 for the 60 mg/kg dosage every 8 hours and 0.66 for the 90 mg/kg dosage every 12 hours.

Metabolism: Foscarnet is excreted in the urine and undergoes negligible hepatic metabolism.[9]

Excretion: Foscarnet's plasma half-life is approximately 4.0 hours for the 60 mg/kg regimen administered every 8 hours and about 3.3 hours for the 90 mg/kg regimen administered every 12 hours. Foscarnet exhibits a prolonged urinary excretion half-life of 87.5 hours, which may be attributed to its accumulation in bone.

Administration

Available Dosage Forms and Strengths

Foscarnet exhibits poor bioavailability when orally administered, possibly due to the poor metabolism of the drug and its inclination to deposit within bone and cartilage.[3] As a result, foscarnet is most commonly administered intravenously. The dosing and rate of administration are determined based on the patient's age and weight and the specific viral infection (ie, CMV versus HSV or VZV). While the IV route is the most commonly used, foscarnet may administered via the intravitreal route by experienced clinicians as a treatment for viral ophthalmic complications.[10] Foscarnet should not be administered by rapid or bolus intravenous injection; instead, it should be delivered using an infusion pump.

For peripheral line administration, dilute foscarnet injection to the appropriate concentration using 5% dextrose in water (D5W) or normal saline (NS).

Adult Dosage

Specific dosing regimens based on indication are listed below.

AIDS-associated CMV retinitis:

• Foscarnet is not considered a first-line treatment for this condition.
• Induction: 90 mg/kg/dose IV every 12 hours for 2 to 3 weeks, or 60 mg/kg/dose IV every 8 hours for 2 to 3 weeks.
• Maintenance: 90 mg/kg/dose IV every 24 hours, or 120 mg/kg/dose IV every 24 hours.

Acyclovir-resistant mucocutaneous HSV infection:

• 40 mg/kg/dose IV every 8 to 12 hours until healed; alternately, apply 1% cream 5 times daily until healed (requires pharmacy compounding)
• Immunocompromised patients must maintain adequate hydration before and during IV treatment.[11]

Ganciclovir-resistant CMV (off-label):

• Induction: 90 mg/kg/dose IV for a minimum of 2 weeks; alternately, 60 mg/kg/dose IV every 8 hours for a minimum of 2 weeks.
• Maintenance: 90 mg/kg/dose IV every 24 hours, or 120 mg/kg/dose IV every 24 hours.[12][13]
• Immunocompromised patients must maintain adequate hydration before and during IV treatment.

Acyclovir-resistant varicella (off-label):

• 90 mg/kg/dose IV every 12 hours.
• Immunocompromised patients must maintain adequate hydration before and during IV treatment.

Acyclovir-resistant herpes zoster (off-label):

• For adults with CMV infection and retinitis, foscarnet is commonly administered at about 1 mg/kg/min.[12][13]   
• For all patients, the therapy duration depends on the patient's immune status and the progress of the lesions.

Specific Patient Populations

Hepatic impairment: Intravenous foscarnet can cause mild-to-moderate serum alanine aminotransferase (ALT) elevations, particularly in patients with multiorgan disease. These asymptomatic elevations often resolve with continued therapy. Rare cases of cholestatic liver injury have been reported. Rapid renal excretion and minimal hepatic metabolism likely account for its low hepatotoxicity.[9]

Renal impairment: Significant dosing reductions are necessary in cases of renal compromise. Limited safety data exist for patients with serum creatinine >2.8 mg/dL or creatinine clearance <50 mL/min. Renal function must be monitored, with dose adjustments as needed. If creatinine clearance drops below 0.4 mL/min/kg, discontinue foscarnet, hydrate the patient, and monitor until renal function improves. Due to the lack of dosing guidelines, foscarnet is not recommended for patients undergoing hemodialysis. Clinicians should refer to package inserts and institutional protocols in such instances.

Pregnancy considerations: There are no well-controlled studies of foscarnet in pregnant women, and animal studies do not always predict human response. Foscarnet should be administered during pregnancy only if indicated. In animal studies, foscarnet did not impair fertility or general reproductive performance, but a mild increase in skeletal anomalies at subtherapeutic exposure levels was observed. These studies are insufficient to determine teratogenic risk at human exposure levels.  

Breastfeeding considerations: Foscarnet excretion in human breast milk has not been determined, but studies in rats revealed higher concentrations in milk than in blood. Due to the risk of severe adverse effects in nursing infants, a decision should be made to either discontinue the drug or breastfeed, considering the drug's importance to the mother. The CDC advises HIV-infected mothers not to breastfeed to prevent postnatal transmission of HIV.

Pediatric patients: Foscarnet's safety in pediatric patients has not been established. The drug accumulates in teeth and bones, with animal studies showing enamel defects. Although the effects on skeletal development are unclear, bone deposition is expected to be higher in children, making its use in pediatric populations a concern. While foscarnet is effective for treatment-resistant infections, its associated nephrotoxicity necessitates careful renal monitoring. In pediatric patients, bone and tooth deposition risk requires a thorough evaluation, and treatment should only proceed if the therapeutic benefits outweigh these potential risks.[14]

Older patients: Foscarnet has not been specifically studied in patients older than 65, but its use in older adults shows a similar adverse event profile across all ages. Foscarnet is primarily excreted by the kidneys. Since renal function tends to decline with age, careful dosing is crucial to avoid toxicity in older individuals.

Adverse Effects

While there are multiple adverse effects associated with foscarnet administration, the most notable include nausea, electrolyte derangements, and nephrotoxicity. Of these 3 significant adverse effects, the reports of renal insufficiency are a relatively more common event in patients receiving this drug. Any acute reduction in renal function is reversible; therefore, it is crucial to address it once identified. Foscarnet affects the renal tubular cells via direct cytotoxic mechanisms, and the degree of drug-induced toxicity directly correlates to the dosage administered.[15] Along with renal tubular damage, foscarnet can cause crystal nephropathy by deposition of crystals in the glomerular capillaries. These crystals are often a mix of sodium and calcium salts. The molecular aspects of foscarnet allow it to form complexes with these ions, leading to the deposition of these crystals in the glomerular network.[16] Foscarnet has been associated with reversible acute kidney injury (AKI), distal tubular acidosis, and arginine vasopressin resistance (AVP-R, formerly nephrogenic diabetes insipidus). The reported incidence of foscarnet-related nephrotoxicity varies widely, ranging from 20% to 66%. Early screening for crystalluria should be conducted in patients receiving foscarnet to identify potential risks and prevent the onset of acute kidney injury.[17]

Due to these adverse renal effects, monitoring renal function while on foscarnet therapy is essential. Any elevation in plasma creatine observed within 2 weeks of initiating foscarnet therapy could be a sign of renal tubular injury; this often presents as acute tubular injury, with granular or muddy brown casts in the urine and a triphasic sequence involving an acute drop in GFR, followed by an elevation in GFR and then an eventual resolution of kidney function.[18] In some instances, foscarnet can also cause AVP-R.[19]

Electrolyte derangement, another adverse effect of foscarnet, often presents with hypocalcemia and hypomagnesemia.[20] Hypocalcemia may be due to the formation of the foscarnet and calcium ion complex, or it may result from foscarnet-induced hypomagnesemia, which leads to both hypocalcemia (due to hypomagnesemia-induced hypoparathyroidism state) and hypokalemia (due to excess renal potassium wasting). Due to these possible electrolyte abnormalities, it is essential to perform routine complete metabolic panels to prevent systemic adverse events such as cardiac arrhythmias and obtain a baseline EKG before initiation of treatment.

Patient intolerance due to nausea and other gastrointestinal symptoms is a well-known and often reported adverse event of foscarnet and is a primary reason it is difficult to administer to patients. The administration of foscarnet usually involves concurrent IV and oral hydration to suppress nausea. Nausea can also be mitigated by providing the patient with antiemetics and slowing the drug infusion rate.[21]

Less commonly reported adverse events due to foscarnet administration include seizures, genital ulcers, and anemia. Genital ulcers are more common in males, possibly due to a topical toxic effect resulting from medication concentration in the urine. There are also reports of QT prolongation and torsades de pointes.

Drug-Drug Interactions

• Concomitant administration of cidofovir with foscarnet should be avoided due to the increased risk of additive nephrotoxicity, which can lead to significant renal impairment. Similarly, pimozide and thioridazine should not be used together with foscarnet, as both can exacerbate QT prolongation, increasing the risk of serious cardiac arrhythmias.

• Pentamidine: Use with foscarnet requires caution due to the potential for hypocalcemia and renal impairment.

• Nephrotoxic drugs: Avoid concurrent use of foscarnet with nephrotoxic agents such as aminoglycosides, amphotericin B, cyclosporine, acyclovir, methotrexate, and tacrolimus unless the potential benefits outweigh the risks, as this combination may increase the likelihood of renal toxicity.

• Diuretics: Thiazide diuretics are recommended over loop diuretics when diuresis is necessary, as loop diuretics may interfere with the renal elimination of foscarnet and heighten toxicity risk.

• Ritonavir: Monitor for abnormal renal function when using foscarnet with ritonavir.

• QT-prolonging drugs: Avoid co-administration of Class IA and Class III antiarrhythmics such as quinidine, procainamide, dofetilide, amiodarone, and sotalol with foscarnet due to an increased risk of QT prolongation and torsades de pointes.

Contraindications

According to the product labeling, foscarnet is contraindicated for patients with severe hypersensitivity reactions such as angioedema or a history of anaphylactic reactions to it. Foscarnet is relatively contraindicated for patients with underlying diseases that increase the effect of the adverse reaction profile of the drug. With the health care provider’s medical discretion, the drug is administered with extreme caution or not at all in patients who have abnormal EKG readings due to chronic cardiac problems, chronic kidney disease, underlying electrolyte abnormalities (which have to be corrected before administering foscarnet) or seizure disorders.

Box Warnings

Nephrotoxicity is the primary concern with foscarnet administration. Clinicians must monitor serum creatinine levels frequently, adjust doses based on changes in renal function, and ensure adequate hydration during foscarnet therapy. Foscarnet-induced alterations in plasma minerals and electrolytes have been linked to seizure activity. Therefore, patients should be closely monitored for these changes and their potential consequences. Mineral and electrolyte supplementation may be necessary. Foscarnet is indicated solely for immunocompromised patients with CMV retinitis and mucocutaneous infections caused by acyclovir-resistant HSV. A recent study revealed an increased risk of seizures, nephrotoxicity, and electrolyte imbalance associated with foscarnet.[22]

Monitoring

Given the various adverse effects associated with foscarnet administration, it is essential to monitor specific parameters. The 3 main monitoring components are 24-hour creatinine clearance, ECG, and baseline electrolyte measurements. Clinicians must obtain a baseline complete blood count to monitor hematocrit, hemoglobin, and white blood cell counts. As a part of maintenance therapy, providers should evaluate calcium, potassium, sodium, magnesium, and phosphorus levels weekly. Foscarnet can cause hypokalemic hyperchloremic metabolic acidosis.[23] Various symptoms, such as muscle twitching and anxiety, warrant more frequent monitoring of electrolyte levels.[24] Monitoring calcium ion status is especially useful for detecting renal dysfunction during the early period of foscarnet administration.[25] 

The frequency of monitoring may vary depending on the patient's specific medical history and treatment course. Clinicians should also check the patient's hydration status before initiating the infusion of foscarnet to avoid symptoms like nausea. Lastly, the patient and provider should monitor for signs of hypersensitivity reactions with foscarnet to prevent complications. Dosing the drug appropriately, depending on the patient's medical history and current drug tolerance status, is crucial.

Toxicity

Signs and Symptoms of Overdose

Clinical features of foscarnet toxicity include seizures, nephrotoxicity, paresthesias, and electrolyte imbalances. Severe overdose may result in coma and fatal respiratory or cardiac arrest.

Management of Overdose

To prevent irreversible damage, the patient should have frequent bloodwork and constant monitoring for renal impairment, electrolyte derangement, and seizures in overdose situations. The risk of nephrotoxicity can be mitigated by concurrent administration of 0.9% normal saline (about 0.5 to 1.0 L) or dextrose 5% water solution. While a history of chronic renal disease can increase the risk of foscarnet toxicity, it is also important to withhold the administration of other potentially nephrotoxic drugs such as ACE inhibitors, angiotensin II receptor blockers, amphotericin B, vancomycin, or aminoglycosides to reduce the risk of additional renal damage.[26][27] While there is no particular antidote for foscarnet overdose, it can be prevented through adequate prophylactic hydration or urgent hemodialysis to decrease drug plasma levels.

Enhancing Healthcare Team Outcomes

Managing the administration of foscarnet to immunocompromised individuals infected with HSV, CMV, or VZV viruses requires an interprofessional team effort by healthcare professionals comprised of physicians, nurses, lab technicians, infectious disease specialists, pharmacists, and social workers. Such a team would be able to enhance the optimal outcomes during the administration of this drug. Prompt action in the diagnosis of infection and administration of the drug is fundamental to the optimal efficacy of this therapy.[28]

Additionally, since this drug is not available orally and is administered most commonly via intravenous routes, it is of utmost importance to have the team involved with consistently monitoring the drug’s effect on the patient’s condition, especially during dosing changes.[29] Potential obstacles to ineffective therapy with foscarnet include inefficient interprofessional communication between team members, inconsistency in surveillance of the patient’s progress with the treatment, or concurrent usage of drugs that may interfere with foscarnet therapy.[30] 

Compliance and overdose are aspects of the medication that require emphasis during patient education. The education should come from all team members, such as physicians, specialists, nurses, and pharmacists. Since appropriate dosing of this drug is very crucial, clinicians must always be on the same page with the individualized aspect of therapy: the patient’s past medical history, inpatient and outpatient medication list, and changes in dosages of the foscarnet therapy regimen should always be available and consistent between all of them. With renal dysfunction being a major concern associated with this drug, the interprofessional team needs to monitor renal function.[31][18] Consultation with nephrology is recommended in cases of foscarnet overdose or nephrotoxicity.

Upon completion of therapy, the patient’s primary care physician or infectious disease physician must schedule follow-up visits to assess remission status versus recurrence; this is a crucial part of treatment as it catches any early recurrence of disease and prevents the need to reinitiate therapy (thereby exposing the patient to more adverse effects). An interprofessional team approach and communication among clinicians are crucial to decreasing potential adverse effects, improving disease course, and improving patient outcomes related to foscarnet therapy.