March 26, 2017
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Foscavir

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Foscavir

FOSCAVIR®
(foscarnet sodium) Injection




WARNING

RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF FOSCAVIR. FREQUENT MONITORING OF SERUM CREATININE, WITH DOSE ADJUSTMENT FOR CHANGES IN RENAL FUNCTION, AND ADEQUATE HYDRATION WITH ADMINISTRATION OF FOSCAVIR IS IMPERATIVE. (See Administration; Hydration.)

SEIZURES, RELATED TO ALTERATIONS IN PLASMA MINERALS AND ELECTROLYTES, HAVE BEEN ASSOCIATED WITH FOSCAVIR TREATMENT. THEREFORE, PATIENTS MUST BE CAREFULLY MONITORED FOR SUCH CHANGES AND THEIR POTENTIAL SEQUELAE. MINERAL AND ELECTROLYTE SUPPLEMENTATION MAY BE REQUIRED.

FOSCAVIR IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIRRESISTANT HSV INFECTIONS. (See INDICATIONS).

DRUG DESCRIPTION

FOSCAVIR is the brand name for foscarnet sodium. The chemical name of foscarnet sodium is phosphonoformic acid, trisodium salt. Foscarnet sodium is a white, crystalline powder containing 6 equivalents of water of hydration with an empirical formula of Na3CO5P•6 H2O and a molecur weight of 300.1. The Structural formula is:

FOSCAVIR® (foscarnet sodium) Structural Formula Illustration

FOSCAVIR has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. FOSCAVIR INJECTION is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of FOSCAVIR contains 24 mg of foscarnet sodium hexahydrate in Water for Injection, USP. Hydrochloric acid may have been added to adjust the pH of the solution to 7.4. FOSCAVIR INJECTION contains no preservatives.

Virology

Mechanism Of Action

Foscarnet exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases.

Antiviral Activity In Cell Culture

The quantitative relationship between the cell culture susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to foscarnet and clinical response to therapy has not been established and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their EC50 values are listed below (Table 1). The combination antiviral activity of foscarnet and ganciclovir or acyclovir are not antagonistic in cell culture.

TABLE 1
Foscarnet Inhibition of Virus Replication in Cell Culture

Virus EC50 value (μM)
CMV 50-800*
Ganciclovir resistant CMV 190
HSV-1, HSV-2 10-130
HSV-TK negative mutant 67
HSV-DNA polymerase mutants 5-443
*Mean = 269 ìM

Antiviral Activity In Vivo

Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of subjects treated with FOSCAVIR. Although median time to progression of CMV retinitis was increased in subjects treated with FOSCAVIR, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual subjects (Table 2).

TABLE 2
Blood and Urine Culture Results from CMV Retinitis Patients*

Blood +CMV -CMV
Baseline 27 34
End of Induction 1 60
Urine +CMV -CMV
Baseline 52 6
End of Induction 21 37
*A total of 77 subjects were treated with FOSCAVIR in two clinical trials (FOS-03 and ACTG-015/915). Not all subjects had blood or urine cultures done and some subjects had results from both cultures.
(60 mg/kg FOSCAVIR TID for 2–3 weeks).

Resistance

Cell culture: CMV and HSV isolates with reduced susceptibility to foscarnet have been selected in cell culture by passage of wild type virus in the presence of increasing concentrations of the drug. All foscarnet resistant isolates are known to be generated through amino acid substitutions in the viral DNA polymerase pUL54 (CMV) or pUL30 (HSV) (Table 3).

TABLE 3
Summary of Foscarnet Resistance-associated DNA Polymerase Amino Acid

CMV pUL54 T419M, T552N, S585A, F595I, Q807A, M844T/V, V946L
HSV-1 pUL30 Y577H, E597D, A605V, L702H, V714M, L774F, L788M, D780N, L782I, P797T, L802F, V813M, V817M, Y818C, T821M, R842S, S889A, F891C, V892M, D907V, A910V, SRA914-916LCV, V958L, R959H
HSV-2 pUL30 -

In vivo: Limited clinical data are available on the development of clinical resistance to foscarnet and many pathways to resistance likely exist. Substitutions documented in the literature in treated patients as associated with foscarnet resistance, are listed in Table 4.

TABLE 4
Summary of Foscarnet Resistance-associated Amino Acid Substitutions

CMV pUL54 N495K, Q578H/L, D588E/N, T700A, V715M, E756D/K/Q, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, T838A, G841A/S, del 981-982
HSV-1 pUL30 S599L, D672N, R700G, V715G, A719T/V, S724N, E798K, G841C/S, A910T, Y941H
HSV-2 pUL30 A724T, S725G, S729N, Q732R, L783M, D785N, T844I, L850I, D912V
Note: Many additional pathways to foscarnet resistance likely exist

The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Cross-Resistance: The amino acid substitutions that resulted in reduced susceptibility to foscarnet and either ganciclovir, acyclovir and/or cidofovir are summarized in Tables 5 and 6.

TABLE 5
Summary of CMV DNA polymerase Amino Acid Substitutions Conferring

Cross-resistant to ganciclovir CMV pUL54 Q578H, D588N, E756K, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982
Cross-resistant to cidofovir CMV pUL54 Q578H, D588N, E756K, L773V, V812L, T813S, A834P, G841A, del 981-982

TABLE 6
Summary of HSV DNA polymerase Amino Acid Substitutions Conferring Foscarnet Resistance with Cross-Resistance to Acyclovir and/or Cidofovir

Cross-resistant to acyclovir HSV-1 pUL30 E597D, S599L, A605V, D672N, R700G, L702H, V714M, V715G, A719T/V, S724N, L774F, L778M, D780N, L782I, P797T, E798K, L802F, V813M, V817M, Y818C, T821M, G841C/S, R842S, S889A, F891C/Y, V892M, D907V, A910V/T, SRA914-916LCV, Y941H, V958L, V959H
HSV-2 pUL30 A724T, S725G, S729N, Q732R, L783M, D785N, T844I, D912V
Marginally cross-resistant to cidofovir HSV-1 pUL30 V714M, A719V, S724N, L778M, L802F, Y818C, T821M, G841S
HSV-2 pUL30 L783M

What are the possible side effects of foscarnet (Foscavir)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using foscarnet and call your doctor at once if you have any of these serious side effects:

  • urinating less than usual or not at all;
  • drowsiness, confusion, mood changes, increased thirst, loss of appetite, nausea and vomiting;
  • swelling, weight gain, feeling short of breath;
  • numbness or tingling around your mouth or in your hands or feet;
  • dry mouth, increased thirst, restless...

Read All Potential Side Effects and See Pictures of Foscavir »

What are the precautions when taking foscarnet sodium injection (Foscavir)?

Before using foscarnet, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, kidney disease (including being on dialysis), dehydration, low electrolyte levels (calcium, magnesium, potassium, phosphate), nervous system problems (e.g., seizure history), heart disease, a low sodium diet.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic...

Read All Potential Precautions of Foscavir »

Last reviewed on RxList: 3/13/2017
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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