FOSCARNET — foscarnet sodium
Fresenius Kabi USA, LLC
Foscarnet Sodium Injection
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. (See ADMINISTRATION section; Hydration.)
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.
FOSCARNET IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR-RESISTANT HSV INFECTIONS. (See INDICATIONS section).
Foscarnet Sodium Injection is the brand name for foscarnet sodium. The chemical name of foscarnet sodium is phosphonoformic acid, trisodium salt. Foscarnet sodium is a white to almost white crystalline powder containing 6 equivalents of water of hydration with an empirical formula of Na3 CO5 P•6 H2 O and a molecular weight of 300.04. The structural formula is:
Foscarnet Sodium Injection has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. Foscarnet Sodium Injection is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of Foscarnet Sodium Injection 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. Foscarnet Sodium Injection contains no preservatives.
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.
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.
*Mean = 269 μM
|Virus||EC50 value (μM)|
|CMVGanciclovir resistant CMVHSV-1, HSV-2HSV-TK negative mutantHSV-DNA polymerase mutants||50-800*19010-130675-443|
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 foscarnet. Although median time to progression of CMV retinitis was increased in subjects treated with foscarnet, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual subjects (Table 2).
*A total of 77 subjects were treated with foscarnet 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 foscarnet TID for 2–3 weeks).
|End of Induction†||1||60|
|End of Induction†||21||37|
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).
|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|
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.
Note: Many additional pathways to foscarnet resistance likely exist
|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|
The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.
|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|
|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|
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