FOSCAVIR

FOSCAVIR- foscarnet sodium injection
AstraZeneca LP

BOXED 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 section; 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 ACYCLOVIR-RESISTANT HSV INFECTIONS. (See INDICATIONS and USAGE section.)

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 Na3 CO5 P•6 H2 0 and a molecular weight of 300.1. The structural formula is:

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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 and/or sodium hydroxide may have been added to adjust the pH of the solution to 7.4. FOSCAVIR INJECTION contains no preservatives.

VIROLOGY

Mechanism of Action:

FOSCAVIR is an organic analogue of inorganic pyrophosphate that inhibits replication of herpesviruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).

FOSCAVIR 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. FOSCAVIR does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to FOSCAVIR. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to FOSCAVIR and may not respond to therapy with FOSCAVIR. The combination of FOSCAVIR and ganciclovir has been shown to have enhanced activity in vitro.

Antiviral Activity in vitro and in vivo:

The quantitative relationship between the in vitro susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to FOSCAVIR 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 (IC50 ), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their IC50 values are listed below (Table 1).

TABLE 1 FOSCARNET Inhibition of virus multiplication in cell culture
*
Mean = 269 µm

Virus

IC50 (μM)

CMV

50-800*

HSV-1, HSV-2

10-130

Ganciclovir resistant CMV

190

HSV-TK negative mutant

67

HSV-DNA polymerase mutants

5 — 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 patients treated with FOSCAVIR. Although median time to progression of CMV retinitis was increased in patients treated with FOSCAVIR, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual patients.

TABLE 2 BLOOD AND URINE CULTURE RESULTS FROM CMV RETINITIS PATIENTS *
*
A total of 77 patients were treated with FOSCAVIR in two clinical trials (FOS-03 and ACTG-015/915). Not all patients had blood or urine cultures done and some patients had results from both cultures.
(60mg/kg FOSCAVIR TID for 2-3 weeks)

Blood

+CMV

-CMV

Baseline

27

34

End of Induction

1

60

Urine

+CMV

-CMV

Baseline

52

6

End of Induction

21

37

Resistance:

Strains of both HSV and CMV that are resistant to FOSCAVIR can be readily selected in vitro by passage of wild type virus in the presence of increasing concentrations of the drug. All FOSCAVIR resistant mutants are known to be generated through mutation in the viral DNA polymerase gene. CMV strains with double mutations conferring resistance to both FOSCAVIR and ganciclovir have been isolated from patients with AIDS. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

CLINICAL PHARMACOLOGY

Pharmacokinetics:

The pharmacokinetics of foscarnet has been determined after administration as an intermittent intravenous infusion during induction therapy in AIDS patients with CMV retinitis. Observed plasma foscarnet concentrations in four studies (FOS-01, ACTG-015, FP48PK, FP49PK) are summarized in Table 3:

TABLE 3 Foscarnet Pharmacokinetic Characteristics *
*
Values expressed as mean ± S.D. (number of subjects studied) for each parameter
50 mg/kg Q8h for 28 days, samples taken 3 hrs after end of 1 hr infusion (Astra Report 815–04 AC025–1)
90 mg/kg Q12h for 28 days, samples taken 1 hr after end of 2 hr infusioin (Hengge et al., 1993)

Parameter

60 mg/kg Q8h

90 mg/kg Q12h

Cmax at steady-state (μΜ)

589 ± 192 (24)

623 ± 132 (19)

Ctrough at steady-state (μΜ)

114 ± 91 (24)

63 ± 57 (17)

Volume of Distribution (L/kg)

0.41 ± 0.13 (12)

0.52 ± 0.20 (18)

Plasma half-life (hr)

4.0 ±2.0 (24)

3.3 ± 1.4 (18)

Systemic clearance (L/hr)

6.2 ± 2.1 (24)

7.1± 2.7 (18)

Renal clearance (L/hr)

5.6 ± 1.9 (5)

6.4 ± 2.5 (13)

CSF: plasma ratio

0.69 ± 0.19(9)

0.66± 0.11(5)

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