DailyMed Label: Foscavir

DailyMed Label: Foscavir

2023

DailyMed Prescription

Foscavir

foscarnet sodium

Clinigen Limited

NDC: 76310-024

NDC: 76310-024

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 Na 3 CO 5 P• 6 H 2 O and a molecular weight of 300.1. The structural formula is: 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. structural formula

FOSCAVIR is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Combination therapy with FOSCAVIR and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug. SAFETY AND EFFICACY OF FOSCAVIR HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (e.g., PNEUMONITIS, GASTROENTERITIS); CONGENITAL OR NEONATAL CMV DISEASE; OR NONIMMUNOCOMPROMISED INDIVIDUALS. FOSCAVIR is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. SAFETY AND EFFICACY OF FOSCAVIR HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER HSV INFECTIONS (e.g., RETINITIS, ENCEPHALITIS); CONGENITAL OR NEONATAL HSV DISEASE; OR HSV IN NONIMMUNOCOMPROMISED INDIVIDUALS.

CAUTION - DO NOT ADMINISTER FOSCAVIR BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF FOSCAVIR MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS. CARE SHOULD BE TAKEN TO AVOID UNINTENTIONAL OVERDOSE BY CAREFULLY CONTROLLING THE RATE OF INFUSION. THEREFORE, AN INFUSION PUMP MUST BE USED. IN SPITE OF THE USE OF AN INFUSION PUMP, OVERDOSES HAVE OCCURRED.

FOSCAVIR is contraindicated in patients with clinically significant hypersensitivity to foscarnet sodium.

Care must be taken to infuse solutions containing FOSCAVIR only into veins with adequate blood flow to permit rapid dilution and distribution to avoid local irritation (see DOSAGE AND ADMINISTRATION ). Local irritation and ulcerations of penile epithelium have been reported in male patients receiving FOSCAVIR, possibly related to the presence of drug in the urine. Cases of male and female genital irritation/ulceration have been reported in patients receiving FOSCAVIR. Adequate hydration with close attention to personal hygiene may minimize the occurrence of such events. Due to the sodium content of FOSCAVIR (240 micromoles (5.5 mg) of sodium per mL), avoid FOSCAVIR use when intravenous infusion of a large amount of sodium or water may not be tolerated (e.g. in patients with cardiomyopathy). FOSCAVIR should also be avoided in patients on a controlled sodium diet. Anemia has been reported in 33% of patients receiving FOSCAVIR in controlled studies. Granulocytopenia has been reported in 17% of patients receiving FOSCAVIR in controlled studies; however, only 1% (2/189) were terminated from these studies because of neutropenia. CMV Retinitis: Patients should be advised that FOSCAVIR is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during or following treatment. They should be advised to have regular ophthalmologic examinations. Mucocutaneous Acyclovir-Resistant HSV Infections: Patients should be advised that FOSCAVIR is not a cure for HSV infections. While complete healing is possible, relapse occurs in most patients. Because relapse may be due to acyclovir-sensitive HSV, sensitivity testing of the viral isolate is advised. In addition, repeated treatment with FOSCAVIR has led to the development of resistance associated with poorer response. In the case of poor therapeutic response, sensitivity testing of the viral isolate also is advised. Effects on Ability to Drive and Use Machines: Adverse effects such as dizziness and convulsions may occur during FOSCAVIR therapy. Patients who experience seizures, dizziness, somnolence or other adverse reactions that could result in impairment, should be advised to avoid driving or operating machinery. General: Patients should be informed that the major toxicities of foscarnet are renal impairment, electrolyte disturbances, and seizures, and that dose modifications and possibly discontinuation may be required. The importance of close monitoring while on therapy must be emphasized. Patients should be advised of the importance of reporting to their physicians symptoms of perioral tingling, numbness in the extremities or paresthesias during or after infusion as possible symptoms of electrolyte abnormalities. Patients should also be advised to promptly report any cardiac symptoms. Should such symptoms occur, the infusion of FOSCAVIR should be stopped, appropriate laboratory samples for assessment of electrolyte concentrations obtained, and a physician consulted before resuming treatment. The rate of infusion must be no more than 1 mg/kg/minute. The potential for renal impairment may be minimized by accompanying FOSCAVIR administration with hydration adequate to establish and maintain a diuresis during dosing. A possible drug interaction of FOSCAVIR and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with FOSCAVIR and intravenous pentamidine may have caused hypocalcemia; one patient died with severe hypocalcemia. Toxicity associated with concomitant use of aerosolized pentamidine has not been reported. Because FOSCAVIR can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels (e.g., intravenous pentamidine). Renal impairment and symptomatic hypocalcemia have been observed during concurrent treatment with FOSCAVIR and intravenous pentamidine. Because of foscarnet's tendency to cause renal impairment, the use of FOSCAVIR should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B, cyclosporine, acyclovir, methotrexate, tacrolimus and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient. When diuretics are indicated, thiazides are recommended over loop diuretics because the latter inhibit renal tubular secretion, and may impair elimination of FOSCAVIR, potentially leading to toxicity. Abnormal renal function has been observed in clinical practice during the use of FOSCAVIR and ritonavir, or FOSCAVIR, ritonavir, and saquinavir. (See DOSAGE and ADMINISTRATION. ) Because of the risk of QT prolongation and the potential for torsades de pointes, the use of FOSCAVIR should be avoided in combination with agents known to prolong the QT interval including Class IA (e.g., quinidine or procainamide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents, phenothiazines, tricyclic antidepressants, and certain macrolides and fluoroquinolones. Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailability in unfasted rodents is < 20%. No evidence of oncogenicity was reported at plasma drug levels equal to 1/3 and 1/5, respectively, of those in humans (at the maximum recommended human daily dose) as measured by the area-under-the-time/concentration curve (AUC). FOSCAVIR showed genotoxic effects in the BALB/3T3 in vitro transformation assay at concentrations greater than 0.5 mcg/mL and an increased frequency of chromosome aberrations in the sister chromatid exchange assay at 1000 mcg/mL. A high dose of foscarnet (350 mg/kg) caused an increase in micronucleated polychromatic erythrocytes in vivo in mice at doses that produced exposures (area under curve) comparable to that anticipated clinically. ​There are no adequate and well-controlled studies of FOSCAVIR in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal Data: FOSCAVIR did not adversely affect fertility and general reproductive performance in rats. The results of peri- and post-natal studies in rats were also negative. However, these studies used exposures that are inadequate to define the potential for impairment of fertility at human drug exposure levels. Daily subcutaneous doses up to 75 mg/kg administered to female rats prior to and during mating, during gestation, and 21 days post-partum caused a slight increase (< 5%) in the number of skeletal anomalies compared with the control group. Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation caused an increase in the frequency of skeletal anomalies/variations. On the basis of estimated drug exposure (as measured by AUC), the 150 mg/kg dose in rats and 75 mg/kg dose in rabbits were approximately one-eighth (rat) and one-third (rabbit) the estimated maximal daily human exposure. These studies are inadequate to define the potential teratogenicity at levels to which women will be exposed. It is not known whether FOSCAVIR is excreted in human milk; however, in lactating rats administered 75 mg/kg, FOSCAVIR was excreted in maternal milk at concentrations three times higher than peak maternal blood concentrations. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. The safety and effectiveness of FOSCAVIR in pediatric patients have not been established. FOSCAVIR is deposited in teeth and bone and deposition is greater in young and growing animals. FOSCAVIR has been demonstrated to adversely affect development of tooth enamel in mice and rats. The effects of this deposition on skeletal development have not been studied. Since deposition in human bone has also been shown to occur, it is likely that it does so to a greater degree in developing bone in pediatric patients. Administration to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits for treatment outweigh the risks. No studies of the efficacy or safety of FOSCAVIR in persons 65 years of age or older have been conducted. However, FOSCAVIR has been used in patients age 65 years of age and older. The pattern of adverse events seen in these patients is consistent across all age groups. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. (See DOSAGE AND ADMINISTRATION ).

THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see

A possible drug interaction of FOSCAVIR and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with FOSCAVIR and intravenous pentamidine may have caused hypocalcemia; one patient died with severe hypocalcemia. Toxicity associated with concomitant use of aerosolized pentamidine has not been reported. Because FOSCAVIR can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels (e.g., intravenous pentamidine). Renal impairment and symptomatic hypocalcemia have been observed during concurrent treatment with FOSCAVIR and intravenous pentamidine. Because of foscarnet's tendency to cause renal impairment, the use of FOSCAVIR should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B, cyclosporine, acyclovir, methotrexate, tacrolimus and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient. When diuretics are indicated, thiazides are recommended over loop diuretics because the latter inhibit renal tubular secretion, and may impair elimination of FOSCAVIR, potentially leading to toxicity. Abnormal renal function has been observed in clinical practice during the use of FOSCAVIR and ritonavir, or FOSCAVIR, ritonavir, and saquinavir. (See DOSAGE and ADMINISTRATION. ) Because of the risk of QT prolongation and the potential for torsades de pointes, the use of FOSCAVIR should be avoided in combination with agents known to prolong the QT interval including Class IA (e.g., quinidine or procainamide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents, phenothiazines, tricyclic antidepressants, and certain macrolides and fluoroquinolones.

FOSCAVIR (foscarnet sodium) INJECTION, 24 mg/mL for intravenous infusion, is supplied in 250 mL glass bottles or polypropylene based infusion bags containing 6000 mg foscarnet sodium (24 mg/mL) as follows: NDC 76310-024-15 250 mL bottle NDC 76310-024-25 250 mL bottles, cases of 10 NDC 76310-024-41 250 mL infusion bag NDC 76310-024-45 250 mL infusion bag, cases of 10 Single-dose. Discard unused portion. Store between 20° and 25°C (68° and 77°F) [See USP Controlled Room Temperature]. Protect from excessive heat (above 40°C) and from freezing. If refrigerated or exposed to temperatures below the freezing point, precipitation may occur. By keeping the bottle or infusion bag at room temperature with repeated shaking, the precipitate can be brought into solution again. FOSCAVIR INJECTION should be used only if the bottle or infusion bag and its seal(s) are intact, a vacuum is present, and the solution is clear and colorless. Do not remove the infusion bag from the overwrap until ready for use. Manufactured for: Clinigen Healthcare Ltd., DE14 2WW, UK Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA FOSCAVIR is a trademark of Clinigen Healthcare Ltd. Date of revision: October 2020 Logos

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 7 : TABLE 7 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 Q12hr for 28 days, samples taken 1 hr after end of 2 hr infusion (Hengge et al., 1993) Parameter 60 mg/kg Q8h 90 mg/kg Q12h C max at steady-state (μM) 589 ± 192 (24) 623 ± 132 (19) C trough at steady-state (μM) 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) ‡ In vitro studies have shown that 14 – 17% of foscarnet is protein bound at plasma drug concentrations of 1 – 1000 μM. The foscarnet terminal half-life determined by urinary excretion was 87.5 ± 41.8 hours, possibly due to release of foscarnet from bone. Postmortem data on several patients in European clinical trials provide evidence that foscarnet does accumulate in bone in humans; however, the extent to which this occurs has not been determined. Adults with Impaired Renal Function: The pharmacokinetic properties of foscarnet have been determined in a small group of adult subjects with normal and impaired renal function, as summarized in Table 8 : TABLE 8 Pharmacokinetic Parameters (mean ± S.D.) After a Single 60 mg/kg Dose of FOSCAVIR in 4 Groups* of Adults with Varying Degrees of Renal Function *Group 1 patients had normal renal function defined as a creatinine clearance (CrCl) of >80 mL/min, Group 2 CrCl was 50 – 80 mL/min, Group 3 CrCl was 25 – 49 mL/min and Group 4 CrCl was 10 – 24 mL/min. Parameter Group 1 (N=6) Group 2 (N=6) Group 3 (N=6) Group 4 (N=4) Creatinine clearance (mL/min) 108 ± 16 68 ± 8 34 ± 9 20 ± 4 Foscarnet CL (mL/min/kg) 2.13 ± 0.71 1.33 ± 0.43 0.46 ± 0.14 0.43 ± 0.26 Foscarnet half-life (hr) 1.93 ± 0.12 3.35 ± 0.87 13.0 ± 4.05 25.3 ± 18.7 Total systemic clearance (CL) of foscarnet decreased and half-life increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of foscarnet in patients with renal impairment (see DOSAGE AND ADMINISTRATION ). The pharmacokinetics of foscarnet and ganciclovir were not altered in 13 patients receiving either concomitant therapy or daily alternating therapy for maintenance of CMV disease. There is no clinically significant interaction with zidovudine (AZT), or probenecid.

NDC 76310-024-15 Foscavir ® (foscarnet sodium) injection 6000 mg/250 mL (24 mg/mL) For Central Intravenous Infusion Only Must Be Diluted for Peripheral Intravenous Infusion Rx only Single-dose. Discard unused portion. Mfd. for: Clinigen Healthcare Ltd., DE14 2WW, UK. Distributed by: Hospira Inc., Lake Forest, IL 60045 USA. FOSCAVIR is a trademark of Clinigen Healthcare Ltd. (Clinigen and Hospira logos) BOTTLE LABEL PRINCIPAL DISPLAY PANEL