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Foscarnet (Foscarnet Sodium) - Warnings and Precautions

 
 



WARNING

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

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

FOSCARNET SODIUM INJECTION IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR-RESISTANT HSV INFECTIONS. (See INDICATIONS section.)

 

WARNINGS

Renal Impairment: THE MAJOR TOXICITY OF FOSCARNET SODIUM IS RENAL IMPAIRMENT (see ADVERSE REACTIONS section). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during foscarnet sodium treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORING section). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of foscarnet sodium injection. Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances <50 mL/min are limited.

SINCE FOSCARNET SODIUM HAS THE POTENTIAL TO CAUSE RENAL IMPAIRMENT, DOSE ADJUSTMENT BASED ON SERUM CREATININE IS NECESSARY. Hydration may reduce the risk of nephrotoxicity. It is recommended that 750 to 1000 mL of 0.9% sodium chloride injection or 5% dextrose solution should be given prior to the first infusion of foscarnet sodium to establish diuresis. With subsequent infusions, 750 to 1000 mL of hydration fluid should be given with 90 to 120 mg/kg of foscarnet sodium, and 500 mL with 40 to 60 mg/kg of foscarnet sodium. Hydration fluid may need to be decreased if clinically warranted.

After the first dose, the hydration fluid should be administered concurrently with each infusion of foscarnet sodium.

Mineral and Electrolyte Abnormalities: Foscarnet sodium has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONS section). Foscarnet sodium may also be associated with a dose-related decrease in ionized serum calcium which may not be reflected in total serum calcium. This effect is likely to be related to chelation of divalent metal ions such as calcium by foscarnet. Patients should be advised to report symptoms of low ionized calcium such as perioral tingling, numbness in the extremities and paresthesias. Particular caution and careful management of serum electrolytes is advised in patients with altered calcium or other electrolyte levels before treatment and especially in those with neurologic or cardiac abnormalities and those receiving other drugs known to influence minerals and electrolytes (see PATIENT MONITORING and Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of foscarnet sodium infusion may also affect the decrease in ionized calcium. Therefore, an infusion pump must be used for administration to prevent rapid intravenous infusion ( see DOSAGE AND ADMINISTRATION section ) . Slowing the infusion rate may decrease or prevent symptoms.

Seizures: Seizures related to mineral and electrolyte abnormalities have been associated with foscarnet sodium treatment (see WARNING section; Mineral and Electrolyte Abnormalities ). Several cases of seizures were associated with death. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions.

PRECAUTIONS

General:

Care must be taken to infuse solutions containing foscarnet sodium 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 foscarnet sodium, possibly related to the presence of drug in the urine. Cases of male and female genital irritation/ulceration have been reported in patients receiving foscarnet. Adequate hydration with close attention to personal hygiene may minimize the occurrence of such events.

Hemopoietic System: Anemia has been reported in 33% of patients receiving foscarnet sodium in controlled studies. Granulocytopenia has been reported in 17% of patients receiving foscarnet sodium in controlled studies; however, only 1% (2/189) were terminated from these studies because of neutropenia.

Information for Patients

CMV Retinitis: Patients should be advised that foscarnet sodium 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 foscarnet sodium 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 foscarnet sodium 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.

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. Should such symptoms occur, the infusion of foscarnet sodium injection 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 real impairment may be minimized by accompanying foscarnet sodium injection administration with hydration adequate to establish and maintain a diuresis during dosing.

Drug Interactions:

A possible drug interaction of foscarnet sodium and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with foscarnet sodium 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.

Since foscarnet decreases serum concentrations of ionized calcium, concurrent treatment with other drugs known to influence serum calcium concentrations should be used with particular caution. Fatalities have been reported in post-marketing surveillance during concomitant therapy with foscarnet and pentamidine.

Because of foscarnet’s tendency to cause renal impairment, the use of foscarnet sodium should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient.

Abnormal renal function has been observed in clinical practice during the use of foscarnet sodium and ritonavir, or foscarnet sodium, ritonavir, and saquinavir. (See DOSAGE AND ADMINISTRATION ).

Ganciclovir: 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailabilty 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).

Foscarnet sodium 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.

Pregnancy:

Teratogenic Effect

Pregnancy, Category C: Foscarnet sodium 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.

There are no adequate and well controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, foscarnet sodium injection should be used during pregnancy only if clearly needed.

Nursing Mothers:

It is not known whether foscarnet sodium is excreted in human milk; however, in lactating rats administered 75 mg/kg, foscarnet sodium was excreted in maternal milk at concentrations three times higher than peak maternal blood concentrations.

Pediatric Use:

The safety and effectiveness of foscarnet sodium in pediatric patients have not been established. Foscarnet sodium is deposited in teeth and bone and deposition is greater in young and growing animals. Foscarnet sodium 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.

Geriatric Use:

No studies of the efficacy or safety of foscarnet sodium in persons 65 years of age or older have been conducted. However, foscarnet sodium 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 .)

Page last updated: 2009-09-28

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