Foscarnet Sodium 24 mg/mL Injection — NDC 70121-1744-7 (Billing 70121-1744-07)

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. 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 mL to 1,000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of foscarnet sodium to establish diuresis. With subsequent infusions, 750 mL to 1,000 mL of hydration fluid should be given with 90 mg/kg to 120 mg/kg of foscarnet sodium, and 500 mL with 40 mg/kg 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. Cases of status epilepticus have been reported. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions.

Hypersensitivity Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported post-marketing in patients receiving foscarnet sodium (see ADVERSE REACTIONS section ). If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted. QT prolongation and torsade de pointes Foscarnet sodium has been associated with prolongation of the QT interval, an ECG abnormality that has been associated with torsades de pointes, which has been reported during post-marketing surveillance for foscarnet sodium (see ADVERSE REACTIONS section ).

Some of these patients had confounding risk factors such as underlying cardiac disease, electrolyte abnormalities and oth… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS THE MAJOR TOXICITY OF FOSCARNET SODIUM IS RENAL IMPAIRMENT (see WARNINGS section ). Approximately 33% of 189 patients with AIDS and CMV retinitis who received foscarnet sodium (60 mg/kg TID), without adequate hydration, developed significant impairment of renal function (serum creatinine ≥ 2.0 mg/dL). The incidence of renal impairment in subsequent clinical trials in which 1,000 mL of normal saline or 5% dextrose solution was given with each infusion of foscarnet sodium was 12% (34/280).

Foscarnet sodium has been associated with changes in serum electrolytes including hypocalcemia (15% to 30%), hypophosphatemia (8% to 26%) and hyperphosphatemia (6%), hypomagnesemia (15% to 30%), and hypokalemia (16% to 48%) (see WARNINGS section ). The higher percentages were derived from those patients receiving hydration. Foscarnet sodium treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies (see WARNINGS section ).

Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions predisposing the patient to seizures. The rate of seizures did not increase with duration of treatment. Three cases were associated with overdoses of foscarnet sodium (see OVERDOSAGE section ).

In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in Table 9. These figures were calculated without reference to drug relationship or severity. TABLE 9: Adverse Events Reported in Five Controlled US Clinical Trials n = 189 n = 189 Fever 65% Abnormal Renal Function 27% Nausea 47% Vomiting 26% Anemia 33% Headache 26% Diarrhea 30% Seizures 10% From the same controlled studies, adverse events categorized by investigator as “severe” are shown in Table 10.

Although death was specifically attributed to foscarnet sodium in only one case, other complications of foscarnet sodium (i.e. renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths (see WARNINGS section ). TABLE 10: Severe Adverse Events n = 189 Death 14% Abnormal Renal Function 14% Marrow Suppression 10% Anemia 9% Seizures 7% From the five initial U.S. controlled trials of foscarnet sodium, the following list of adverse events has been compiled regardless of causal relationship to foscarnet sodium.

Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications. Incidence of 5% or Greater Body as a Whole: fever, fatigue, rigors, asthenia, malaise, pain, infection, sepsis, death Central and Peripheral Nervous System : headache, paresthesia, dizziness, involuntary muscle contractions, hypoesthesia, neuropathy, seizures including grand mal seizures (see WARNINGS ) Gastrointestinal System: anorexia, nausea, diarrhea, vomiting, abdominal pain Hematologic: anemia, granulocytopenia, leukopenia, neutropenia (see PRECAUTIONS ) Metabolic and Nutritional: mineral and electrolyte imbalances (see WARNINGS ) including hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia Psychiatric: depression, confusion, anxiety Respiratory System: coughing, dyspnea Skin and Appendages: rash, increased sweating Urinary System: alterations in renal function including increased serum creatinine, decreased creatinine clearance, and abnormal renal function (see WARNINGS ) Special Senses: vision abnormalities Incidence between 1% and 5% Application Site: injection site pain, injection site inflammation Body as a Whole: back pain, chest pain (including reports of transient chest pain as part of infusion reactions), edema, influenza-like symptoms, bacterial infections, moniliasis, fungal infections, abscess Cardiovascular: hypertension, palpitations, ECG abnormalities including sinus tachycardia, first degree AV block and non-specific ST-T segment changes, hypotensi… [Excerpted — this section continues on DailyMed.]

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.

Because foscarnet sodium 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 foscarnet sodium and intravenous 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, 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 foscarnet sodium, potentially leading to toxicity. 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 ). Because of the risk of QT prolongation and the potential for torsades de pointes, the use of foscarnet sodium 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.

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 sodium.

Adequate hydration with close attention to personal hygiene may minimize the occurrence of such events. Due to the sodium content of foscarnet sodium (240 micromoles (5.5 mg) of sodium per mL), avoid foscarnet sodium use when intravenous infusion of a large amount of sodium or water may not be tolerated (e.g., in patients with cardiomyopathy). Foscarnet sodium should also be avoided in patients on a controlled sodium diet.

Hematopoietic 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.

Effects on Ability to Drive and Use Machines: Adverse effects such as dizziness and convulsions may occur during foscarnet sodium 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 foscarnet sodium 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 foscarnet sodium 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.

Because foscarnet sodium 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., int… [Excerpted — this section continues on DailyMed.]