Foscarnet (Foscarnet Sodium) - Indications and Dosage

INDICATIONS AND USAGE

CMV Retinitis: Foscarnet sodium injection is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Combination therapy with foscarnet sodium and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug. SAFETY AND EFFICACY OF FOSCARNET SODIUM HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (e.g., PNEUMONITIS, GASTROENTERITIS); CONGENITAL OR NEONATAL CMV DISEASE; OR NON-IMMUNOCOMPROMISED INDIVIDUALS.

Mucocutaneous Acyclovir-Resistant HSV Infections: Foscarnet sodium injection is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. SAFETY AND EFFICACY OF FOSCARNET SODIUM HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER HSV INFECTIONS (e.g., RETINITIS, ENCEPHALITIS); CONGENITAL OR NEONATAL HSV DISEASE; OR HSV IN NON-IMMUNOCOMPROMISED INDIVIDUALS.

DOSAGE AND ADMINISTRATION

CAUTION—DO NOT ADMINISTER FOSCARNET SODIUM BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF FOSCARNET SODIUM 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.

ADMINISTRATION

Foscarnet sodium is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The standard 24 mg/mL solution may be used with or without dilution when using a central venous catheter for infusion. When a peripheral vein catheter is used, the 24 mg/mL solution must be diluted to 12 mg/mL with 5% dextrose in water or with a 0.9% sodium chloride injection prior to administration to avoid local irritation of peripheral veins. Since the dose of foscarnet sodium is calculated on the basis of body weight, it may be desirable to remove and discard any unneeded quantity from the bottle before starting with the infusion to avoid overdosage. Dilutions and/or removals of excess quantities should be accomplished under aseptic conditions. Solutions thus prepared should be used within 24 hours of first entry into a sealed bottle. To reduce the risk of nephrotoxicity, creatinine clearance (mL/min/kg) should be calculated even if serum creatinine is within the normal range, and doses should be adjusted accordingly.

Hydration: 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.

Compatibility with Other Solutions/Drugs: Other drugs and supplements can be administered to a patient receiving foscarnet sodium. However, care must be taken to ensure that foscarnet sodium is only administered with 0.9% sodium chloride injection or 5% dextrose solution and that no other drug or supplement is administered concurrently via the same catheter. Foscarnet has been reported to be chemically incompatible with 30% dextrose, amphotericin B, and solutions containing calcium such as Ringer’s lactate and TPN. Physical incompatibility with other IV drugs has also been reported including acyclovir sodium, ganciclovir, trimetrexate glucuronate, pentamidine isethionate, vancomycin, trimethoprim/sulfamethoxazole, diazepam, midazolam, digoxin, phenytoin, leucovorin, and prochlorperazine. Because of foscarnet’s chelating properties, a precipitate can potentially occur when divalent cations are administered concurrently in the same catheter.

Parenteral drug products must be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored or contain particulate matter should not be used.

Accidental Exposure: Accidental skin and eye contact with foscarnet sodium solution may cause local irritation and burning sensation. If accidental contact occurs, the exposed area should be flushed with water.

DOSAGE

THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATES SHOULD NOT BE EXCEEDED. ALL DOSES MUST BE INDIVIDUALIZED FOR PATIENTS’ RENAL FUNCTION.

Induction Treatment: The recommended initial dose of foscarnet sodium for patients with normal renal function is:

• For CMV retinitis patients, either 90 mg/kg (1.5 to 2 hour infusion) every twelve hours or 60 mg/kg (minimum one hour infusion) every eight hours over 2 to 3 weeks depending on clinical response.

• For acyclovir-resistant HSV patients, 40 mg/kg (minimum one hour infusion) either every 8 or 12 hours for 2 to 3 weeks or until healed.

An infusion pump must be used to control the rate of infusion. Adequate hydration is recommended to establish a diuresis (see Hydration for recommendation), both prior to and during treatment to minimize renal toxicity (see WARNINGS ), provided there are no clinical contraindications.

Maintenance Treatment: Following induction treatment the recommended maintenance dose of foscarnet sodium for CMV retinitis is 90 mg/kg/day to 120 mg/kg/day (individualized for renal function) given as an intravenous infusion over 2 hours. Because the superiority of the 120 mg/kg/day has not been established in controlled trials, and given the likely relationship of higher plasma foscarnet levels to toxicity, it is recommended that most patients be started on maintenance treatment with a dose of 90 mg/kg/day. Escalation to 120 mg/kg/day may be considered should early reinduction be required because of retinitis progression. Some patients who show excellent tolerance to foscarnet sodium may benefit from initiation of maintenance treatment at 120 mg/kg/day earlier in their treatment.

An infusion pump must be used to control the rate of infusion with all doses. Again, hydration to establish diuresis both prior to and during treatment is recommended to minimize renal toxicity, provided there are no clinical contraindications (see WARNINGS ).

Patients who experience progression of retinitis while receiving foscarnet sodium maintenance therapy may be retreated with the induction and maintenance regimens given above or with a combination of foscarnet sodium injection and ganciclovir (see CLINICAL TRIALS section). Because of physical incompatibility, foscarnet sodium and ganciclovir must NOT be mixed.

Use in Patients with Abnormal Renal Function: Foscarnet sodium should be used with caution in patients with abnormal renal function because reduced plasma clearance of foscarnet will result in elevated plasma levels (see CLINICAL PHARMACOLOGY ). In addition, foscarnet sodium has the potential to further impair renal function (see WARNINGS ). 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.

Renal function must be monitored carefully at baseline and during induction and maintenance therapy with appropriate dose adjustments for foscarnet sodium as outlined below (see Dose Adjustment and PATIENT MONITORING ). During foscarnet sodium therapy if creatinine clearance falls below the limits of the dosing nomograms (0.4 mL/min/kg), foscarnet sodium should be discontinued, the patient hydrated, and monitored daily until resolution of renal impairment is ensured.

Dose Adjustment: Foscarnet sodium dosing must be individualized according to the patient’s renal function status. Refer to Table 9 for recommended doses and adjust the dose as indicated. Even patients with serum creatinine in the normal range may require dose adjustment; therefore, the dose should be calculated at baseline and frequently thereafter.

To use this dosing guide, actual 24-hour creatinine clearance (mL/min) must be divided by body weight (kg), or the estimated creatinine clearance in mL/min/kg can be calculated from serum creatinine (mg/dL) using the following formula (modified Cockcroft and Gault equation):

For males: ((140 − age) /(serum creatinine x 72)) (x 0.85 for females) = mL/min/kg

TABLE 9
Foscarnet Sodium Dosing Guide Induction
	HSV: Equivalent to		CMV: Equivalent to
	80 mg/kg/day total	120 mg/kg/day total	180 mg/kg/day total
CrCl (mL/min/kg)	(40 mg/kg Q12h)	(40 mg/kg Q8h)	(60 mg/kg Q8h)	(90 mg/kg Q12h)
>1.4	40 Q12h	40 Q8h	60 Q8h	90 Q12h
>1.0-1.4	30 Q12h	30 Q8h	45 Q8h	70 Q12h
>0.8-1.0	20 Q12h	35 Q12h	50 Q12h	50 Q12h
>0.6-0.8	35 Q24h	25 Q12h	40 Q12h	80 Q24h
>0.5-0.6	25 Q24h	40 Q24h	60 Q24h	60 Q24h
≥0.4-0.5	20 Q24h	35 Q24h	50 Q24h	50 Q24h
<0.4	Not Recommended	Not Recommended	Not Recommended	Not Recommended

MAINTENANCE
* > means “greater than”; † ≥means “greater than or equal to”; ‡ < means “less than”
	CMV: Equivalent to
CrCl (mL/min/kg)	90 mg/kg/day (once daily)	120 mg/kg/day (once daily)
>* 1.4	90 Q24h	120 Q24h
>* 1.0-1.4	70 Q24h	90 Q24h
>* 0.8-1.0	50 Q24h	65 Q24h
>* 0.6-0.8	80 Q48h	105 Q48h
>* 0.5-0.6	60 Q48h	80 Q48h
≥† 0.4-0.5	50 Q48h	65 Q48h
<‡ 0.4	Not Recommended	Not Recommended

PATIENT MONITORING

The majority of patients will experience some decrease in renal function due to foscarnet sodium administration. Therefore it is recommended that creatinine clearance, either measured or estimated using the modified Cockcroft and Gault equation based on serum creatinine, be determined at baseline, 2-3 times per week during induction therapy and at least every one to two weeks during maintenance therapy, with foscarnet sodium dose adjusted accordingly (see Dose Adjustment ). More frequent monitoring may be required for some patients. It is also recommended that a 24-hour creatinine clearance be determined at baseline and periodically thereafter to ensure correct dosing (assuming verification of an adequate collection using creatinine index). Foscarnet sodium should be discontinued if creatinine clearance drops below 0.4 mL/min/kg.

Due to foscarnet sodium’s propensity to chelate divalent metal ions and alter levels of serum electrolytes, patients must be monitored closely for such changes. It is recommended that a schedule similar to that recommended for serum creatinine (see above) be used to monitor serum calcium, magnesium, potassium and phosphorus. Particular caution is advised in patients with decreased total serum calcium or other electrolyte levels before treatment, as well as in patients with neurologic or cardiac abnormalities, and in patients receiving other drugs known to influence serum calcium levels. Any clinically significant metabolic changes should be corrected. Also, patients who experience mild (e.g., perioral numbness or paresthesias) or severe (e.g., seizures) symptoms of electrolyte abnormalities should have serum electrolyte and mineral levels assessed as close in time to the event as possible.

Careful monitoring and appropriate management of electrolytes, calcium, magnesium and creatinine are of particular importance in patients with conditions that may predispose them to seizures (see WARNINGS ).

HOW SUPPLIED

Foscarnet sodium injection, 24 mg/mL for intravenous infusion, is supplied in glass bottles as follows:

NDC No.	Container	Concentration	Fill	Quantity
0409-3863–05	Bottle	24 mg/mL	500 mL	12 per Case
0409–3863–02	Bottle	24 mg/mL	250 mL	12 per Case

Foscarnet sodium injection should be used only if the bottle and seal are intact, a vacuum is present, and the solution is clear and colorless.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from excessive heat (above 40°C) and from freezing.

Revised: July, 2008

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