Foscarnet (Page 5 of 7)

OVERDOSAGE

In controlled clinical trials performed in the United States, overdosage with foscarnet was reported in 10 out of 189 patients. All 10 patients experienced adverse events and all except one made a complete recovery. One patient died after receiving a total daily dose of 12.5 g for three days instead of the intended 10.9 g. The patient suffered a grand mal seizure and became comatose. Three days later the patient expired with the cause of death listed as respiratory/cardiac arrest. The other nine patients received doses ranging from 1.14 times to 8 times their recommended doses with an average of 4 times their recommended doses. Overall, three patients had seizures, three patients had renal function impairment, four patients had paresthesias either in limbs or periorally, and five patients had documented electrolyte disturbances primarily involving calcium and phosphate.

Overdose (up to 20 times the recommended dose) has been reported in post-marketing use of foscarnet. Some of these post-marketing reports were relative overdoses in that the dose of foscarnet had not been adjusted in patients with a reduced renal function. The pattern of adverse events associated with a foscarnet overdose is consistent with the known adverse event profile of the drug.

There is no specific antidote for foscarnet overdose. Hemodialysis and hydration may be of benefit in reducing drug plasma levels in patients who receive an overdosage of foscarnet, but the effectiveness of these interventions has not been evaluated. The patient should be observed for signs and symptoms of renal impairment and electrolyte imbalance. Medical treatment should be instituted if clinically warranted.

DOSAGE AND ADMINISTRATION

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

Instructions for Administration and Preparation

Foscarnet Sodium Injection is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The rate of infusion must be no more than 1 mg/kg/minute. An individualized dose of Foscarnet Sodium Injection should be calculated on the basis of body weight (mg/kg), renal function, indication of use and dosing frequency (refer to DOSAGE subsection). 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.

An individualized dose at the required concentration (24 mg per mL or 12 mg per mL) for the route of administration (central line or peripheral line) needs to be aseptically prepared prior to dispensing. The standard 24 mg per 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 per mL injection must be diluted to a 12 mg per mL concentration with 5% dextrose in water or with a normal saline solution prior to administration to avoid local irritation of peripheral veins. 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.

Hydration

Hydration may reduce the risk of nephrotoxicity. Clinically dehydrated patients should have their condition corrected before initiating Foscarnet Sodium Injection therapy. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of Foscarnet Sodium Injection to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90–120 mg/kg of Foscarnet Sodium Injection, and 500 mL with 40–60 mg/kg of Foscarnet Sodium Injection. Hydration fluid may need to be decreased if clinically warranted. Oral rehydration with similar regimens may be considered in certain patients.

After the first dose, the hydration fluid should be administered concurrently with each infusion of Foscarnet Sodium Injection.

Compatibility With Other Solutions/Drugs

Other drugs and supplements can be administered to a patient receiving Foscarnet Sodium Injection. However, care must be taken to ensure that Foscarnet Sodium Injection is only administered with normal saline 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 proclorperazine. 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 Injection for patients with normal renal function is:

  • For CMV retinitis patients, either 90 mg/kg (1-1/2 to 2 hour infusion) every twelve hours or 60 mg/kg (minimum one hour infusion) every eight hours over 2-3 weeks depending on clinical response.
  • For acyclovir-resistant HSV patients, 40 mg/kg (minimum one hour infusion) either every 8 or 12 hours for 2-3 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 Injection 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 Injection 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 Injection maintenance therapy may be retreated with the induction and maintenance regimens given above or with a combination of foscarnet and ganciclovir (see CLINICAL TRIALS section). Because of physical incompatibility, foscarnet and ganciclovir must NOT be mixed.

Use in Patients with Abnormal Renal Function

Foscarnet Sodium Injection 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 Injection 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 Injection as outlined below (see Dose Adjustment and PATIENT MONITORING). During Foscarnet Sodium Injection therapy if creatinine clearance falls below the limits of the dosing nomograms (0.4 mL/min/kg), Foscarnet Sodium Injection should be discontinued, the patient hydrated, and monitored daily until resolution of renal impairment is ensured.

Foscarnet Sodium Injection is not recommended in patients undergoing hemodialysis because dosage guidelines have not been established.

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