Foscavir Prescribing Information
Hydration may reduce the risk of nephrotoxicity. Clinically dehydrated patients should have their condition corrected before initiating FOSCAVIR therapy. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90–120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. 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 FOSCAVIR.
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.
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 contraindicated in patients with clinically significant hypersensitivity to foscarnet sodium.
THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see
THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see ADVERSE REACTIONSsection). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during FOSCAVIR treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORINGsection). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of FOSCAVIR. 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 FOSCAVIR 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 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90-120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. 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 FOSCAVIR.
FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONSsection). FOSCAVIR 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 MONITORINGand Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of FOSCAVIR infusion may also affect the decrease in ionized calcium.
Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR 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.
Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving FOSCAVIR (see ADVERSE REACTIONSsection). If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted.
FOSCAVIR 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 postmarketing surveillance for FOSCAVIR (see ADVERSE REACTIONSsection). Some of these patients had confounding risk factors such as underlying cardiac disease, electrolyte abnormalities and other concomitant medications.
Use with caution in patients who have a history of QT prolongation, in patients who are taking medications known to prolong the QT interval (see PRECAUTIONSsection), in patients with electrolyte disturbances, or in patients who have other risk factors for QT prolongation. Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with FOSCAVIR.
FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia (15-30%), hypophosphatemia (8–26%) and hyperphosphatemia (6%), hypomagnesemia (15–30%), and hypokalemia (16–48%) (see
THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see ADVERSE REACTIONSsection). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during FOSCAVIR treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORINGsection). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of FOSCAVIR. 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 FOSCAVIR 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 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90-120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. 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 FOSCAVIR.
FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONSsection). FOSCAVIR 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 MONITORINGand Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of FOSCAVIR infusion may also affect the decrease in ionized calcium.
Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR 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.
Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving FOSCAVIR (see ADVERSE REACTIONSsection). If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted.
FOSCAVIR 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 postmarketing surveillance for FOSCAVIR (see ADVERSE REACTIONSsection). Some of these patients had confounding risk factors such as underlying cardiac disease, electrolyte abnormalities and other concomitant medications.
Use with caution in patients who have a history of QT prolongation, in patients who are taking medications known to prolong the QT interval (see PRECAUTIONSsection), in patients with electrolyte disturbances, or in patients who have other risk factors for QT prolongation. Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with FOSCAVIR.
FOSCAVIR treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies (see
THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see ADVERSE REACTIONSsection). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during FOSCAVIR treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORINGsection). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of FOSCAVIR. 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 FOSCAVIR 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 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90-120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. 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 FOSCAVIR.
FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONSsection). FOSCAVIR 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 MONITORINGand Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of FOSCAVIR infusion may also affect the decrease in ionized calcium.
Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR 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.
Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving FOSCAVIR (see ADVERSE REACTIONSsection). If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted.
FOSCAVIR 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 postmarketing surveillance for FOSCAVIR (see ADVERSE REACTIONSsection). Some of these patients had confounding risk factors such as underlying cardiac disease, electrolyte abnormalities and other concomitant medications.
Use with caution in patients who have a history of QT prolongation, in patients who are taking medications known to prolong the QT interval (see PRECAUTIONSsection), in patients with electrolyte disturbances, or in patients who have other risk factors for QT prolongation. Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with FOSCAVIR.
In controlled clinical trials performed in the United States, overdosage with FOSCAVIR 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 FOSCAVIR. Some of these post-marketing reports were relative overdoses in that the dose of FOSCAVIR had not been adjusted in patients with a reduced renal function. The pattern of adverse events associated with a FOSCAVIR overdose is consistent with the known adverse event profile of the drug.
There is no specific antidote for FOSCAVIR overdose. Hemodialysis and hydration may be of benefit in reducing drug plasma levels in patients who receive an overdosage of FOSCAVIR, 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.
In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in
n = 189 | n = 189 | ||
Fever | 65% | Abnormal Renal Function | 27% |
Nausea | 47% | Vomiting | 26% |
Anemia | 33% | Headache | 26% |
Diarrhea | 30% | Seizures | 10% |
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
n = 189 | |
Death | 14% |
Abnormal Renal Function | 14% |
Marrow Suppression | 10% |
Anemia | 9% |
Seizures | 7% |
THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT (see ADVERSE REACTIONSsection). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during FOSCAVIR treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORINGsection). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of FOSCAVIR. 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 FOSCAVIR 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 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90-120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. 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 FOSCAVIR.
FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONSsection). FOSCAVIR 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 MONITORINGand Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of FOSCAVIR infusion may also affect the decrease in ionized calcium.
Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR 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.
Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving FOSCAVIR (see ADVERSE REACTIONSsection). If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted.
FOSCAVIR 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 postmarketing surveillance for FOSCAVIR (see ADVERSE REACTIONSsection). Some of these patients had confounding risk factors such as underlying cardiac disease, electrolyte abnormalities and other concomitant medications.
Use with caution in patients who have a history of QT prolongation, in patients who are taking medications known to prolong the QT interval (see PRECAUTIONSsection), in patients with electrolyte disturbances, or in patients who have other risk factors for QT prolongation. Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with FOSCAVIR.
n = 189 | |
Death | 14% |
Abnormal Renal Function | 14% |
Marrow Suppression | 10% |
Anemia | 9% |
Seizures | 7% |
From the five initial U.S. controlled trials of FOSCAVIR, the following list of adverse events has been compiled regardless of causal relationship to FOSCAVIR. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications.
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
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.