The chemical name of Foscarnet sodium is phosphonoformic acid, trisodium salt. Foscarnet sodium is a white, crystalline powder containing 6 equivalents of water of hydration with a molecular formula of Na3CO5P•6 H2O and a molecular weight of 300.1. The structural formula is:
Foscarnet sodium has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. Foscarnet sodium injection is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of Foscarnet sodium injection contains 24 mg of Foscarnet sodium hexahydrate in Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH of the solution to 7.4. Foscarnet sodium injection contains no preservatives.
VIROLOGY
Mechanism of Action: Foscarnet sodium is an organic analogue of inorganic pyrophosphate that inhibits replication of herpesviruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).
Foscarnet sodium exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. Foscarnet sodium does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to Foscarnet sodium. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to Foscarnet sodium and may not respond to therapy with Foscarnet sodium. The combination of Foscarnet sodium and ganciclovir has been shown to have enhanced activity in vitro.
Antiviral Activity in vitro and in vivo : The quantitative relationship between the in vitro susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to Foscarnet sodium and clinical response to therapy has not been established and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their IC50 values are listed below (Table 1).
TABLE 1
|
|---|
Foscarnet Inhibition of virus multiplication in cell culture
|
|---|
Virus
|
IC50 (μM)
|
CMV
|
50-800*
|
HSV-1, HSV-2
|
10-130
|
Ganciclovir resistant CMV
|
190
|
HSV-TK negative mutant
|
67
|
HSV-DNA polymerase mutants
|
5-443
|
* Mean = 269 μM
|
Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of patients treated with Foscarnet sodium. Although median time to progression of CMV retinitis was increased in patients treated with Foscarnet sodium, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual patients.
TABLE 2
|
|---|
Blood and Urine Culture Results from CMV Retinitis Patients*
|
|---|
Blood
|
+CMV
|
-CMV
|
Baseline
|
27
|
34
|
End of Induction **
|
1
|
60
|
Urine
|
+CMV
|
-CMV
|
Baseline
|
52
|
6
|
End of Induction**
|
21
|
37
|
* A total of 77 patients was treated with Foscarnet sodium in two clinical trials (FOS-03 and ACTG-015/915). Not all patients had blood or urine cultures done and some patients had results from both cultures.
** (60 mg/kg Foscarnet sodium injection TID for 2 to 3 weeks).
|
Resistance: Strains of both HSV and CMV that are resistant to Foscarnet sodium can be readily selected in vitro by passage of wild type virus in the presence of increasing concentrations of the drug. All Foscarnet sodium resistant mutants are known to be generated through mutation in the viral DNA polymerase gene. CMV strains with double mutations conferring resistance to both Foscarnet sodium and ganciclovir have been isolated from patients with AIDS. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.
Foscarnet - Clinical Pharmacology
Pharmacokinetics: The pharmacokinetics of Foscarnet have been determined after administration as an intermittent intravenous infusion during induction therapy in AIDS patients with CMV retinitis. Observed plasma Foscarnet concentrations in four studies (FOS-01, ACTG-015, FP48PK, FP49PK) are summarized in Table 3:
TABLE 3
|
|---|
Foscarnet Pharmacokinetic Characteristics*
|
|---|
* Values expressed as mean ± S.D. (number of subjects studied) for each parameter
† 50 mg/kg Q8h for 28 days, samples taken 3 hrs after end of 1 hr infusion (Astra Report 815-04 AC025-1)
‡ 90 mg/kg Q12h for 28 days, samples taken 1 hr after end of 2 hr infusion (Hengge et al., 1993)
|
Parameter
|
60 mg/kg Q8h
|
90 mg/kg Q12h
|
Cmax at steady-state (μM)
|
589 ± 192 (24)
|
623 ± 132 (19)
|
Ctrough at steady-state (μM)
|
114 ± 91 (24)
|
63 ± 57 (17)
|
Volume of Distribution (L/kg)
|
0.41 ± 0.13 (12)
|
0.52 ± 0.20 (18)
|
Plasma half-life (hr)
|
4.0 ± 2.0 (24)
|
3.3 ± 1.4 (18)
|
Systemic clearance (L/hr)
|
6.2 ± 2.1 (24)
|
7.1 ± 2.7 (18)
|
Renal clearance (L/hr)
|
5.6 ± 1.9 (5)
|
6.4 ± 2.5 (13)
|
CSF:plasma ratio
|
0.69 ± 0.19 (9)†
|
0.66 ± 0.11 (5)‡
|
Distribution: In vitro studies have shown that 14 to 17% of Foscarnet is protein bound at plasma drug concentrations of 1 to 1000 μM.
The Foscarnet terminal half-life determined by urinary excretion was 87.5 ± 41.8 hours, possibly due to release of Foscarnet from bone. Postmortem data on several patients in European clinical trials provide evidence that Foscarnet does accumulate in bone in humans; however, the extent to which this occurs has not been determined. In animal studies (mice), 40% of an intravenous dose of Foscarnet sodium was deposited in bone in young animals and 7% was deposited in adult animals.
Special Populations:
Adults with Impaired Renal Function: The pharmacokinetic properties of Foscarnet have been determined in a small group of adult subjects with normal and impaired renal function, as summarized in Table 4:
TABLE 4
|
|---|
Pharmacokinetic Parameters (mean ± S.D.) After a Single 60 mg/kg Dose of Foscarnet Sodium in 4 Groups* of Adults with Varying Degrees of Renal Function
|
|---|
* Group 1 patients had normal renal function defined as a creatinine clearance (CrCl) of >80 mL/min, Group 2 CrCl was 50 to 80 mL/min, Group 3 CrCl was 25 to 49 mL/min and Group 4 CrCl was 10 to 24 mL/min.
|
Parameter
|
Group 1
(N=6)
|
Group 2
(N=6)
|
Group 3
(N=6)
|
Group 4
(N=4)
|
Creatinine clearance (mL/min)
|
108 ± 16
|
68 ± 8
|
34 ± 9
|
20 ± 4
|
Foscarnet CL (mL/min/kg)
|
2.13 ± 0.71
|
1.33 ± 0.43
|
0.46 ± 0.14
|
0.43 ± 0.26
|
Foscarnet half-life (hr)
|
1.93 ± 0.12
|
3.35 ± 0.87
|
13.0 ± 4.05
|
25.3 ± 18.7
|
Total systemic clearance (CL) of Foscarnet decreased and half-life increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of Foscarnet in patients with renal impairment (see DOSAGE AND ADMINISTRATION).
Clinical Studies
CMV Retinitis: A prospective, randomized, controlled clinical trial (FOS-03) was conducted in 24 patients with AIDS and CMV retinitis comparing treatment with Foscarnet sodium to no treatment. Patients received induction treatment of Foscarnet sodium, 60 mg/kg every 8 hours for 3 weeks, followed by maintenance treatment with 90 mg/kg/day until retinitis progression (appearance of a new lesion or advancement of the border of a posterior lesion greater than 750 microns in diameter). All diagnoses and determinations of retinitis progression were made from masked reading of retinal photographs. The 13 patients randomized to treatment with Foscarnet sodium had a significant delay in progression of CMV retinitis compared to untreated controls. Median times to retinitis progression from study entry were 93 days (range 21 to >364) and 22 days (range 7 to 42), respectively.
In another prospective clinical trial of CMV retinitis in patients with AIDS (ACTG-915), 33 patients were treated with two to three weeks of Foscarnet sodium induction (60 mg/kg TID) and then randomized to either 90 mg/kg/day or 120 mg/kg/day maintenance therapy. The median times from study entry to retinitis progression were not significantly different between the treatment groups, 96 (range 14 to >176) days and 140 (range 16 to >233) days, respectively.
In study ACTG 129/FGCRT SOCA study 107 patients with newly diagnosed CMV retinitis were randomized to treatment with Foscarnet sodium (induction: 60 mg/kg TID for 2 weeks; maintenance: 90 mg/kg QD) and 127 were randomized to treatment with ganciclovir (induction: 5 mg/kg BID; maintenance: 5 mg/kg QD). The median time to progression on the two drugs was similar (Fos=59 and Gcv=56 days).
Relapsed CMV Retinitis: The CMV Retinitis Retreatment Trial (ACTG 228/SOCA CRRT) was a randomized, open-label comparison of Foscarnet sodium or ganciclovir monotherapy to the combination of both drugs for the treatment of persistently active or relapsed CMV retinitis in patients with AIDS. Subjects were randomized to one of the three treatments: Foscarnet sodium 90 mg/kg BID induction followed by 120 mg/kg QD maintenance (Fos); ganciclovir 5 mg/kg BID induction followed by 10 mg/kg QD maintenance (Gcv); or the combination of the two drugs, consisting of continuation of the subject’s current therapy and induction dosing of the other drug (as above), followed by maintenance with Foscarnet sodium 90 mg/kg QD plus ganciclovir 5 mg/kg QD (Cmb). Assessment of retinitis progression was performed by masked evaluation of retinal photographs. The median times to retinitis progression or death were 39 days for the Foscarnet sodium group, 61 days for the ganciclovir group and 105 days for the combination group. For the alternative endpoint of retinitis progression (censoring on death), the median times were 39 days for Foscarnet sodium group, 61 days for the ganciclovir group and 132 days for the combination group. Due to censoring on death, the latter analysis may overestimate the treatment effect. Treatment modification due to toxicity were more common in the combination group than in the Foscarnet sodium or ganciclovir monotherapy groups (see ADVERSE REACTIONS section).
Mucocutaneous Acyclovir-Resistant HSV Infections: In a controlled trial, patients with AIDS and mucocutaneous, acyclovir-resistant HSV infection were randomized to either Foscarnet sodium (N=8) at a dose of 40 mg/kg TID or vidarabine (N=6) at a dose of 15 mg/kg per day. Eleven patients were non-randomly assigned to receive treatment with Foscarnet sodium because of prior intolerance to vidarabine. Lesions in the eight patients randomized to Foscarnet sodium healed after 11 to 25 days; seven of the 11 patients non-randomly treated with Foscarnet sodium healed their lesions in 10 to 30 days. Vidarabine was discontinued because of intolerance (N=4) or poor therapeutic response (N=2). In a second trial, forty AIDS patients and three bone marrow transplant recipients with mucocutaneous, acyclovir-resistant HSV infections were randomized to receive Foscarnet sodium at a dose of either 40 mg/kg BID or 40 mg/kg TID. Fifteen of the 43 patients had healing of their lesions in 11 to 72 days with no difference in response between the two treatment groups.
Indications and Usage for Foscarnet
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.
Contraindications
Foscarnet sodium injection is contraindicated in patients with clinically significant hypersensitivity to Foscarnet sodium.
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 EffectPregnancy, 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.)
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 1000 mL of 0.9% sodium chloride injection 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 5. These figures were calculated without reference to drug relationship or severity.
TABLE 5 − 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 6. Although death was specifically attributed to Foscarnet sodium injection 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 6 − 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 injection, 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 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 (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: 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, 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, hypotension, flushing, cerebrovascular disorder (see WARNINGS)
Central and Peripheral Nervous System: tremor, ataxia, dementia, stupor, generalized spasms, sensory disturbances, meningitis, aphasia, abnormal coordination, leg cramps, EEG abnormalities (see WARNINGS)
Gastrointestinal: constipation, dysphagia, dyspepsia, rectal hemorrhage, dry mouth, melena, flatulence, ulcerative stomatitis, pancreatitis
Hematologic: thrombocytopenia, platelet abnormalities, thrombosis, white blood cell abnormalities, lymphadenopathy
Liver and Biliary: abnormal A-G ratio, abnormal hepatic function, increased SGPT, increased SGOT
Metabolic and Nutritional: hyponatremia, decreased weight, increased alkaline phosphatase, increased LDH, increased BUN, acidosis, cachexia, thirst, hypocalcemia (see WARNINGS)
Musculo-Skeletal: arthralgia, myalgia
Neoplasms: lymphoma-like disorder, sarcoma
Psychiatric: insomnia, somnolence, nervousness, amnesia, agitation, aggressive reaction, hallucination
Respiratory System: pneumonia, sinusitis, pharyngitis, rhinitis, respiratory disorders, respiratory insufficiency, pulmonary infiltration, stridor, pneumothorax, hemoptysis, bronchospasm
Skin and Appendages: pruritus, skin ulceration, seborrhea, erythematous rash, maculo-papular rash, skin discoloration
Special Senses: taste perversions, eye abnormalities, eye pain, conjunctivitis
Urinary System: albuminuria, dysuria, polyuria, urethral disorder, urinary retention, urinary tract infections, acute renal failure, nocturia, facial edema
Selected adverse events occurring at a rate of less than 1% in the five initial U.S. controlled clinical trials of Foscarnet sodium include: syndrome of inappropriate antidiuretic hormone secretion, pancytopenia, hematuria, dehydration, hypoproteinemia, increases in amylase and creatinine phosphokinase, cardiac arrest, coma, and other cardiovascular and neurologic complications.
Selected adverse event data from the Foscarnet vs. Ganciclovir CMV Retinitis Trial (FGCRT), performed by the Studies of the Ocular Complications of AIDS (SOCA) Research Group, are shown in Table 7 (see CLINICAL TRIALS section).
TABLE 7 − FGCRT: Selected Adverse Events*
|
|---|
* Values for the treatment groups refer only to patients who completed at least one follow-up visit − i.e., 113 to 119 patients in the ganciclovir group and 93 to 100 in the Foscarnet group. “Events” denotes all events observed and “patients” the number of patients with one or more of the indicated events.
† Per person-year at risk
‡ Final frozen SOCA I database dated October 1991.
|
Event
|
GANCICLOVIR
|
Foscarnet
|
No. of
Events
|
No. of
Patients
|
Rates†
|
No. of
Events
|
No. of
Patients
|
Rates†
|
|
Absolute neutrophil count decreasing to <0.50 x 109per liter
|
63
|
41
|
1.30
|
31
|
17
|
0.72
|
Serum creatinine increasing to >260 µmol per liter (>2.9 mg/dL)
|
6
|
4
|
0.12
|
13
|
9
|
0.30
|
Seizure‡
|
21
|
13
|
0.37
|
19
|
13
|
0.37
|
Catheterization- related infection
|
49
|
27
|
1.26
|
51
|
28
|
1.46
|
Hospitalization
|
209
|
91
|
4.74
|
202
|
75
|
5.03
|
Selected adverse events from ACTG Study 228 (CRRT) comparing combination therapy with Foscarnet sodium injection or ganciclovir monotherapy are shown in Table 8. The most common reason for a treatment change in patients assigned to either Foscarnet sodium injection or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity.
TABLE 8
CRRT: Selected Adverse Events
|
|---|
* Pts. = patients with event; † Rate = events/person/year;‡ ANC = absolute neutrophil count
|
|
Foscarnet Sodium
N=88
|
Ganciclovir
N=93
|
Combination
N=93
|
|
No.
Events
|
No.
Pts.*
|
Rate†
|
No.
Events
|
No.
Pts.*
|
Rate†
|
No.
Events
|
No.
Pts.*
|
Rate†
|
Anemia (Hgb <70 g/L)
|
11
|
7
|
0.20
|
9
|
7
|
0.14
|
19
|
15
|
0.33
|
Neutropenia‡
|
|
|
|
|
|
|
|
|
|
ANC <0.75 x 109 cells/L
|
86
|
32
|
1.53
|
95
|
41
|
1.51
|
107
|
51
|
1.91
|
ANC <0.50 x 109 cells/L
|
50
|
25
|
0.91
|
49
|
28
|
0.80
|
50
|
28
|
0.85
|
Thrombocytopenia
|
|
|
