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
|
|
|
|
|
|
|
|
|
|
|
Platelets <50 x 109/L
|
28
|
14
|
0.50
|
19
|
8
|
0.43
|
40
|
15
|
0.56
|
|
Platelets <20 x 109/L
|
1
|
1
|
0.01
|
6
|
2
|
0.05
|
7
|
6
|
0.18
|
|
Nephrotoxicity
|
|
|
|
|
|
|
|
|
|
|
Creatinine >260 µmol/L
(>2.9 mg/dL)
|
9
|
7
|
0.15
|
10
|
7
|
0.17
|
11
|
10
|
0.20
|
|
Seizures
|
6
|
6
|
0.17
|
7
|
6
|
0.15
|
10
|
5
|
0.18
|
|
Hospitalizations
|
86
|
53
|
1.86
|
111
|
59
|
2.36
|
118
|
64
|
2.36
|
Adverse events that have been reported in post-marketing surveillance include: ventricular arrhythmia, prolongation of QT interval, gamma GT increased, diabetes insipidus (usually nephrogenic), renal calculus, and muscle disorders including myopathy, myositis, muscle weakness and rare cases of rhabdomyolysis. Cases of vesiculobullous eruptions including erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson Syndrome have been reported. In most cases, patients were taking other medications that have been associated with toxic epidermal necrolysis or Stevens-Johnson Syndrome.
|
