Foscarnet (Foscarnet Sodium) - Side Effects and Adverse Reactions

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 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, hypercalcemia (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*
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 109 per 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

* 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.

^‡ Final frozen SOCA I database dated October 1991.

^§ Per person-year at risk

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
	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

† Pts. = patients with event; ‡Rate = events/person/year;§ANC = absolute neutrophil count

Adverse events that have been reported in post-marketing surveillance include: ventricular arrhythmia, prolongation of QT interval, 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.