A possible drug interaction of FOSCARNET and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with FOSCARNET 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. Because foscarnet can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels (e.g., intravenous pentamidine). Renal impairment and symptomatic hypocalcemia have been observed during concurrent treatment with foscarnet and intravenous pentamidine.
Because of foscarnet’s tendency to cause renal impairment, the use of foscarnet 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 foscarnet, potentially leading to toxicity.
Abnormal renal function has been observed in clinical practice during the use of foscarnet and ritonavir, or foscarnet, ritonavir, and saquinavir. (See DOSAGE and ADMINISTRATION.)
Because of the risk of QT prolongation and the potential for torsades de pointes, the use of foscarnet 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.
Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailability 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 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.
There are no adequate and well-controlled studies of foscarnet in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Animal Data: Foscarnet 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.
It is not known whether foscarnet is excreted in human milk; however, in lactating rats administered 75 mg/kg, foscarnet was excreted in maternal milk at concentrations three times higher than peak maternal blood concentrations. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
The safety and effectiveness of foscarnet in pediatric patients have not been established. Foscarnet is deposited in teeth and bone and deposition is greater in young and growing animals. Foscarnet 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.
No studies of the efficacy or safety of foscarnet in persons 65 years of age or older have been conducted. However, foscarnet 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).
THE MAJOR TOXICITY OF FOSCARNET IS RENAL IMPAIRMENT (see WARNINGS section). Approximately 33% of 189 patients with AIDS and CMV retinitis who received foscarnet (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 normal saline or 5% dextrose solution was given with each infusion of foscarnet was 12% (34/280).
Foscarnet 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 WARNINGS section). The higher percentages were derived from those patients receiving hydration.
Foscarnet 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 (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 9. These figures were calculated without reference to drug relationship or severity.
|n = 189||n = 189|
|Fever||65%||Abnormal Renal Function||27%|
From the same controlled studies, adverse events categorized by investigator as “severe” are shown in Table 10. Although death was specifically attributed to foscarnet in only one case, other complications of foscarnet (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths (see WARNINGS section).
|n = 189|
|Abnormal Renal Function||14%|
From the five initial U.S. controlled trials of foscarnet, the following list of adverse events has been compiled regardless of causal relationship to foscarnet. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications.
Incidence of 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, neutropenia (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 (including reports of transient chest pain as part of infusion reactions), 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
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 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 11 (see CLINICAL TRIALS section).
* Values for the treatment groups refer only to patients who completed at least one follow-up visit – i.e., 133 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
|No. ofEvents||No. of Patients||Rates†||No. ofEvents||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|
Selected adverse events from ACTG Study 228 (CRRT) comparing combination therapy with foscarnet or ganciclovir monotherapy are shown in Table 12. The most common reason for a treatment change in patients assigned to either foscarnet or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity.
* Pts. = patients with event; †Rate = events/person/year; ‡ANC = absolute neutrophil count
|No. Events||No. Pts.*||Rate†||No. Events||No. Pts.*||Rate†||No. Events||No. Pts.*||Rate†|
|Anemia (Hgb <70g/L)||11||7||0.20||9||7||0.14||19||15||0.33|
|Neutropenia‡ ANC <0.75 x 109 cells/L ANC <0.50 x 109 cells/L||8650||3225||1.530.91||9549||4128||1.510.80||10750||5128||1.910.85|
|Thrombocytopenia Platelets <50 x 109 /L Platelets <20 x 109 /L||281||141||0.500.01||196||82||0.430.05||407||156||0.560.18|
|Nephrotoxicity Creatinine >260 μmol/L (>2.9 mg/dL)||9||7||0.15||10||7||0.17||11||10||0.20|
Adverse events that have been reported in post-marketing surveillance include: administration site extravasation, localized edema, hypersensitivity reactions (including anaphylactic shock, urticaria and angioedema) (see WARNINGS section), gastrointestinal hemorrhage, increased lipase, glomerulonephritis, nephrotic syndrome, proteinuria, status epilepticus, ventricular arrhythmia, prolongation of QT interval, torsade de pointes (see WARNINGS section), gamma GT increased, diabetes insipidus (usually nephrogenic), renal calculus, Fanconi syndrome acquired, renal tubular acidosis, renal tubular necrosis, crystal-induced nephropathy, hypercalcemia, hypernatremia, esophageal ulceration 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.
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