Foscavir

Retinitis 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. Mucocutaneous Acyclovir Resistant HSV Infections 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.

DOSAGE AND ADMINISTRATION CAUTION - DO NOT ADMINISTER FOSCAVIR BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF FOSCAVIR MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS. CARE SHOULD BE TAKEN TO AVOID UNINTENTIONAL OVERDOSE BY CAREFULLY CONTROLLING THE RATE OF INFUSION. THEREFORE, AN INFUSION PUMP MUST BE USED. IN SPITE OF THE USE OF AN INFUSION PUMP, OVERDOSES HAVE OCCURRED.

Renal Impairment THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT . 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 . 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. Mineral and Electrolyte Abnormalities FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia . 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 . 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. Therefore, an infusion pump must be used for administration to prevent rapid intravenous infusion . Slowing the infusion rate may decrease or prevent symptoms. Seizures Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR treatment . 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. Hypersensitivity Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving FOSCAVIR . If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted.

QT prolongation and torsade de pointes 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 . 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 , 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.

CONTRAINDICATIONS FOSCAVIR is contraindicated in patients with clinically significant hypersensitivity to foscarnet sodium.

Pregnancy There are no adequate and well-controlled studies of FOSCAVIR 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: FOSCAVIR 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.

Nursing Mothers It is not known whether FOSCAVIR is excreted in human milk; however, in lactating rats administered 75 mg/kg, FOSCAVIR 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.

ADVERSE REACTIONS THE MAJOR TOXICITY OF FOSCAVIR IS RENAL IMPAIRMENT . Approximately 33% of 189 patients with AIDS and CMV retinitis who received FOSCAVIR (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 FOSCAVIR was 12% (34/280). 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%) . The higher percentages were derived from those patients receiving hydration. FOSCAVIR treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies . 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 FOSCAVIR . 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. TABLE 9 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 10 . Although death was specifically attributed to FOSCAVIR in only one case, other complications of FOSCAVIR (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths . TABLE 10 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 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. 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 Gastrointestinal System: anorexia, nausea, diarrhea, vomiting, abdominal pain Hematologic: anemia, granulocytopenia, leukopenia, neutropenia Metabolic and Nutritional: mineral and electrolyte imbalances including hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia Psychiatric: depression, confusion, anxiety Respiratory System: coughing, dyspnea Skin and Appendages: rash, increased sweating Urinary System: alterations in renal function including increased serum creatinine, decreased creatinine clearance, and abnormal renal function 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 Central and Peripheral Nervous System: tremor, ataxia, dementia, stupor, generalized spasms, sensory disturbances, meningitis, aphasia, abnormal coordination, leg cramps, EEG abnormalities 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 FOSCAVIR 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 . TABLE 11 FGCRT: Selected Adverse Events* * 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 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 10 9 per liter 63 41 1.30 31 17

0.72Serum

creatinine increasing to >260 μmol per liter (>2.9 mg/dL) 6 4 0.12 13 9

0.30Seizure

‡ 21 13 0.37 19 13

0.37Catheterization-related

infection 49 27 1.26 51 28

1.46Hospitalization

209 91 4.74 202 75

5.03Selected

adverse events from ACTG Study 228 (CRRT) comparing combination therapy with FOSCAVIR or ganciclovir monotherapy are shown in Table 12 . The most common reason for a treatment change in patients assigned to either FOSCAVIR or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity. TABLE 12 CRRT: Selected Adverse Events * Pts. = patients with event; †Rate = events/person/year; ‡ANC = absolute neutrophil count Foscavir 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 <70g/L) 11 7 0.20 9 7 0.14 19 15

0.33Neutropenia‡

ANC <0.75 x 10 9 cells/L ANC <0.50 x 10 9 cells/L 86 50 32 25 1.53 0.91 95 49 41 28 1.51 0.80 107 50 51 28 1.91

0.85Thrombocytopenia Platelets

<50 x 10 9 /L Platelets <20 x 10 9 /L 28 1 14 1 0.50 0.01 19 6 8 2 0.43 0.05 40 7 15 6 0.56

0.18Nephrotoxicity Creatinine

>260 μmol/L (>2.9 mg/dL) 9 7 0.15 10 7 0.17 11 10

0.20Seizures

6 6 0.17 7 6 0.15 10 5

0.18Hospitalizations

86 53 1.86 111 59 2.36 118 64

2.36Adverse

events that have been reported in post-marketing surveillance include: administration site extravasation, localized edema, hypersensitivity reactions (including anaphylactic shock, urticaria and angioedema) , gastrointestinal hemorrhage, increased lipase, glomerulonephritis, nephrotic syndrome, proteinuria, status epilepticus, ventricular arrhythmia, prolongation of QT interval, torsade de pointes , 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.