250 ML foscarnet sodium 24 MG/ML Injection

INDICATIONS 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 injection and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug. SAFETY AND EFFICACY OF FOSCARNET SODIUM INJECTION 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 Foscarnet sodium injection is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. SAFETY AND EFFICACY OF FOSCARNET SODIUM INJECTION 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 & ADMINISTRATION CAUTION - DO NOT ADMINISTER FOSCARNET SODIUM INJECTION BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF FOSCARNET SODIUM INJECTION 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. ADMINISTRATION Instructions for Administration and Preparation Foscarnet sodium injection is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The rate of infusion must be no more than 1 mg/kg/minute. An individualized dose of foscarnet sodium injection should be calculated on the basis of body weight (mg/kg), renal function, indication of use and dosing frequency (refer to DOSAGE subsection). To reduce the risk of nephrotoxicity, creatinine clearance (mL/min/kg) should be calculated even if serum creatinine is within the normal range, and doses should be adjusted accordingly. An individualized dose at the required concentration (24 mg/mL or 12 mg/mL) for the route of administration (central line or peripheral line) needs to be aseptically prepared prior to dispensing. The standard 24 mg/mL solution may be used with or without dilution when using a central venous catheter for infusion. When a peripheral vein catheter is used, the 24 mg/mL injection must be diluted to a 12 mg/mL concentration with 5% dextrose in water or with a normal saline solution prior to administration to avoid local irritation of peripheral veins. Dilutions and/or removals of excess quantities should be accomplished under aseptic conditions. Solutions thus prepared should be used within 24 hours of first entry into a infusion bag. Hydration Hydration may reduce the risk of nephrotoxicity. Clinically dehydrated patients should have their condition corrected before initiating foscarnet sodium injection therapy. It is recommended that 750-1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of foscarnet sodium injection to establish diuresis. With subsequent infusions, 750-1000 mL of hydration fluid should be given with 90-120 mg/kg of foscarnet sodium injection, and 500 mL with 40-60 mg/kg of foscarnet sodium injection. Hydration fluid may need to be decreased if clinically warranted. Oral rehydration with similar regimens may be considered in certain patients. After the first dose, the hydration fluid should be administered concurrently with each infusion of foscarnet sodium injection. Compatibility With Other Solutions/Drugs Other drugs and supplements can be administered to a patient receiving foscarnet sodium injection. However, care must be taken to ensure that foscarnet sodium injection is only administered with normal saline or 5% dextrose solution and that no other drug or supplement is administered concurrently via the same catheter. Foscarnet has been reported to be chemically incompatible with 30% dextrose, amphotericin B, and solutions containing calcium such as Ringer’s lactate and TPN. Physical incompatibility with other IV drugs has also been reported including acyclovir sodium, ganciclovir, trimetrexate glucuronate, pentamidine isethionate, vancomycin, trimethoprim/sulfamethoxazole, diazepam, midazolam, digoxin, phenytoin, leucovorin, and proclorperazine. Because of foscarnet’s chelating properties, a precipitate can potentially occur when divalent cations are administered concurrently in the same catheter. Parenteral drug products must be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored or contain particulate matter should not be used. Accidental Exposure Accidental skin and eye contact with foscarnet sodium solution may cause local irritation and burning sensation. If accidental contact occurs, the exposed area should be flushed with water. DOSAGE THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATES SHOULD NOT BE EXCEEDED. ALL DOSES MUST BE INDIVIDUALIZED FOR PATIENTS’ RENAL FUNCTION. Induction Treatment The recommended initial dose of foscarnet sodium injection for patients with normal renal function is: For CMV retinitis patients, either 90 mg/kg (1-1/2 to 2 hour infusion) every twelve hours or 60 mg/kg (minimum one hour infusion) every eight hours over 2-3 weeks depending on clinical response. For acyclovir-resistant HSV patients, 40 mg/kg (minimum one hour infusion) either every 8 or 12 hours for 2-3 weeks or until healed. An infusion pump must be used to control the rate of infusion. Adequate hydration is recommended to establish a diuresis (see Hydration for recommendation), both prior to and during treatment to minimize renal toxicity (see WARNINGS), provided there are no clinical contraindications. Maintenance Treatment Following induction treatment the recommended maintenance dose of foscarnet sodium injection for CMV retinitis is 90 mg/kg/day to 120 mg/kg/day (individualized for renal function) given as an intravenous infusion over 2 hours. Because the superiority of the 120 mg/kg/day has not been established in controlled trials, and given the likely relationship of higher plasma foscarnet levels to toxicity, it is recommended that most patients be started on maintenance treatment with a dose of 90 mg/kg/day. Escalation to 120 mg/kg/day may be considered should early reinduction be required because of retinitis progression. Some patients who show excellent tolerance to foscarnet sodium injection may benefit from initiation of maintenance treatment at 120 mg/kg/day earlier in their treatment. An infusion pump must be used to control the rate of infusion with all doses. Again, hydration to establish diuresis both prior to and during treatment is recommended to minimize renal toxicity, provided there are no clinical contraindications (see WARNINGS). Patients who experience progression of retinitis while receiving foscarnet sodium injection maintenance therapy may be retreated with the induction and maintenance regimens given above or with a combination of foscarnet sodium injection and ganciclovir (see CLINICAL TRIALS section). Because of physical incompatibility, foscarnet sodium injection and ganciclovir must NOT be mixed. Use in Patients with Abnormal Renal Function Foscarnet sodium injection should be used with caution in patients with abnormal renal function because reduced plasma clearance of foscarnet will result in elevated plasma levels (see CLINICAL PHARMACOLOGY). In addition, foscarnet sodium injection has the potential to further impair renal function (see WARNINGS). 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. Renal function must be monitored carefully at baseline and during induction and maintenance therapy with appropriate dose adjustments for foscarnet sodium injection as outlined below (see Dose Adjustment and PATIENT MONITORING). During foscarnet sodium injection therapy if creatinine clearance falls below the limits of the dosing nomograms (0.4 mL/min/kg), foscarnet sodium injection should be discontinued, the patient hydrated, and monitored daily until resolution of renal impairment is ensured. Foscarnet sodium injection is not recommended in patients undergoing hemodialysis because dosage guidelines have not been established. Dose Adjustment Foscarnet sodium injection dosing must be individualized according to the patient’s renal function status. Refer to Table 13 below for recommended doses and adjust the dose as indicated. Even patients with serum creatinine in the normal range may require dose adjustment; therefore, the dose should be calculated at baseline and frequently thereafter. To use this dosing guide, actual 24-hour creatinine clearance (mL/min) must be divided by body w

WARNINGS Renal Impairment THE MAJOR TOXICITY OF FOSCARNET SODIUM INJECTION 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 injection 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 INJECTION 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 1,000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of foscarnet sodium injection to establish diuresis. With subsequent infusions, 750 to 1,000 mL of hydration fluid should be given with 90 to 120 mg/kg of foscarnet sodium injection, and 500 mL with 40 to 60 mg/kg of foscarnet sodium injection. 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 injection. Mineral and Electrolyte Abnormalities Foscarnet sodium injection has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONS section). Foscarnet sodium injection 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 injection 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 injection treatment (see WARNING section; Mineral and Electrolyte Abnormalities ). 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 foscarnet sodium injection (see ADVERSE REACTIONS section). If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted. QT prolongation and torsade de pointes Foscarnet sodium injection 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 foscarnet sodium injection (see ADVERSE REACTIONS section). 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 (see PRECAUTIONS section), 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 foscarnet sodium injection.

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

CLINICAL PHARMACOLOGY Pharmacokinetics The pharmacokinetics of foscarnet has 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 7: TABLE 7 Foscarnet Pharmacokinetic Characteristics* Parameter 60 mg/kg Q8h 90 mg/kg Q12h C max at steady-state (μM) 589 ± 192 (24) 623 ± 132 (19) C trough 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) ‡ *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 Q12hr for 28 days, samples taken 1 hr after end of 2 hr infusion (Hengge et al., 1993) Distribution In vitro studies have shown that 14 – 17% of foscarnet is protein bound at plasma drug concentrations of 1 – 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. 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 8: TABLE 8 Pharmacokinetic Parameters (mean ± S.D.) After a Single 60 mg/kg Dose of foscarnet sodium injection in 4 Groups* of Adults with Varying Degrees of Renal Function 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 *Group 1 patients had normal renal function defined as a creatinine clearance (CrCl) of >80 mL/min, Group 2 CrCl was 50 – 80 mL/min, Group 3 CrCl was 25 – 49 mL/min and Group 4 CrCl was 10 – 24 mL/min. 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). Drug Interaction 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. There is no clinically significant interaction with zidovudine (AZT), or probenecid. CLINICAL TRIALS 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 injection to no treatment. Patients received induction treatment of foscarnet sodium injection , 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 injection 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 – >364) and 22 days (range 7 – 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 injection 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 – >176) days and 140 (range 16 – >233) days, respectively. In study ACTG 129/FGCRT SOCA study 107 patients with newly diagnosed CMV retinitis were randomized to treatment with foscarnet sodium injection (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 injection 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 injection 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 injection 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 the foscarnet sodium injection 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 modifications due to toxicity were more common in the combination group than in the foscarnet sodium injection 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 injection (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 injection because of prior intolerance to vidarabine. Lesions in the eight patients randomized to foscarnet sodium injection healed after 11 to 25 days; seven of the 11 patients non-randomly treated with foscarnet sodium injection 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 injection 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.