Data Sheet

Foscavir

foscarnet trisodium hexahydrate 24 mg/mL
intravenous solution for infusion.

Presentation

IV solution - a clear, colourless, particle-free, sterile, isotonic solution (pH 7.4) containing 24 mg/mL (8 µmol/mL) foscarnet trisodium hexahydrate, hydrochloric acid q.s. and water q.s.

Uses

Actions

Antiviral and pharmacological properties

Foscarnet is an antiviral agent with a broad spectrum, inhibiting human viruses of the herpes group including herpes simplex virus type 1 and 2, human herpes virus 6, varicella zoster virus, Epstein-Barr virus and cytomegalovirus (CMV) and some retroviruses including human immunodeficiency virus (HIV) at concentrations not affecting normal cell growth. Foscarnet also inhibits the viral DNA polymerase from hepatitis B virus. Foscarnet exerts its antiviral activity by a direct inhibition of viral specific DNA polymerase and reverse transcriptase at concentrations that do not affect cellular DNA polymerases. Foscarnet does not require activation (phosphorylation) by thymidine kinase or other kinases, and therefore is active in vitro against HSV mutants deficient in thymidine kinase (TK). CMV strains resistant to ganciclovir may be sensitive to foscarnet. Sensitivity test results, expressed as concentration of the drug required to inhibit growth of virus by 50% in cell culture (IC₅₀), vary greatly depending on the assay method used and cell type employed.

A number of sensitive viruses and their IC₅₀ are listed below.

Following treatment with foscarnet, clinical unresponsiveness can appear which may be due to appearance of virus strains with decreased sensitivity towards foscarnet. Termination of treatment with foscarnet should then be considered.

The mean foscarnet 50% inhibition value (IC₅₀) for more than one hundred clinical CMV isolates was approximately 270 µmol/L, while a reversible inhibition of normal cell growth was observed at about 1,000 µmol/L.

Therapeutic Properties

CMV retinitis in patients with AIDS

Following induction therapy over 2-3 weeks, foscarnet produced stabilization of retinal lesions in approximately 90% of cases treated. However, since CMV causes latent infections and since foscarnet exerts a virustatic activity, relapses are likely in the majority of patients with persistent immunodeficiency once treatment is discontinued. Institution of a once daily maintenance regimen at doses ranging from 90-120 mg/kg, following completion of induction therapy, has produced a delay in time to retinitis progression. In patients experiencing progression of retinitis while receiving maintenance therapy or off therapy, reinstitution of induction therapy has shown equal efficacy to the initial course.

Acyclovir unresponsive HSV infections in the immunocompromised host

For treatment of acyclovir unresponsive mucocutaneous infections, foscarnet was administered at 40 mg/kg every 8 hours over 2-3 weeks or until healing occurred. In a prospective randomised study in patients with AIDS, foscarnet treated patients healed within 11-25 days, had a complete relief of pain within 9 days and stopped shedding HSV virus within 7 days.

There is no evidence of an increased myelotoxicity when foscarnet is used in combination with zidovudine (AZT).

Pharmacokinetics

Following IV administration in man foscarnet plasma concentrations follow a multi-exponential decay pattern with several half-lives. The initial decline has a half-life of approximately 2-4 hours if renal function is normal. An apparent terminal half-life of approximately 1 to 8 days has been recorded, probably reflecting the slow release of foscarnet from bone.

The plasma clearance of foscarnet after intravenous administration to man varies between 130-160 mL/min. The mean volume of distribution of foscarnet at steady state varies between 0.4-0.6 L/kg.

Foscarnet is eliminated by the kidney mainly through glomerular filtration. Renal clearance is approximately 130 mL/min.

There is no metabolic conversion of foscarnet, and the binding to human plasma proteins is less than 20%. Foscarnet is distributed to the cerebrospinal fluid and concentrations ranging from 10 to 70% of the concurrent plasma concentrations have been observed in HIV infected patients.

In man, up to 20% of the cumulative intravenous dose has not been excreted in the urine 7 days after cessation of infusion, and can be assumed to have been deposited in bone. The molecular similarity to phosphate and pyrophosphate, and the ability to form metal and calcium ion complexes may explain the rapid interchange of foscarnet with the calcium pools, including the inorganic matrix of bone. The binding of foscarnet to the inorganic matrix of bone has no known effect on bone marrow. At present there are no studies available on the effects of foscarnet binding in growing bone.

The table below shows pharmacokinetic properties of foscarnet in AIDS patients treated for CMV infections (mainly retinitis) using either TID or BID dosage regimens.

* Mean ± SD (number of subjects studied) for each parameter
** 50 mg/kg Q8h for 28 days, samples taken 3h after end of 1h infusion

Indications

• Treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
• Treatment of acyclovir resistant HSV infections in immunocompromised patients. The safety and efficacy of Foscavir for the treatment of other HSV infections (e.g. retinitis, encephalitis); congenital or neonatal disease; or HSV in immunocompetent individuals has not been established.

Dosage and Administration

Contact with the skin and eyes may cause local irritation and a burning sensation. If accidental contact occurs, the exposed area should be rinsed immediately with cold water.

Administration

FOSCAVIR must be given by the intravenous route only, either via a central venous line or directly into peripheral veins.

When peripheral veins are used, FOSCAVIR 24 mg/mL must be diluted with glucose (dextrose) 5% or normal saline to a concentration of 12 mg/mL immediately prior to administration. (See WARNINGS AND PRECAUTIONS regarding total daily sodium intake).

FOSCAVIR 24 mg/mL solution may be given without dilution via a central vein.

CAUTION - Do not administer foscarnet by rapid intravenous injection.

Adults

CMV retinitis

Induction therapy

Foscarnet can be administered over 2-3 weeks, depending on clinical response, as intermittent infusions every 8 hours at a dose of 60 mg/kg in patients with normal renal function (see dosing chart below). The infusion time should not be shorter than one hour for the 60 mg/kg dose.

The dose of foscarnet should be adjusted to the renal function as assessed by estimated creatinine clearance.

Maintenance therapy

For maintenance therapy, following induction therapy of CMV retinitis, foscarnet is administered seven days a week as a once daily infusion over 2 hours at a dose determined by renal function as assessed by estimated creatinine clearance. In patients with normal renal function the dose range is 90-120 mg/kg/day. Dosage must be individualised for patients renal function (see dosing chart below). It is recommended to initiate therapy at 90 mg/kg and increase up to 120 mg/kg in patients in whom retinitis is progressing and who show good tolerance to the lower dose.

The dosage used can be calculated from the following dosage charts or from experience obtained with the patient during the induction phase by correlating their renal function with plasma levels.

These dosage recommendations are approximate and actual dosing should always be based on the clinical situation.

HSV infections

Induction therapy

Foscarnet should be administered at a dose of 40 mg/kg, over one hour, every 8 hours, in patients with normal renal function (see dosing chart below). The infusion time should not be shorter than 1 hour. The time taken for healing depends on the size of the initial lesion and foscarnet therapy should continue until complete re-epithelialization occurs, usually 2-3 weeks. A clinical response to foscarnet therapy should be evident after one week's treatment; therapy in patients showing no response at this time should be re-assessed.

Maintenance therapy

The efficacy of FOSCAVIR maintenance therapy in the treatment of acyclovir resistant HSV infections has not been established.

Foscavir dosing charts

Induction therapy

Maintenance therapy

Foscarnet is not recommended for use in patients undergoing haemodialysis as dosage guidelines have not been established.

Hydration

Renal toxicity can be reduced by adequate hydration of the patient. Prior to the first foscarnet infusion it is recommended that diuresis be established by hydration with 0.5 - 1.0 L normal saline. Subsequently add 0.5 - 0.1 L normal saline to each infusion. In compliant patients, oral hydration with similar hydration regimens has been used. Clinically dehydrated patients should have their condition corrected before initiating foscarnet therapy.

Duration of Treatment

An initial induction treatment period of 2-3 weeks is recommended, depending on the clinical response, followed by maintenance therapy for as long as considered appropriate.

Paediatric

The experience of using foscarnet in children is limited.

Contraindications

Hypersensitivity to foscarnet.

Foscarnet should not be used in patients on treatment with IV pentamidine since both medicines affect the serum calcium level and are potentially nephrotoxic.

Long term treatment with forscanet is contraindicated in patients with a reasonable prognosis (e.g. bone marrow transplant patients) because the animal toxicological data are limited and insufficient to ensure safety in man over an extended period.

Warnings and Precautions

Foscarnet should be used with caution in patients with reduced renal function. Since renal function impairment may occur at any time during foscarnet administration, serum creatinine should be monitored every second day during induction therapy and once weekly during maintenance therapy. Appropriate dose adjustments should be made if renal function is affected. (See DOSAGE AND ADMINISTRATION). To minimise the potential of renal function impairment, adequate hydration should be maintained in all patients.

Due to the propensity of foscarnet to chelate bivalent metal ions, such as calcium, foscarnet administration may be associated with an acute decrease of ionised serum calcium proportional to the rate of foscarnet infusion, which may not be reflected in total serum calcium levels. Particular caution is advised in patients with decreased calcium levels before treatment and in those receiving other medicines known to influence serum calcium levels. The electrolytes, especially calcium and magnesium, should be assessed prior to and during foscarnet therapy and deficiencies corrected.

Foscarnet has local irritating properties, and when excreted in high concentrations in the urine it may induce genital irritation and sometimes ulcerations. Careful personal hygiene is recommended after urination to lessen the potential for local irritation.

Foscarnet is a trisodium salt. Allowance must be made for the sodium content of foscarnet and its diluent in the total daily sodium intake of the patient. Each mL of FOSCAVIR (24 mg/mL foscarnet sodium) contains 240 µmol (5.5 mg) of sodium.

Due to their mechanism of action, loop diuretics should not be used during FOSCAVIR therapy. When diuretics are indicated, thiazides are recommended.

Use in pregnancy

There has been no clinical experience of the effects of FOSCAVIR on human pregnancy and it is not recommended for administration to pregnant women. Studies in animals have not demonstrated an effect on the reproductive process or the foetus. Studies in mice indicate that the placental transfer of foscarnet is low.

Use in lactation

No information is available on levels of foscarnet which may appear in human breast milk and it is not recommended for administration during lactation. Animal studies indicate foscarnet passes into the milk of lactating rats at concentrations approximately 3 times higher than those in maternal plasma.

Use in children

There are insufficient data available either in vivo or in vitro to establish any possible effect in growing bone.

Effects on ability to drive and use machinery

Adverse effects as dizziness and convulsions may occur during foscarnet therapy. The physician is advised to discuss this issue with the patient, and based upon the condition of the disease and the tolerance of medication, give his/her recommendation in the individual case.

Adverse Effects

The majority of patients who receive FOSCAVIR are severely immuno-compromised and suffering from serious viral infections. Patients' physical status, the severity of the underlying disease, other infections and concurrent therapies contribute to adverse events observed during the use of FOSCAVIR.

Clinical trial experience

The adverse events and frequencies shown in the table below are based on the foscarnet primary clinical trial database. This includes adverse experiences reported at any time during induction, maintenance or follow-up treatment in 5 clinical trials involving 188 patients with CMV retinitis. Adverse events are presented by frequency and body System-Organ Class (SOC). In these clinical trials, hydration and attention to electrolyte balance was not consistently given; the frequency of some adverse events will be lower when current recommendations are followed (see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS).

Frequency of adverse reactions from the primary clinical trial database

^a This frequency is based on 2 reports of electrocardiogram abnormal from 188 patients in the primary clinical trial database; the post-marketing reporting rate is 'Very Rare'.

^b This frequency is based on 1 report of acidosis from 188 patients in the primary clinical trial database; the post-marketing reporting rate is 'Rare".

Post-marketing and other experience

Reporting rates for events detected in studies other than those in the primary clinical trial database and /or from spontaneous post-marketing reports are shown in the table below.

Reporting rates for events detected in other clinical studies or from spontaneous post-marketing reports.

^a This reporting rate is based on 7 reports of renal pain from two prospective clinical trials involving 107 patients (trials 90FP48 and 91FP49). There were no reports in the primary clinical trial database; the post-marketing reporting rate is 'Very Rare'.

^b This reporting rate is based on 3 spontaneous reports of QT prolongations from 80 000 patients.

Interactions

Since foscarnet can impair renal function, additive toxicity may occur when used in combination with other nephrotoxic medicines such as aminoglycosides, amphotericin B, and cyclosporin A. Moreover, since foscarnet can reduce serum levels of ionised calcium, extreme caution is advised when used concurrently with other medicines known to influence serum clacium levels, like IV pentamidine. Renal impairment and symptomatic hypocalcaemia (Trousseau's and Chvostek's signs) have been observed during concurrent treatment with foscarnet and IV petamidine. Abnormal renal function has been reported in connection with the use of foscarnet in combination with ritonavir and / or saquinavir.

There is no pharmacokinetic interaction with zidovudine (AZT), ganciclovir, didanosine (ddI) or zalcitabine (ddC).

Due to their mechanism of action, loop diuretics should not be used during FOSCAVIR therapy.

Overdosage

Overdose has been reported during the use of Foscavir, the highest being some 20 times the recommended dose. Some of the cases were relative overdoses, in that the dose of the drug used had not been promptly adjusted for a patient experiencing reduced renal function.

There are cases where it has been reported that no clinical sequalae were consequent on the overdose.

The pattern of adverse events reported in association with an overdose of Foscavir is in accordance with the known adverse event profile of the drug.

Haemodialysis increases Foscavir elimination and may be of benefit in relevant cases.

Pharmaceutical Precautions

Shelf Life and Storage Conditions

The shelf life is 36 months. Store at room temperature (15-30°C). Do not refrigerate. If refrigerated or exposed to temperatures below freezing point precipitation may occur. By keeping the bottle at room temperature with repeated shaking, the precipitate can be brought back into solution again.

FOSCAVIR contains no preservative and once the sterility seal of a bottle has been broken the solution should be discarded within 24 hours.

Individually dispensed doses of foscarnet can be aseptically transferred to plastic infusion bags by the hospital pharmacy. The physico-chemical stability of foscarnet and dilutions thereof in equal parts with sodium chloride 9 mg/mL or dextrose 50 mg/mL in PVC bags is 7 days.

Incompatibility

FOSCAVIR is not compatible with glucose 30% solution, amphotericin B, acyclovir sodium, ganciclovir, pentamidine isethionate, trimethoprim-sulphamethoxazole, vancomycin hydrochloride, or with solutions containing calcium.

As the compatibility of FOSCAVIR with other agents has not been fully investigated, it is recommended that other agents should not be infused in the same line until further experience is gained.

Medicine Classification

Prescription Medicine.

Package Quantities

250 mL glass infusion bottle

Further Information

List of Excipients:

Water for injection

Hydrochloric acid

Pre-Clinical Safety Data

The most pronounced effects noted during general toxicity studies performed with foscarnet are perturbation of some serum electrolytes, and kidney and bone changes.

An observed reduction of serum electrolytes such as calcium and magnesium can be explained by the property of foscarnet to chelate with divalent metal ions. The reduction of ionised calcium and magnesium is, most probably, the explanation for seizures/convulsions seen during and shortly after the infusion of high doses of foscarnet. This reduction may also have a bearing on heart function (e.g. ECG) although the toxicological studies performed did not disclose any such effects. The rate of infusion of foscarnet is critical to disturbances in the homeostatsis of some serum divalent cations.

The mechanism behind the kidney changes, e.g. tubular atrophy, mainly confined to juxtamedullary nephrons, is less clear. The changes were noted in all species investigated. It is known that other complex binders of divalent cations (EDTA and biphosphates) can cause changes of the kidney similar to those of foscarnet. It has been shown that hydration, to induce diuresis, significantly reduces kidney changes during foscarnet treatment.

The bone changes were characterised by increased osteoclast activity and bone resorption. This effect has only been seen in the dog. The reason for these changes may be that foscarnet, due to the structural similarity to phosphate, is incorporated into the hydroxyapatite. Autoradiographic studies showed that foscarnet has a pronounced affinity to bone tissue. Recovery studies revealed that the bone changes were reversible.

Mutagenicity studies showed that foscarnet has a genotoxic potential. The possible explanation for the observed effect in the mutagenicity studies is an inhibition of the DNA polymerase in the cell line used. Foscarnet therapeutically acts by inhibition of the herpes virus specific DNA polymerase. The human cellular polymerase α is about 100 times less sensitive to foscarnet. The carcinogenicity studies performed did not disclose any oncogenic potential. The information gained from teratogenicity and fertility studies did not reveal any adverse events on the reproductive process. However, the results are of limited value since the dose levels used in these studies are below or at most similar (75-150 mg/kg sc) to those used in man for treatment of CMV retinitis.

Name and Address

AstraZeneca Limited
303 Manukau Road, Epsom
P.O. Box 1301
Auckland
Telephone: (09) 623-6300

Date of Preparation

27 August 2007

CDS June 2007