FOSCARNET SODIUM 24 MG / ML SOLUTION FOR INFUSION - summary of medicine characteristics

Foscarnet sodium 24 mg/ml solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection/infusion contains 24 mg foscarnet sodium hexahydrate.

Excipient(s) with known effect

1 ml of solution for injection/infusion contains 5.5 mg sodium.

For the full list of excipients, see section 6.1

Solution for infusion.

Clear colorless solution

4.1 Therapeutic indications

Foscarnet is indicated for induction and maintenance therapy of cytomegalovirus (CMV) retinitis in patients with AIDS.

Foscarnet is also indicated for the treatment of mucocutaneous Herpes Simplex Virus (HSV) infections, clinically unresponsive to aciclovir in immunocompromised patients. The safety and efficacy of foscarnet for the treatment of other HSV infections (e.g. retinitis, encephalitis); congenital or neonatal disease; or HSV in immunocompetent individuals has not been established.

The diagnosis of aciclovir unresponsiveness can be made either clinically by treatment with intravenous aciclovir (5–10 mg/kg t.i.d) for 10 days without response or by in vitro testing.

4.2 Posology and method of administration

Adults: Induction therapy for CMV retinitis: foscarnet is administered over 2–3 weeks depending on the clinical response, as intermittent infusions every 8 hours at a dose of 60 mg/kg in patients with normal renal function. Dosage must be individualised for patient's renal function (see dosing chart below). The infusion time should not be shorter than 1 hour.

Maintenance therapy: For maintenance therapy, following induction therapy of CMV retinitis, foscarnet is administered seven days a week as long as therapy is considered appropriate. In patients with normal renal function, it is recommended to initiate therapy at 60 mg/kg. Increase to a dose of 90–120 mg/kg may then be considered in patients tolerating the initial dose level and/or those with progressive retinitis. A number of patients have received 90 mg/kg over a 2 hour period as a starting dose for maintenance therapy. Dosage must be reduced in patients with renal insufficiency (see dosage chart at end of dosage section).

Patients who experience progression of retinitis while receiving maintenance therapy may be re-treated with the induction regimen.

Induction therapy of mucocutaneous HSV infections unresponsive to aciclovir: Foscarnet is administered for 2–3 weeks or until healing of lesions, as intermittent infusions at a dose of 40 mg/kg over one hour every 8 hours in patients with normal renal function. Dosage must be individualised for patients renal function (see dosing chart below). The infusion time should not be shorter than 1 hour.

Efficacy of foscarnet maintenance therapy following induction therapy of aciclovir unresponsive HSV infections has not been established.

Caution: Do not administer foscarnet by rapid intravenous injection.

Table 1 Foscarnet Dosing Chart

Induction Therapy

CMV Maintenance Therapy

*A number of patients have received 90 mg/kg as a starting dose for maintenance therapy.

Foscarnet is not recommended in patients undergoing haemodialysis since dosage guidelines have not been established.

Hydration: Renal toxicity of foscarnet can be reduced by adequate hydration of the patient. It is recommended to establish diuresis by hydration with 0.5–1.0 litre of normal saline at 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.

Foscarnet is not recommended for treatment of CMV infections other than retinitis or HSV or for use in non-AIDS or non-immunocompromised patients.

Elderly: As for adults.

Paediatric population: The safety and efficacy of foscarnet in children have not been established. Please refer to sections 4.4 and 5.3.

Renal or hepatic insufficiency: The dose must be reduced in patients with renal insufficiency according to the creatinine clearance level as described in the table above. Dose adjustment is not required in patients with hepatic insufficiency.

Method of administration: Intravenous use, either by a central venous line or in a peripheral vein. Foscarnet 24 mg/ml solution for infusion may be given without dilution via a central vein. See section 6.6 for dilution instructions.

4.3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 and appropriate dose adjustments should be performed according to renal function. Adequate hydration should be maintained in all patients (see section 4.2). The renal function of patients with renal disease or receiving concomitant treatment with other nephrotoxic medicinal products must be closely monitored (see section 4.5).

This medicinal product contains 962.5 mg sodium per dose, equivalent to 48.1% of the WHO recommended maximum daily intake for sodium.

The maximum daily dose of this product is equivalent to 144.4% of the WHO recommended maximum daily intake for sodium.

Foscarnet is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

Foscarnet use should be avoided when a saline load cannot be tolerated (e.g. in cardiomyopathy)

Due to foscarnet's pro­pensity 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. The electrolytes, especially calcium and magnesium, should be assessed prior to and during foscarnet therapy and deficiencies corrected.

Foscarnet has been associated with cases of prolongation of QT interval and more rarely with cases of torsade de pointes (see section 4.8). Patients with known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances (hypokalaemia, hypomagnesaemia), bradycardia, as well as patients with underlying cardiac diseases such as congestive heart failure or who are taking medications known to prolong the QT interval should be carefully monitored due to increased risk of ventricular arrhythmia. Patients should be advised to promptly report any cardiac symptoms.

Foscarnet is deposited in teeth, bone and cartilage. Animal data show that deposition is greater in young animals. The safety of foscarnet and its effect on skeletal development have not been investigated in children. Please refer to section 5.3.

Seizures, related to alterations in plasma minerals and electrolytes, have been associated with foscarnet treatment. Cases of status epilepticus have been reported. Therefore, patients must be carefully monitored for such changes and their potential sequelae. Mineral and electrolyte supplementation may be required.

Foscarnet is excreted in high concentrations in the urine and may be associated with significant genital irritation and/or ulceration. To prevent irritation and ulceration, close attention to personal hygiene is recommended and cleaning of the genital area after each micturition is recommended.

Should patients experience extremity paraesthesia or nausea, it is recommended to reduce the speed of infusion.

When diuretics are indicated, thiazides are recommended.

Development of resistance: If the administration of Foscarnet does not lead to a therapeutic response or leads to a worsened condition after an initial response, this may result from a reduced sensitivity of viruses towards foscarnet. In this case, termination of Foscarnet therapy and a change to an appropriate other medicinal product should be considered.

4.5 Interaction with other medicinal products and other forms of interaction Since foscarnet can impair renal function, additive toxicity may occur when used in combination with other nephrotoxic active substances such as aminoglycosides, amphotericin B, ciclosporin A, aciclovir, methotrexate and tacrolimus. Moreover, since foscarnet can reduce serum levels of ionised calcium, extreme caution is advised when used concurrently with other active substances known to influence serum calcium levels, like i.v. pentamidine. Renal impairment and symptomatic hypocalcaemia (Trousseau's and Chvostek's signs) have been observed during concurrent treatment with foscarnet and i.v. pentamidine. Abnormal renal function has been reported in connection with the use of foscarnet in combination with ritonavir and/or saquinavir.

Due to the potential increased risk of QT prolongation and torsade de pointes, foscarnet should be used with caution with active substances known to prolong QT interval, notably class IA (e.g. quinidine) and III (e.g. amiodarone, sotalol), antiarrhythmic agents or neuroleptic active substances. Close cardiac monitoring should be performed in cases of co-administration.

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

Pharmaceutical interactions (incompatibilities for infusion) are described in section 6.2.

4.6 Fertility, pregnancy and lactation

Fertility

There are no data available regarding the influence of foscarnet on fertility.

No effects on fertility were observed in animal studies (see section 5.3).

Women of childbearing potential / contraception in males and females

Women capable of childbearing should use effective contraception methods during foscarnet therapy.

Men treated with foscarnet should not father a child during or up to 6 months after therapy.

Pregnancy

There are no or limited amount of data from the use of foscarnet in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Foscarnet is not recommended during pregnancy.

Lactation

There is insufficient information on the excretion of foscarnet in human milk.

Available pharmacodynamic/to­xicological data in animals have shown excretion of foscarnet in milk (for details see section 5.3).

A risk to the newborns/infants cannot be excluded.

Foscarnet should not be used during breast-feeding.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from foscarnet therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

Foscarnet has moderate influence on the ability to drive and use machines. Due to the disease itself and possible undesirable effects of foscarnet (such as dizziness and convulsions, see section 4.8), the ability to drive and use machines can be impaired. 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 a recommendation in the individual case.

4.8 Undesirable effects

The majority of patients who receive foscarnet 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 use of foscarnet.

The undesirable effects reported with foscarnet during clinical trials and postmarketing surveillance are shown in the table below. They are listed by SystemOrgan Class (SOC) and in order of frequency, using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Please note that 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 sections 4.2 and 4.4).

Table 2 Frequency of adverse events

a Thrombophlebitis in peripheral veins following infusion of undiluted foscarnet solution has been observed.

b 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.

c Foscarnet is excreted in high concentrations in the urine and may be associated with significant irritation and ulceration in the genital area, particularly after prolonged therapy.

d Transient chest pain has been reported as part of infusion reactions to foscarnet.

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

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

The pattern of adverse events reported in association with an overdose of foscarnet is in accordance with the known adverse event profile of the active substance.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; direct acting antivirals; phosphonic acid derivatives, ATC code: J05AD01

Foscarnet is an antiviral agent with a broad spectrum inhibiting all known human viruses of the herpes group: 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 a 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. CMV strains resistant to ganciclovir may be sensitive to foscarnet. Sensitivity test results expressed as concentration of the active substance 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.

Table 3 Foscarnet inhibition of virus multiplication cell culture

Mean = 269 micrograms

97% of viral antigen synthesis inhibited at 500 micrograms

If no clinical response to foscarnet is observed, viral isolates should be tested for sensitivity to foscarnet since naturally resistant mutants may exist or emerge under selective pressure both in vitro and in vivo.

The mean foscarnet 50% inhibition value for more than one hundred clinical CMV isolates was approximately 270 micrograms/L, while a reversible inhibition of normal cell growth was observed at about 1000 micrograms/L.

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

5.2 Pharmacokinetic properties

Foscarnet is eliminated by the kidneys mainly through glomerular filtration. The plasma clearance after intravenous administration to man varies between 130–160 ml/min and the renal clearance is about 130 ml/min. The half-life is in the order of 24 hours in patients with normal renal function.

The mean volume of distribution of foscarnet at steady state varies between 0.4–0.6 L/kg. There is no metabolic conversion of foscarnet and the binding to human plasma proteins is low (<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.

5.3 Preclinical 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 form chelate with divalent metal ions. The reduction of ionised calcium and magnesium is, most probably the explanation to 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 homeostasis 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 biphosphonates) 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 as increased osteoclast activity and bone resorption. Roughly 20% of the administered active substance is taken up into bone and cartilage and deposition is greater in young and growing animals. This effect has only been seen in the dog. The reason to 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. Foscarnet sodium 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.

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 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 upon 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injection

Hydrochloric acid

6.2 Incompatibilities

This medicinal product must not be mixed with any other medicinal products except those mentioned in section 4.2.

Foscarnet is not compatible with dextrose 30% solution, amphotericin B, aciclovir sodium, ganciclovir, pentamidine isethionate, trimethoprim-sulfamethoxazole and vancomycin hydrochloride. Neither is foscarnet compatible with solutions containing calcium. It is recommended that other drugs should not be infused concomitantly in the same line.

6.3 Shelf life

2 years

After first opening: the product should be used immediately.

After dilution:

Chemical and physical in-use stability has been demonstrated for 9 days at 25°C. From a microbiological point of view, unless the method of opening and dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not refrigerate or freeze. 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 into solution again.

For storage conditions after first opening and/or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type-I, clear glass bottles and with 32 mm chlorobutyl rubber stoppers and sealed with aluminium crimp.

Infusion glass bottles of 250 ml.

6.6 Special precautions for disposal

When peripheral veins are used, the solution of foscarnet 24 mg/ml must be diluted. Individually dispensed doses of foscarnet should be aseptically transferred to plastic infusion bags by the hospital pharmacy and diluted with equal parts of 0.9% sodium chloride (9 mg/ml) or 5% dextrose (50 mg/ml) by the hospital pharmacy. The physico-chemical stability of foscarnet and dilutions foscarnet and dilutions thereof in PVC bags is 9 days. The diluted solutions should be used as soon as possible after preparation but can be stored for up to 24 hours if kept refrigerated.

Each bottle of foscarnet should only be used to treat one patient with a single infusion.

Accidental skin and eye contact with the foscarnet sodium solution may cause local irritation and burning sensation. If accidental contact occurs, the exposed area should be rinsed with water.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Fresenius Kabi Limited

Cestrian Court

Eastgate Way, Manor Park

Runcorn

WA7 1NT

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 08828/0288

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

09/04/2020