Foscarnet sodium Tillomed 24 mg/ml solution for infusion

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 sodium hexahydrate 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.

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

Method of administration: Foscarnet should be administered by the intravenous route only, either by a central venous line or in a peripheral vein.

When peripheral veins are used, the solution of foscarnet 24 mg/ml must be diluted. Individually dispensed doses of foscarnet sodium hexahydrate should be aseptically transferred and diluted with equal parts of 0.9% sodium chloride (9 mg/ml) or 5% glucose (50 mg/ml) by the hospital pharmacy. The diluted solutions should be used as soon as possible after preparation but can be stored for up to 24 hours if kept refrigerated.

The solution of Foscarnet 24 mg/ml may be given without dilution via a central vein.

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 sodium hexahydrate 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 sodium hexahydrate 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.

Special population

Elderly: as for adults

Paediatric population: The safety and efficacy of foscarnet sodium hexahydrate 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.

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

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 medical products must be closely monitored (see section 4.5).

Due to foscarnet sodium hexahydrate's propensity to chelate bivalent metal ions, such as calcium, Foscarnet administration may be associated with an acute decrease of ionized 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 sodium hexahydrate 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 (hypokalemia, 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 sodium hexahydrate is deposited in teeth, bone and cartilage. Animal data show that deposition is greater in younger animals. The safety of foscarnet sodium hexahydrate and its effects 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 sodium hexahydrate 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 use should be avoided when a saline load cannot be tolerated (e.g. in cardiomyopathy)

Foscarnet sodium hexahydrate 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 paresthesia 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 sodium hexahydrate. In this case, termination of Foscarnet therapy and a change to an appropriate other medicinal product should be considered.

This medicinal product contains 1375 mg of sodium per 250 ml bottle, equivalent to 69% of the WHO recommended maximum daily intake of 2g sodium for an adult.

The maximum daily dose of this product during maintenance treatment (i.e. 120mg/kg/day) and without dilution for a patient of 70 kg body weight is equivalent to 96% of the WHO recommended maximum daily intake for sodium.

The maximum daily dose of this product during maintenance treatment (i.e. 120mg/kg/day) and diluted with sodium chloride 9 mg/ml (0.9%) solution to concentration 12 mg/ml for a patient of 70 kg body weight is equivalent to 158% 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.

Since foscarnet sodium hexahydrate can impair renal function, additive toxicity may occur when used in combination with other nephrotoxic drugs such as aminoglycosides, amphotericin B, ciclosporin A, aciclovir, methotrexate and tacrolimus. Moreover, since foscarnet sodium hexahydrate can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs 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 sodium hexahydrate and i.v. pentamidine. Abnormal renal function has been reported in connection with the use of foscarnet sodium hexahydrate 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 drugs known to prolong QT interval, notably class IA (e.g. quinidine) and III (e.g. amiodarone, sotalol), antiarrhythmic agents or neuroleptic drugs. 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.

Fertility

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

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

Women of child-bearing potential/contraception in men and women

Women of childbearing potential and sexually active men have to use effective contraception during and up to 6 months after therapy.

Pregnancy

There are no or limited amount of data from the use of foscarnet sodium hexahydrate 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 sodium hexahydrate in human milk.

Available pharmacodynamic/toxicological data in animals have shown excretion of foscarnet sodium hexahydrate 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 breastfeeding or to discontinue/abstain from foscarnet sodium hexahydrate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman must be taken into account.

Foscarnet sodium hexahydrate has moderate influence on the ability to drive and use machines. Due to the disease itself and possible undesirable effects of foscarnet sodium hexahydrate (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.

The majority of patients who receive Foscarnet are severely immuno-compromised and suffering from serious viral infections. Patient's 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 sodium hexahydrate during clinical trials and post-marketing surveillance are shown in the table below. They are listed by System-Organ 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.

^aThrombophlebitis in peripheral veins following infusion of undiluted foscarnet sodium hexahydrate 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 sodium hexahydrate is excreted in high concentrations in the urine and may be associated with significant irritation and ulceration in the genital area, especially after prolonged therapy

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

Reporting of suspected adverse reactions

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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose has been reported during the use of foscarnet sodium hexahydrate, the highest being some 20 times the recommended dose. Some of the cases were relative overdoses, in that the dose of 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 sequelae were consequent on the overdose.

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

Hemodialysis increases foscarnet sodium hexahydrate elimination and may be of benefit in relevant cases.

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

Foscarnet sodium hexahydrate 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 sodium hexahydrate also inhibits the viral DNA polymerase from hepatitis B virus.

Foscarnet sodium hexahydrate 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 sodium hexahydrate 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 sodium hexahydrate. 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.

Table 3: Foscarnet sodium hexahydrate inhibition of virus multiplication cell culture

* Mean = 269 micrograms

** 97% of viral antigen synthesis inhibited at 500 micrograms

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

The mean foscarnet sodium hexahydrate 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 sodium hexahydrate is used in combination with zidovudine (AZT).

Foscarnet sodium hexahydrate is eliminated by the kidneys mainly through glomerular filtration. The plasma clearance after intravenous administration to man varies between 130-160ml/min and the renal clearance is about 130ml/min. The half-life is in the order of 2-4 hours in patients with normal renal function.

The mean volume of distribution of foscarnet sodium hexahydrate at steady state varies between 0.4-0.6l/kg. There is no metabolic conversion of foscarnet sodium hexahydrate and the binding to human plasma proteins is low (<20%). Foscarnet sodium hexahydrate 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.

The most pronounced effects noted during general toxicity studies performed with foscarnet sodium hexahydrate 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 sodium hexahydrate 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 sodium hexahydrate. 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 sodium hexahydrate 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 sodium hexahydrate. It has been shown that hydration, to induce diuresis, significantly reduces kidney changes during foscarnet sodium hexahydrate treatment.

The bone changes were characterised as increased osteoclast activity and bone resorption. Roughly 20% of the administered drug 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 sodium hexahydrate, due to the structural similarity to phosphate is incorporated into the hydroxyapatite. Autoradiographic studies showed that foscarnet sodium hexahydrate has a pronounced affinity to bone tissue. Recovery studies revealed that the bone changes were reversible. Foscarnet sodium hexahydrate 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 sodium hexahydrate 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 sodium hexahydrate therapeutically acts by inhibition of the herpes virus specific DNA polymerase. The human cellular polymerase is about 100 times less sensitive to foscarnet sodium hexahydrate. 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

Hydrochloric acid, dilute (for pH adjustment)

Water for injections

Foscarnet is not compatible with glucose solution ≥ 30 %, Ringer's acetate, amphotericin B, aciclovir sodium, ganciclovir, pentamidine isethionate, trimethoprim-sulfamethoxazole, and vancomycin hydrochloride. Neither is Foscarnet compatible with electrolyte solutions that contain divalent cations such as Ca²⁺, Mg²⁺, Zn²⁺.It is recommended that other drugs should not be infused concomitantly in the same line.

Foscarnet should not be co-administered with other medicinal products through the same infusion cannula.

The medicinal product must not be mixed with other medicinal products except those listed in section 6.6.

Unopened:

2 years

After opening:

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

After dilution:

Chemical and physical in-use stability has been demonstrated for 36 hours at 2-8° C and 20-25° C, when solution is diluted from 24 mg/ml to 12 mg/ml of foscarnet sodium hexahydrate in PVC bags.

From a microbiological point of view, 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 and would normally not be longer than 24 hours at 2 to 8° C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not refrigerate or freeze.

Foscarnet should not be kept below 8° C precipitation can occur at lower temperatures. Precipitation remains even if the infusion solution is frozen and thawed again.

Foscarnet can be made ready for use again if it has been accidentally stored at refrigerator temperatures or if the infusion solution has been exposed to temperatures below freezing. The bottle should then be shaken vigorously several times and kept at room temperature for 4 hours until all precipitation has completely dissolved.

For storage conditions after dilution of the medicinal product, see section 6.3.

250 ml solution for infusion in glass bottle and bromobutyl rubber stopper with aluminium seal and plastic flip off seal.

Pack sizes: 1 bottle and 10 bottles

Not all pack sizes may be marketed.

Individually dispensed doses of foscarnet sodium hexahydrate 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 0.9% sodium chloride (9 mg/ml) or 5% glucose (50 mg/ml) in PVC bags is 36 hours at 2-8° C and 20-25° C. However, diluted solutions should be refrigerated and storage restricted to 24 hours.

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 hexahydrate 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.