FOSCAVIR Solution for infusion Ref.[8528] Active ingredients: Foscarnet

Foscavir should be used with caution in patients with reduced renal function. Since renal function impairment may occur at any time during Foscavir 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).

Due to the sodium content of Foscavir (240 micromoles (5.5 mg) of sodium per ml), its use should be avoided when a saline load cannot be tolerated (e.g. in cardiomyopathy). This should also be taken into consideration by patients on a controlled sodium diet.

Due to Foscavir’s propensity to chelate bivalent metal ions, such as calcium, Foscavir administration may be associated with an acute decrease of ionised serum calcium proportional to the rate of Foscavir infusion, which may not be reflected in total serum calcium levels. The electrolytes, especially calcium and magnesium, should be assessed prior to and during Foscavir 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.

Foscavir is deposited in teeth, bone and cartilage. Animal data show that deposition is greater in young animals. The safety of Foscavir 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 Foscavir 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.

Foscavir 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 Foscavir 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 Foscavir therapy and a change to an appropriate other medicinal product should be considered.

Since Foscavir 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 Foscavir can reduce serum levels of ionised 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 Foscavir and i.v. pentamidine. Abnormal renal function has been reported in connection with the use of Foscavir in combination with ritonavir and/or saquinavir.

Due to the potential increased risk of QT prolongation and torsade de pointes, Foscavir 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 Foscavir 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 Foscavir therapy.

Men treated with Foscavir 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).

Foscavir 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.

Foscavir should not be used during breast-feeding.

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

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

The undesirable effects reported with Foscavir 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:

Blood and lymphatic system disorders

Very common: Granulocytopenia, anaemia

Common: Leukopenia, thrombocytopenia, neutropenia

Uncommon: Pancytopenia

Immune system disorders

Common: Sepsis

Not known: Hypersensitivity (including anaphylactic reactions), anaphylactoid reactions

Endocrine disorders

Not known: Diabetes insipidus

Metabolism and nutrition disorders

Very common: Decreased appetite, hypokalaemia, hypomagnesaemia, hypocalcaemia

Common: Hyperphosphataemia, hyponatraemia, hypophosphataemia, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, hypercalcaemia, dehydration

Uncommon: Acidosis

Not known: Hypernatraemia

Psychiatric disorders

Common: Aggression, agitation, anxiety, confusional state, depression, nervousness

Nervous system disorders

Very common: Dizziness, headache, paraesthesia

Common: Coordination abnormal, convulsion, hypoaesthesia, muscle contractions involuntary, neuropathy peripheral, tremor

Cardiac disorders

Common: Palpitations, tachycardia

Not known: Electrocardiogram QT prolonged, ventricular arrhythmia, torsade de pointes

Vascular disorders

Common: Hypertension, hypotension, thrombophlebitis^a

Gastrointestinal disorders

Very common: Diarrhoea, nausea, vomiting

Common: Abdominal pain, constipation, dyspepsia, pancreatitis, gastrointestinal haemorrhage

Not known: Oesophageal ulceration

Hepatobiliary disorders

Common: Hepatic function abnormal

Skin and subcutaneous disorders

Very common: Rash

Common: Pruritus

Uncommon: Urticaria, angioedema

Not known: Erythema multiforme, toxic epidermal necrolysis, Stevens Johnson syndrome^b

Musculoskeletal and connective tissue disorders

Common: Myalgia

Not known: Muscular weakness, myopathy, myositis, rhabdomyolysis

Renal and urinary disorders

Common: Renal impairment, renal failure acute, dysuria, polyuria, proteinuria

Uncommon: Glomerulonephritis, nephrotic syndrome

Not known: Renal pain, renal tubular acidosis, crystal nephropathy, haematuria

Reproductive system and breast disorders

Common: Genital discomfort and ulceration^c

General disorders and administration site conditions

Very common: Asthenia, chills, fatigue, pyrexia

Common: Malaise, oedema, chest pain^d, injection site pain, injection site inflammation

Not known: Extravasation

Investigations

Very common: Blood creatinine increased, haemoglobin decreased

Common: Creatinine renal clearance decreased, electrocardiogram abnormal, gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased

Uncommon: Amylase increased, blood creatine phosphokinase increased

^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 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.

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.