VISTIDE 75mg / ml concentrate for injection medication leaflet

Vistide 75 mg/ml concentrate for solution for infusion

Each ml contains 75 mg cidofovir anhydrous. Each vial contains 375 mg/5 ml cidofovir anhydrous asthe active substance.

Each vial contains approximately 2.5 mmol (or 57 mg) sodium per vial (5 ml) as a constituent of theexcipients.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear solution.

The formulation is adjusted to pH 7.4.

Vistide is indicated for the treatment of CMV retinitis in adults with acquired immunodeficiencysyndrome (AIDS) and without renal dysfunction. Vistide should be used only when other agents areconsidered unsuitable.

The therapy should be prescribed by a physician experienced in the management of HIV infection.

Before each administration of Vistide, serum creatinine and urine protein levels should beinvestigated. Vistide must be administered with oral probenecid and intravenous saline as describedbelow (see section 4.4 for appropriate recommendations, and under section 6.6 for information onobtaining probenecid).

Induction treatment. The recommended dose of cidofovir is 5 mg/kg body weight (given as anintravenous infusion at a constant rate over 1 hour) administered once weekly for two consecutiveweeks.

Maintenance treatment. Beginning two weeks after the completion of induction treatment, therecommended maintenance dose of cidofovir is 5 mg/kg body weight (given as an intravenousinfusion at a constant rate over 1 hour) administered once every two weeks.

Suspension of maintenance treatment with cidofovir should be considered in accordance with localrecommendations for the management of HIV infected patients.

The safety and efficacy of Vistide have not been established for the treatment of CMV disease inpatients over 60 years of age. Since elderly individuals frequently have reduced glomerular function,particular attention should be paid to assessing renal function before and during administration of

Vistide.

Renal insufficiency [creatinine clearance ≤ 55 ml/min or ≥ 2+ proteinuria (≥ 100 mg/dl)] is acontraindication for the use of Vistide (see sections 4.3 and 4.4).

The safety and efficacy of Vistide have not been established in patients with hepatic disease andtherefore it should be used with caution in this patient population.

The safety and efficacy of Vistide in children below 18 years of age have not been established. Nodata are available. Vistide is not recommended for use in children below 18 years of age.

Adequate precautions including the use of appropriate safety equipment are recommended for thepreparation, administration and disposal of Vistide. The preparation of Vistide reconstituted solutionshould be done in a laminar flow biological safety cabinet. Personnel preparing the reconstitutedsolution should wear surgical gloves, safety glasses and a closed front surgical-type gown with knitcuffs. If Vistide contacts the skin, wash membranes and flush thoroughly with water. (Seesection 6.6.)

Vistide is for intravenous infusion only. The recommended dose, frequency, or infusion rate must notbe exceeded. Vistide must be diluted in 100 millilitres 0.9% (normal) saline prior to administration.

The entire volume should be infused intravenously into the patient at a constant rate over a period of1 hour by use of a standard infusion pump. To minimise potential nephrotoxicity, oral probenecid andintravenous saline prehydration must be administered with each Vistide infusion (see section 4.4).

Hypersensitivity to the active substance or to any of the excipients.

Cidofovir administration is contraindicated in patients unable to receive probenecid or other sulfa-containing medication (see section 4.4 Prevention of nephrotoxicity).

Vistide is contraindicated in patients with renal insufficiency (see section 4.2).

Concomitant administration of Vistide and other potentially nephrotoxic agents is contraindicated (seesection 4.4).

Direct intraocular injection of Vistide is contraindicated; direct injection may be associated withsignificant decreases in intraocular pressure and impairment of vision.

Vistide is formulated for intravenous infusion only and must not be administered by other methodsincluding intraocular injection or topically. Vistide should be infused only into veins with adequateblood flow to permit rapid dilution and distribution.

The safety and efficacy of Vistide has not been demonstrated in diseases other than CMV retinitis inadults with AIDS.

Renal insufficiency/Haemodialysis

Treatment with Vistide must not be initiated in patients with creatinine clearance ≤ 55 ml/min, or ≥ 2+proteinuria (≥ 100 mg/dl), as the optimum induction and maintenance doses for patients with moderateto severe renal impairment are not known. The efficacy and safety of cidofovir in such conditions hasnot been established.

High flux haemodialysis has been shown to reduce the serum levels of cidofovir by approximately75%. The fraction of the dose extracted during haemodialysis is 51.9 ± 11.0%.

Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to administration ofcidofovir (see section 4.8). The safety of cidofovir has not been evaluated in patients receiving otherknown potentially nephrotoxic agents (e.g. tenofovir, aminoglycosides, amphotericin B, foscarnet,intravenous pentamidine, adefovir and vancomycin).

Vistide should not be administered concurrently with medicinal products containing tenofovirdisoproxil fumarate due to the risk of Fanconi syndrome (see section 4.5).

It is recommended to discontinue potentially nephrotoxic agents at least 7 days before startingcidofovir.

Patients treated at 3.0 mg/kg, 5.0 mg/kg or 10 mg/kg without concomitant probenecid developedevidence of proximal tubular cell injury, including glycosuria, and decreases in serum phosphate, uricacid and bicarbonate, and elevations in serum creatinine. The signs of nephrotoxicity were partiallyreversible in some patients. Concomitant use of probenecid is essential for reducing the pronouncednephrotoxicity of cidofovir to an extent that results in an acceptable benefit/risk balance of cidofovirtherapy.

Prevention of nephrotoxicity

Therapy must be accompanied by administration of oral probenecid and adequate intravenous salineprehydration (see section 6.6 for information on obtaining probenecid) with each cidofovir dose. Allclinical trials relevant to clinical efficacy evaluation were performed using probenecid concomitantlywith cidofovir. Two grams of probenecid should be administered 3 hours prior to the cidofovir doseand one gram administered at 2 and again at 8 hours after completion of the 1 hour cidofovir infusion(for a total of 4 grams). In order to reduce the potential for nausea and/or vomiting associated withadministration of probenecid, patients should be encouraged to eat food prior to each dose ofprobenecid. The use of an anti-emetic may be necessary.

In patients who develop allergic or hypersensitivity symptoms to probenecid (e.g., rash, fever, chillsand anaphylaxis), prophylactic or therapeutic use of an appropriate antihistamine and/or paracetamolshould be considered.

Cidofovir administration is contraindicated in patients unable to receive probenecid because of aclinically significant hypersensitivity to the active substance or medicinal product or to other sulfa-containing medicines. Use of cidofovir without concomitant probenecid has not been clinicallyinvestigated. A probenecid desensitisation program is not recommended for use.

In addition to probenecid, patients must receive a total of one litre of 0.9% (normal) saline solutionintravenously immediately prior to each infusion of cidofovir. Patients who can tolerate the additionalfluid load may receive up to a total of 2 litres of 0.9% saline intravenously with each dose of cidofovir.

The first litre of saline solution should be infused over a 1 hour period immediately before thecidofovir infusion, and the second litre, if given, infused over a 1-3 hour period beginningsimultaneously with the cidofovir infusion or starting immediately after the infusion of cidofovir.

Cidofovir therapy should be discontinued and intravenous hydration is advised if serum creatinineincreases by ≥ 44 µmol/l (≥ 0.5 mg/dl), or if persistent proteinuria ≥ 2+ develops. In patientsexhibiting ≥ 2+ proteinuria, intravenous hydration should be performed and the test repeated. Iffollowing hydration, a ≥ 2+ proteinuria is still observed, cidofovir therapy should be discontinued.

Continued administration of cidofovir to patients with persistent ≥ 2+ proteinuria followingintravenous hydration may result in further evidence of proximal tubular injury, including glycosuria,decreases in serum phosphate, uric acid and bicarbonate, and elevations in serum creatinine.

Interruption, and possibly discontinuation, is required for changes in renal function. For those patientswho fully recover from cidofovir associated renal toxicity, the benefits-risk balance of reintroducingcidofovir has not yet been evaluated.

Patient monitoring

Proteinuria appears to be an early and sensitive indicator of cidofovir-induced nephrotoxicity. Patientsreceiving cidofovir must have their serum creatinine and urine protein levels determined on specimensobtained within 24 hours prior to the administration of each dose of cidofovir. Differential whiteblood cell counts should also be performed prior to each dose of cidofovir (see section 4.8).

Patients receiving cidofovir should be advised to have regular follow-up ophthalmologic examinationsfor possible occurrence of uveitis/iritis and ocular hypotony. In case of uveitis/iritis cidofovir shouldbe discontinued if there is no response to treatment with a topical corticosteroid or the conditionworsens, or if iritis/uveitis reoccurs after successful treatment.

Cidofovir should be considered a potential carcinogen in humans (see section 5.3).

Caution should be applied when considering cidofovir treatment of patients with diabetes mellitus dueto the potential increased risk of developing ocular hypotony.

Male patients should be advised that cidofovir caused reduced testes weight and hypospermia inanimals. Although not observed in clinical studies of cidofovir, such changes may occur in humansand cause infertility. Men should be advised to practice barrier contraceptive methods during and for3 months after treatment with cidofovir (see sections 4.6 and 5.3).

Appropriate precautions should continue to be employed to prevent transmission of HIV.

This medicinal product contains approximately 2.5 mmol (or 57 mg) sodium per vial which should betaken into consideration by patients on a controlled sodium diet.

There is a risk that concomitant treatment of Vistide with products containing tenofovir disoproxilfumarate may give rise to a pharmacodynamic interaction and increase the risk of Fanconi syndrome(see section 4.4).

Probenecid increases the AUC of zidovudine. Patients receiving both drugs should be closelymonitored for zidovudine induced haematological toxicity.

For other NRTI drugs administered concomitantly with probenecid, reference should be made to theirrespective prescribing information for any appropriate recommendations.

Interactions of cidofovir/probenecid and anti-HIV drugs or drugs used to treat common chronic viralinfections in this population, such as HCV- and HBV-related hepatitis, have not been investigated inclinical trials.

Probenecid is known to increase the exposure of many substances (e.g., paracetamol, acyclovir,angiotensin-converting enzyme inhibitors, aminosalicyclic acid, barbiturates, benzodiazepines,bumetanide, clofibrate, methotrexate, famotidine, furosemide, nonsteroidal anti-inflammatory agents,theophylline, and zidovudine).

Therefore, when co-prescribing cidofovir/probenecid with other agents, it is important for prescribersto consult the current probenecid SmPC (or an appropriate drug reference source) and the respectiveprescribing information of the other co-administered products for full information regarding druginteractions and other features of that product.

Women of childbearing potential have to use effective contraception during and after treatment withcidofovir. Men should be advised to practice barrier contraceptive methods during and for 3 monthsafter treatment with cidofovir (see section 4.4).

There are no data from the use of cidofovir in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Vistide is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether cidofovir/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment withcidofovir.

There are no studies of cidofovir on the fertility of men or women. Male patients should be advisedthat cidofovir caused reduced testes weight and hypospermia in animals. Although not observed inclinical studies of cidofovir, such changes may occur in humans and cause infertility.

Cidofovir has negligible influence on the ability to drive and use machines. Adverse reactions such asasthenia may occur during cidofovir therapy. The physician is advised to discuss this issue with thepatient, and based upon the condition of the disease and the tolerance of medication, give hisrecommendation in the individual case.

The table below lists the adverse reactions identified through clinical trials or post-marketingsurveillance by system organ class (SOC) and frequency. Within each frequency grouping, adversereactions are presented in order of decreasing seriousness. Frequencies are defined as: very common(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or not known (cannot beestimated from the available data). Adverse reactions identified from post-marketing experience areincluded in italics.

Adverse reactions possibly or probably related to cidofovir based on clinical trial experience andpost-marketing surveillance

System Organ Class Adverse reactions

Very common Neutropenia

Very common Headache

Common Iritis, uveitis, hypotony of the eye(see section 4.4)

Ear and labyrinth disorders

Not known Hearing impaired

Common Dyspnea

Very common Nausea, vomiting

Common Diarrhoea

Not known Pancreatitis

Very common Alopecia, rash

Very common Proteinuria, blood creatinine increased(see section 4.4)

Common Renal failure

Uncommon Fanconi syndrome acquired

Very common Asthenia, fever

Common Chills

Reports of renal failure (plus events possibly caused by renal failure, e.g. blood creatinine increased,proteinuria, glycosuria) received during post-marketing surveillance include some which were fatal.

Cases of acute renal failure have been reported after only one or two doses of cidofovir.

The finding of any glycosuria, proteinuria/aminoaciduria, hypouricemia, hypophosphatemia and/orhypokalemia, should prompt for the consideration of cidofovir-related Fanconi syndrome.

The following table lists adverse reactions possibly or probably related to probenecid based on clinicaltrial experience:

System Organ Class Adverse reactions

Common Headache

Very common Nausea, vomiting

Very common Rash

Very common Fever

Common Asthenia, chills

In addition probenecid may also cause other adverse reactions including anorexia, gingival pain,flushing, alopecia, dizziness, anaemia, and pollakiuria. Hypersensitivity reactions, with dermatitis,pruritus, urticaria and, rarely, anaphylaxis, and Stevens-Johnson syndrome have occurred. There havebeen reports of leukopenia, hepatic necrosis, nephrotic syndrome, and aplastic anaemia. Haemolyticanaemia has also occurred, and may be associated with G6DP deficiency. Therefore, when co-prescribing probenecid with cidofovir, it is important for prescribers to consult the current probenecid

SmPC (or an appropriate drug reference source) for full information on the safety profile and otherfeatures of that product.

Two cases of cidofovir overdose have been reported. In both cases, the overdose occurred during thefirst induction dose and no additional cidofovir therapy was administered. One patient received asingle dose of 16.4 mg/kg and the other patient received a single dose of 17.3 mg/kg. Both patientswere hospitalised and received prophylactic oral probenecid and vigorous hydration for 3 to 7 days.

One of these patients experienced a minor transient change in renal function, while the other patienthad no change in renal function (see section 4.4).

Pharmacotherapeutic group: Antivirals for systemic use, nucleosides and nucleotides excludingreverse transcriptase inhibitors, ATC code: J05AB12

Cidofovir is a cytidine analogue with in vitro and in vivo activity against human cytomegalovirus(HCMV). HCMV strains resistant to ganciclovir may still be susceptible to cidofovir.

Cidofovir suppresses HCMV replication by selective inhibition of viral DNA synthesis. Biochemicaldata support selective inhibition of HSV-1, HSV-2 and HCMV DNA polymerases by cidofovirdiphosphate, the active intracellular metabolite of cidofovir.

Cidofovir diphosphate inhibits these viral polymerases at concentrations that are 8- to 600-fold lowerthan those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma. Incorporationof cidofovir into viral DNA results in reductions in the rate of viral DNA synthesis.

Cidofovir enters cells by fluid-phase endocytosis and is phosphorylated to cidofovir monophosphateand subsequently to cidofovir diphosphate. Prolonged antiviral effects of cidofovir are related to thehalf-lives of its metabolites; cidofovir diphosphate persists inside cells with a half-life of 17-65 hoursand a cidofovir phosphate-choline adduct has a half-life of 87 hours.

Cidofovir is active in vitro against HCMV, a member of the herpesviridae family. Antiviral activity isseen at concentrations significantly below those which cause cell death.

The in vitro sensitivity to cidofovir is shown in the following table:

Cidofovir inhibition of virusmultiplication in cell culture

Virus IC50 (µM)wild-type CMV isolates 0.7 (± 0.6)ganciclovir-resistant CMV isolates 7.5 (± 4.3)foscarnet-resistant CMV isolates 0.59 (± 0.07)

In vivo activity against HCMV was confirmed with controlled clinical studies of cidofovir for thetreatment of CMV retinitis in patients with AIDS, which demonstrated statistically significant delaysin time to CMV retinitis progression for patients on cidofovir when compared to control patients. Themedian times to retinitis progression in the two efficacy studies (GS-93-106 and GS-93-105), were120 days and not reached for the treatment arms vs. 22 days and 21 days for the untreated (deferredtreatment) arms, respectively.

In study GS-93-107 conducted in patients who had relapsed after treatment with other agents, themedian time to retinitis progression was 115 days.

Viral resistance

Following in vitro selection of ganciclovir-resistant HCMV isolates, cross-resistance betweenganciclovir and cidofovir was seen with ganciclovir-selected mutations in the HCMV DNApolymerase gene but not with mutations in the UL97 gene. No cross-resistance between foscarnet andcidofovir was seen with foscarnet-selected mutants. Cidofovir-selected mutants had a mutation in the

DNA polymerase gene and were cross-resistant to ganciclovir, but susceptible to foscarnet.

The major route of elimination of cidofovir was by renal excretion of unchanged drug by acombination of glomerular filtration and tubular secretion. In patients with normal renal function, 80to 100% of the intravenous dose was recovered in the urine over 24 hours as unchanged cidofovir. Nometabolites of cidofovir have been detected in serum or urine of patients.

At the end of a one-hour infusion of cidofovir 5 mg/kg administered with concomitant oralprobenecid, the mean (± SD) serum concentration of cidofovir was 19.6 (± 7.18) µg/ml. The meanvalues of total serum clearance, volume of distribution at steady-state and terminal elimination half-life were 138 (± 36) ml/h/kg, 388 (± 125) ml/kg and 2.2 (± 0.5) h, respectively. Dose-independentkinetics were demonstrated with single doses of cidofovir given over the dose range 3 to 7.5 mg/kg.

In vitro protein binding

In vitro protein binding of cidofovir to plasma or serum protein was 10% or less over the cidofovirconcentration range 0.25 to 25 µg/ml.

Preclinical animal studies demonstrated that nephrotoxicity was the major dose-limiting toxicity ofcidofovir. Evidence for a nephroprotective effect for probenecid was shown in a 52-week studyconducted in cynomolgus monkeys administered cidofovir 2.5 mg/kg once weekly intravenously with1 g of probenecid given orally.

In a 26-week intravenous toxicity study, a significant increase in incidence of mammaryadenocarcinomas was seen in female rats and of Zymbal’s gland carcinomas in male and female rats atsubtherapeutic plasma levels of cidofovir. In a separate study, once weekly subcutaneous injections ofcidofovir for 19 consecutive weeks resulted in mammary adenocarcinomas in female rats at doses aslow as 0.6 mg/kg/week. In both studies, tumours were observed within 3 months of dosing. Notumours were observed in cynomolgus monkeys administered cidofovir intravenously once weekly for52 weeks at doses up to 2.5 mg/kg/week.

Mutagenicity and reproductive toxicology

Studies have shown that cidofovir is clastogenic in vitro at 100 µg/ml and is embryotoxic in rats andrabbits.

No mutagenic response was elicited by cidofovir at dose levels up to 5 mg/plate, in the presence andabsence of metabolic activation by rat liver S-9 fraction, in microbial assays involving Salmonellatyphimurium for base pair substitutions or frameshift mutations (Ames) and Escherichia coli forreverse mutations.

An increase in formation of micronucleated polychromatic erythrocytes was observed in vivo in micereceiving a high, toxic intraperitoneal dose of cidofovir (≥ 2,000 mg/kg).

Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro withoutmetabolic activation (S-9 fraction). At the 4 cidofovir levels (12.5 to 100 µg/ml) tested, thepercentage of damaged metaphases and number of aberrations per cell increased in a concentration-dependent manner.

Male patients should be advised that cidofovir caused reduced testes weight and hypospermia inanimals. No adverse effects on fertility or general reproduction were seen following once weeklyintravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to15 mg/kg/week. Female rats dosed intravenously once weekly at 1.2 mg/kg/week or higher for up to6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births per litterand increased early resorptions per litter. Peri- and post-natal development studies in which femalerats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects onviability, growth, behaviour, sexual maturation or reproductive capacity in the offspring. Dailyintravenous administration of cidofovir during the period of organogenesis led to reduced fetal bodyweights when administered to pregnant rats at 1.5 mg/kg/day and to pregnant rabbits at 1.0 mg/kg/day.

A significantly increased foetal incidence of external, soft tissue and skeletal anomalies occurred inrabbits at 1.0 mg/kg/day, which was also maternally toxic. The no-observable-effect doses forembryotoxicity were 0.5 mg/kg/day in rats and 0.25 mg/kg/day in rabbits.

Sodium hydroxide

Hydrochloric acid

Water for injections

This medicinal product must not be mixed with other medicinal products or diluents except thosementioned in section 6.6.

3 years.

From a microbiological point of view, the product must be used immediately.

Chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 - 8ºC whendilution is performed under controlled and validated aseptic conditions. Storage beyond 24 hours orfreezing is not recommended. Refrigerated solutions should be allowed to warm to room temperatureprior to use.

Do not store above 30°C. Do not refrigerate or freeze.

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

5 ml clear glass vials with a 5 ml nominal fill volume. The container/closure components include:

Type I clear borosilicate glass vials, Teflon faced grey butyl plug stoppers, and aluminium crimp sealswith a flip off plastic tab. Each pack contains one 5 ml vial.

Vistide is supplied in single-use vials. Partially used vials should be discarded.

Method of preparation and administration

Vistide vials should be visually inspected for particulate matter and discolouration prior toadministration.

With a syringe, transfer under aseptic conditions the appropriate dose of Vistide from the vial to aninfusion bag containing 100 ml 0.9% (normal) saline solution, and mix thoroughly. The entire volumeshould be infused intravenously into the patient at a constant rate over a period of 1 hour by use of astandard infusion pump. Vistide should be administered by health care professionals adequatelyexperienced in the care of AIDS patients.

The chemical and physical stability of Vistide admixed with saline has been demonstrated in glassbottles, in infusion bags composed of either polyvinyl chloride (PVC) or ethylene/propylenecopolymer, and in PVC based vented IV administration sets. Other types of IV set tubing and infusionbags have not been studied.

Compatibility with Ringer’s Solution, Lactated Ringer’s Solution or bacteriostatic infusion fluids hasnot been evaluated.

Handling and disposal

Adequate precautions including the use of appropriate safety equipment are recommended for thepreparation, administration and disposal of Vistide. The preparation of Vistide reconstituted solutionshould be done in a laminar flow biological safety cabinet. Personnel preparing the reconstitutedsolution should wear surgical gloves, safety glasses and a closed front surgical-type gown with knitcuffs. If Vistide contacts the skin, wash membranes and flush thoroughly with water. Excess Vistideand all other materials used in the admixture preparation and administration should be placed in aleak-proof, puncture-proof container for disposal. Any unused product or waste material should bedisposed of in accordance with local requirements.

Obtaining probenecid

Probenecid is not supplied with Vistide and should be obtained via the Marketing Authorisation

Holder of probenecid. However, in case of difficulty in obtaining probenecid the local representativeof the Marketing Authorisation Holder of Vistide should be contacted for information (see alsosections 4.2 and 4.4).

Gilead Sciences International Limited

Cambridge

CB21 6GT

United Kingdom

EU/1/97/037/001

Date of first authorisation : 23 April 1997

Date of last renewal : 23 April 2007

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu/.