Consumer medicine information

Empovir

Cidofovir

BRAND INFORMATION

Brand name

Empovir

Active ingredient

Cidofovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Empovir.

What is in this leaflet

This leaflet answers some common questions about EMPOVIR®. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking EMPOVIR against the benefits that are expected. This leaflet does not contain everything about EMPOVIR. Your doctor has been provided with full information and can answer any questions you may have. Follow your doctor's advice even if it differs from what is in this leaflet.

Please read this leaflet carefully and keep it in a safe place so you may refer to it later.

What EMPOVIR is used for

Cidofovir is used to treat an eye infection called CMV retinitis in patients with AIDS (Acquired Immunodeficiency Syndrome). Cidofovir will not cure CMV retinitis but may improve your condition by delaying progression of the disease. The safety and efficacy of cidofovir has not been demonstrated in diseases other than CMV retinitis in patients with AIDS.

Cidofovir must be administered by a healthcare professional (doctor or nurse) in a hospital setting.

What is CMV retinitis?

CMV retinitis is an eye infection caused by a virus named cytomegalovirus (CMV). CMV attacks the retina of the eye and may cause loss of vision, and eventually lead to blindness.

Patients with AIDS are at high risk of developing CMV retinitis or other forms of CMV disease such as colitis (an inflammatory bowel disease). Treatment for CMV retinitis is necessary to reduce the potential for blindness.

How EMPOVIR works

Cidofovir is an antiviral medicine which blocks the replication of CMV by interfering with viral DNA production.

The use of Cidofovir to treat your condition can lead to side-effects, which are discussed below.

Before you are given EMPOVIR

When you must not be given it

You must not have EMPOVIR if you have a history of severe allergic reactions to EMPOVIR or to any of the ingredients listed at the end of this leaflet.

Do not have EMPOVIR if you have, or have had, any of the following medical conditions, unless you have discussed it with your doctor:

  • If you are allergic to cidofovir or any of the other ingredients of this medicine (listed in section Product description).
  • If you have ever had kidney disease.
  • If you cannot take the medicine probenecid because of a serious allergy to probenecid or other sulfacontaining medicines (e.g. sulfamethoxazole).
    Talk to your doctor or pharmacist or nurse before using cidofovir.
  • Kidney damage is the major side effect of cidofovir treatment. Therefore, your doctor may need to monitor carefully, particularly if you already have kidney problems or are on haemodialysis.
  • If you have diabetes mellitus cidofovir should be used with caution in diabetic patients due to the potential increased risk of developing low pressure in the eye (ocular hypotony).

During treatment with cidofovir you should receive regular follow-up eye examinations for possible eye irritation, inflammation or swelling. If you get pain, redness or itching of the eye or changes in your vision, tell your doctor promptly.

Cidofovir caused reduced testes weight and low sperm count (hypospermia) in animals. Although not observed in human studies of cidofovir, such changes may occur in humans and cause infertility. Men should practice barrier birth control methods during and for 3 months after treatment with cidofovir. Cidofovir is not used for the treatment of HIV infection.

Cidofovir will not stop you passing HIV infection onto other people so you should continue to take precautions to avoid infecting others.

Children

Cidofovir has not been studied in children. Therefore, this medicine should not be used in children.

Females: You should not be given cidofovir if you are pregnant. If you become pregnant while receiving this medication, you must inform your doctor immediately. Cidofovir has been shown to cause damage in unborn animals and should not be used during pregnancy unless the potential benefits justify the risks to the foetus. If you could get pregnant, you must use an effective method of contraception to stop you getting pregnant during treatment with cidofovir and for 1 month afterwards.

You should not be given cidofovir if you are breastfeeding.

It is not known whether cidofovir is passed on to the baby in human milk. Because many medicines are passed through to human milk, nursing mothers should stop cidofovir or stop breast-feeding if they continue to receive cidofovir.

In general, women with HIV should not breast-feed in order to avoid passing HIV to their infant through the milk.

If you are not sure whether you should start having EMPOVIR, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to:

  • any other medicines

Tell your doctor if you have or have had any medical conditions, especially the following:

  • diabetes mellitus
  • kidney problems

Taking other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription, as these may interact with cidofovir or probenecid. It is very important to tell your doctor if you are receiving other medicines that may damage your kidneys.

These include:

  • tenofovir containing medicines, used to treat HIV-1 infection and/or chronic infection and/or chronic hepatitis B infection aminoglycosides, pentamidine or vancomycin for bacterial infections)
  • amphotericin B (for fungal infection)
  • foscarnet (for viral infection)
  • adefovir (for HBV infection)

These medicines must be stopped at least 7 days before taking cidofovir. Probenecid may interact with other medicines commonly used in the treatment of AIDS and AIDS-related illnesses, such as zidovudine (AZT). If you are taking zidovudine, you should discuss with your doctor whether to temporarily stop taking zidovudine or decrease the dose of zidovudine by 50% on days when cidofovir and probenecid are given. The potential for interactions between cidofovir and anti-HIV protease inhibitors has not been studied.

Cidofovir with food and drink

Food should be taken before you are given cidofovir. Your doctor may instruct you to drink plenty of fluids before receiving cidofovir.

If you have not told your doctor about any of the above, tell them before you start having EMPOVIR.

While you are receiving EMPOVIR

Things you must do:

  • Tell your doctor immediately if you become pregnant while taking EMPOVIR.
  • Tell all of the doctors, dentists and pharmacists who are treating you that you are taking EMPOVIR.
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking EMPOVIR.
  • Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor may want to do some tests from time to time to check on your progress and detect any unwanted side effects.

Things to be careful of:

  • Cidofovir may cause short-term side effects such as fatigue or weakness. If you drive or operate machinery, discuss this with your doctor to get advice about stopping these activities based upon your disease and your tolerance of the medicine.
  • EMPOVIR contains 2.5 mmol (or 57 mg) sodium per vial which should be taken into consideration if you are on a controlled sodium diet.

How EMPOVIR is given

EMPOVIR is given by intravenous infusion (a drip into a vein). It must not be administered by other methods including intraocular injection (direct injection into the eye) or topically (on the skin).

EMPOVIR must be given by a doctor or nurse with appropriate experience in treating people with AIDS.

The doctor or nurse will transfer the appropriate dose of EMPOVIR from the vial to an infusion bag containing 100 mL 0.9% (normal) saline solution. The entire volume of the bag will be infused into your vein at a constant rate over a period of 1 hour using a standard infusion pump. The recommended dose, frequency of use, or rate of infusion must not be exceeded. At the end of this leaflet, there is further information for healthcare professionals on how to administer EMPOVIR To lower the risk of kidney damage, probenecid tablets and intravenous fluids (saline solution) must be given on the day of each EMPOVIR(See sub-sections “How to take probenecid with EMPOVIR” and “How IV fluids are given before EMPOVIR” below.)

Dose in adults

The dose you will need is calculated based on your body weight.

Starting (induction) treatment
The recommended dose of EMPOVIRin patients with normal kidney function is 5 mg per kg of body weight given once weekly for two consecutive weeks.

Maintenance treatment
Beginning two weeks after completion of induction treatment, the recommended maintenance dose of EMPOVIR in patients with normal kidney function is 5 mg per kg of body weight given once every two weeks.

Dose adjustment

If you have kidney problems, EMPOVIR may not be appropriate treatment for you. Samples of your urine and/or blood will be taken before each infusion of EMPOVIR and used for testing kidney function.

For patients with evidence of decreased kidney function, your EMPOVIR dose may be interrupted or stopped depending on your individual case.

If you use more EMPOVIR than you should

If you have accidentally been given more EMPOVIR than prescribed for you, tell your doctor immediately.

How to take probenecid with EMPOVIR

Probenecid tablets are given to lower the risk of kidney damage. You must take 3 doses of probenecid tablets orally on the same day as EMPOVIRas shown in the following table:

Probenecid is only taken on the same day that EMPOVIR is given.

How IV fluids are given before EMPOVIR

Normal saline is given to lower the risk of kidney damage. You should receive a total of one litre of 0.9% (normal) saline solution intravenously (as a drip into a vein) before each EMPOVIR dose. The saline solution should be infused over a 1 hour period immediately before the EMPOVIR. If you can tolerate the additional fluid load, your doctor may administer a second litre of fluid. If administered, the second litre of saline should be given either at the start of the EMPOVIR or immediately afterwards, and infused over a 1 to 3 hour period.

Your doctor may also tell you to drink plenty of fluids.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

How long is EMPOVIR given

EMPOVIR is usually given every two weeks after induction treatment. Your doctor will decide how many such maintenance doses you will need.

Ask your doctor if you want to know more about the dose of EMPOVIR you receive.

Overdose

As EMPOVIR is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any side effects after being given EMPOVIR, tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital. You may need urgent medical attention.

Symptoms of a Cidofovir overdose include the side effects listed below in the "Side Effects" section, but are usually of a more severe nature.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are receiving EMPOVIR.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist immediately. Do not be alarmed by the following lists of side effects. You may not experience any of them.

Very commonly observed side effects with cidofovir are: protein in urine, increased blood creatinine (a measure of kidney function), low white blood cell counts, hair loss, fever, abnormal physical weakness or lack of energy, headache, feeling sick (nausea), being sick (vomiting), skin rash.

Other commonly side effects include chills, reduced pressure in the eyes, inflammation of the eyes, any pain, redness or itching of the eyes, kidney failure, difficulty breathing (dyspnoea), loose stools (diarrhoea). These should be immediately reported to your doctor.

Tell your doctor as soon as possible if you notice any of the following side effect since these may be serious: allergic reaction, infection, chills, no relief from eye infection, loss of appetite, diarrhoea, liver problems, decrease in red blood cell counts, liver toxicity, shortness of breath, inflammation of the eyes, kidney failure, abnormally low level of phosphate in blood, rare disorder of kidney function that results in excess amounts of glucose, salts, uric acid, potassium, and certain amino acids being excreted in the urine, protein in urine, excess glucose in urine, feeling of incomplete urination, increased urea in blood (indicates decreased removal from blood by kidneys).

Very commonly observed side effects which may be due to probenecid are: feeling sick, being sick, rash and fever.

Commonly observed side effects which may be due to probenecid are: headache, chills, abnormal physical weakness or lack of energy.

The other side effects with probenecid include loss of appetite, gum pain, flushing, hair loss, dizziness, frequent urination, allergic reactions (itching, rash), rare serious disorder of skin and mucous membrane, decrease in number of all types of blood cells specifically red blood cell due to premature destruction, kidney and liver disease.

  • You should also read the probenecid CMI.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell.

Product Description

EMPOVIR is supplied as a sterile concentrate for dilution for intravenous infusion in clear, glass vials containing 375 mg of the active ingredient, cidofovir as the dihydrate formulated in 5 mL water for injections at a concentration of 75 mg/mL. The formulation is pH-adjusted with sodium hydroxide (and hydrochloric acid if needed) and contains no preservatives.

Active ingredient: Cidofovir as the dihydrate.

Other ingredient: sodium hydroxide, hydrochloric acid, water for injections

Storage

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label.

Store below 25°C. Do not refrigerate or freeze.

Do not throw away any medicines via waste water or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

Sponsored by

Emcure Pharmaceuticals Pty Ltd
Shop 3, 26 Henley Road,
Homebush, West
NSW, 2140, Australia

Registration Numbers

AUST R 287040

Where to get further information

Your doctor is the best person to answer any further questions you may have about EMPOVIR.

Anything your doctor tells you about EMPOVIR should be followed even if it is different from what is in this leaflet.

Date of Preparation: April 2018

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Empovir

Active ingredient

Cidofovir

Schedule

S4

 

1 Name of Medicine

Cidofovir.

2 Qualitative and Quantitative Composition

It is supplied in clear glass vials, each containing 375 mg of the anhydrous cidofovir in 5 mL aqueous solution at a concentration of 75 mg/mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Empovir is a sterile, hypertonic aqueous solution for intravenous injection only. The solution is clear and colourless.

4 Clinical Particulars

4.1 Therapeutic Indications

Empovir is indicated in adults for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).

4.2 Dose and Method of Administration

Before each administration of Empovir, serum creatinine and urine protein levels should be investigated.
The recommended dosage, frequency, or infusion rate must not be exceeded. Empovir must be diluted in 100 mL 0.9% (normal) saline prior to administration. To minimise potential nephrotoxicity, oral probenecid and intravenous saline prehydration must be administered with each Empovir infusion.
Product is for single use in one patient only. Discard any residue.
Empovir must not be administered by intraocular injection.

Method of preparation and administration.

As with all parenteral products, Empovir vials should be visually inspected for particulate matter and discoloration prior to administration. Do not re-autoclave prior to use.
With a syringe, transfer under aseptic conditions the appropriate dose of Empovir from the vial to an infusion bag containing 100 mL 0.9% (normal) saline solution, and mix thoroughly. The entire volume should be infused intravenously into the patient at a constant rate over a period of 1 hour by use of a standard infusion pump. Empovir should be administered by health care professionals adequately experienced in the care of AIDS patients.

Dosage in adults.

Induction treatment.

The recommended dose of Empovir is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks.

Maintenance treatment.

Beginning two weeks after the completion of induction treatment, the recommended maintenance dose of Empovir is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once every two weeks.

Dosage reduction guidelines.

For patients with changes in renal function during therapy, the dose of cidofovir must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.027 to 0.043 mmol/L (0.3 to 0.4 mg/dL) above baseline.
Empovir therapy should be discontinued and intravenous hydration is advised if serum creatinine increases by ≥ 0.044 mmol/L (≥ 0.5 mg/dL), or if persistent proteinuria ≥ 2+ develops.

Probenecid.

A course of probenecid, administered orally with each Empovir dose may reduce the potential for nephrotoxicity. All clinical trials relevant to clinical efficacy evaluation were performed using probenecid concomitantly with cidofovir. Therefore to minimise the potential for nephrotoxicity, a course of probenecid should be administered orally with each Empovir dose. Two grams should be administered 3 hours prior to the Empovir dose and one gram administered at 2 and again at 8 hours after completion of the 1 hr Empovir infusion (for a total of 4 grams). In order to reduce the potential for nausea and/or vomiting associated with administration of probenecid, patients should be encouraged to eat food prior to each dose of probenecid. The use of an anti-emetic may be necessary. In patients who develop allergic or hypersensitivity symptoms to probenecid (e.g. rash, fever, chills and anaphylaxis), prophylactic or therapeutic use of an appropriate antihistamine and/or paracetamol should be considered (see Section 4.3 Contraindications).

Hydration.

To minimise the potential for nephrotoxicity, patients should receive a total of one litre of 0.9% (normal) saline solution intravenously immediately prior to each infusion of Empovir. Patients who can tolerate the additional fluid load may receive up to a total of 2 litres of 0.9% saline intravenously with each dose of Empovir. The first litre of saline solution should be infused over a 1 hr period immediately before the Empovir infusion, and the second litre, if given, infused over a 1-3 hr period beginning simultaneously with the Empovir infusion or starting immediately after the infusion of Empovir.

Dosage in elderly.

The safety and efficacy of cidofovir have not been established for the treatment of CMV disease in patients 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 Empovir.

Dosage in children and neonates.

The safety and efficacy of cidofovir have not been established for the treatment of CMV disease in patients under eighteen years of age. Therefore, Empovir is not recommended for use in children under eighteen years.

Dosage in renal insufficiency.

Renal insufficiency is a contraindication for the use of Empovir (also see Section 4.3 Contraindications). Treatment with Empovir should not be initiated in patients with serum creatinine > 0.133 mmol/L (> 1.5 mg/dL), creatinine clearance ≤ 0.92 mL/s (≤ 55 mL/min), or ≥ 2+ proteinuria (≥ 100 mg/dL), as the optimum induction and maintenance doses for patients with moderate to severe renal impairment are not known.

Dosage in hepatic insufficiency.

The safety and efficacy of cidofovir have not been established in patients with hepatic disease.

Monitoring advice.

Proteinuria appears to be an early and sensitive indicator of cidofovir-induced nephrotoxicity. Patients receiving Empovir must have their serum creatinine and urine protein levels determined on specimens obtained within 24 to 48 hours prior to the administration of each dose of Empovir. In patients exhibiting ≥ 2+ proteinuria, intravenous hydration should be performed and the test repeated. If following hydration, a ≥ 2+ proteinuria is still observed, Empovir therapy should be discontinued. Continued administration of Empovir to patients with persistent ≥ 2+ proteinuria following intravenous 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.
During treatment, these parameters should be investigated prior to the administration of each infusion, and the treatment should be stopped in case of abnormality. In case of complete recovery, the reintroduction of cidofovir has not yet been evaluated.
White blood cell counts, including the differential neutrophil count, should also be performed prior to each dose of Empovir.
Patients should be monitored for signs and symptoms of uveitis/iritis during Empovir therapy.
Patients receiving Empovir should be advised to have regular follow-up ophthalmologic examinations.

4.3 Contraindications

Empovir is contraindicated in patients with renal impairment [serum creatinine > 0.133 mmol/L (> 1.5 mg/dL) or creatinine clearance ≤ 0.92 mL/s (≤ 55 mL/min) or proteinuria ≥ 100 mg/dL (≥ 2+ proteinuria)]. Concomitant administration of cidofovir and potentially nephrotoxic agents is contraindicated. Patients should discontinue such agents at least 7 days before starting treatment with cidofovir. Examples of agents having potential nephrotoxicity include: amphotericin B, foscarnet, intravenous pentamidine, intravenous aminoglycoside antibiotics, vancomycin and non-steroidal anti-inflammatory agents.
The benefits of Empovir must be weighed against the risk of renal damage in patients who have been recently treated with nephrotoxic drugs.
Empovir is also contraindicated in patients with hypersensitivity to cidofovir.
Empovir is contraindicated in patients with a history of clinically significant hypersensitivity to probenecid or other sulfur-containing medicines.
Empovir is contraindicated during pregnancy.
Direct intraocular injection of cidofovir is contraindicated; direct injection may be associated with significant decreases in intraocular pressure and impairment of vision.

4.4 Special Warnings and Precautions for Use

Empovir should be infused only into veins with adequate blood flow to permit rapid dilution and distribution. Therapy should be accompanied by administration of oral probenecid and adequate intravenous saline prehydration.
Empovir should not be used in patients unable to receive probenecid because of hypersensitivity. In patients unable to receive probenecid because of a clinically significant hypersensitivity to the drug, a probenecid desensitisation program is not recommended for use.

Use in hepatic impairment.

No data available.

Use in renal impairment.

Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to administration of cidofovir. Patients previously treated with foscarnet may have an increased risk of nephrotoxicity. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indication of nephrotoxicity. Some patients receiving cidofovir have had evidence of proximal tubular cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of cidofovir.
Renal impairment is the major toxicity of cidofovir. To minimise possible nephrotoxicity, intravenous hydration with normal saline and oral administration of probenecid must be given with each cidofovir injection. Renal function must be monitored (serum creatinine and urine protein) prior to each dose and dose may need to be adjusted for changes in renal function as appropriate.
Uveitis and/or iritis may occur during cidofovir therapy. Treatment with corticosteroids with or without cycloplegic agents may be considered. In some cases, reduced intraocular pressure has been reported in conjunction with uveitis/iritis.
Decreased intraocular pressure/ocular hypotony may develop during cidofovir therapy and in some cases has been associated with decreased visual acuity. The risk of decreased intraocular pressure may be increased in patients with pre-existing diabetes mellitus. Intraocular pressure should be monitored during cidofovir therapy.
Neutropenia has been observed in patients receiving cidofovir. Neutrophil counts should be monitored while receiving cidofovir therapy.

Excipients.

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

Check the following before use.

Renal function (serum creatinine and urine protein) must be measured and the results reviewed, within 48 hours prior to each dose of Empovir. Interruption, and possibly discontinuation, is required for changes in renal function (see Section 4.2 Dose and Method of Administration).
Neutrophil counts should be monitored regularly.

Animal toxicity.

Preclinical animal studies demonstrated that nephrotoxicity was the major dose-limiting toxicity of cidofovir. Evidence for a nephroprotective effect for probenecid was shown in a 52-week study conducted in cynomolgus monkeys administered cidofovir 2.5 mg/kg once weekly intravenously with 30 mg/kg of probenecid given orally.

Carcinogenicity, mutagenicity and impaired fertility.

In animal studies cidofovir was genotoxic, carcinogenic and teratogenic, and caused hypospermia. Cidofovir should be considered a potential carcinogen in humans. Male patients should be advised that cidofovir caused reduced testes weight and hypospermia in animals. Such changes may occur in humans and cause infertility. Men should be advised to practise barrier contraceptive methods during and for 3 months after treatment with cidofovir.
Chronic, two year carcinogenicity studies in rats and mice have not been carried out to evaluate the carcinogenic potential of cidofovir. However, a 26 week toxicology study evaluating once weekly subscapular subcutaneous injections of cidofovir in rats was terminated at 19 weeks because of the induction, in females, of palpable masses, the first which was detected after six doses. The masses were diagnosed as mammary adenocarcinomas which developed at doses as low as 0.6 mg/kg/week, equivalent to 0.04 times the human systemic exposure at the recommended intravenous cidofovir dose based on AUC comparisons.
In a 26-week intravenous toxicology study in which rats received 0.6, 3, or 15 mg/kg cidofovir once weekly, a significant increase in mammary adenocarcinomas in female rats as well as a significant increase in Zymbal's gland carcinomas (no human equivalent) in male and female rats were seen at the high dose but not at the lower two doses. The high dose was equivalent to 1.1 times the human systemic exposure at the recommended dose of cidofovir, based on the comparisons of AUC measurements. In light of the results of these studies, cidofovir should be considered to be a carcinogen in rats as well as a potential carcinogen in humans.
Cynomolgus monkeys received intravenous cidofovir, alone and in conjunction with concomitant oral probenecid, intravenously once weekly for 52 weeks at doses resulting in exposures of approximately 0.7 times the human systemic exposure at the recommended dose of cidofovir. No tumours were detected. However, the study was not designed as a carcinogenicity study due to the small number of animals at each dose and the short duration of treatment.
Cidofovir induced chromosomal aberrations in human peripheral lymphocytes in vitro (without metabolic activation) and an increase in micronucleated polychromatic erythrocytes in vivo. Cidofovir was not genotoxic in microbial mutagenicity assays (Salmonella typhimurium (Ames) and Escherichia coli).
Studies show that cidofovir caused inhibition of spermatogenesis in rats and monkeys. However, no adverse effects on fertility or reproduction were seen following once weekly intravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/kg/week (equivalent to 1.1 times the recommended human dose based on AUC comparisons). Female rats dosed intravenously once weekly at 1.2 mg/kg/week (equivalent to 0.09 times the recommended human dose based on AUC) or higher, for up to 6 weeks prior to mating and for two weeks post-mating had decreased litter sizes and live births per litter and increased early resorptions per litter. Peri- and post-natal development studies in which female rats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7 of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects on viability, growth, behaviour, sexual maturation or reproductive capacity in the offspring.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Probenecid.

Probenecid is known to interact with the metabolism or renal tubular secretion of many drugs (e.g. paracetamol, aciclovir, angiotensin-converting enzyme inhibitors, aminosalicylic acid, barbiturates, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, frusemide, nonsteroidal anti-inflammatory agents, theophylline, and zidovudine). Concomitant medications should be carefully assessed.
Patients who are being treated with zidovudine should temporarily discontinue zidovudine administration or decrease their zidovudine dose by 50% on days when cidofovir is administered, because probenecid reduces the clearance of zidovudine.

Nephrotoxic agents.

Concomitant administration of Empovir and agents with nephrotoxic potential (e.g. intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents) is contraindicated.
The benefits of Empovir must be weighed against the risk of renal damage in patients who have been treated recently with nephrotoxic drugs.
Interactions of cidofovir, probenecid, and anti-HIV drugs, including anti-HIV protease inhibitors, have not been investigated in clinical trials.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
Cidofovir was embryotoxic (reduced fetal body weights) in rats and rabbits at subtherapeutic dose levels, following daily intravenous dosing during the period of organogenesis. An increased incidence of fetal external, soft tissue and skeletal anomalies (meningocele, short snout, and short maxillary bones) occurred in rabbits at the high dose (1.0 mg/kg/day) which was maternally toxic but less than the recommended human dose based on AUC.
There are no adequate and well controlled studies in pregnant women. The drug should not be used during pregnancy.
Women of childbearing potential should be advised to use effective contraception during and for 1 month after treatment with cidofovir.
It is not known whether cidofovir is excreted in human milk. Because many drugs are excreted in human milk, nursing mothers should be instructed to discontinue cidofovir or discontinue nursing if they continue to receive cidofovir. Passage of drug-related compound across the placental barrier was observed in pregnant rats. Excretion of drug-related material into milk of lactating animals was not examined.

4.7 Effects on Ability to Drive and Use Machines

Adverse effects such as asthenia may occur during cidofovir 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 recommendation in the individual case.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions reported have been grouped by frequency according to the following criteria.
Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1000 and < 1/100; Rare ≥ 1/10,000 and < 1/1000; Very Rare < 1/10,000.

Blood and lymphatic system disorders.

Very common: neutropenia.

Nervous system disorders.

Very common: headache.

Eye disorders.

Common: iritis, uveitis, hypotony of the eye (see Section 4.4 Special Warnings and Precautions for Use).

Ear and labyrinth disorders.

Not known: hearing impaired.

Respiratory, thoracic and mediastinal disorders.

Common: dyspnea.

Gastrointestinal disorders.

Very common: nausea, vomiting.
Common: diarrhoea.
Not known: pancreatitis.

Skin and subcutaneous tissue disorders.

Very common: alopecia, rash.

Renal and urinary disorders.

Very common: proteinuria, blood creatinine increased (see Section 4.4 Special Warnings and Precautions for Use).
Common: renal failure.
Uncommon: Fanconi syndrome acquired.

General disorders and administration site conditions.

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/or hypokalemia, should prompt for the consideration of cidofovir-related Fanconi syndrome.
The following text lists adverse reactions possibly or probably related to probenecid based on clinical trial experience:

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

Very common: nausea, vomiting.

Skin and subcutaneous tissue disorders.

Very common: rash.

General disorders and administration site conditions.

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 have been reports of leukopenia, hepatic necrosis, nephrotic syndrome, and aplastic anaemia. Haemolytic anaemia has also occurred, and may be associated with G6PD deficiency. Therefore, when coprescribing 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 other features of that product.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Two cases of cidofovir overdose have been reported. In both cases, the overdose occurred during the first induction dose and no additional cidofovir therapy was administered. One patient received a single dose of 16.4 mg/kg and the other patient received a single dose of 17.3 mg/kg. Both patients were 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 patient had no change in renal function.
Treatment is symptomatic and supportive, including respiratory and cardiovascular function. Hydration should be considered following overdose as clinically indicated. Monitor electrolytes and fluid status following a significant exposure. Evaluate renal function including urinalysis for proteinuria with all suspected overdoses. Obtain full blood count with differential following a significant overdose or as indicated.
High flux haemodialysis has been shown to reduce the serum concentrations of cidofovir by approximately 75%, although rebound was displayed after dialysis was stopped.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Cidofovir has in vitro and in vivo activity against human cytomegalovirus (HCMV).

Mechanism of action.

Cidofovir suppresses CMV replication by selective inhibition of viral DNA synthesis. Biochemical data support selective inhibition of HSV-1, HSV-2 and CMV DNA polymerases by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits these viral polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma. Incorporation of 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 monophosphate and subsequently to cidofovir diphosphate. In addition, a cidofovir phosphate-choline adduct is formed. The metabolism of cidofovir is neither dependent on, nor facilitated by, viral infections. Prolonged antiviral effects of cidofovir are related to the half-lives of metabolites; cidofovir diphosphate persists inside cells with a half-life of 17-65 hours. Additionally, the phosphate-choline species has a half-life of 87 hours.

Antiviral activity.

Cidofovir is active in vitro against CMV, a member of the herpesviridae family. Antiviral activity is seen at concentrations significantly below those which cause death in cell monolayers. The in vitro sensitivity to cidofovir is shown in Table 1.

Viral resistance.

Following in vitro selection of ganciclovir-resistant human CMV isolates, cross-resistance between ganciclovir and cidofovir was seen with ganciclovir-selected mutations in the CMV DNA polymerase gene but not with mutations in the UL97 gene. No cross-resistance between foscarnet and cidofovir 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.

Clinical trials.

Three phase II/III clinical studies of cidofovir have been conducted in HIV-infected patients with CMV retinitis. Studies directly comparing cidofovir with ganciclovir or foscarnet have not been conducted. The use of cidofovir has been investigated only in situations where foscarnet and/or ganciclovir were ineffective or where the retinitis was in an early stage.
Study GS-93-106 was an open-label, multi-centre study, involving 48 previously untreated patients with peripheral CMV retinitis. Patients were randomised to either immediate treatment with cidofovir (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), or to have cidofovir therapy delayed until disease progression. Concomitant intravenous hydration and oral probenecid were administered with each dose of cidofovir. Forty-eight patients were enrolled in the study, 23 were randomised to the deferred treatment group and 25 to the immediate treatment group. Sixteen of the 23 patients in the deferred treatment group, crossed over and received cidofovir treatment following documented progression. The two groups were comparable with regard to baseline characteristics. Retinal progression was recorded by full field bilateral retinal photographs. The median time to progression for the deferred treatment group was 22 days (95% Confidence limits, 10 to 27 days) and for the immediate treatment group was 120 days (95% Confidence limits 40 to 134 days). This difference was statistically significant. However, limited numbers of patients remained on treatment over time.
In another open-label study, GS-93-107, 100 patients with relapsing CMV retinitis (failing treatment with ganciclovir and/or foscarnet or demonstrating intolerance to either of these agents), were randomised to receive cidofovir 5 mg/kg/week for 2 weeks and then either 5 mg/kg (n=49) or 3 mg/kg (n=51) every second week. Patients also received concomitant probenecid and intravenous hydration with each cidofovir dose. Based on the masked readings of retinal photographs, the median (95% CI) time for retinal progression for the 5 mg/kg group and the 3 mg/kg group was 115 days (70, not reached) and 49 days (35, 52) respectively. The difference was statistically significant. However, limited numbers of patients remained on treatment over time.
Study GS-93-105 was a randomised controlled multi-centre study of cidofovir for the treatment of previously untreated peripheral CMV retinitis in HIV-positive patients. Patients were randomised to immediate or deferred treatment, with cross-over allowed following clinical ophthalmic documentation of CMV retinitis progression. The induction dose was 5 mg/kg/week for the first two weeks, and then maintenance therapy of either 3 mg/kg (low group) or 5 mg/kg (high group) every second week. The results from an interim review of the first 64 patients have been analysed, with 26 patients assigned to the deferral group, 26 to the low dose group, and 12 patients assigned to the high dose group. The major outcome measure was retinitis progression, with the low dose group having a median (95% CI) time to progression of 64 days compared with 21 days (10, 27) for the deferred group. The high dose group had not reached the median (95% CI) time to progression (25, not reached), compared to the deferred group. The rates of visual loss were similar among the three groups.

5.2 Pharmacokinetic Properties

Absorption.

No data available.

Distribution.

Cidofovir must be administered with probenecid. The pharmacokinetics of cidofovir, without and with probenecid as: the pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose independent pharmacokinetics were demonstrated after one hour infusions of 1.0 (n=5), 3.0 (n=10), 5.0 (n=2) and 10.0 (n=8) mg/kg. (See Table 2 for pharmacokinetic parameters) The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV- infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hour infusions of 3.0 (n=12), 5.0 (n=6) and 7.5 (n=4) mg/kg (See Table 2). Approximately 70 to 85% of the cidofovir dose administered with concomitant probenecid was excreted as unchanged drug within 24 hours. When the cidofovir dose was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.

Metabolism.

There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n=5) without probenecid.

Excretion.

In patients with normal renal function, approximately 80 to 100% of the cidofovir dose was recovered unchanged in urine within 24 hours (n=27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir. No metabolites of cidofovir have been detected in serum or urine of patients.

In vitro protein binding.

In vitro protein binding of cidofovir to plasma or serum protein was 10% or less over the cidofovir concentration range 0.25 to 25 microgram/mL.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cidofovir as the dihydrate, sodium hydroxide, hydrochloric acid, water for injections.

6.2 Incompatibilities

The chemical and physical stability of Empovir admixed with saline has been demonstrated in glass bottles, in infusion bags composed of either polyvinyl chloride (PVC) or ethylene/propylene copolymer, and in PVC based vented IV administration sets. Other types of IV set tubing and infusion bags have not been studied.
No data are available to support the addition of other drugs or supplements to the recommended admixture for intravenous infusion. Compatibility with Ringer's Solution, Lactated Ringer's Solution or bacteriostatic infusion fluids has not been evaluated.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at a temperature below 25°C. Do not refrigerate or freeze.
If not intended for use immediately after preparation, Empovir infusion admixtures may be stored temporarily for up to 24 hours in a refrigerator (2-8°C) when reconstitution is performed under aseptic conditions. Storage beyond 24 hours or freezing is not recommended. Refrigerated solutions should be allowed to warm to room temperature prior to use.
Empovir is supplied in single-use vials. Partially used vials should be discarded.

6.5 Nature and Contents of Container

Sterile Empovir solution is supplied in single use 5 mL clear glass vials with a 5 mL nominal fill volume.
Each pack contains one 5 mL vial together with the package leaflet. AUSTR: 287040.

6.6 Special Precautions for Disposal

Handling and disposal.

Adequate precautions including the use of appropriate safety equipment are recommended for the preparation, administration and disposal of Empovir. The preparation of Empovir should be done in a laminar flow biological safety cabinet. Personnel preparing the drug should wear surgical gloves, safety glasses and a closed front surgical-type gown with knit cuffs. If Empovir contacts the skin, wash membranes and flush thoroughly with water. Excess Empovir and all other materials used in the admixture preparation and administration should be placed in a leak-proof, puncture-proof container for disposal.

6.7 Physicochemical Properties

Empovir (cidofovir) is an acyclic nucleoside phosphonate analogue. Cidofovir is a white to off white crystalline powder. Solubility in 5 M aqueous Sodium Hydroxide solution is 180 mg/mL at pH about 7.4. Its molecular formula is C8H14N3O6P.2H2O and has a molecular weight of 315.22 (279.19 for anhydrous).
The formulation is pH adjusted to 7.4 with sodium hydroxide and/or hydrochloric acid and contains no preservatives. In addition to cidofovir, the ingredients are water for injections, sodium hydroxide and hydrochloric acid.

Chemical structure.

Chemical name: 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC).

CAS number.

CAS 113852-37-2 (cidofovir anhydrous).
CAS 149394-66-1 (cidofovir dihydrate).

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes