CIDOFOVIR ZENTIVA 75 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Cidofovir Zentiva 75 mg/ml Concentrate for Solution for Infusion EFG

This medicinal product is subject to additional monitoring, which will allow for quick identification of new safety information. You can help by reporting any side effects you may get. The last section of this leaflet includes information on how to report side effects.

Read all of this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

1. What is Cidofovir Zentiva and what is it used for
2. What you need to know before you use Cidofovir Zentiva
3. How to use Cidofovir Zentiva
4. Possible side effects
5. Storage of Cidofovir Zentiva
6. Contents of the pack and other information

1. What is Cidofovir Zentiva and what is it used for

Cidofovir is used to treat an eye infection called cytomegalovirus (CMV) retinitis in patients with AIDS (Acquired Immune Deficiency Syndrome).Cidofovir will not cure your CMV retinitis, but it can improve your condition by delaying the progression of the disease.

The safety and efficacy of cidofovir in diseases other than CMV retinitis in patients with AIDS have not been established.

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 called cytomegalovirus (CMV). CMV attacks the retina of the eye and can lead to loss of vision and eventually blindness. Patients with AIDS are at high risk of developing CMV retinitis or other forms of CMV disease, such as colitis (an inflammatory disease of the intestine). Treatment for CMV retinitis is necessary to reduce the risk of blindness.

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

2. What you need to know before you use Cidofovir Zentiva

Do not use Cidofovir Zentiva

• if you are allergicto cidofovir or any of the other ingredients of this medicine (listed in section 6).
• if you have had kidney disease in the past.
• if you cannot take the medicine probeneciddue to a severe allergy to probenecid or any other medicine that contains sulfonamides (e.g., sulfamethoxazole).

If any of these apply to you, talk to your doctor. You should not be given cidofovir.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with cidofovir.

• •Kidney damage is the main side effect of treatment with cidofovir. Therefore, your doctor may need to monitor you closely, especially if you already have kidney problems or are on hemodialysis.
• • If you have diabetes mellitus.Cidofovir should be used with caution in diabetic patients due to the potential increased risk of developing low eye pressure (ocular hypotony).

During treatment with cidofovir, you should have your eyes checked frequentlyfor possible eye irritation, inflammation, or swelling. Report promptly to your doctor if you notice pain, redness, or itching of the eye or changes in your vision.

Cidofovir caused a reduction in testicular weight and low sperm count (hypospermia)in animals. Although this has not been observed in human studies with cidofovir, such changes may occur and cause infertility in humans. Men should use barrier contraceptive methods during and up to 3 months after treatment with cidofovir.

Cidofovir is not used to treat HIV infection. Cidofovir will not prevent you from passing HIV infection to others, so you should continue to take precautions to avoid infecting others.

Children

Cidofovir has not been studied in children. Therefore, its use is not recommended in children.

Other medicines and Cidofovir Zentiva

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those obtained without a prescription, as they may interact with cidofovir or probenecid.

It is very important that you tell your doctor if you are taking other medicines that may harm your kidneys.

This includes:

• Medicines containing tenofovir, used to treat HIV-1 infection and/or chronic hepatitis B.
• Aminoglycosides, pentamidine, or vancomycin (for bacterial infections)
• Amphotericin B (for fungal infections)
• Foscarnet (for viral infections)
• Adefovir (for hepatitis B infection)

These medicines should be stopped at least 7 daysbefore taking cidofovir.

Probenecid may interact with other medicines commonly used in the treatment of AIDS and AIDS-related diseases, such as zidovudine (AZT). If you are taking zidovudine, you should talk to your doctor about stopping zidovudine or reducing the dose by 50% on the days when you are given cidofovir and probenecid.

Potential interactions between cidofovir and HIV protease inhibitors have not been studied.

Using Cidofovir Zentiva with food and drinks

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

Pregnancy and breastfeeding

Cidofovir should not be given if you are pregnant.If you become pregnant while receiving this medicine, you should tell your doctor immediately. Cidofovir has been shown to cause harm to the unborn baby in animal studies and should not be used during pregnancy unless the potential benefits justify the potential risks to the fetus.

Women of childbearing age should use effective contraceptive methodsduring treatment with cidofovir and for 6 months after the end of treatment.

Men should use effective contraceptive measures and not father a childwhile on treatment with cidofovir and for 3 months after the end of treatment.

Cidofovir should not be given if you are breastfeeding.It is not known whether cidofovir passes into breast milk. Because many medicines are excreted in breast milk, breastfeeding mothers should stop cidofovir or stop breastfeeding if they continue to receive cidofovir.

Generally, HIV-infected women should not breastfeedto avoid passing HIV to their baby through breast milk.

Driving and using machines

Cidofovir may cause short-term side effects such as fatigue or weakness. If you drive or use machines, talk to your doctor for advice on whether to stop these activities based on your condition and tolerance to the medicine.

Cidofovir 75 mg/ml Concentrate for Solution for Infusion EFG contains sodium

Patients on low-sodium diets should note that this medicine contains 2.5 mmol (or 57 mg) of sodium per vial.

3. How to use Cidofovir Zentiva

Cidofovir 75 mg/ml Concentrate for Solution for Infusion EFG is given by intravenous infusion (drip into a vein). It should not be administered by other methods, including intraocular injection (directly into the eye) or topical application (on the skin). Cidofovir should be given by a doctor or nurse with experience in treating patients with AIDS.

The doctor or nurse will transfer the appropriate dose of cidofovir from the vial to an infusion bag containing 100 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion. 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, and infusion rate should not be exceeded. Additional information for healthcare professionals on how to administer cidofovir can be found at the end of this leaflet.

To reduce the risk of kidney damage, probenecid tablets and intravenous fluids (sodium chloride 9 mg/ml (0.9%) solution for infusion) should be given on the day of each cidofovir infusion. (See the subheadings "How to take probenecid with cidofovir" and "How to give intravenous fluids before cidofovir" below).

Dose in adults

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

Induction treatment

The recommended dose of cidofovir in patients with normal kidney function is 5 mg per kg of body weight given once a week for two consecutive weeks.

Maintenance treatment

Starting two weeks after completing the induction treatment, the recommended maintenance dose of cidofovir 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, cidofovir may not be the right treatment for you. Urine and/or blood samples will be taken before each administration of cidofovir and used to monitor your kidney function. In the case of patients with evidence of reduced kidney function, treatment with cidofovir may be interrupted or discontinued, depending on the individual case.

If you use more Cidofovir Zentiva than you should

If you have been accidentally given more cidofovir than prescribed, inform your doctor immediately.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, telephone: 91 562 04 20, indicating the medicine and the amount ingested.

How to take probenecid with cidofovir

Probenecid tablets are given to reduce the risk of kidney damage.You should take 3 doses of probenecid tablets by mouth on the same day as cidofovir, as indicated in the following table:

Probenecid is taken only on the same day as cidofovir.

How to give intravenous fluids before cidofovir

Sodium chloride 9 mg/ml (0.9%) solution for infusion is given to reduce the risk of kidney damage.You should receive a total of 1 liter of sodium chloride 9 mg/ml (0.9%) solution for infusion by intravenous infusion (drip into a vein) before each dose of cidofovir. The sodium chloride 9 mg/ml (0.9%) solution for infusion should be administered by infusion over a period of 1 hour, immediately before the infusion of cidofovir. If you can tolerate the additional fluid load, your doctor may administer a second liter of fluids. If this is given, the second liter of sodium chloride 9 mg/ml (0.9%) solution for infusion should be administered by infusion over a period of 1 to 3 hours, starting either at the beginning of the cidofovir infusion or immediately after. Your doctor will also instruct you to drink plenty of fluids.

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

4. Possible side effects

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

These side effects usually go away when treatment with cidofovir is stopped. If you think any of the side effects you are experiencing are serious or if you notice any side effects not listed in this leaflet, tell your doctor or pharmacist immediately.

The most common side effect observed with cidofovir is kidney damage.

Very common side effects

(May affect more than 1 in 10 patients)

low white blood cell counts, headache, nausea, vomiting, protein in the urine, increased creatinine in the blood (a measure of kidney function), hair loss, rash, weakness/fatigue, and fever.

Common side effects

(May affect between 1 and 10 in 100 patients)

eye inflammation, reduced eye pressure, difficulty breathing or shortness of breath, diarrhea, and chills.

Any pain, redness, itching of the eye, or changes in vision should be reported promptly to your doctor for review of treatment.

Additional adverse reactions have been observed during the post-marketing period, including kidney failure, kidney tubule cell damage, pancreatitis, and hearing disturbances.

Possible side effects of probenecid

Very common side effects possibly related to probenecid

(May affect more than 1 in 10 patients)

nausea, vomiting, rash, and fever.

Common side effects possibly related to probenecid

(May affect between 1 and 10 in 100 patients)

headache, weakness/fatigue, chills, and allergic reactions.

You should take food before each dose to reduce the risk of nausea and/or vomiting associated with taking probenecid. The administration of antiemetics (medicines to prevent vomiting), antihistamines, and/or paracetamol may be advised by your doctor to reduce the side effects of probenecid.

Probenecid may cause other side effects, including loss of appetite, gum pain, flushing, hair loss, dizziness, low red blood cell count, and increased frequency of urination. Allergic reactions can occur with inflammation of the skin, itching, hives, and, rarely, severe allergic reactions and serious skin reactions. Cases of reduced white blood cell count, liver toxicity, kidney toxicity, and destruction of red blood cells have been reported. Reduction in blood cells and platelets has also been observed.

Therefore, before giving you probenecid, your doctor should consult the available information on the safety of probenecid. You should also read the package leaflet for probenecid.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Cidofovir Zentiva

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 carton, after EXP.

Do not store above 25°C. Do not refrigerate or freeze.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container contents and additional information

Composition of Cidofovir Zentiva 75 mg/ml concentrate for solution for infusion EFG

The active substance of Cidofovir 75 mg/ml is cidofovir.Each ml contains 75 mg of anhydrous cidofovir. Each vial contains 375 mg/5 ml of anhydrous cidofovir.

The other components are sodium hydroxide, hydrochloric acid, water for injectable preparations.

Appearance of the product and container contents

Cidofovir is supplied as a sterile concentrate for solution for infusion, in transparent glass vials containing 375 mg of the active substance, anhydrous cidofovir, formulated in 5 ml of water for injectable preparations at a concentration of 75 mg/ml. The pH of the formula has been adjusted with sodium hydroxide (and hydrochloric acid if necessary) and does not contain preservatives.

Marketing authorization holder and manufacturer

Marketing authorization holder:

Zentiva k.s.,

U kabelovny 130,

Dolní Mecholupy,

102 37 Prague 10

Czech Republic

Manufacturer:

MIAS Pharma Limited

Suite 2, Stafford House, Strand Road

Portmarnock, Co. Dublin

Ireland

or

Tillomed Malta Limited,

Malta Life Sciences Park,

LS2.01.06 Industrial Estate,

San Gwann, SGN 3000, Malta

Further information on this medicinal product can be obtained from the local representative of the marketing authorization holder:

Zentiva Spain S.L.U.

Avenida de Europa, 19, Edificio 3, Planta 1.

28224 Pozuelo de Alarcón, Madrid

Spain

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Date of last revision of this leaflet: March 2022.

This information is intended only for healthcare professionals:

The vials of cidofovir must be visually inspected before use. If visible particles or discoloration are observed, the vial must not be used.

Adequate precautions are recommended, including the use of appropriate safety equipment, for the preparation, administration, and disposal of cidofovir. The preparation of the cidofovir diluted solution must be performed in a biological safety cabinet with laminar flow. The personnel dedicated to the preparation of the solution must wear surgical gloves, safety glasses, and a closed surgical-type gown with cuffed sleeves. If cidofovir comes into contact with the skin, it must be washed and rinsed with plenty of water.

The appropriate dose of cidofovir must be transferred from the vial to the infusion bag that will contain 100 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion. The total volume of the bag must be infused intravenously into the patient's vein at a constant rate over a period of 1 hour, using a standard infusion pump. The recommended dose, frequency of use, and infusion rate must not be exceeded.

The chemical stability of cidofovir mixtures with sodium chloride 9 mg/ml (0.9%) solution for infusion has been demonstrated in glass bottles, in infusion bags made of polyvinyl chloride (PVC) or propylene/ethylene copolymer, and in PVC intravenous administration equipment. Other types of IV tubes and infusion bags have not been studied.

Compatibility with Ringer's solution, Ringer's lactate solution, or bacteriostatic infusion liquids has not been evaluated.

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

A physical and chemical stability in use of 24 hours between 2 – 8°C has been demonstrated when the dilution is performed under controlled and validated aseptic conditions.It is not recommended to store it for more than 24 hours or to freeze it. The refrigerated infusion bags must be allowed to reach room temperature before use.

Cidofovir is presented in single-use vials. Partially used vials must be discarded.