CIDOFOVIR TILMOMED

PACKAGE LEAFLET: INFORMATION FOR THE USER

Cidofovir Tillomed 75 mg/ml concentrate for solution for infusion

This medicinal product is subject to additional monitoring. This will allow rapid identification
of new safety information. You can help by reporting any side effects you experience while taking
this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before using this medicine because it contains important
information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any side effect, including those not listed in this leaflet, consult your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

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

Cidofovir Tillomed is indicated for the treatment of an eye infection called cytomegalovirus (CMV) retinitis in patients with AIDS (acquired immunodeficiency syndrome).
Cidofovir will not cure your CMV retinitis, but it may improve your condition by slowing the progression of the disease.
The safety and efficacy of cidofovir have not been demonstrated in diseases other than CMV retinitis in patients with AIDS.
Cidofovir must be administered by healthcare personnel (physician or nurse) in a hospital setting.

What is CMV retinitis?
CMV retinitis is an eye infection caused by a virus called cytomegalovirus (CMV). This virus affects the retina of the eye and may lead to vision loss and even blindness. Patients with acquired immunodeficiency syndrome (AIDS) are at high risk of developing CMV retinitis or other conditions caused by cytomegalovirus, such as colitis (an inflammatory disease of the intestine). Treatment of CMV retinitis is necessary to reduce the potential risk of blindness.
Cidofovir is an antiviral medicine that blocks CMV replication by interfering with viral DNA production.

2. What you should know before using Cidofovir Tillomed

Do not use cidofovir

• If you are allergic to cidofovir or to any of the other ingredients of this medicine (listed in section 6).
• If you have previously had kidney disease.
• If you cannot take probenecid due to a severe allergy to this substance or to other medicinal products containing sulfur (e.g. sulfamethoxazole).

Inform your doctor if any of these conditions apply to you. Cidofovir must not be
administered to you.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using cidofovir.

• Kidney damage is the main side effect of cidofovir treatment. 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, as they may be at increased risk of developing low eye pressure (ocular hypotony).

During treatment with cidofovir, you must have regular eye examinations
to check for possible eye irritation, inflammation, or swelling. If you experience eye pain, redness or
itching, or changes in vision, inform your doctor immediately.
Cidofovir has caused testicular atrophy and low sperm count (oligospermia) in
laboratory animals. Although these changes have not been observed in human studies with
cidofovir, they could still occur in humans and may lead to infertility. Men must use barrier methods of
contraception during treatment and for 3 months after
completing cidofovir treatment.
Cidofovir is not indicated for the treatment of HIV infections. Cidofovir will not prevent
the transmission of HIV infection to others; therefore, you must continue to take precautions
to avoid infecting other people.
Use in children
Cidofovir has not been studied in children. Therefore, this medicine must not be used
in children.
Other medicines and cidofovir
Inform your doctor or pharmacist if you are taking or have recently taken any other
medicines, including those without a prescription, as they may interact with cidofovir or probenecid.
It is very important that you inform your doctor if you are taking other medicines that may
damage the kidneys.
These include:

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

The use of these medicines must be discontinued at least 7 days before starting cidofovir.
Probenecid may interact with other medicines commonly used in the treatment of AIDS and AIDS-related conditions, such as zidovudine (AZT). If you are taking zidovudine, you should discuss with your doctor the possibility of temporarily stopping it or reducing the dose by 50% on days of cidofovir and probenecid administration.
Potential interactions between cidofovir and anti-HIV protease inhibitors have not been studied.
Use of cidofovir with food and drinks
Cidofovir must be taken with food. Your doctor may advise you to drink plenty of fluids
before taking cidofovir.
Pregnancy and breastfeeding
If you are pregnant, cidofovir must not be administered to you. If you become pregnant while
taking this medicine, inform your doctor immediately. Cidofovir has been shown to cause fetal harm and must not be used during pregnancy unless the potential benefits outweigh the risks to the fetus.
Women of childbearing potential must use effective contraception during treatment with
cidofovir and for 6 months after completion of treatment.
Men must use effective contraception and must not father a child during treatment
with cidofovir and for three months after completing treatment.
Cidofovir must not be prescribed to you if you are breastfeeding. It is not known whether cidofovir passes into breast milk. Since many medicines do pass into breast milk, women who are breastfeeding should either discontinue cidofovir therapy or stop breastfeeding if they continue cidofovir treatment.
In general, women with HIV infection should not breastfeed to avoid transmitting the HIV virus to their infants through breast milk.
Driving and using machines
Cidofovir may cause short-term side effects such as fatigue or weakness. If you need to drive or operate machinery, discuss this with your doctor to determine whether you should refrain from these activities based on your medical condition and your individual response to the medicine.
Cidofovir Tillomed 75 mg/ml concentrate for solution for infusion contains sodium
This medicine contains 57 mg of sodium (the main component of table salt) per vial (5 ml), equivalent to 3% of the recommended maximum daily sodium intake for an adult (2 g).

3. How to use Cidofovir Tillomed

Cidofovir Tillomed 75 mg/ml concentrate for solution for infusion is administered by
intravenous infusion (intravenous drip). It must not be administered by any other routes, including
intraocular injection (direct injection into the eye) or topical route (on the skin).
Administration of cidofovir must be performed by a doctor or a nurse experienced in the treatment of
people with AIDS.
The doctor or nurse will transfer the appropriate dose of cidofovir from the vial into an infusion bag
containing 100 ml of 0.9% isotonic 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. It is important not to
exceed the recommended doses, frequency of administration, or infusion rate. Additional information
for healthcare professionals on how to administer cidofovir is provided at the end of this leaflet.
To reduce the risk of kidney damage, probenecid tablets and intravenous fluid infusion (saline
solution) must be given on the same day as each cidofovir infusion (See the sections below “How to use
probenecid with cidofovir” and “How are intravenous fluids given before cidofovir”)
Dosage in adults
The required dose is calculated based on body weight.
Induction therapy
The recommended dose of cidofovir for patients with normal renal function is 5 mg per kg of body weight
to be administered once weekly for two consecutive weeks.
Maintenance therapy
Starting two weeks after completion of induction therapy, the recommended maintenance dose is 5 mg
per kg of body weight administered once every two weeks.
Dose adjustment
If you have kidney problems, treatment with cidofovir may not be suitable for you. Before each cidofovir
infusion, urine and/or blood samples will be taken to assess kidney function. In case of impaired renal
function, it may be necessary, depending on the situation, to interrupt or discontinue cidofovir
administration.
If you use more cidofovir than you should
In case of accidental administration of a higher amount of cidofovir than prescribed, inform your doctor
immediately.
How to use probenecid with cidofovir
Probenecid tablets are administered to reduce the risk of kidney damage. You must take 3 doses of
probenecid tablets orally on the same day as cidofovir, as indicated in the table below:

Probenecid should be taken only on the same day as cidofovir administration.
How intravenous fluids are given before cidofovir
Isotonic saline solution is administered to reduce the risk of kidney damage. You must receive 1 liter of 0.9% saline solution intravenously (by intravenous infusion) before each dose of cidofovir. The saline solution should be infused over 1 hour immediately before the cidofovir infusion. If you are able to tolerate an additional fluid load, your doctor may administer a second liter of physiological saline solution. If given, the second liter of physiological saline should be started either during or immediately after the cidofovir infusion and infused over 1–3 hours. Your doctor may also instruct you to drink plenty of fluids.
If you have any doubts about the use of this medicine, consult 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 disappear at the end of cidofovir treatment. If any of the side effects worsen,
or if you notice any side effect not listed in this leaflet, inform your doctor or pharmacist immediately.
The most commonly occurring side effect following administration of cidofovir has been kidney damage.

Very common side effects ( may affect more than 1 in 10 people )
low white blood cell count, headache, nausea, vomiting, presence of protein in urine, increased creatinine in blood (a measure of kidney function), hair loss, rash, weakness/tiredness, and fever.

Common side effects (may affect up to 1 in 10 people)
inflammation of the eye, reduced eye pressure, difficult or laboured breathing, shortness of breath, diarrhoea, and chills.

If you develop pain, redness or itching in the eye or changes in vision, inform your doctor immediately so that your treatment with this medicine can be reassessed.

Other reactions reported during the post-marketing phase include renal failure, kidney tubular cell damage, pancreatitis, and hearing impairment.

Possible side effects of probenecid

Very common side effects possibly related to probenecid treatment
( may affect more than 1 in 10 people )
nausea, vomiting, rash, and fever.

Common side effects possibly related to probenecid treatment
( may affect up to 1 in 10 people )
headache, weakness/tiredness, chills, and allergic reactions.

To reduce the possibility of nausea and/or vomiting associated with probenecid treatment, you should take food before each dose of probenecid. Your doctor may advise you to take other medicines such as antiemetics (anti-vomiting medicines), antihistamines and/or paracetamol to reduce probenecid side effects.

Probenecid may also cause other side effects including loss of appetite, gum pain, facial flushing, hair loss, dizziness, reduced red blood cell count, and increased frequency of urination. Allergic reactions associated with skin inflammation, itching, urticaria, and, rarely, severe allergic reactions and serious skin reactions have occurred. There have been reports of reduced white blood cell count, liver toxicity, kidney toxicity, and destruction of red blood cells. Decreases in blood cell count and platelets have also occurred.

Therefore, before administering probenecid, your doctor should consult the Summary of Product Characteristics in force for further information on probenecid safety. Read the probenecid package leaflet.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cidofovir Tillomed

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp.". The expiry date refers to the last day of that month.
Do not store above 25 °C. Do not refrigerate or freeze.

Period of validity after dilution:
Chemical and physical in-use stability has been demonstrated for 36 hours at 2–8 °C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2–8 °C, unless dilution takes place under controlled and validated aseptic conditions. Freezing is not recommended.
Before administration, solutions previously stored in the refrigerator must be brought to room temperature.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Cidofovir Tillomed 75 mg/ml concentrate for solution for infusion contains
The active substance is cidofovir. Each ml contains 75 mg of cidofovir as cidofovir dihydrate. Each
vial (5 ml) contains 375 mg of cidofovir as cidofovir dihydrate.
The other components are sodium hydroxide, hydrochloric acid and water for injections. Sodium
hydroxide and hydrochloric acid are used to adjust the pH of the solution.
Description of the appearance of Cidofovir Tillomed and contents of the pack
Cidofovir Tillomed is a concentrate for solution for infusion. It is available as a clear, colourless solution contained in a transparent glass vial of 5 ml.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Tillomed Italia S.r.l.
Viale Richard 1, Torre A, 20143,
Milan, Italy
Manufacturer
Tillomed Malta Limited
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000, Malta
This medicinal product is authorised in the European Economic Area countries under the following names
Country name Medicinal product name
Finland Cidofovir Macure 75 mg/ml infuusiokonsentraatti, liuosta varten
Norway Cidofovir Macure
Denmark Cidofovir Macure 75 mg/ml koncentrat til infusionsvæske, opløsning
Sweden Cidofovir Macure 75 mg/ml koncentrat till infusionsvätska, lösning
Italy Cidofovir Tillomed
Netherlands Cidofovir Tillomed 75 mg/ml concentraat voor oplossing voor infusie
France Cidofovir Tillomed 75 mg/ml solution à diluer pour perfusion

The following information is intended exclusively for healthcare professionals:

Vials of cidofovir should be inspected visually before use. If visible particles or discoloration are present, the vial must not be used.
Appropriate precautions should be taken during the preparation, administration, and disposal of cidofovir, including the use of suitable protective equipment. The diluted cidofovir solution should be prepared in a laminar airflow biological safety cabinet. Personnel preparing the solution must wear surgical gloves, safety goggles, and a surgical gown with cuffs, open at the back. If cidofovir comes into contact with the skin or mucous membranes, the affected areas should be thoroughly rinsed with water.
The appropriate dose of cidofovir should be transferred from the vial into an infusion bag containing 100 ml of 0.9% isotonic saline solution. The entire volume of the bag must be administered intravenously to the patient at a constant rate over a period of 1 hour, using a standard infusion pump. It is important not to exceed the recommended dose, frequency of administration, or infusion rate.
The chemical stability of cidofovir mixed with saline solution has been demonstrated in glass vials, polyvinyl chloride (PVC) infusion bags, ethylene/propylene copolymer infusion bags, and in perforated PVC administration sets for intravenous delivery. Other types of infusion catheters and infusion bags have not been studied.
Compatibility of cidofovir with Ringer's solution, lactated Ringer's solution, or bacteriostatic infusion fluids has not been evaluated.
Shelf-life after dilution: see section 5.
Cidofovir is available in single-use vials. Partially used vials must be discarded.