PREVYMIS 240 MG CONCENTRATE FOR INFUSION SOLUTION

2. What you need to know before you are given PREVYMIS

PREVYMIS must not be given to you:

• if you are allergic to letermovir or any of the other ingredients of this medicine (listed in section 6).
• if you are taking any of the following medicines:
• • pimozide - used for Tourette's syndrome
  • ergot alkaloids (such as ergotamine and dihydroergotamine) - used for migraine headaches.
• if you are taking the following herbal medicine:
• • St. John's Wort (Hypericum perforatum)

PREVYMIS must not be given to you if any of the above situations apply to you. If you are unsure, consult your doctor, pharmacist or nurse before you are given PREVYMIS.

If you are taking PREVYMIS with cyclosporine, do not take the following medicines:

• dabigatran - used to prevent blood clots
• atorvastatin, simvastatin, rosuvastatin, pitavastatin - to treat high cholesterol

Warnings and precautions

If you are also taking a medicine to treat high cholesterol (see list of medicines in the section "Other medicines and PREVYMIS"), you must inform your doctor immediately if you have unexplained muscle pain or weakness, especially if you are feeling unwell or have a fever. Then, it may be necessary to change your medicine or dose. For more information, see the leaflet for your other medicine.

Additional blood tests may be needed to monitor the following medicines:

• cyclosporine, tacrolimus, sirolimus
• voriconazole

Children and adolescents

PREVYMIS must not be used in children who weigh less than 5 kg who have received a stem cell transplant (bone marrow transplant) or in children who weigh less than 40 kg who have received a kidney transplant. This is because PREVYMIS has not been studied in these groups.

Other medicines and PREVYMIS

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because PREVYMIS may affect the way other medicines work and other medicines may affect the way PREVYMIS works. Your doctor or pharmacist will inform you if it is safe to use PREVYMIS with other medicines.

There are some medicines that you must not takewith PREVYMIS (see list in "PREVYMIS must not be given to you:".

There are some additional medicines that you must not takewith PREVYMIS and cyclosporine (see list in "If you are taking PREVYMIS with cyclosporine, do not take the following medicines:".

Also, inform your doctor if you are taking any of the following medicines. This is because your doctor may need to change your medicines or change the dose of your medicines:

• alfentanil - for severe pain
• fentanyl - for severe pain
• quinidine - for heart rhythm disorders

• cyclosporine, tacrolimus or sirolimus - used to prevent transplant rejection
• voriconazole - for fungal infections
• statins, such as atorvastatin, fluvastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin - to treat high cholesterol
• gliburide, repaglinide - for high blood sugar
• carbamazepine, phenobarbital, phenytoin - for seizures or epilepsy
• dabigatran, warfarin - used to thin the blood or prevent blood clots
• midazolam - used as a sedative
• amiodarone - used to correct irregular heartbeats
• oral steroid contraceptives - for birth control
• omeprazole, pantoprazole - for stomach ulcers and other stomach problems
• nafcillin - for bacterial infections
• rifabutin, rifampicin - for fungal infections
• thioridazine - for psychiatric disorders
• bosentan - for high blood pressure in the lungs
• efavirenz, etravirine, nevirapine, lopinavir, ritonavir - for HIV
• modafinil - to stay awake

You can ask your doctor or pharmacist for a list of medicines that may interact with PREVYMIS.

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. It is not recommended to use PREVYMIS during pregnancy. This is because PREVYMIS has not been studied during pregnancy and it is not known whether PREVYMIS could harm the baby during pregnancy.

Breast-feeding

If you are breast-feeding or plan to breast-feed, ask your doctor for advice before taking this medicine. Breast-feeding is not recommended while taking PREVYMIS. This is because it is not known whether PREVYMIS passes into breast milk and could pass to your baby.

Driving and using machines

PREVYMIS may have a minor influence on your ability to drive and use machines (see section 4 Possible side effects later). Some patients have reported fatigue (feeling very tired) or dizziness (feeling like you are spinning) during treatment with PREVYMIS. If you experience any of these effects, do not drive or use machines until the effect goes away.

PREVYMIS contains sodium

PREVYMIS contains sodium. If you are on a low-sodium diet, talk to your doctor before you are given this medicine.

Each 240 mg vial contains 23 mg of sodium (main component of table salt/cooking salt). This is equivalent to 1.15% of the maximum recommended daily sodium intake for an adult.

Each 480 mg vial contains 46 mg of sodium (main component of table salt/cooking salt). This is equivalent to 2.30% of the maximum recommended daily sodium intake for an adult.

PREVYMIS contains cyclodextrin

Each 40 mg dose of this medicine contains 300 mg of cyclodextrin.

Each 60 mg dose of this medicine contains 450 mg of cyclodextrin.

Each 120 mg dose of this medicine contains 900 mg of cyclodextrin.

Each 240 mg dose of this medicine contains 1,800 mg of cyclodextrin.

Each 480 mg dose of this medicine contains 3,600 mg of cyclodextrin.

If you have kidney problems, talk to your doctor before taking this medicine.

3. How PREVYMIS is given

Your dose of PREVYMIS depends on your weight and whether you are also taking cyclosporine. Your doctor will decide the correct dose of PREVYMIS.

PREVYMIS will be given to you by infusion (drip) into a vein over about 1 hour.

PREVYMIS will be given to you once a day.

The recommended intravenous doses of PREVYMIS are shown in Table 1.

Table1: Recommended dose of PREVYMIS concentrate for solution for infusion with or without cyclosporine

If you are given too much PREVYMIS

If you think you have been given too much PREVYMIS, tell your doctor immediately.

If you miss a dose of PREVYMIS

It is very important that you do not miss or skip any dose of PREVYMIS.

• If you miss your appointment to receive PREVYMIS, contact your doctor immediately to schedule another appointment.

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

4. Possible side effects

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

Common:may affect up to 1 in 10 people

• diarrhea
• nausea
• vomiting

Uncommon:may affect up to 1 in 100 people

• allergic reaction (hypersensitivity) - signs may include hives, difficulty breathing, rash, swelling or itching
• loss of appetite
• altered taste
• headache
• feeling of spinning (vertigo)
• stomach pain
• abnormalities in laboratory tests to check liver function (e.g. elevated liver enzymes)
• muscle spasms
• elevated creatinine in blood tests
• feeling of tiredness (fatigue)
• swelling of hands or feet

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist or nurse, even if it is not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of PREVYMIS

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 and vial after EXP. The expiry date is the last day of the month shown.

This medicine does not require any special storage conditions. Store in the original package to protect from light.

Chemical and physical stability have been demonstrated for 48 hours at 25°C and for 48 hours between 2 and 8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution has taken place in controlled and validated aseptic conditions.

Any unused portion of the infusion solution should be discarded.

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 PREVYMIS

The active ingredient is letermovir. Each vial contains 240 mg or 480 mg of letermovir. Each ml of concentrate contains 20 mg.

The other components are: hydroxypropyl betadex (cyclodextrin), sodium chloride, sodium hydroxide (E524), water for injectable preparations. See section 2 "PREVYMIS contains sodium" and "PREVYMIS contains cyclodextrin".

Appearance of the Product and Container Contents

PREVYMIS 240 mg and 480 mg concentrate for solution for infusion (sterile concentrate) is a clear, colorless liquid and may contain some small translucent or white particles belonging to the medicinal product.

The 240 mg and 480 mg concentrate for solution for infusion is packaged in transparent glass vials. Each vial is packaged in a box.

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:{MM/YYYY}.

Detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu.

_____________________________________________________________________________

This information is intended for healthcare professionals only:

Instructions for Administration of PREVYMIS Concentrate for Solution for Infusion

The vials of PREVYMIS concentrate for solution for infusion are for single use. Discard any unused portion.

Administration through a 0.2 μm or 0.22 μm Sterile PES In-Line Filter

PREVYMIS concentrate for solution for infusion may contain some small translucent or white particles belonging to the medicinal product. Administration of the diluted solution of PREVYMIS always requires the use of a 0.2 μm or 0.22 μm sterile PES in-line filter, regardless of whether these particles are visible in the vial or in the diluted solution (see sections 4.2 and 6.6).

Preparation

PREVYMIS concentrate for solution for infusion must be diluted before intravenous administration.

• Inspect the contents of the vial before dilution to check for changes in color or the presence of particles. PREVYMIS concentrate for solution for infusion is a clear, colorless solution and may contain some small translucent or white particles belonging to the medicinal product.
• Do not use the vial if the solution is cloudy, shows changes in color, or contains elements other than some small translucent or white particles.

• Do not use PREVYMIS concentrate for solution for infusion with intravenous administration bags and infusion equipment materials that contain polyurethane or the plasticizer diethylhexyl phthalate (DEHP). Materials that do not contain phthalates also do not contain DEHP.
• Do not shake the vial of PREVYMIS.
• For the 480 mg or 240 mg dose, add a single-dose vial (either 12 ml (240 mg dose) or 24 ml (480 mg dose)) of PREVYMIS concentrate for solution for infusion to a 250 ml intravenous administration bag preloaded with 0.9% sodium chloride or 5% dextrose, and mix the diluted solution by gentle inversion. Do not shake. If a vial is added to a 250 ml intravenous diluent bag, the final concentration ranges of letermovir would be 0.9 mg/ml (for the 240 mg dose) and 1.8 mg/ml (for the 480 mg dose).

For the 120 mg or 60 mg dose, prepare PREVYMIS concentrate for solution for infusion as indicated in Table 1, in 9 mg/ml (0.9%) sodium chloride or 5% dextrose, and mix the diluted solution by gentle inversion. Do not shake.

For the 40 mg dose, prepare PREVYMIS concentrate for solution for infusion as indicated in Table 2, in 9 mg/ml (0.9%) sodium chloride or 5% dextrose, and mix the diluted solution by gentle inversion. Do not shake.

Table 1: Preparation of PREVYMIS Intravenous Solution for 120 mg or 60 mg Dose

Table 2: Preparation of PREVYMIS Intravenous Solution for 40 mg Dose

• Once diluted, the PREVYMIS solution is clear and its color varies between colorless and yellow. Color variations within this range do not affect the quality of the medicinal product. The diluted solution should be visually inspected before administration to check for particles or color changes. Discard the diluted solution if it is cloudy, shows color changes, or contains elements other than some small translucent or white particles.

Administration

• The diluted solution should be administered through a 0.2 μm or 0.22 μm sterile PES in-line filter.
• Do not administer the diluted solution through a filter other than a 0.2 μm or 0.22 μm sterile PES in-line filter.
• Administer exclusively by intravenous infusion.
• After dilution, PREVYMIS should be administered by intravenous infusion over a total duration of approximately 60 minutes through a peripheral or central venous catheter. The entire contents of the intravenous administration bag should be administered.

Intravenous Solutions Compatible and Other Medicinal Products

• PREVYMIS concentrate for solution for infusion is compatible with 0.9% sodium chloride and 5% dextrose solutions.
• The following medicinal products are compatible.
• This medicinal product should not be mixed with other medicinal products, except those mentioned in the following list.
• PREVYMIS should not be administered through the same intravenous line (or cannula) as other medicinal products and diluent combinations, except those indicated below.

List of Compatible Medicinal Products when PREVYMIS and Other Medicinal Products* are Prepared in 0.9% Sodium Chloride

• Consult the prescribing information to confirm compatibility for simultaneous co-administration.

List of Compatible Medicinal Products when PREVYMIS and Other Medicinal Products* are Prepared in 5% Dextrose

• Consult the prescribing information to confirm compatibility for simultaneous co-administration.

† Lipid complex amphotericin B is compatible with PREVYMIS. However, liposomal amphotericin B is incompatible (see section 6.2).

Compatible Materials for Intravenous Administration Bags and Infusion Equipment

PREVYMIS is compatible with the following materials for intravenous administration bags and infusion equipment. No other materials for intravenous administration bags or infusion equipment should be used except those indicated below.

Intravenous Administration Bag Materials

Polyvinyl chloride (PVC), vinyl acetate and ethylene (EVA), and polyolefin (polypropylene and polyethylene)

Infusion Equipment Materials

PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene-butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS)

Plasticizers

Tri(2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate (BBP)

Catheters

Radiopaque polyurethane

Incompatible Medicinal Products

PREVYMIS concentrate for solution for infusion is physically incompatible with amiodarone hydrochloride, liposomal amphotericin B, aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam hydrochloride, mycophenolate mofetil hydrochloride, ondansetron, and palonosetron.

Incompatible Materials for Intravenous Administration Bags and Infusion Equipment

PREVYMIS is incompatible with diethylhexyl phthalate (DEHP) plasticizers and intravenous administration tubing that contains polyurethane.

Disposal of Unused Medicinal Product and All Materials that Have Come into Contact with It

Disposal of unused medicinal product and all materials that have come into contact with it should be carried out in accordance with local regulations.