HyQvia
human normal immunoglobulin
This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.
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.
What HyQvia is and what it is used for
What you need to know before you use HyQvia
How to use HyQvia
Possible side effects
How to store HyQvia
Contents of the pack and other information
HyQvia contains two solutions for infusion (drip) under the skin (subcutaneous or SC infusion).
It is supplied as a package containing one vial of human normal immunoglobulin 10% (the active substance) and one vial of recombinant human hyaluronidase (a substance which helps the human normal immunoglobulin 10% reach your blood).
Human normal immunoglobulin 10% belongs to a class of medicines called “human normal immunoglobulins”. Immunoglobulins are also known as antibodies and are found in healthy people’s blood. Antibodies are part of the immune system (the body’s natural defences) and help your body to fight infections.
The vial of immunoglobulins has been prepared from the blood of healthy people. The medicine works in exactly the same way as the immunoglobulins naturally present in the blood. The recombinant human hyaluronidase is a protein that makes it easier for the immunoglobulins to be infused (dripped) under the skin and to reach your blood system.
HyQvia is used in patients with a weak immune system, who do not have enough antibodies in their blood and tend to get frequent infections. Regular and sufficient doses of HyQvia can raise abnormally low immunoglobulin levels in your blood to normal levels (replacement therapy).
HyQvia is prescribed as replacement therapy to patients who do not have sufficient antibodies, including the following groups:
patients with an inborn inability or reduced ability to produce antibodies (primary immunodeficiencies).
patients who experience severe or recurrent infections due to a weakened immune system resulting from other conditions or treatments
if you are allergic to immunoglobulins, hyaluronidase, recombinant hyaluronidase or any
of the other ingredients of this medicine (listed in section 6, “Contents of the pack and other information”).
if you have antibodies against immunoglobulin A (IgA) in your blood. This may occur if you have IgA deficiency. Since HyQvia contains trace amounts of IgA, you might have an allergic
reaction.
into a blood vessel (intravenously).
The following warnings and precautions should be taken into consideration before you receive or use HyQvia. If you have any questions, talk to your doctor or nurse.
The data on the effects of long-term use of recombinant human hyaluronidase on pregnancy,
breast-feeding and fertility are limited. HyQvia should only be used by pregnant and breast-feeding women after discussion with your physician.
Allergicreactions
You may be allergic to immunoglobulins without knowing it. Allergic reactions such as sudden fall in blood pressure or anaphylactic shock (a sharp fall in blood pressure with other symptoms such as swelling of the throat, breathing difficulties and skin rash) are rare but they can occasionally occur even if you have not previously had problems with similar treatments. You are at increased risk of
allergic reactions if you have IgA deficiency with anti-IgA antibodies. Signs or symptoms of these rare allergic reactions include:
feeling light-headed, dizzy or faint,
skin rash and itchiness, swelling in the mouth or throat, difficulty breathing, wheezing,
abnormal heart rate, chest pain, blueness of lips or fingers and toes,
blurred vision.
Your doctor or nurse will first infuse HyQvia slowly, and carefully monitor you throughout the first infusions so that any allergic reaction can be detected and treated immediately.
► If you notice any of these signs during the infusion, tell your doctor or nurse immediately.
He or she will decide whether to slow down the infusion rate or stop the infusion completely.
Infusionspeed
It is very important to infuse the medicine at the correct speed. Your doctor or nurse will advise you on the appropriate infusion speed to use when you are infusing HyQvia at home (see section 3, “How to use HyQvia”).
Monitoringduringinfusion
Certain side effects may occur more frequently if:
you are receiving HyQvia for the first time.
you have received another immunoglobulin and have been switched to HyQvia.
there has been a long interval (e.g., more than 2 or 3 infusion intervals) since you last received HyQvia.
► In such cases, you will be closely monitored during your first infusion and for the first
hour after your infusion has stopped.
In all other cases you should be monitored during the infusion and for at least 20 minutes after you receive HyQvia for the first few infusions.
Hometreatment
Before you start home treatment you should assign a person as guardian. You and your guardian will be trained to detect early signs of side effects, especially allergic reactions. This guardian should help you keep an eye on potential side effects. During the infusion you must look out for first signs of side effects (for further details see section 4, “Possible side effects”).
► If you experience any side effects, you or your guardian must stop the infusion immediately and contact a doctor.
► If you experience a severe side effect, you or your guardian must seek emergency
treatment immediately.
Spreadoflocalisedinfections
Do not infuse HyQvia into or around an infected or red swollen area on your skin because it may cause the infection to spread.
No long-term (chronic) changes in the skin were observed in the clinical studies. Any long-term inflammation, lumps (nodules) or inflammation that occur at the infusion site and last more than a few days should be reported to your physician.
Effectsonbloodtests
HyQvia contains many different antibodies, some of which can affect blood tests (serological tests).
► Tell your doctor about your treatment with HyQvia before any blood test.
InformationonthesourcematerialofHyQvia
The human normal immunoglobulin 10% of HyQvia and human serum albumin (an ingredient of the recombinant human hyaluronidase) are made from human plasma (the liquid part of blood). When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include:
careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and
the testing of each donation and pools of plasma for signs of viruses/infections.
Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are used, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.
The measures taken for the manufacture of HyQvia are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus and for the non-enveloped hepatitis A virus and parvovirus B19.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in HyQvia, are protective.
It is strongly recommended that every time you use HyQvia, the following data are recorded in your treatment diary:
the date of administration,
the batch number of the medicine, and
the injected volume, flow rate, the number and location of infusion sites.
The same indications, dose and frequency of infusion as for adults apply for children and adolescents (0-18 years).
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
Vaccinations
HyQvia may reduce the effect of some virus vaccines such as measles, rubella, mumps and chicken pox (live virus vaccines). Therefore, after receiving HyQvia, you may have to wait for up to 3 months before receiving certain vaccines. You may have to wait for up to 1 year after receiving HyQvia before you can receive your measles vaccine.
► Please tell your vaccinating doctor or nurse about your treatment with HyQvia.
Patients may experience side effects (for example dizziness or nausea) during treatment with HyQvia that might affect the ability to drive and use machines. If this happens, you should wait until the reactions have disappeared.
This medicine contains 5.0 – 60.5 mg sodium (main component of cooking/table salt) in each recombinant human hyaluronidase vial of HyQvia. This is equivalent to 0.25 – 3% of the recommended maximum daily dietary intake of sodium for an adult. The IG 10% component is essentially sodium-free.
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.
HyQvia has to be infused under the skin (subcutaneous or SC administration).
Treatment with HyQvia will be started by your doctor or nurse, but you may be allowed to use the medicine at home once you have received the first few infusions under medical supervision and you (and/or your guardian) have been adequately trained. You and your doctor will decide if you can use HyQvia at home. Do not begin treatment with HyQvia at home until you have received complete instructions.
Dosing
Your doctor will calculate the correct dose for you based on your body weight, any previous treatment you may have received and your response to treatment. The recommended starting dose is one that supplies 400 to 800 mg of active substance per kg of bodyweight per month. In the beginning you will receive one quarter of this dose at 1-week intervals. This will be increased step-wise to larger doses
at 3- to 4-week intervals with the next infusions. Sometimes your doctor may recommend that larger doses are split and given at two sites at once. Your doctor may also adjust your dose depending on
your response to treatment.
Startingtreatment
Your treatment will be started by a doctor or nurse experienced in treating patients with a weak immune system and in guiding patients for home treatment. You will be watched carefully throughout the infusion and for at least 1 hour after stopping the infusion to see how well you tolerate the medicine. In the beginning your doctor or nurse will use a slow infusion speed and gradually increase it during the first infusion and in the following infusions. Once the doctor or nurse has found the right dose and speed of infusion for you, you may be allowed to give the treatment to yourself at home.
Hometreatment
You will be instructed in:
Germ-free (aseptic) infusion techniques,
The use of an infusion pump or syringe driver (if needed),
Keeping a treatment diary, and
Measures to be taken in case of severe side effects.
You must carefully follow your doctor’s instructions regarding the dose, infusion speed and schedule for infusing HyQvia so that your treatment works for you.
Subjects < 40 kg | Subjects ≥ 40 kg | |||
Interval/Minutes | First Two Infusions (mL/hour/infusion site) | Subsequent 2-3 Infusions (mL/hour/infusion site) | First Two Infusions (mL/hour/infusion site) | Subsequent 2 to 3 Infusions (mL/hour/infusion site) |
10 minutes | 5 | 10 | 10 | 10 |
10 minutes | 10 | 20 | 30 | 30 |
10 minutes | 20 | 40 | 60 | 120 |
10 minutes | 40 | 80 | 120 | 240 |
Remainder of infusion | 80 | 160 | 240 | 300 |
Ask your doctor or pharmacist or nurse if another needle size would be more appropriate for you. Any change of needle size would have to be supervised by the treating physician.
If you think that you used more HyQvia than you should, speak to your doctor as soon as possible.
Do not infuse a double dose of HyQvia to make up for a missed dose. If you think that you have missed a dose speak to your doctor as soon as possible.
If you have any further questions on the use of this medicine, ask your doctor, or pharmacist or nurse.
2. Gather all supplies: Collect all items for your infusion. Items include: dual vial unit(s) of HyQvia, infusion supplies (subcutaneous needle set, solution container (bag or syringe), sterile clear bandage and tape, pump tubing, transfer devices, syringes, gauze and tape), sharps container, pump, and treatment logbook and other supplies as needed. |
|
3. Prepare a clean work area. | |
4. Wash hands: Wash your hands thoroughly. Place all gathered supplies and open them as directed by your healthcare professional. |
|
least 30 seconds). |
|
Remove HyQvia from the box:
Allow vials to reach room temperature. This may take up to 60 minutes. Do not use heating devices including microwave.
Do not heat up or shake HyQvia.
Check each vial of HyQvia before using:
Expiration date: Do not use beyond expiration date.
Colour:
The recombinant human hyaluronidase should be clear and colourless.
The human normal immunoglobulin 10% should be clear and colourless or pale yellow.
If either liquid is cloudy or has particles, do not use.
Cap: Purple protective cap is on the dual vial unit. Do not use the product if it does not have the cap.
Open HyQvia dual vial unit(s):
Remove purple protective cap(s) and make sure the blue vial caps are removed. If not, manually remove the blue caps to expose the vial stoppers.
Prepare to transfer the recombinant human hyaluronidase component of HyQvia by wiping each vial stopper with an alcohol swab, if directed and allow to air dry (at
downward. Push the air into the vial. pointing upward. same syringe. remove any remaining air. |
|
human hyaluronidase. |
|
administered. | (a) (b)
|
Prepare recombinant human hyaluronidase vial (HY):
Remove the smaller sterile syringe from package and attach to a non-vented spike or needle (device).
Pull back on the plunger, fill the smaller syringe with air equal to the amount of recombinant human hyaluronidase in the HY vial(s).
Remove the cap of needle/non-vented transfer device.
Insert the tip of the needle/non-vented transfer device into the centre of the vial stopper and push straight
Turn the vial upside down, with the needle/non-vented transfer device remaining in the vial. The syringe tip will be
Withdraw the full contents of the recombinant human hyaluronidase into the syringe.
Repeat Step 6, if more than one vial of recombinant human hyaluronidase is needed for your dose.
If possible, combine all of the recombinant human hyaluronidase needed for the entire dose of IgG into the
Point the syringe tip up and remove any air bubbles by pointing the syringe tip up and gently tapping the syringe with your finger. Slowly and carefully push the plunger to
Prepare the needle set with the recombinant human hyaluronidase (HY):
Attach the syringe filled with recombinant human hyaluronidase to the needle set
Push the plunger of smaller syringe to remove the air and fill the needle set up to the needle wings with the recombinant
Note: Your healthcare professional may recommend using a “Y” connector (for more than one site) or other needle set configuration.
Prepare human normal immunoglobulin 10% vial:
Prepare to transfer the immunoglobulin 10% component of HyQvia by wiping each vial stopper with an alcohol swab, if directed and allow to air dry (at least 30 seconds).
The human normal immunoglobulin 10% of HyQvia may be infused either
by pooling from the vials either into larger syringe (a) or an infusion bag (b) as directed by your healthcare professional, depending upon the pump to be used; or
directly from the IG vial. Insert the spike of the vented pump tubing or spike and venting needle into human normal immunoglobulin 10% vial(s). Fill the administration pump tubing and set aside until the recombinant human hyaluronidase has been administered.
If more than one vial is required for a full dose, spike subsequent vials after the first vial has been fully
9. Prepare the pump: Follow the manufacturer’s instructions for preparing the pump. | |
o Select sites on the opposite sides of the body if instructed to infuse in two sites for doses above 600 mL. |
|
90-degree angle to skin
| |
12. Check for proper needle placement before starting the infusion if instructed by your healthcare professional. |
|
|
Prepare the infusion site:
Choose an infusion site(s) in either the middle to upper abdomen or thigh. See image for infusion site locations.
Avoid bony areas, visible blood vessels, scars and any areas of inflammation or infection.
Rotate infusion sites by choosing opposite sides of the body between future infusions.
If instructed by your health care professional, clean the infusion site(s) with an alcohol swab. Allow to dry (at least 30 seconds).
Insert the needle:
Remove the needle cover. Firmly grasp and pinch at least 2 to 2.5 cm of skin between two fingers.
Insert needle completely to the wings of the needle with a rapid motion straight into the skin at a 90-degree angle. Wings of needle should lay flat on the skin.
Secure needle in place with sterile tape.
Repeat this step if you have a second infusion site.
Secure the needle to the skin:
Secure the needle(s) in place by putting a sterile clear bandage over the needle.
Check infusion site(s) occasionally throughout the infusion for dislodgement or leaking.
increase as tolerated. of 60 to 120 mL/hour and increase as tolerated. |
|
15. Administer the human normal immunoglobulin 10%: After infusing all of the content of the smaller syringe (recombinant human hyaluronidase), remove the syringe from the hub of the needle set. Attach the pump tubing or, the larger syringe containing human normal immunoglobulin 10% to the needle set. Administer the human normal immunoglobulin 10% with a pump at the rates prescribed by your healthcare professional and start the infusion. | |
immunoglobulin 10% up to the needle wings. | |
o Dispose of the sharps container using instructions provided with the container, or contact your healthcare professional. |
|
your treatment record/log book. professional. |
Administer the recombinant human hyaluronidase infusion first:
Slowly push the plunger of the smaller syringe with the recombinant human hyaluronidase at an initial rate per infusion site to approximately 1 to 2 mL per minute and
If using a pump, prepare the pump to infuse the recombinant human hyaluronidase at an initial rate per infusion site
Flush the pump tubing when the infusion is complete if instructed by your healthcare professional:
If instructed by your healthcare professional, attach a saline bag to the pump tubing/needle set to push the human normal
Remove needle set:
Remove the needle set by loosening the dressing on all edges.
Pull the needle wings straight up and out.
Gently press a small piece of gauze over the needle site and cover with a protective dressing.
Throw away the needle(s) into the sharps container.
Record the infusion:
Remove the peel-off label from HyQvia vial, which has the product lot number and expiration date, and place the label in
Write down the date, time, dose, site(s) of infusion (to assist in rotating sites) and any reactions after each infusion.
Throw away any unused product in the vial and the disposable supplies as recommended by your healthcare
Follow up with physician as directed.
Like all medicines, this medicine can have side effects, although not everybody gets them. Certain side effects, such as headache, chills, or body aches, may be reduced by slowing the infusion rate.
Serioussideeffects
Infusions of medicines like HyQvia can occasionally result in serious, but rare, allergic reactions. You may experience a sudden fall in blood pressure and, in isolated cases, anaphylactic shock. Doctors are aware of these possible side effects and will monitor you during and after the initial infusions.
Typical signs or symptoms include: feeling light-headed, dizzy or faint, skin rash and itchiness, swelling in the mouth or throat, difficulty breathing, wheezing, abnormal heart rate, chest pain, blueness of lips or fingers and toes, blurred vision.
Tell your doctor or nurse immediately if you notice any of these signs during the infusion.
When using HyQvia at home, you must perform the infusion in the presence of an assigned guardian person who will help you watch out for allergic reactions, stop the
infusion, and get help if necessary.
Please also see section 2 of this leaflet about the risk of allergic reactions and using HyQvia at home.
Verycommonsideeffects(mayaffectmorethan1in 10 infusions):
Infusion site pain, including mild to moderate discomfort and tenderness. These reactions usually go away within a few days.
Commonsideeffects(mayaffectupto 1in 10infusions):
Reactions at the infusion site: These include redness, swelling, itching, hardening, and rash at the site of infusion. These reactions usually go away within a few days. Headache, tiredness, nausea, vomiting, diarrhoea, abdominal pain, muscle or joint pain, chest pain, fever, feeling weak or unwell.
Uncommonsideeffects(mayaffectupto1in100infusions):
Chills, migraine, increasedblood pressure, dizziness, abdominal bloating, skin rash/allergic rash/redness, itching, pain in chest, arms and/or legs, genital swelling (resulting from spread of swelling from the infusion site), swelling of the legs, feet and ankles, positive blood tests for antibodies.
Frequencynotknown(cannotbeestimatedfromtheavailabledata):
Hypersensitivity, influenza-like illness, and infusion site leakage, inflammation of the layers lining the brain (aseptic meningitis).
Sideeffectsseenwithsimilarmedicines
The following side effects have been observed with infusion of medicines like human normal immunoglobulin 10% given under the skin (subcutaneously). Although these side effects have so far not been seen with HyQvia, it is possible that someone using HyQvia may get them:
Trembling, oral tingling, fast heart beat, allergic reactions, flushing or pallor, coldness of hand or feet, shortness of breath, swelling of face, excessive sweating, muscle stiffness, change in liver function blood tests (alanine aminotransferase increased).
The following rare side effects have been observed in patients using medicines like human normal immunoglobulin 10% given into a vein (intravenously). These reactions have not been seen with HyQvia, but there is a small possibility that someone using HyQvia may get them:
Blood clots in blood vessels (thromboembolic reactions) leading to heart attack, stroke, blockage of deep veins, or of blood vessels supplying the lung (pulmonary embolism), kidney disorder or failure, destruction of red blood cells (haemolysis).
If you get 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 via thenationalreporting
systemlistedinAppendixV. By reporting side effects, you can help provide more information on the safety of this medicine.
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 and carton after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C to 8°C). Do not freeze. Do not shake.
Keep the vials in the outer carton in order to protect from light.
Do not use this medicine if the solutions are cloudy or have particles or deposits. After opening, dispose of any unused solutions in the vials.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment.
HyQvia is a dual vial unit containing:
a solution of recombinant human hyaluronidase (Step 1 of HyQvia/Infuse first) and
a solution of human normal immunoglobulin 10% (Step 2 of HyQvia/Infuse second).
The contents of eachvial are described below:
Recombinanthumanhyaluronidase
This vial contains recombinant human hyaluronidase.
The other ingredients are sodium chloride, sodium phosphate, human albumin, ethylenediaminetetraacetic acid (EDTA) disodium, calcium chloride and water for injections (see also section 2, “HyQvia contains sodium”).
Humannormalimmunoglobulin10%
One mL of the solution in this vial contains 100 mg of human normal immunoglobulin, of which at least 98% is immunoglobulin G (IgG).
The active substance of HyQvia is human normal immunoglobulin. This medicine contains trace amounts of immunoglobulin A (IgA) (not more than 140 micrograms/mL, 37 micrograms on average).
The other ingredients of this vial are glycine and water for injections.
HyQvia is supplied as a pack containing:
one glass vial of recombinant human hyaluronidase, and
one glass vial of human normal immunoglobulin 10%.
The recombinant human hyaluronidase is a clear and colourless solution.
The human normal immunoglobulin 10% is a clear and colourless or pale yellow solution.
The following pack sizes are available:
Recombinant human hyaluronidase | Human normal immunoglobulin 10% | ||
Volume (mL) | Protein (grams) | Volume (mL) | |
1.25 | 2.5 | 25 | |
2.5 | 5 | 50 | |
5 | 10 | 100 | |
10 | 20 | 200 | |
15 | 30 | 300 | |
Not all pack sizes may be marketed.
MarketingAuthorisationHolder: Baxalta Innovations GmbH Industriestrasse 67
A-1221 Vienna Austria
Manufacturer:
Baxalta Belgium Manufacturing SA Boulevard René Branquart 80
B-7860 Lessines Belgium
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
Takeda, UAB
Tel: +370 521 09 070
Такеда България ЕООД Тел.: +359 2 958 27 36
Takeda Pharmaceuticals Czech Republic s.r.o.
Tel: +420 234 722 722
Takeda Pharma Kft.
Tel: +36 1 270 7030
Takeda Pharma A/S
Tlf: +45 46 77 10 10
Τakeda HELLAS SA Tel: +30 2106387800
Takeda GmbH
Tel: +49 (0)800 825 3325
Takeda Nederland B.V.
Tel: +31 20 203 5492
Takeda Pharma AS
Tel: +372 6177 669
Takeda AS
Tlf: +47 800 800 30
Τakeda ΕΛΛΑΣ ΑΕ Tηλ: +30 210 6387800
Takeda Pharma Ges.m.b.H. Tel: +43 (0) 800-20 80 50
Takeda Farmacéutica España S.A
Tel: +34 917 90 42 22
Takeda Pharma Sp. z o.o.
tel: +48223062447
Takeda France SAS
Tel. + 33 1 40 67 33 00
Takeda Farmacêuticos Portugal, Lda.
Tel: + 351 21 120 1457
Takeda Pharmaceuticals Croatia d.o.o.
Tel: +385 1 377 88 96
Takeda Pharmaceuticals SRL
Tel: +40 21 335 03 91
Takeda Products Ireland Ltd
Tel: 1800 937 970
Takeda Pharmaceuticals farmacevtska družba d.o.o.
Tel: + 386 (0) 59 082 480
Vistor hf.
Sími: +354 535 7000
Takeda Pharmaceuticals Slovakia s.r.o.
Tel: +421 (2) 20 602 600
Takeda Italia S.p.A.
Tel: +39 06 502601
Takeda Oy
Puh/Tel: 0800 774 051
Τakeda ΕΛΛΑΣ ΑΕ Τηλ.: +30 2106387800
Takeda Pharma AB
Tel: 020 795 079
Takeda Latvia SIA
Tel: +371 67840082
Takeda UK Ltd
Tel: +44 (0) 2830 640 902
Taking into account the PRAC Assessment Report for the non-interventional imposed PASS final study report for the medicinal product(s) mentioned above, the scientific conclusions of CHMP are as follows:
The final study report submitted by the MAH complies with their obligation to perform a PASS to evaluate the long-term safety and use of HyQvia in patients receiving treatment with HyQvia as imposed at the time of the initial marketing authorisation.
Therefore, in view of available data regarding the PASS final study report, the PRAC considered that changes to the conditions of the marketing authorisation were warranted.
The CHMP agrees with the scientific conclusions made by the PRAC.
On the basis of the scientific conclusions for the results of the study for the medicinal product(s) mentioned above, the CHMP is of the opinion that the benefit-risk balance of these medicinal product(s) is unchanged, subject to the proposed changes to the product information.
The CHMP is of the opinion that the terms of the marketing authorisation(s) of the medicinal product(s) mentioned above should be varied.
