BORTEZOMIB BIOTECH PHARMA LIMITED 3.5 MG POWDER FOR SOLUTION FOR INJECTION - patient leaflet, side effects, dosage

1. WHAT BORTEZOMIB BIOTECH PHARMA LIMITED IS AND WHAT IT IS USED FOR

Bortezomib Biotech Pharma Limited contains the active substance bortezomib, a so-called ‘proteasome inhibitor’. Proteasomes play an important role in controlling cell function and growth. By interfering with their function, bortezomib can kill cancer cells.

Bortezomib Biotech Pharma Limited is used for the treatment of multiple myeloma (a cancer of the bone marrow) in patients older than 18 years:

• alone or together with the medicines pegylated liposomal doxorubicin or dexamethasone, for patients whose disease is worsening (progressive) after receiving at least one prior treatment and for whom blood stem cell transplantation was not successful or is unsuitable.
• in combination with the medicines melphalan and prednisone, for patients whose disease has not been previously treated and are unsuitable for high-dose chemotherapy with blood stem cell transplantation.
• in combination with the medicines dexamethasone or dexamethasone together with thalidomide, for patients whose disease has not been previously treated and before receiving high-dose chemotherapy with blood stem cell transplantation (induction treatment).

Bortezomib Biotech Pharma Limited is used for the treatment of mantle cell lymphoma (a type of cancer affecting the lymph nodes) in patients 18 years or older in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously treated and for whom blood stem cell transplantation is unsuitable.

2. WHAT YOU NEED TO KNOW BEFORE YOU USE BORTEZOMIB BIOTECH PHARMALIMITED

• rituximab, cyclophosphamide, doxorubicin and prednisone. Weight increase

„ -i ™ . . , , , , < 4 « -Bacterial and viral infections

Bortezomib Biotech Pharma Limited is given intravenously or subcutaneously on days 1,4,8 . T....... Uncommon side effects fmav affect more than 1 in 100 neonlel

Do not use Bortezomib Biotech Pharma Limited:

• if you are allergic to bortezomib, boron or to any of the other ingredients of this medicine (listed in section 6).
• if you have certain severe lung or heart problems

Warnings and precautions

You should tell your doctor if you have any of the following:

• low numbers of red or white blood cells
• bleeding problems and/or low number of platelets in your blood
• diarrhea, constipation, nausea or vomiting
• fainting, dizziness or light-headedness in the past
• kidney problems
• moderate to severe liver problems
• numbness, tingling, or pain in the hands or feet (neuropathy) in the past
• heart or blood pressure problems
• shortness ofbreath or cough
• seizures
• shingles (localised including around the eyes or spread across the body)
• symptoms of tumor lysis syndrome such as muscle cramping, muscle weakness, confusion,

and 11, followed by a‘rest period’without treatment. The duration of a treatment cycle is 21 T _ .

days(3 weeks). You might receive up to 8 cycles (24 weeks). ’ Inflammation ofthe pancreas, obstruction ofthe bile duct

m . ..... , „ „ , „ ____ , ’Genital pain, problem having an erection

The following medicinal products are given on day 1 of each Bortezomib Biotech Pharma o w…

Limited 21 -day treatment cycle as intravenous infusions: „.8

2 2 2 ’Thirst

Rituximab at 375 mg/m ,cyclophospha­mideat750mg/m and doxorubicin at 50 mg/m. ’Hepatitis

• Prednisone is given orally at 100 mg/m2 on days 1,2,3,4 and 5 ofthe Bortezomib Biotech T. ■.■ j ,… ,

PF I' 'rdtr tm t 1 ’Injection site or injection device related disorders

arma imi e ea en eye e. ’Skin reactions and disorders (which may be severe and life threatening), skin ulcers

How Bortezomib Biotech Pharma Limited is given . Bruises, falls and injuries

This medicine is for intravenous or subcutaneous use. Bortezomib Biotech Pharma Limited . inflammation or haemorrhage of the blood vessels that can appear as small red or purple

will be administered by a health care professional experienced in the use of cytotoxic dots (usually on the legs) to large bruise-like patches under the skin or tissue

medicines. ’Benign cysts

Bortezomib Biotech Pharma Limited powder has to be dissolved before administration. This. a severe reversible brain condition which includes seizures, high blood pressure, will be done by a healthcare professional. The resulting solution is then either injected into a headaches, tiredness, confusion, blindness or other vision problems.

vein or under the skin. Injection into a vein is rapid, taking 3 to 5 seconds. Injection under the

skin is in either the thighs or the abdomen. Rare side effects <may affect UPto 1 in 1’000 PeoPle)

, -Heart problems to include heart attack, angina

If you are given too much Bortezomib Biotech Pharma Limited , -

hjsnin p

As this medicine is being given by your doctor or nurse, it is unlikely that you will be given .

too much. In the unlikely event of an overdose, your doctor will monitor you for side effects. " discoloration of the vems

• Inflammation ofthe spinal nerve

• Hepatitis
• Severe allergic reaction (anaphylactic reaction) signs of which may include difficulty breathing, chest pain or chest tightness, and/or feeling dizzy/faint, severe itching of the skin or raised lumps on the skin, swelling of the face, lips, tongue and /or throat, which may cause difficulty in swallowing, collapse
• Movement disorders, paralysis, twitching

Vertigo

• Hearing loss, deafness
• Disorders that affect your lungs, preventing your body from getting enough oxygen. Some of these include difficulty breathing, shortness of breath, shortness of breath without exercise, breathing that becomes shallow, difficult or stops, wheezing
• Blood clots in your lungs
• Yellow discoloration of the eyes and skin (j aundice)
• Lump in the eyelid (chalazion), red and swollen eyelids

Rare side effects (may affect up to 1 in 1,000 people)

• Blood clot in small blood vessels (thrombotic microangiopathy)

Reporting of side effects

If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via

visual loss or disturbances and shortness ofbreath

• memory loss, trouble thinking, difficulty with walking or loss of vision. These may be signs of a serious brain infection and your doctor may suggest further testing and follow-up.

You will have to take regular blood tests before and during your treatment with Bortezomib Biotech Pharma Limited, to check your blood cell counts regularly.

If you have mantle cell lymphoma and are given the medicine rituximab with Bortezomib

4. POSSIBLE SIDE EFFECTS                                                    

’Problems with your ear, bleeding from your ear

• T. , , T.. , Underactivity of your thyroid gland
• Like all medicmes, Bortezomib Biotech Pharma Limited can cause side effects, although not n rn.- ■ j r i + ui i \

i_ j x Ai_ o x-xu rc 4. v -Budd-Chian syndrome (the clmical symptoms caused by blockage ofthe hepatic veins)

everybody gets them. Some of these effects may be senous. x.

If you are given Bortezomib Biotech Pharma Limited for multiple myeloma or mantle cell * chanSes m or abnormal bowel function

lymphoma, tell your doctor straight away if you notice any ofthe following symptoms: * HIeeciing in the brain

, . , -Yellow discolouration ofeyes and skin (jaundice)

Yellow Card Scheme Website: or search for MHRA Yellow Card in the Google Play or Apple App Store.By reporting side effects you can help provide more information on the safety of this medicine.

5. HOWTO STORE BORTEZOMIB BIOTECH PHARMALIMITED

Biotech Pharma Limited you should tell your doctor: -confusion, visual loss or disturbances, blindness, seizures, headaches ? Se?ous aPerfic reacti°n (^aphylactic shock) signs of which may include difficulty

• if you think you have hepatitis infection now or have had it in the past. In a few cases, shortness of breath swelling of vour feet or chances in vour heart beat high blood breathing, chest pain or chest tightness, anchor feeling dizzy/famt, severe itching of the skin

patients who have had hepatitis B might have a repeated attack of hepatitis, which can be p™ fee^ness faftZ; or mised lumps on the skin, swellmgofthe face, lips, tongue and/or throat, which may cause

fatal. If you have a history of hepatitis B infection you will be carefully checked by your . coughi;g andbreathing difficulties ortightness in the chest . R^tdiTorders0⁸’ “

doctor for signs of active hepatitis B. 6 6 ’Breast disorders

You must read the package leaflets ofall medicinal products to be taken in combination with Treatment with Bortezomib Biotech Pharma Limited can very coimnonly cause a decrease in -Vaginaltears

• Bortezomib Biotech Pharma Limited for information related to these medicines before 1116 numbers ofredandwhite:blood cells and platelets in your blood. Therefore,you will have Genital swelling

starting treatment with Bortezomib Biotech Pharma Limited. When thalidomide is used, o take re^to blood tests before and during your treatment with Bortezomib Biotech Pharma -Inability to tolerate alcohol consumption

particular attention to pregnancy testing and prevention requirements is needed (see 11111 ’ oc ec your 00 ce c°un sregu ary. -Wasting, or loss of body mass

• Pregnancy and breast-feeding in this section). You may experience a reduction in the number of: Increased appetite
• Children and adolescents " platelets> which may make you be more prone to bruising, or to bleeding without obvious Fistula
• Bortezomib Biotech Pharma Limited should not be used in children and adolescents because injury (e.g., bleeding from your bowels, stomach, mouth and gum or bleeding in the brain or Jointefiusion
• it is not known how the medicine will affect them. bleeding from the liver) Cysts in the lmmg of jomts (synovial cysts)

-redbloodcells,whichcan­causeanaemia,wit­hsymptomssuchas­tirednessandpa­leness -Fracture

• Other medicines and Bortezomib Biotech Pharma Limited … -white blood cells may make you more prone to infections or flu-like symptoms Breakdown ofmuscle fibers leading to other complications

Please tell your doctor, or pharmacist if you are taking, nave recently taken or might take any „ , ..... , , _ , ~ ®

Keep this medicine out ofthe sight and reach of children.

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

Do not store this medicinal product above 30°C and keep the vial in the outer carton in order to protect from light.

The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. However, the reconstituted solution is stable for 8 hours at 25 °C stored in the original vial and/or a syringe, with a total storage time for the reconstituted medicine not exceeding 8 hours prior to administration.

Bortezomib Biotech Pharma Limited is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements

6. CONTENT OF THE PACK AND OTHER INFORMATION

What Bortezomib Biotech Pharma Limited contains

omermeaicines.

In particular, tell your doctor if you are using medicines containing any of the following active substances:

• ketoconazole, used to treat fungal infections
• ritonavir, used to treat HIV infection
• rifampicin, an antibiotic used to treat bacterial infections
• carbamazepine, phenytoin or phenobarbital used to treat epilepsy
• St. John’s Wort (Hypericum perforatum), used for depression or other conditions
• oral antidiabetics

Pregnancy and breast-feeding

You should not use Bortezomib Biotech Pharma Limited if you are pregnant, unless clearly necessary.

Both men and women receiving Bortezomib Biotech Pharma Limited must use effective contraception during and for up to 3 months after treatment. If, despite these measures, pregnancy occurs, tell your doctor immediately.

You should not breast-feed while using Bortezomib Biotech Pharma Limited. Discuss with your doctor when it is safe to restart breast-feeding after finishing your treatment.

Thalidomide causes birth defects and foetal death. When Bortezomib Biotech Pharma Limited is given in combination with thalidomide you must follow the pregnancy prevention programme for thalidomide (see package leaflet for thalidomide).

Driving and using machines

Bortezomib Biotech Pharma Limited might cause tiredness, dizziness, fainting, or blurred vision. Do not drive or operate tools or machines if you experience such side effects; even if you do not, you should still be cautious.

• the side effects, you may get are listed below: Cancer ofthe kidney

Very common side effects (may affect more than 1 in 10 people) * Psoriasis sⁿ condition

• Sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet, „ ,
• due to nerve damage Paleness of the skm
• Reduction in the number ofred blood cells and or white blood cells (see above) Increaseofpla­teletsorplasma­cells(atypeof­whitecell)inthe­blood
• Fever * Abnormal reaction to blood transfusions
• Feeling sick (nausea) or vomiting, loss of appetite ’Partial or total loss of vision
• Constipation with or without bloating (can be severe) * Decreased sex drive
• Diarrhoea: if this happens, it is important that you drink more water than usual. Your doctor * Drooling

may give you another medicine to control diarrhoea ’Bulgmg eyes

• Tiredness (fatigue), feeling weak * Sensitivity to light
• Muscle pain, bone pain ’Rapid breathing
• Rectal pain

Common side effects (may affect up to 1 in 10 people) , feectaj pafe

• Low blood pressure, sudden fall ofblood pressure on standing which may lead to fainting . Gallstones
• High blood pressure . Hernia
• Reduced functioning of your kidneys . injuries
• Headache . Brittle or weak nails
• General ill feeling, pain, vertigo, light-headedness, a feeling of weakness or loss of -Abnormal protein deposits in your vital organs

consciousness , coma

• Shivering . intestinai uicers
• Infections, including pneumonia, respiratory infections, bronchitis, fungal infections, -Multi-organfailure coughing with phlegm, flu like illness -Death
• Shingles (localised including around the eyes or spread across the body)
• Chest pains or shortness ofbreath with exercise If you glven B°rtezomib Biotech PharmaLimited together with other medicines for the

• – The active substance is bortezomib. Each vial contains 3.5 mg of bortezomib (as a mannitol boronic ester).

• – The other ingredient is mannitol (E 421).

Intravenous reconstitution: After reconstitution, 1 ml of solution for intravenous injection contains 1 mg bortezomib.

Subcutaneous reconstitution: After reconstitution, 1 ml of solution for subcutaneous injection contains 2.5 mg bortezomib.

What Bortezomib Biotech Pharma Limited looks like and contents ofthe pack

Bortezomib Biotech Pharma Limited 3.5 mg powder for solution for injection is a white to off-white lyophilised mass.

Each carton contains a 10 ml tubular clear glass vial (Type I) with a grey butyl rubber plug (Slotted) and an aluminium Flip-off-Seal (Red Color).

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Biotech Pharma Limited

Ambe House, Commerce Way,

Edenbridge, Kent, TNB 6ED,

United Kingdom

Manufacturer

Venus Pharma GmbH

AmBahnhofl-3

D-59368,Weme

3. HOWTO USE BORTEZOMIB BIOTECH PHARMALIMITED

• Different types ofrash ucu.uiicii.iui muuuc ucii lympiiuiiiu. me siuc ciicuus youinay gei aiu nsicu. uuiuw. Germany

Your doctor will work out your dose of Bortezomib Biotech Pharma Limited according to your height and weight (body surface area). The usual starting dose of Bortezomib Biotech Pharma Limited is 1.3 mg/m2 body surface area twice a week.

Your doctor may change the dose and total number of treatment cycles, depending on your response to the treatment on the occurrence of certain side effects and on your underlying conditions (e.g. liverproblems).

Progressive multiple myeloma

When Bortezomib Biotech Pharma Limited is given alone, you will receive 4 doses of Bortezomib Biotech Pharma Limited intravenously or subcutaneously on days 1,4,8 and 11, followed by a 10-day ‘rest period’ without treatment. This 21-day period (3 weeks) corresponds to one treatment cycle. You might receive up to 8 cycles (24 weeks).

You may also be given Bortezomib Biotech Pharma Limited together with the medicines pegylated liposomal doxorubicin or dexamethasone.

Tear off Area------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

• 1. RECONSTITUTION FOR INTRAVENOUS INJECTION

Note: Bortezomib Biotech Pharma Limited is a cytotoxic agent. Therefore, caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended.

ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING OF Bortezomib Biotech Pharma Limited SINCE NO PRESERVATIVE IS PRESENT.

• 1.1) Preparation of the 3.5 mg vial: carefully add 3.5 ml of sterile, 9 mg/ml (0.9%) sodium chloride solution for injection to the vial containing the Bortezomib Biotech Pharma Limited powder by using a syringe of the appropriate size without removing the vial stopper. Dissolution of the lyophilised powder is completed in less than 2 minutes.

The concentration of the resulting solution will be 1 mg/ml. The solution will be clear and colourless, with a final pH of 4 to 7. You do not need to check the pH of the solution.

• 1.2) Before administration, visually inspect the solution for particulate matter and discolouration. If any discolouration or particulate matter is observed, the solution should be discarded. Be sure that the correct dose is being given for the intravenous route of administration (1 mg/ml).

• 1.3) The reconstituted solution is preservative free and should be used immediately after preparation. However, the chemical and physical in-use stability has been demonstrated for 8 hours at 25°C stored in the original vial and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to

Very Common side effects (may affect more than 1 in 10 people) This medicinal duct is authorised in the Member States of the EEA under the

• Redness ofthe skin -Pneumonia following names:

-Loss of appetite

• __ \ . , , ..... 1 i . Sensitivity, numbness, tingling or burning sensation ofthe skin, or pain in the hands or feet, Portugal: Bortezomib Venus Pharma
• Heartburn, bloating, belching, wmd, stomach pam,bleedmg from your bowels or stomach due to nerve damage France:BORTEZO­MIBVENUSPHARMA3,5mg,pou­drepoursoluti­oninjectable
• Alteration of liver functioning , jqausea and vomiting Ireland: Bortezomib Biotech Pharma 3.5 mg powder for solution for injection
• A sore mouth or lip, dry mouth, mouth ulcers or throat pain . Diarrhoea Romania: Bortezomib BIOTECH 3,5mg pulbere pentru solujie inj ectabila
• Weight loss, loss oftaste -Mouth ulcers
• Muscle cramps, muscle spasms, muscle weakness, pain in your limbs , Constipation This leaflet was last revised in February 2019.
• Blurred vision -Muscle pain, bone pain

• – Infection of the outermost layer of the eye and the inner surface of the eyelids -Hair loss and abnormal hair texture

(conjunctivitis) m- j x- v 1

\ T ,, , 7 -Tiredness, feeling weak

• Nosebleeds
• Fever

use are the responsibility ofthe user. Only the 3.5 mg vial can be administered subcutaneously, as described below. use are the responsibility of the user.

It is not necessary to protect the reconstituted medicinal product from light. It is not necessary to protect the reconstituted medicinal product from light.

• 1. RECONSTITUTION FOR SUBCUTANEOUS INJECTION

• 2. ADMINISTRATION Note: Bortezomib Biotech Pharma Limited is a cytotoxic agent. Therefore, caution should be 2. ADMINISTRATION

• Once dissolved, withdraw the appropriate amount ofthe reconstituted solution according to used during handling and preparation. Use of gloves and other protective clothing to prevent Once dissolved, withdraw the appropriate amount ofthe reconstituted solution according to

calculated dose based upon the patient's Body Surface Area. skin contact is recommended. calculated dose based upon the patient's Body Surface Area.

• Confirm the dose and concentration in the syringe prior to use. (check that the syringe is ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT * Confirm the dose and concentration in the syringe prior to use. (check that the syringe is

marked as intravenous administration). HANDLING OF Bortezomib Biotech Pharma Limited SINCE NO PRESERVATIVE IS marked as subcutaneous administration).

• Inject the solution as a 3–5 second bolus intravenous injection through a peripheral or PRESENT. -Injectthesolu­tionsubcutane­ously,undera45–90°angle.

cenfrelintrave­nouscathetermto­avein 1.1) Preparation ofthe 3.5 mg vial: carefully add 1.4 ml ofsterile, 9 mg/ml (0.9%) sodium ’ ^constituted solution is administered subcutaneously through the thighs (right orleft)

-The reconstituted solution is admimstered subcutaneously through the thighs (right or left) chloride solution for inj ection to the vial containing the Bortezomib Biotech Pharma Limited or abdomen (nght or left).

or aoaomen (ngnt or lettj. powder by using a syringe of the appropriate size without removing the vial stopper. "Injection sites should be rotated for successive injections.

• Flush the peripheral or intravenous catheter with sterile, 9 mg/ml (0.9%) sodium chloride Dissolutionof­thelyophilised­powderiscomple­tedinlessthan2mi­nutes. If local injection site reactions occur following Bortezomib Biotech Pharma Limited

sohitmn. The concentration of resuiting solution will be 2.5 mg/ml. The solution will be clear and injection subcutaneously, either a less concentrated Bortezomib Biotech Pharma Limited

Bortezomib Biotech Pharma Limited 3.5 mg powder for solution for injection IS FOR colourless, witha final pH of4 to 7. You do notneed to checkthepH ofthe solution. solution (1 mg/ml instead of 2.5 mg/ml) may be admimstered subcutaneously or a switch to

SUBCUTANEOUS OR INTRAVENOUS USE. Do not give by other routes. Intrathecal , „ n … t . t.. .. , „ , intravenous injection is recommended.

1–2) Before admmi stratum, visually inspect the solution for particulate matter and „ a ~ r ,.. ......

discolouration. If any discolouration or particulate matter is observed, the solution should be J* °2*der s°lutl(in for injection IS FOR

discarded. Be sure that the correct dose is being given for the subcutaneous route of SUBCUTANEOUS OR INTRAVENOUS USE. Do not give by other routes. Intrathecal

• 3. DISPOSAL administration (2 5 mg/ml) administration has resulted in death.