Consumer medicine information

Bortezomib Baxter

Bortezomib

BRAND INFORMATION

Brand name

Bortezomib Baxter

Active ingredient

Bortezomib

Schedule

SUMMARY CMI

Bortezomib Baxter

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Bortezomib Baxter?

Bortezomib Baxter contains the active ingredient bortezomib. Bortezomib Baxter is used to treat adults with multiple myeloma (cancer of the bone marrow). It is prescribed for patients who have not been previously treated for multiple myeloma. It is also prescribed for patients who have received one or more prior treatments and whose cancer is still progressing. Bortezomib Baxter is also used for the treatment of mantle cell lymphoma (a type of cancer affecting the lymph nodes) in adults in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously treated. For more information, see Section 1. Why am I using Bortezomib Baxter? in the full CMI.

2. What should I know before I use Bortezomib Baxter?

Do not use if you have ever had an allergic reaction to bortezomib or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Bortezomib Baxter? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Bortezomib Baxter and affect how it works. Tell your doctor if you are taking any other medicines, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Bortezomib Baxter?

Overall treatment with Bortezomib Baxter must be done under the supervision of a doctor. Your treatment with Bortezomib Baxter may be given by a healthcare professional (eg doctor or nurse) experienced in the administration of oncology medicines. More instructions can be found in Section 4. How do I use Bortezomib Baxter? in the full CMI.

5. What should I know while using Bortezomib Baxter?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Bortezomib Baxter. If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you are having Bortezomib Baxter. If you plan to have surgery, tell your doctor or dentist that you are having Bortezomib Baxter. If you become pregnant or your partner becomes pregnant while being given Bortezomib Baxter, tell your doctor immediately.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how Bortezomib Baxter affects you. Bortezomib Baxter may cause tiredness, light-headedness, dizziness, fainting, double or blurred vision in some people. Make sure you know how you react to Bortezomib Baxter before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy, light headed or have double or blurred vision.
Drinking alcohol	If you drink alcohol, dizziness or light-headedness may be worse.

For more information, see Section 5. What should I know while using Bortezomib Baxter? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Bortezomib Baxter

Active ingredient: bortezomib

Consumer Medicine Information (CMI)

This leaflet provides important information about using Bortezomib Baxter. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Bortezomib Baxter.

Where to find information in this leaflet:

1. Why am I using Bortezomib Baxter?
2. What should I know before I use Bortezomib Baxter?
3. What if I am taking other medicines?
4. How do I use Bortezomib Baxter?
5. What should I know while using Bortezomib Baxter?
6. Are there any side effects?
7. Product details

1. Why am I using Bortezomib Baxter?

Bortezomib Baxter contains the active ingredient bortezomib. Bortezomib Baxter belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines. These medicines are used to kill cancer cells.

Bortezomib Baxter is used to treat adults with multiple myeloma (cancer of the bone marrow).

It is prescribed for patients who have not been previously treated for multiple myeloma. It is also prescribed for patients who have received one or more prior treatments and whose cancer is still progressing.

Bortezomib Baxter is also used for the treatment of mantle cell lymphoma (a type of cancer affecting the lymph nodes) in adults in combination with the medicines rituximab, cyclophosphamide, doxorubicin and prednisone, for patients whose disease has not been previously treated.

2. What should I know before I use Bortezomib Baxter?

Warnings

Do not use Bortezomib Baxter if:

you are allergic to bortezomib or boron or mannitol, or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have blood disorder with a low level of red or white blood cells or platelets. This disorder may become worse during treatment with Bortezomib Baxter.
are suffering from diarrhoea or vomiting as this may become worse during treatment with Bortezomib Baxter.
have a history of fainting, dizziness or light-headedness.
have kidney problems
have liver problems, including hepatitis infection
have problems with numbness, tingling or pain in the hands or feet (neuropathy). This effect may be worsened by treatment with Bortezomib Baxter.
have seizures
have any bleeding problems
have problems with your heart
have lung or breathing problems
have any other medical conditions
take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Like most medicines used to treat cancer, Bortezomib Baxter is not recommended for use during pregnancy.

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether Bortezomib Baxter passes into breast milk. Therefore there is a possibility that the breast-fed baby may be affected.

If you wish to restart breast-feeding after your Bortezomib Baxter treatment, you must discuss this with your doctor or nurse, who will tell you when it is safe to do so.

Tell your doctor if you are trying to make your partner pregnant.

Both men and women receiving Bortezomib Baxter and their partners must use a reliable method of contraception during and for 3 months after receiving Bortezomib Baxter.

If you have not told your doctor about any of the above, tell them before you start treatment with Bortezomib Baxter.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are taking any of the following:

amiodarone, a medicine used to treat irregular heartbeat
medicines used to treat viral infections such as flu, herpes and HIV
isoniazid, a medicine used to treat tuberculosis
nitrofurantoin, a medicine used to treat urinary tract infections
ketoconazole, a medicine used to treat fungal infections
ritonavir, a medicine used to treat HIV infection
rifampicin, a medicine used to treat infections such as tuberculosis
medicines used to treat high cholesterol levels in the blood
medicines used to treat diabetes
medicines that may lower blood pressure
medicine used to treat epilepsy such as carbamazepine and phenobarbital
phenytoin, a medicine used in preventing seizures
St John's Wort (Hypericum perforatum).

Some medicines may interfere with Bortezomib Baxter and affect how it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Bortezomib Baxter.

4. How do I use Bortezomib Baxter?

How much to use

Your doctor will decide what dose you will receive. The dose will be calculated from your height and weight. It will also depend on factors such as kidney function, liver function and other medicines you are being given.

The safety of treatment with Bortezomib Baxter in people with severe kidney function problems had not been well-studied.

The usual starting dose is 1.3 milligrams per square meter body surface area.

Your doctor may change the dose during treatment depending on your response.

Ask your doctor if you want to know more about the dose of Bortezomib Baxter you receive.

When to take Bortezomib Baxter

Multiple Myeloma

One cycle of treatment with Bortezomib Baxter may consist of a total of 4 doses given over 3 weeks. Doses are given on days 1, 4, 8 and 11 followed by a ten day break from the treatment.

When Bortezomib Baxter is given with thalidomide and dexamethasone, the treatment consists of a total of 3 cycles (9 weeks) for the induction stage. During the induction stage, Bortezomib Baxter is administered twice weekly (days 1, 4, 8 and 11).

When Bortezomib Baxter is given with dexamethasone, the treatment consists of a total of 4 cycles (12 weeks). Bortezomib Baxter will be administered twice weekly (days 1, 4, 8 and 11).

When Bortezomib Baxter is given with melphalan and prednisone, one cycle of treatment is 6 weeks and the treatment consists of a total of 9 cycles (54 weeks). In Cycles 1-4, Bortezomib Baxter is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortezomib Baxter is administered once weekly (days (1, 8, 22 and 29).

Mantle Cell Lymphoma

When Bortezomib Baxter is given with rituximab, cyclophosphamide, doxorubicin and prednisone, one cycle is 3 weeks and the treatment consists of a total of up to 8 cycles (24 weeks). For each cycle, Bortezomib Baxter is given on days 1, 4, 8 and 11, followed by a ten day break from the treatment.

Your doctor will decide on the number of cycles of Bortezomib Baxter needed. This will depend on how you respond to treatment.

How to take Bortezomib Baxter

Bortezomib Baxter will be dissolved in sterile sodium chloride (salt) solution for injection. The solution is given as an injection into your vein (intravenously) over 3 to 5 seconds. The injection tube will be rinsed with a small quantity of sterile sodium chloride (salt) solution.

The solution can also be given subcutaneously as an injection into your thighs (right or left), or abdomen (right or left). Bortezomib Baxter must be given intravenously or subcutaneously only. Bortezomib Baxter must not be given into the space around the spinal cord (intrathecally).

If you take too much Bortezomib Baxter

As Bortezomib Baxter is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However if you experience any side effects after being given Bortezomib Baxter, tell you doctor or nurse immediately or go to the Emergency Department at your nearest hospital.

You may need urgent medical attention.

5. What should I know while using Bortezomib Baxter?

Things you should do

Call your doctor straight away if you

Develop any symptoms of an allergic reaction, which may include:
- shortness of breath
- wheezing or difficulty breathing
- swelling of the face, lips, tongue or other parts of the body
- rash, itching or hives on the skin.

Be sure to keep all your doctor's appointments so your progress can be checked.

Your doctor will want to do some blood, urine and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor.

It is important to have your follow-up doses of Bortezomib Baxter at the appropriate times to get the best effects from your treatment.

Be sure to follow up your doctor's instructions about other medicines you should take, and other things you should do.

You may need to take other medicines to help prevent unwanted effects of Bortezomib Baxter. You may also need to drink extra fluids if you experience vomiting and/or diarrhoea. Ask your doctor or pharmacist if you have any questions.

Tell any other doctors, dentists and pharmacists who are treating you that you are having Bortezomib Baxter.

If you are about to be started on any new medicines, tell your doctor, dentist or pharmacist that you are having Bortezomib Baxter.

If you plan to have surgery, tell your doctor or dentist that you are having Bortezomib Baxter.

If you become pregnant or your partner becomes pregnant while being given Bortezomib Baxter, tell your doctor immediately.

Bortezomib Baxter can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it's painful or difficult to urinate.
Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.

Remind any doctor, dentist or pharmacist you visit that you are using Bortezomib Baxter.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Bortezomib Baxter affects you.

Bortezomib Baxter may cause tiredness, light-headedness, dizziness, fainting, double or blurred vision in some people. Make sure you know how you react to Bortezomib Baxter before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy, light headed or have double or blurred vision.

You may feel dizzy or faint when you get up quickly after sitting or lying down.

Getting up slowly may help.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, dizziness or light-headedness may be worse.

Looking after your medicine

Bortezomib Baxter will be stored in the hospital pharmacy or on the hospital ward in a cool dry place, where the temperature stays below 30°C.

Getting rid of any unwanted medicine

Your doctor, nurse or pharmacist will dispose of any leftover medicine.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being treated with Bortezomib Baxter.

Less serious side effects

Less serious side effects

What to do

Gastrointestinal related:

feeling sick (nausea) or vomiting
diarrhoea
constipation
loss of appetite, and/or weight, fear of gaining weight
uncomfortable feeling in the stomach or belching after eating
stomach pain
blockage in the intestine
bad taste in the mouth

Physical pain and swelling related:

headache
tiredness, generally feeling unwell, weakness

Hair and skin related:

small blisters in clusters on the skin (herpes)
rash, itching
redness of the skin or redness and pain at injection site
hair loss

Blood pressure

low blood pressure (dizziness, light headedness or fainting)
high blood pressure

Other

dizziness
dehydration
cough
blurred vision

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Central nervous system related:

sensitivity, numbness, tingling or burning sensation of the skin, or pain in the hands or feet
fever, chills
trouble sleeping, sweating, anxiety, mood swings, confusion or depression

Blood and bruising related:

anaemia (a condition in which there is a decreased number of red blood cells)
bleeding or bruising more easily than normal

Physical pain and swelling related:

painful, swollen joints
pain in your limbs, back pain, bone pain, muscle cramps
swelling (around the eyes or in the ankles, wrists, arms, legs or face)
pins and needles and unpleasant sensations
aching muscles, muscle tenderness or weakness not caused by exercise
chest pain

Infection related:

frequent infections such as fever, severe chills, sore throat or mouth ulcers
herpes virus or hepatitis infections
pneumonia

Other

difficulty in breathing
allergic reaction

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

If you think you are having an allergic reaction to Bortezomib Baxter, tell you doctor immediately or go to the Emergency Department at your nearest hospital.

Symptoms usually include some or all of the following:

rash, itching or hives on the skin
shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Bortezomib Baxter contains

Active ingredient (main ingredient)	bortezomib 3.5 mg (for Bortezomib Baxter 3.5 mg Vials)
Other ingredients (inactive ingredients)	Mannitol Nitrogen

Do not take this medicine if you are allergic to any of these ingredients.

What Bortezomib Baxter looks like

Bortezomib Baxter is a white to off-white powder in a glass vial.

The vial is contained in a carton. Each carton contains 1 single-use vial.

Before injection, Bortezomib Baxter powder is dissolved in a small quantity of sterile, sodium chloride solution. The solution for injection is clear and colourless.

Bortezomib Baxter 3.5 mg vial (AUST R 379611)

Who distributes Bortezomib Baxter

Baxter Healthcare Pty Ltd
1 Baxter Drive
Old Toongabbie
NSW 2146, Australia

This leaflet was prepared in August 2022.

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Bortezomib Baxter

Active ingredient

Bortezomib

Schedule

1 Name of Medicine

Bortezomib.

2 Qualitative and Quantitative Composition

Bortezomib Baxter (bortezomib) is an antineoplastic agent for intravenous injection (IV) or subcutaneous (SC) use only. Each single dose vial contains:
3.5 mg of bortezomib as a sterile lyophilised powder. It also contains 35 mg mannitol.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection. White to off-white cake or powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Bortezomib Baxter, in combination with melphalan and prednisone is indicated for the treatment of patients with previously untreated multiple myeloma who are not candidates for high dose chemotherapy.
Bortezomib Baxter, as part of combination therapy, is indicated for induction therapy prior to high dose chemotherapy with autologous stem cell rescue for patients under 65 years of age with previously untreated multiple myeloma.
Bortezomib Baxter is also indicated for the treatment of multiple myeloma patients who have received at least one prior therapy, and who have progressive disease.
Bortezomib Baxter in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma.

4.2 Dose and Method of Administration

Bortezomib Baxter may be administered:
Intravenously (at a concentration of 1 mg/mL) as a 3-5 second bolus injection; or
Subcutaneously (at a concentration of 2.5 mg/mL).
Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
Bortezomib Baxter is for intravenous or subcutaneous use only. Intrathecal administration has resulted in death.

Recommended dosage.

Previously untreated multiple myeloma - transplant eligible.

1. Bortezomib Baxter plus thalidomide-dexamethasone.

During the induction stage, Bortezomib Baxter (bortezomib) is administered twice weekly in combination with thalidomide-dexamethasone for three 3-week treatment cycles. The treatment regimen is shown in Table 1.

2. Bortezomib Baxter plus dexamethasone.

Bortezomib Baxter (bortezomib) is administered as an IV injection in combination with oral dexamethasone for four 3-week treatment cycles as shown in Table 2.

Previously untreated multiple myeloma - non-transplant eligible. Bortezomib Baxter (bortezomib) for injection is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 3. In Cycles 1-4, Bortezomib Baxter is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortezomib Baxter is administered once weekly (days 1, 8, 22 and 29).

Dose management guidelines. Dose modification and re-initiation of therapy when Bortezomib Baxter is administered in combination with melphalan and prednisone.
Prior to initiating a new cycle of therapy:
Platelet count should be ≥ 70 x 10⁹/L and the ANC should be ≥ 1.0 x 10⁹/L;
Non-hematological toxicities should have resolved to Grade 1 or baseline.
See Table 4.

For additional information concerning melphalan and prednisone, see manufacturer's Product Information documents.

Relapsed/ refractory multiple myeloma.

Recommended dose.

The recommended dose of Bortezomib Baxter is 1.3 mg/m²/dose administered twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib Baxter.
It is recommended that patients with a confirmed complete response receive 2 additional cycles of Bortezomib Baxter beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of Bortezomib Baxter therapy.
For extended therapy of more than 8 cycles, Bortezomib Baxter may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (days 1, 8, 15, and 22) followed by a 13-day rest period (days 23 to 35) (See Section 5.1 Pharmacodynamic Properties, Clinical trials for a summary of dose administration during clinical trials).

Dose modification and reinitiation of therapy.

Bortezomib Baxter therapy should be withheld at the onset of any Grade 3 nonhaematological or Grade 4 haematological toxicities excluding neuropathy as discussed above (see Section 4.4 Special Warnings and Precautions for Use). Once the symptoms of the toxicity have resolved, Bortezomib Baxter therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1.0 mg/m²/dose; 1.0 mg/m²/dose reduced to 0.7 mg/m²/dose). Table 5 contains the recommended dose modification for the management of patients who experience Bortezomib Baxter-related neuropathic pain and/or peripheral sensory neuropathy. Severe autonomic neuropathy resulting in treatment interruption or discontinuation has been reported. Patients with pre-existing severe neuropathy should be treated with Bortezomib Baxter only after careful risk/benefit assessment.
Previously untreated mantle cell lymphoma.

Recommended dosage in combination with rituximab, cyclophosphamide, doxorubicin and prednisone.

Bortezomib Baxter (bortezomib) for injection is administered at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11, followed by a 10 day rest period on days 12-21. This 3 week period is considered a treatment cycle. Six Bortezomib Baxter cycles are recommended, although for patients with a response first documented at cycle 6, two additional Bortezomib Baxter cycles may be given. At least 72 hours should elapse between consecutive doses of Bortezomib Baxter.
The following medicinal products are administered on Day 1 of each Bortezomib Baxter 3 week treatment cycle as intravenous infusions: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², and doxorubicin at 50 mg/m².
Prednisone is administered orally at 100 mg/m² on Days 1, 2, 3, 4 and 5 of each treatment cycle.

Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma.

Prior to initiating a new cycle of therapy:
Platelet count should be ≥ 100 x 10⁹/L and absolute neutrophil count (ANC) should be ≥ 1.5 x 10⁹/L;
Haemoglobin should be ≥ 8 g/dL;
Non-hematologic toxicity should have recovered to Grade 1 or baseline.
Bortezomib Baxter treatment must be withheld at the onset of any ≥ Grade 3 Bortezomib Baxter-related non haematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities (also see Section 4.4 Special Warnings and Precautions for Use). For dose adjustments, see Table 6. Colony stimulating factors may be administered for haematologic toxicity according to local standard practice. Platelet transfusion for the treatment of thrombocytopenia may be considered.

In addition, when Bortezomib Baxter is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Product Information documents.

Method of administration.

Intravenous injection (IV).

Bortezomib Baxter is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0.9% sodium chloride solution for injection.

Subcutaneous injection (SC).

The reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injection sites should be rotated for successive injections.
If local injection site reactions occur following Bortezomib Baxter injection subcutaneously, a less concentrated Bortezomib Baxter solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously or change to IV injection.
When Bortezomib Baxter is given in combination with other medicinal products, refer to the Product Information for these products for instructions for administration.

Instructions for use and handling and disposal.

Administration precautions.

Bortezomib Baxter is an antineoplastic. Caution should be used during handling and preparation. Proper aseptic technique should be used. Use of gloves and other protective clothing to prevent skin contact is recommended. In clinical trials, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib Baxter was not associated with tissue damage.
When administered subcutaneously, alternate sites for each injection (thigh or abdomen). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib Baxter is for IV and subcutaneous use only. Do not administer Bortezomib Baxter intrathecally.

Reconstitution/preparation for administration.

Prior to use, the contents of each vial must be reconstituted only with 0.9% sodium chloride solution for injection according to the following instructions based on route of administration. See Table 7.

The reconstituted product should be a clear and colourless solution.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. If any discolouration or particulate matter is observed, the reconstituted product should not be used.
Bortezomib Baxter is for single use in one patient only. Discard any residue.

Procedure for proper disposal.

Any unused product or waste material should be disposed of in accordance with local requirements.

Dosage adjustment in.

Renal insufficiency.

Based on the data from a small study, the pharmacokinetics of bortezomib are not influenced by mild (CrCL = 40-59 mL/min/1.73 m², n=10) or moderate (CrCL = 20-39 mL/min/1.73 m², n=9) renal impairment. Therefore, dosing adjustments of bortezomib are not necessary for these patients. The effect of severe renal impairment (CrCl < 20 mL/min/1.73 m²) has not been determined. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure (see Section 5.2 Pharmacokinetic Properties).

Hepatic insufficiency.

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezomib Baxter dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib Baxter at a reduced dose of 0.7 mg/m² per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² may be considered based on patient tolerance (see Table 8).

4.3 Contraindications

Bortezomib Baxter is contraindicated in patients with hypersensitivity to bortezomib, boron or mannitol.

4.4 Special Warnings and Precautions for Use

Overall treatment with Bortezomib Baxter must be done under the supervision of a physician, however administration of the drug product may be done by a healthcare professional experienced in the administration of oncology medications.
There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib Baxter is for intravenous or subcutaneous use only. Do not administer Bortezomib Baxter Intrathecally.
Overall, the safety profile of patients treated with bortezomib in monotherapy was similar to that observed in patients treated with bortezomib in combination with melphalan and prednisone.

Peripheral neuropathy.

Bortezomib treatment causes a peripheral neuropathy (PN) that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening (including ≥ Grade 3) during treatment with bortezomib. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperaesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
In the Phase 3 study comparing bortezomib IV vs. SC the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for SC and 41% for IV (p = 0.0124). Grade ≥ 3 peripheral neuropathy occurred in 6% of subjects in the SC treatment group, compared with 16% in the IV treatment group (p = 0.0264). Therefore, patients with pre-existing PN or at high risk of peripheral neuropathy may benefit from starting Bortezomib Baxter subcutaneously.
Patients experiencing new or worsening peripheral neuropathy may require a change in dose, schedule or route of administration to SC (see Section 4.2 Dose and Method of Administration).
Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the phase III multiple myeloma study of bortezomib IV vs. dexamethasone. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase II studies (see Section 4.8 Adverse Effects (Undesirable Effects)).
In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. Information on autonomic neuropathy and its contribution to these undesirable effects is limited.
The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension.

Patients developing orthostatic hypotension on bortezomib did not have evidence of orthostatic hypotension prior to treatment with bortezomib. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of bortezomib.
In phase II and III studies, the incidence of hypotension (postural, orthostatic and hypotension not otherwise specified) was 11% to 12%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope receiving medications known to be associated with hypotension and with patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids and/or sympathomimetics (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiac disorders.

Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or an existing heart disease should be closely monitored. In the phase III study of bortezomib IV vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13%, respectively. The incidence of heart failure events (acute pulmonary oedema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary oedema) was similar in the bortezomib and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary disorders.

There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving bortezomib. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. In the event of new or worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and patients treated appropriately.
In a clinical trial, two patients given high-dose cytarabine (2 g/m² per day) by continuous infusion with daunorubicin and bortezomib for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy.

Thrombotic microangiopathy.

There have been cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome (TTP/HUS) reported in patients who received proteasome inhibitors. Some of these events have been fatal. Patients receiving Bortezomib Baxter should be monitored for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Bortezomib Baxter and evaluate patients for possible TTP/HUS. If the diagnosis of TTP/HUS is excluded, Bortezomib Baxter can be reinitiated. The safety of reinitiating bortezomib therapy in patients previously experiencing TTP/HUS is not known.

Posterior reversible encephalopathy syndrome (PRES).

There have been reports of PRES in patients receiving bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue Bortezomib Baxter. The safety of reinitiating bortezomib therapy in patients previously experiencing PRES is not known.

Seizures.

Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

Amyloidosis.

A phase 1/2 single-agent bortezomib dose-escalation study was conducted in patients with previously treated light-chain Amyloidosis. At planned interim analysis, no new safety concerns were observed and no evidence of target organ damage was found during the study.

Laboratory tests.

Complete blood counts (CBC) should be frequently monitored throughout treatment with bortezomib.

Thrombocytopenia/neutropenia.

Bortezomib treatment is associated with thrombocytopenia and neutropenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Platelet counts were lowest at Day 11 of each cycle of bortezomib treatment and typically recovered to baseline by the next cycle. The pattern of platelet count decrease and recovery remained consistent, in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in any of the regimens studied.
Platelet counts should be monitored prior to each dose of Bortezomib Baxter. Bortezomib Baxter therapy should be held when the platelet count is < 25,000/microL (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). There have been reports of gastrointestinal and intracerebral hemorrhage in association with bortezomib. Transfusion and supportive care may be considered at the discretion of the physician.
In the single-agent multiple myeloma study of bortezomib vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pre-treatment platelet count is shown in Table 9 for the phase III study. The incidence of significant bleeding events (≥ Grade 3) was similar on both the bortezomib (4%) and dexamethasone (5%) arms.

In the combination study of bortezomib with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia adverse events (≥ Grade 4) was 32% versus 2% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm. The incidence of bleeding adverse events (≥ Grade 3) was 1.7% (4 patients) in the VcR-CAP arm and was 1.2% (3 patients) in the R-CHOP arm.
There were no deaths due to bleeding events in either arm. There were no CNS bleeding events in the VcR-CAP arm; there was 1 bleeding event in the R-CHOP arm. Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm.
The incidence of neutropenia (≥ Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥ Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Colony-stimulating factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm.

Gastrointestinal adverse events.

Bortezomib treatment can cause nausea, diarrhoea, constipation and vomiting (see Section 4.8 Adverse Effects (Undesirable Effects)) sometimes requiring use of antiemetics and antidiarrhoeals. Fluid and electrolyte replacement should be administered to prevent dehydration. Since patients receiving bortezomib therapy may experience vomiting and/or diarrhoea, patients should be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.

Tumour lysis syndrome.

Because Bortezomib Baxter is a cytotoxic agent and can rapidly kill malignant cells the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Herpes zoster virus reactivation.

Antiviral prophylaxis is recommended in patients being treated with Bortezomib Baxter (see Section 4.8 Adverse Effects (Undesirable Effects)).

Multiple myeloma.

Antiviral prophylaxis was administered to 26% of the patients in the Vc+M+P arm. The incidence of herpes zoster among patients in the Vc+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.

Mantle cell lymphoma.

Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR-CAP arm. The incidence of herpes zoster among patients in the VcR-CAP arm was 4.6% for patients not administered antiviral prophylaxis compared to 0.8% for patients administered antiviral prophylaxis.

Hepatitis B virus (HBV) reactivation and infection.

When rituximab is used in combination with Bortezomib Baxter, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with Bortezomib Baxter. Antiviral prophylaxis should be considered. Refer to the local Product Information of rituximab for more information.

Hepatic events.

Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib. There is limited re-challenge information in these patients.

Use in hepatic impairment.

Patients with moderate and severe hepatic impairment should be treated with caution at reduced starting doses of Bortezomib Baxter and closely monitored for toxicities. The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in 51 cancer patients with varying degrees of hepatic impairment treated bortezomib doses ranging from 0.5 to 1.3 mg/m² (see Table 8 for definition of hepatic impairment). When compared to patients with normal hepatic function, mild hepatic impairment did not alter bortezomib dose-normalised AUC. However, the dose-normalised mean AUC values were increased by approximately 60% in patients with moderate to severe hepatic impairment.

Use in renal impairment.

The incidence of serious undesirable effects may increase in patients with renal impairment compared to patients with normal renal function. Renal complications are frequent in patients with multiple myeloma. Such patients should be monitored closely. The safety of bortezomib in patients with severe renal impairment (CrCl < 20 mL/min/1.73 m²) has not been established. The effect of dialysis on bortezomib plasma concentrations has also not been determined. However, since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.

Use in MCL patients eligible for autologous stem cell transplantation.

The pivotal study in previously untreated MCL patients mainly studied patients ineligible for autologous stem cell transplantation, and evidence of efficacy and safety in patients eligible for transplantation is more limited. In particular, there are no data directly informing about the use of VcR-CAP as an induction regimen in previously untreated MCL patients who have subsequently received a transplant.

Use in the elderly.

No data available.

Paediatric use.

The safety and effectiveness of Bortezomib Baxter in children has not been established.

Effects on laboratory tests.

None known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro and animal ex vivo studies indicate that bortezomib is a weak inhibitor of cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6, and 3A4. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of bortezomib.
A drug-drug interaction study assessing the effect of ketoconazole (a potent CYP3A4 inhibitor) on the pharmacokinetics of IV bortezomib showed a bortezomib AUC mean increase of 35%, based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir).
In a drug-drug interaction study assessing the effect of omeprazole (a potent inhibitor of CYP2C19) on the pharmacokinetics of IV bortezomib there was no significant effect on the pharmacokinetics of bortezomib, based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. The concomitant use of Bortezomib Baxter with strong CYP3A4 inducers is not recommended, as efficacy may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital (phenobarbitone) and St John's Wort. In the same drug-drug interaction study, the effect of dexamethasone, a weaker CYP3A4 inducer was assessed. There was no significant effect on bortezomib pharmacokinetics based on data from 7 patients.
Patients who are concomitantly receiving Bortezomib Baxter and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.
During clinical trials, hypoglycaemia and hyperglycaemia were reported in diabetic patients receiving oral hypoglycaemics. Patients on oral antidiabetic agents receiving Bortezomib Baxter treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Patients should be cautioned about the use of concomitant medications that may be associated with peripheral neuropathy (such as amiodarone, anti-virals, isoniazid, nitrofurantoin, or statins), or with a decrease in blood pressure.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies with bortezomib were not performed but degenerative changes seen in the testes and ovary in a rat general toxicity study suggest that bortezomib may affect male and female fertility.
(Category C)
Women of child bearing potential should avoid becoming pregnant while being treated with Bortezomib Baxter. The placental transfer of bortezomib is unknown, but any occurrence may disrupt cycling in the developing foetus, although teratogenicity was not observed in rats and rabbits at maximum tolerated doses.
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (approximately 0.5 mg/m²/day) when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m² based on body surface area and calculated on a single-dose basis. Increased postimplantation loss and reduced foetal weights were seen in rabbits at the highest dose tested, which was a maternally toxic dose. Litter values were unaffected by a nonmaternotoxic dose (approximately 0.3 mg/m²/day).
No placental transfer studies have been conducted with bortezomib. There are no adequate and well-controlled studies in pregnant women. If Bortezomib Baxter is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the foetus.
Patients should be advised to use effective contraceptive measures to prevent pregnancy.
It is not known whether bortezomib or its metabolites are excreted in animal or human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breast-fed infants from Bortezomib Baxter, women should be advised against breast-feeding while being treated with Bortezomib Baxter.

4.7 Effects on Ability to Drive and Use Machines

Bortezomib may cause tiredness, dizziness, fainting or blurred vision. Patients should be advised not to drive or operate machinery if they experience these symptoms.

4.8 Adverse Effects (Undesirable Effects)

Summary of clinical trials of bortezomib IV in patients with previously untreated multiple myeloma.

Results from the GIMEMA and IFM2005 studies.

Table 10 describes the safety data from the GIMEMA and IFM2005 studies in patients with previously untreated multiple myeloma who were eligible for autologous stem cell transplantation, and received Bortezomib IV (1.3 mg/m²) in combination with thalidomide (100 mg, then 200 mg) and dexamethasone (40 mg) in the GIMEMA study, or dexamethasone (40 mg) in the IFM2005 study.

During consolidation therapy of the GIMEMA study, grade 3-4 adverse events were similar to those reported during induction, although rates were much lower. Notably, the rate of grade 3-4 peripheral neuropathy was 1.2% with VcTD consolidation compared to 0% with TD consolidation.

Results from the VISTA study.

Table 11 describes safety data from the VISTA study in 340 patients with previously untreated multiple myeloma who received bortezomib IV (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²).

Herpes zoster virus reactivation.

Antiviral prophylaxis is recommended in patients being treated with Bortezomib Baxter. In the VISTA study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with VcMP compared with MP (14% vs 4% respectively). Antiviral prophylaxis was administrated to 26% of the patients in the VcMP arm. The incidence of herpes zoster among patients in the VcMP treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis. Similar results were observed during the IFM2005 study; herpes zoster was more common in patients treated with bortezomib-based regimen compared to control regimen (9.2% vs. 2.1%). During consolidation, the GIMEMA study reported similar rates (0.6%) of grade 3-4 incidences of herpes zoster between the two study arms (p = 1.0000).

Summary of clinical trials of bortezomib IV in patients with relapsed/refractory multiple myeloma.

The adverse events most commonly reported, regardless of causality, in the APEX study in relapsed/ refractory multiple myeloma patients (See Section 5.1 Pharmacodynamic Properties, Clinical trials) are presented in Table 12. All adverse events occurring at ≥ 10% are included.

Summary of clinical trials of bortezomib IV vs. SC in patients with relapsed multiple myeloma.

The safety and efficacy of bortezomib SC were evaluated in one Phase III study at the recommended dose of 1.3 mg/m². This was a randomized, comparative study of bortezomib IV vs. SC in 222 patients with relapsed multiple myeloma. See Table 13.

Although, in general safety data were similar for the IV and SC treatment groups, Table 14 highlights differences larger than 10% in the overall incidence of adverse drug reactions between the two treatment arms.

Patients who received bortezomib subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment emergent adverse drug reactions that were grade 3 or higher in toxicity (57% vs 70% respectively; p-value is 0.0784), and a 5% lower incidence of discontinuation of bortezomib (22% vs 27%; p-value is 0.5052). The overall incidence of diarrhoea (24% for the SC arm vs 36% for the IV arm; p-value is 0.0572), gastrointestinal and abdominal pain (6% for the SC arm vs 19% for the IV arm; p-value is 0.0049), asthenic conditions (27% for SC arm vs 39% for IV arm), upper respiratory tract infections (14% SC arm vs 26% IV arm; p-value is 0.0903) and peripheral neuropathy NEC (38% SC arm vs 53% IV arm; p-value is 0.0444) were 12% - 15% lower in the subcutaneous group than the intravenous group. In addition, the incidence of peripheral neuropathies that were grade 3 or higher in toxicity was 10% lower (6% for SC vs 16% for IV; p-value is 0.0264), and the discontinuation rate due to peripheral neuropathies was 8% lower for the subcutaneous group (5%) as compared to the intravenous group (14%); p-value is 0.0771.
58 percent of patients (85/147) developed a reaction at the site of subcutaneous injection. Only 2 (1.4%) subjects were reported as having severe reactions. These severe local reactions were 1 case of pruritus and 1 case of redness. These reactions seldom led to dose modifications and all resolved in a median of 6 days (bortezomib treatment modification based on local reactions was needed in 2 subjects (1 treatment discontinuation; 1 drug withholding and reduction in study drug concentration from 2.5 mg/mL to 1 mg/mL).

Serious adverse events (SAEs).

In the APEX study, 44% of patients from the bortezomib treatment arm experienced a SAE during the study, as did 43% of dexamethasone-treated patients. The most commonly reported SAEs in the bortezomib treatment arm were pyrexia (6%), diarrhoea (5%), dyspnoea and pneumonia (4%) and vomiting (3%). In the dexamethasone group, the most common SAEs were pneumonia (7%), pyrexia (4%) and hyperglycaemia (3%). Twenty five percent (25%) and 18% of bortezomib and dexamethasone patients respectively were discontinued from treatment due to adverse events assessed as drug related by the investigators. The most common for bortezomib discontinuation was peripheral neuropathy (8%) and for dexamethasone was psychotic disorder and hyperglycaemia (2% each).
In the APEX study, 4 deaths were considered to be bortezomib-related: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four (4) deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis and 1 case of sudden death at home. In the phase II studies 2 deaths were reported and considered by the investigator to be possibly related to bortezomib: 1 case of cardiopulmonary arrest and 1 case of respiratory failure.

Adverse reactions.

The following adverse reactions were considered to have at least a possible or probable causal relationship to bortezomib by the investigators during 5 non-comparative phase II studies and 1 comparative phase III trial (APEX) in 663 patients with relapsed or refractory multiple myeloma, of whom 331 received bortezomib as single agent. The safety database comprises data from patients with multiple myeloma or B-cell lymphocytic leukaemia. Patients were treated with bortezomib as a single agent, or in combination with dexamethasone.
Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.

Infections and infestations.

Common: herpes zoster, pneumonia, bronchitis, sinusitis, nasopharyngitis, herpes simplex.
Uncommon: candidal infection, gastroenteritis, upper and lower respiratory tract infection, infection, influenza, fungal infection, sepsis, urinary tract infection, catheter related infection, haemophilus infection, pneumonia pneumococcal, post herpetic neuralgia, bacteraemia, blepharitis, bronchopneumonia, cytomegalovirus infection, infectious mononucleosis, varicella, oral candidiasis, pleural infection.

Blood and lymphatic system disorders.

Very common: thrombocytopenia (see Section 4.4 Special Warnings and Precautions for Use), anaemia, neutropenia.
Common: leukopenia, lymphopenia.
Uncommon: lymphadenopathy, febrile neutropenia, pancytopenia, haemolytic anaemia, thrombocytopenic purpura.

Immune system disorders.

Uncommon: hypersensitivity, immunocomplex mediated hypersensitivity.

Metabolism and nutritional disorders.

Very common: appetite decreased.
Common: dehydration, hyperglycaemia, hypokalaemia.
Uncommon: hypercalcaemia, hyperkalaemia, hyperuricaemia, hyponatraemia, hypernatraemia, hypocalcaemia, hypomagnesaemia, hypophosphataemia, hypoglycaemia, appetite increased, cachexia, vitamin B12 deficiency, tumour lysis syndrome (see Section 4.4 Special Warnings and Precautions for Use).

Endocrine disorders.

Uncommon: inappropriate antidiuretic hormone (ADH) secretion.

Psychiatric disorders.

Common: insomnia, anxiety, confusion, depression.
Uncommon: agitation, delirium, restlessness, mood swings, mental status changes, sleep disorder, irritability, hallucinations, abnormal dreams.

Nervous system disorders.

Very common: peripheral neuropathy, peripheral sensory neuropathy (see Section 4.4 Special Warnings and Precautions for Use), headache, paraesthesia.
Common: dizziness (excluding vertigo), dysgeusia, peripheral neuropathy aggravated, polyneuropathy, dysaesthesia, hypoaesthesia, tremor.
Uncommon: convulsions, syncope, disturbance in attention, increased activity, ageusia, somnolence, migraine, peripheral motor neuropathy, jerky movements, dizziness postural, sciatica, cognitive disorder, mononeuropathy, paresis, restless leg syndrome, speech disorder, intracranial haemorrhage, paraplegia, subarachnoid haemorrhage.

Eye disorders.

Common: vision blurred (see Section 4.4 Special Warnings and Precautions for Use), eye pain.
Uncommon: dry eye, conjunctivitis, eye discharge, vision abnormal, eye haemorrhage, photophobia, eye irritation, lacrimation increased, conjunctival hyperaemia, eye swelling.

Ear and labyrinth disorders.

Common: vertigo.
Uncommon: tinnitus, deafness, hypoacusis, hearing impaired.

Cardiac disorders.

Uncommon: development or exacerbation of congestive heart failure (see Section 4.4 Special Warnings and Precautions for Use), cardiac failure, ventricular hypokinesia, pulmonary oedema and acute pulmonary oedema, cardiac arrest, cardiogenic shock, tachycardia, sinus tachycardia, supraventricular tachycardia, arrhythmia, atrial fibrillation, palpitations, sinus arrest, atrioventricular block complete, angina pectoris, angina unstable, myocardial infarction.
Rare: new onset of decreased left ventricular ejection fraction.

Vascular disorders.

Common: hypotension, orthostatic and postural hypotension (see Section 4.4 Special Warnings and Precautions for Use), phlebitis, haematoma, hypertension.
Uncommon: flushing, petechiae, hot flushes, ecchymosis, purpura, cerebral hemorrhage, vasculitis, vein discolouration, vein distended, wound hemorrhage, pulmonary hypertension, cerebrovascular accident.

Respiratory, thoracic and mediastinal disorders.

Very common: dyspnoea.
Common: epistaxis, dyspnoea exertional, cough, rhinorrhoea.
Uncommon: nasal congestion, wheezing, pleural effusion, hoarseness, chest wall pain, hypoxia, pulmonary congestion, rhinitis, asthma, hyperventilation, orthopnoea, sinus pain, throat tightness, productive cough, respiratory alkalosis, respiratory arrest, tachypnoea.

Gastrointestinal disorders (see Section 4.4 Special Warnings and Precautions for Use).

Very common: nausea, diarrhoea, vomiting, constipation.
Common: abdominal pain, dyspepsia, loose stools, abdominal pain upper, flatulence, abdominal distension, hiccups, mouth ulceration, pharyngolaryngeal pain, stomatitis, dry mouth.
Uncommon: ileus paralytic, abdominal discomfort, eructation, gastrointestinal motility disorder, oral pain, retching, antibiotic associated colitis, change in bowel habit, diarrhoea haemorrhagic, gastrointestinal haemorrhage, spleen pain, colitis, dysphagia, oesophagitis, gastritis, gastro-oesophageal reflux disease, gastrointestinal pain, gingival bleeding, gingival pain, haematemesis, hiatus hernia, irritable bowel syndrome, oral mucosal petechiae, rectal haemorrhage, salivary hypersecretion, tongue coated, tongue discolouration, enteritis, faecal impaction, acute pancreatitis.

Hepatobiliary disorders (see Section 4.4 Special Warnings and Precautions for Use).

Uncommon: hyperbilirubinaemia, hepatitis, hepatic haemorrhage, hypoproteinaemia.

Skin and subcutaneous tissue disorders.

Very common: rash.
Common: pruritus, erythema, periorbital oedema, urticaria, rash pruritic, sweating increased, dry skin, eczema.
Uncommon: night sweats, rash erythematous, alopecia, contusion, pruritus generalised, rash macular, rash papular, skin nodule, rash, generalized, dermatitis, eyelid oedema, nail disorder, photosensitivity reaction, skin discolouration, dermatitis atopic, hair texture abnormal, heat rash, psoriasis, vasculitic rash, face oedema, pressure sore, ichthyosis.

Musculoskeletal and connective tissue disorders.

Very common: myalgia.
Common: pain in limb, muscle cramps, arthralgia, bone pain, peripheral swelling, muscle weakness, back pain, musculoskeletal pain.
Uncommon: joint stiffness, buttock pain, joint swelling, muscle spasms, muscle twitching or sensation of heaviness, muscle stiffness, swelling, pain in jaw.

Renal and urinary disorders.

Common: renal impairment, dysuria.
Uncommon: renal failure acute, renal colic, haematuria, proteinuria, urinary frequency, difficulty in micturition, renal failure, oliguria, urinary retention, loin pain, urinary incontinence, micturition urgency.

General disorders and administration site conditions.

Very common: fatigue (see Section 4.4 Special Warnings and Precautions for Use), pyrexia.
Common: weakness, rigors, malaise, influenza like illness, oedema peripheral, pain, lethargy, oedema, chest pain, asthenia.
Uncommon: fall, mucosal inflammation, feeling cold, chest pressure sensation, injection site phlebitis, mucosal haemorrhage, tenderness, injection site erythema, neuralgia, chest discomfort, groin pain, chest tightness, extravasation inflammation.

Investigations.

Common: weight decreased, blood lactate dehydrogenase increased.
Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood creatinine increased, blood urea increased, gamma-glutamyltransferase increased, blood amylase increased, blood bilirubin increased, blood phosphate decreased, liver function tests abnormal, red blood cell count decreased, weight increased, white blood cell count decreased, blood bicarbonate decreased, heart rate irregular, C-reactive protein increased.

Injury, poisoning and procedural complications.

Uncommon: catheter related complications, post procedural pain, post procedural haemorrhage, burns.

Reproductive system and breast disorders.

Uncommon: testicular pain, erectile dysfunction.

Potentially immunocomplex-mediated reactions (see Section 4.4 Special Warnings and Precautions for Use).

Uncommon: potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis.

Summary of clinical trial in patients with previously untreated mantle cell lymphoma.

Table 15 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received bortezomib (1.3 mg/m²) administered IV in combination with rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and prednisone (100 mg/m²) (VcR-CAP) in a prospective randomized study (LYM-3002).
The incidences of Grade ≥ 3 bleeding events were similar between the 2 arms (4 patients in the VcR-CAP arm and 3 patients in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved without sequelae in the VcR-CAP arm.
Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the R-CHOP arm. Respiratory tract and lung infections were reported, with the predominant preferred term of pneumonia (VcR-CAP 8% versus R-CHOP 5%).
HBV infection with fatal outcomes occurred in 0.8% (n = 2) of patients in the non-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) and 0.4% (n = 1) of patients receiving bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP). The overall incidence of hepatitis B infections was similar in patients treated with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively) (see Section 4.4 Special Warnings and Precautions for Use).
In general, the safety profile of bortezomib in mantle cell lymphoma was relatively consistent to that observed in patients with multiple myeloma with main differences described below. Additional adverse drug reactions identified associated with the use of the combination therapy (VcR-CAP) were hepatitis B infection (< 1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to bortezomib alone. Notable differences in the mantle cell lymphoma patient population as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders.

Herpes zoster virus reactivation.

Antiviral prophylaxis is recommended in patients being treated with Bortezomib Baxter.
Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR-CAP arm. The incidence of herpes zoster among patients in the VcR-CAP arm was 4.6% for patients not administered antiviral prophylaxis compared to 0.8% for patients administered antiviral prophylaxis.
Antiviral prophylaxis was administered to 102 of 242 patients (42%) in the R-CHOP arm. The incidence of herpes zoster among patients in the R-CHOP arm was 2.1% for patients not administered antiviral prophylaxis compared to 0% for patients administered antiviral prophylaxis.

Post marketing experience.

Clinically significant adverse reactions are listed if they have been reported during post approval use of bortezomib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders.

Rare: disseminated intravascular coagulation.
Very rare: thrombotic microangiopathy.

Cardiac disorders.

Rare: atrioventricular block complete, cardiac tamponade, pericarditis, ventricular arrhythmias, sinus and ventricular tachycardia.

Ear and labyrinth disorders.

Rare: deafness bilateral.

Eyes disorder.

Rare: ophthalmic herpes, optic neuropathy, blindness, chalazion/blepharitis.

Gastrointestinal disorders.

Uncommon: intestinal obstruction.
Rare: ischemic colitis, acute pancreatitis.

Hepatobiliary disorders.

Rare: liver failure.

Infections and infestations.

Rare: herpes meningoencephalitis, septic shock.
Very rare: progressive multifocal leukoencephalopathy^a.

Immune system disorders.

Rare: angioedema.
Very rare: anaphylactic reaction.

Nervous system disorders.

Rare: encephalopathy, autonomic neuropathy, posterior reversible encephalopathy syndrome.
Unknown: Guillain-Barre syndrome^b.

Respiratory, thoracic and mediastinal disorders.

Rare: acute diffuse infiltrative pulmonary disease (see Section 4.4 Special Warnings and Precautions for Use), pulmonary hypertension.

Skin and subcutaneous tissue disorders.

Rare: acute febrile neutrophilic dermatosis (Sweet's syndrome).
Very rare: Stevens-Johnson Syndrome and toxic epidermal necrolysis.
^a Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with bortezomib.
^b GBS has been reported in patients treated with bortezomib in the post-market setting with an unknown frequency, causality has not been established.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Cardiovascular safety pharmacology studies in monkeys and dogs showed that IV doses approximately two to three times the recommended clinical dose on a mg/m² basis are associated with increases in heart rate, decreases in contractility, hypotension and death. The decreased cardiac contractility and hypotension responded to acute intervention with positive ionotropic or pressor agents. In dog studies, a slight increase in the corrected QT interval was observed at a lethal dose.
In patients, overdosage more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for bortezomib overdosage. In the event of overdosage, patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or ionotropic agents) and body temperature (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis which can affect multiple signalling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumour growth in vivo in nonclinical tumour models, including multiple myeloma.
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.

Clinical trials.

All response and progression data listed below for both previously untreated multiple myeloma in non-transplant eligible patients and relapsed/ refractory multiple myeloma were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. The response and progression data for transplant-eligible multiple myeloma patients were assessed using the International Myeloma Working Group (IMWG) criteria.
Previously untreated multiple myeloma.

Transplant eligible.

The safety and efficacy of bortezomib, as induction therapy prior to stem cell transplantation in previously untreated multiple myeloma patients, has been assessed in two Phase III trials.
A Phase III, randomised (1:1), open-label, multi-centre study conducted by the Italian Myeloma Network - GIMEMA, randomised 480 transplant-eligible patients under the age of 65 to receive three 3-week cycles of bortezomib (1.3 mg/m², days 1, 4, 8, 11) in combination with thalidomide (100 mg, days 1-14 in cycle 1, then 200 mg daily) and dexamethasone (40 mg, days 1, 2, 4, 5, 8, 9, 11, 12) (Vc-TD), or thalidomide and dexamethasone (TD) prior to tandem autologous transplant. Three months following transplant, patients received two cycles of consolidation treatment; patients randomized to receive Vc-TD induction received two 35-day cycles of bortezomib (1.3 mg/m², days 1, 8, 15, 22), thalidomide (100 mg daily) and dexamethasone (40 mg, days 1, 2, 8, 9, 15, 16, 22, 23) consolidation; patients randomized to receive thalidomide-dexamethasone induction received two 35-day cycles of thalidomide-dexamethasone consolidation. The primary endpoint of the study was response rate ≥ nCR following induction therapy.
Patients randomized to Vc-TD arm achieved significantly higher rates of complete plus near complete response and very good partial response or better, compared to the thalidomide-dexamethasone arm following induction treatment. This difference was maintained following both transplant and consolidation therapy. Response rates are presented in Table 16.

In addition, compared with the TD arm, Progression Free Survival (PFS) was also significantly longer for patients randomized to the Vc-TD arm (HR, 0.629 [CI: 0.451 - 0.878], p = 0.0061). The estimated 3-year PFS rate was 68% in the VTD arm and 56% in TD (p = 0.0057) (see Figure 1). 58 (24.5%) and 86 (36%) patients progressed or died, respectively. The estimated 3-year probability of progression or relapse was 29% in the Vc-TD versus 39% in the TD arm (HR, 0.609 [CI: 0.425-0.873], p = 0.0073; p = 0.0061 by Kaplan-Meier analysis) (see Figure 2).

The IFM-2005, Phase III, randomised (1:1:1:1), multi-centre, open-label study was conducted to compare the efficacy and safety of bortezomib-dexamethasone (Vc-Dex) and vincristine-doxorubicin-dexamethasone (VAD) as induction therapy prior to HDT-ASCT, and to evaluate the impact of post-induction consolidation therapy. Patients in this study were randomised to receive VAD plus no consolidation (arm A1), VAD plus dexamethasone, cyclophosphamide, etoposide, cis-platin (DCEP) consolidation (arm A2), Vc-Dex plus no consolidation (arm B1), or Vc-Dex plus DCEP consolidation (arm B2).
A total of 482 patients aged ≤ 65 years were randomised; 240 patients received four 3-week cycles of bortezomib (1.3 mg/m²), days 1, 4, 8 and 11 plus dexamethasone (40 mg) days 1 - 4 (all cycles) and days 9 - 12 (cycles 1 and 2), while 242 patients received four 4-week cycles of VAD. The primary endpoint of this study was the CR/nCR rate post-induction.
Patients randomized to the Vc-Dex arm achieved significantly higher rates of complete plus near complete response and very good partial response or better, compared to the VAD arm following induction treatment. Based on an intention to treat analysis, response rates were similar regardless of whether patients received DCEP consolidation or not. Efficacy results are presented in Table 17.

A total of 184/218 (84.4%) and 197/223 (88.3%) evaluable patients who received VAD and Vc-Dex induction, respectively, underwent autologous stem cell transplantation. The number of patients who received a second transplantation was 41 (20.8%) in the Vc-Dex arm, compared to 50 (27.2%) for patients in the VAD arm. Post-transplant response rates are shown in Table 18.

In addition, the median PFS was 29.7 months among patients who received VAD versus 36.0 months among patients who received Vc-Dex induction, with 128 (52.9%) of 242 and 110 (45.8%) of 240 patients, respectively, having progressed (p = 0.064, or p = 0.057 if adjusted for initial stratification factors) after median follow-up of 31.2 months.

Non-transplant eligible.

The VISTA study is a prospective phase III, international, randomized (1:1), open-label clinical study of 682 patients, conducted to determine whether bortezomib (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m²) and prednisone (60 mg/m²) in patients with previously untreated multiple myeloma unsuitable for high dose chemotherapy with stem cell transplantation. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Baseline demographics and patient characteristics are summarized in Table 19.

At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and patients in the MP arm were offered VcMP treatment. Survival continued to be followed after the interim analysis. Median follow-up in the initial analysis (Table 20 and Figure 1) was 16.3 months. Median follow-up in the last survival analysis (Figure 2) was 36.7 months. Median overall survival in the MP arm was 43.1 months and was not reached in the VcMP arm. Fifty percent of subjects in the MP arm subsequently received bortezomib.

The time to progression (TTP) was significantly longer on the bortezomib arm (see Figure 3).

A significant survival advantage is shown with bortezomib (see Figure 4).

Relapsed/ refractory multiple myeloma. The safety and efficacy of bortezomib were evaluated in 2 studies at the recommended dose of 1.3 mg/m²: The APEX study - a phase III randomised, stratified, open-label, comparative study, versus Dexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy, and a phase II single-arm study of 202 patients with relapsed and refractory multiple myeloma, who had received at least 2 prior lines of treatment and who were progressing on their most recent treatment (see Table 21 and Table 22).

APEX study (phase III).

In the APEX study described above, patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline grade ≥ 2 peripheral neuropathy or platelet counts < 50,000/microL. A total of 627 patients were evaluable for response. Stratification factors were based on the number of lines of prior therapy the patient had previously received (1 previous line versus more than 1 line of therapy), time of progression relative to prior treatment (progression during or within 6 months of stopping their most recent therapy versus relapse > 6 months after receiving their most recent therapy), and screening β2-microglobulin levels (≤ 2.5 mg/L versus > 2.5 mg/L).
Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered bortezomib, regardless of disease status. At this time of study termination, a final statistical analysis was performed. Due to this early termination of the study, the median duration of follow-up for surviving patients (n = 534) is limited to 8.3 months. The time to event analyses and response rates from the APEX trial are presented in Table 23.

For the 121 patients achieving a response (CR or PR) on the bortezomib arm, the median duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm.
Treatment with bortezomib led to a significantly longer TTP, a significantly prolonged survival and a significantly higher response rate, compared to treatment with dexamethasone in patients who have received more than one prior therapy as well as in patients who have received only one prior line of therapy.
Both in patients who were refractory to their last prior therapy and those who were not refractory, overall survival was significantly longer and response rate was significantly higher on the bortezomib arm. Of the 669 patients enrolled, 245 (37%) were 65 years of age or older. Response parameters as well as TTP remained significantly better for bortezomib independently of age. Regardless of β2-microglobulin levels at baseline, all efficacy parameters (time to progression and overall survival, as well as response rate) were significantly improved on the bortezomib arm.
The time to progression (TTP) was significantly longer on the bortezomib arm (see Figure 5).

As shown in Figure 6, bortezomib had a significant survival advantage relative to dexamethasone (p < 0.05). The median follow-up was 8.3 months.

Randomized, open-label clinical study in relapsed multiple myeloma comparing bortezomib IV and SC.

An open label, randomized, phase III non-inferiority study compared the efficacy and safety of the subcutaneous administration (SC) of bortezomib versus the intravenous administration (IV). This study included 222 patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m² of bortezomib by either the SC or IV route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response CR) to therapy with bortezomib alone after 4 cycles were allowed to receive dexamethasone 20 mg daily on the day of and day after bortezomib administration. Patients with baseline grade ≥ 2 peripheral neuropathy or platelet counts < 50,000/microL were excluded. A total of 218 patients were evaluable for response.
Stratification factors were based on the number of lines of prior therapy the patient had received (1 previous line versus more than 1 line of therapy), and international staging system (ISS) stage (incorporating beta2-microglobulin and albumin levels; Stages I, II, or III). The baseline patient and disease characteristics were comparable between the SC and IV arms.
This study met its primary objective of non-inferiority for response rate (CR + PR) after 4 cycles of single agent bortezomib for both the SC and IV routes, with an ORR of 42% in both groups. In addition, all secondary endpoints relating to efficacy showed comparable results between SC and IV administration (Table 24).

Table 25 presents a cross-tabulation summary of best response by algorithm after 4 cycles versus after 8 cycles for patients who received dexamethasone. Eighty-two subjects in the SC treatment group and 39 subjects in the IV treatment group received dexamethasone after cycle 4.
Dexamethasone had a similar effect on improvement of response on both treatment arms: 30% (SC) and 30% (IV) of patients with no response at end of Cycle 4 obtained a response later in subsequent cycles (cycle 5 through 8).
13% (SC) and 13% (IV) of patients with PR at end of Cycle 4 obtained a CR later in subsequent cycles (cycle 5 through 8).

Relative to previously reported outcomes, the ORR after 8 cycles of treatment (52% in both treatment groups) and time to progression (median 10.4 months and 9.4 months in SC and IV treatment groups, respectively), including the effect of the addition of dexamethasone from cycle 5 onwards, were higher than observed in prior registration study with single agent IV bortezomib, APEX, (38% ORR and median TTP of 6.2 months for the bortezomib arm). Time to Progression and ORR was also higher compared to the subgroup of patients on APEX that received only 1 prior line of therapy (43% ORR and median TTP of 7.0 months) (Table 20).

Phase II studies.

The safety and efficacy of bortezomib were evaluated in an open-label, single-arm, multi-centre study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy. The median number of prior therapies was six. Dosing regimens and baseline patient and disease characteristics are summarised in Table 21 and Table 22. The study employed dose modifications for toxicity (see Section 4.2 Dose and Method of Administration). Responses to bortezomib alone in the phase II study are shown in Table 26.
In general, patients who had confirmed Complete Response received 2 additional cycles of bortezomib treatment beyond confirmation. The median time to response was 38 days (range 30 to 127 days). The median survival of all patients enrolled was 16 months (range < 1 to 18+ months). The response rate to bortezomib was independent of the number and types of prior therapies.

Patients who did not obtain an optimal response to therapy with bortezomib alone were able to receive high-dose dexamethasone in conjunction with bortezomib (i.e. 40 mg dexamethasone with each dose of bortezomib administered orally as 20 mg on the day of and 20 mg the day after bortezomib administration, (i.e. Days 1, 2, 4, 5, 8, 9, 11, and 12), thus 160 mg over 3 weeks. Eighteen percent (13/74) of patients achieved or had an improved response (CR 11% or PR 7%) with combination treatment.
A small dose-response study was performed in 54 patients with multiple myeloma who received a 1.0 mg/m²/dose or a 1.3 mg/m²/dose twice weekly for two out of three weeks. A single complete response was seen at each dose, and there were overall (CR + PR) response rates of 30% (8/27) at 1.0 mg/m² and 38% (10/26) at 1.3 mg/m².
Previously untreated mantle cell lymphoma. Study LYM-3002 was a Phase III, randomized, open-label study comparing the efficacy and safety of the combination of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP; n = 243) to that of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n = 244) in adult patients with previously untreated mantle cell lymphoma (Stage II, III or IV). Patients of median age 66 years enrolled in this trial were either ineligible (e.g. due to age or comorbidity; n = 407) or were not considered (e.g. due to transplant unavailability, financial unaffordability or patient refusal, despite being medically eligible; n = 80) for stem-cell transplantation.
Patients in the VcR-CAP treatment arm received bortezomib (1.3 mg/m² IV) on Days 1, 4, 8, 11 (rest period days 12-21), rituximab (375 mg/m² IV) on Day 1; cyclophosphamide (750 mg/m² IV) on Day 1; doxorubicin (50 mg/m² IV) on Day 1; and prednisone (100 mg/m² orally) on Day 1 through Day 5 of the 21 day bortezomib treatment cycle. For patients with a response first documented at cycle 6, two additional treatment cycles were given.
The primary efficacy endpoint was progression-free survival based on Independent Review Committee (IRC) assessment. Secondary endpoints included, time to progression (TTP), time to next anti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response rate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration. The response criteria used to assess efficacy were based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma (IWRC).
The demographic and baseline disease characteristics were generally well balanced between the two treatment arms: median patient age was 66 years, 74% were male, 66% were Caucasian and 32% Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥ 3, and 74% had Stage IV disease. Treatment duration (median = 17 weeks) and duration of follow-up (median = 40 months) were comparable in both treatment arms. A median of 6 cycles was received by patients in both treatment arms with 14% of subjects in the VcR-CAP group and 17% of patients in the R-CHOP group receiving 2 additional cycles. The majority of the patients in both groups received 6 or more cycles of treatment, 83% in the R-CHOP group and 84% in the VcR-CAP group.
A statistically significant benefit in favour of the VcR-CAP treatment group was observed for the median values for PFS, TTP, TNT, TFI and overall survival, over the entire duration of the study.
At a median follow up of 40 months, a 59% improvement in the primary endpoint of PFS [hazard ratio (HR) 0.63, 95% CI 0.50 - 0.79; p < 0.001] was observed in the VcR-CAP group (median = 24.7 months) as compared to the R-CHOP group (median 14.4 months). The median duration of complete response was more than double in the VcR-CAP group (42.1 months) compared with the R-CHOP group (18 months) and the duration of overall response was 21.4 months longer in the VcR-CAP group.
At a median follow-up of 40 months, median OS (56.3 months in the R-CHOP group, and not reached in the VcR CAP group) favoured the VcR-CAP group, (estimated HR = 0.80; p = 0.173). There was a trend towards prolonged overall survival favouring the VcR-CAP group; at this point in time, with the estimated 4-year survival rate was 53.9% in the R-CHOP group and 64.4% in the VcR-CAP group.
Overall survival demonstrated statistical significance in the final analysis, after a median follow-up of 82 months. Median OS in the VcR-CAP group was 90.7 months, almost three years more than the OS achieved in the R-CHOP group, which was 55.7 months (HR-0.66; p = 0.001).
Efficacy results are presented in Table 27.

5.2 Pharmacokinetic Properties

Following intravenous bolus administration of a 1.0 mg/m² and 1.3 mg/m² dose to eleven patients with multiple myeloma, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 nanogram/mL respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 nanogram/mL for the 1.0 mg/m² dose and 89 to 120 nanogram/mL for the 1.3 mg/m² dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 - 193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 L/h following the first dose for doses of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h following subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
In the PK/PD substudy in Phase III trial, following an IV bolus or subcutaneous (SC) injection of a 1.3 mg/m² dose to multiple myeloma patients (n = 14 for IV, n = 17 for SC), the total systemic exposure after repeat dose administration (AUC_last) was equivalent (151 nanogram.h/mL vs 155 nanogram.h/mL) for SC and IV administration. The C_max after SC administration (20.4 nanogram/mL) was lower than IV (223 nanogram/mL). The AUC_last geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% - 122.80%.

Distribution.

The mean distribution volume of bortezomib ranged from 1659 litres to 3294 litres (489 to 1884 L/m²) following single- or repeat-dose IV administration of 1.0 mg/m² or 1.3 mg/m² to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues.

Protein binding.

Over a bortezomib concentration range of 10 to 1000 nanogram/mL, the in vitro protein binding averaged 83% in human plasma. The percent of bortezomib bound to plasma proteins was not concentration dependent.

Metabolism.

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, 2D6, 2C9, and 1A2. The major metabolic pathway is deboronation, with the two main metabolites formed undergoing subsequent hydroxylation. One of the two main deboronated metabolites was shown to be inactive as a 26S proteasome inhibitor. Pooled plasma data from 8 patients at 10 min and 30 min after IV dosing indicate that the plasma levels of metabolites are low compared to the parent drug.

Excretion.

The elimination pathways of bortezomib have not been evaluated in vivo.

Renal impairment.

A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), Mild (CrCL = 40 - 59 mL/min/1.73 m², n = 10), Moderate (CrCL = 20 - 39 mL/min/1.73 m², n = 9), and Severe (CrCL < 20 mL/min/1.73 m², n = 3). A group of dialysis patients who were dosed after dialysis was also included in the study (n = 8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m² of bortezomib twice weekly. Clearance of bortezomib was comparable among all the groups. However, the number of patients with severe renal impairment was insufficient to allow reliable conclusions regarding this group (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Formal studies in patients with severely impaired hepatic function have not been conducted to date; consequently caution is recommended when administering bortezomib to these classes of patients (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Bortezomib showed clastogenic activity at a high concentration (3 microgram/mL) in an in vitro chromosomal aberration assay using Chinese hamster ovary cells. Clastogenic activity was not observed in vivo in a mouse micronucleus test using intravenous doses of up to 3 mg/m². Bortezomib was not genotoxic in in vitro tests for bacterial gene mutation.

Carcinogenicity.

Carcinogenicity studies have not been conducted with bortezomib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, nitrogen.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Unopened vials.

Store below 30°C. Keep the container in the outer carton in order to protect from light.

Reconstituted solution.

Bortezomib Baxter contains no antimicrobial preservative. The reconstituted solution should be used immediately. If storage is necessary, hold at 2°C to 8°C for no longer than 24 hours, or at 25°C for no longer than 8 hours before discarding.

6.5 Nature and Contents of Container

Type 1 glass 10 mL vial with a grey chlorobutyl rubber stopper and an aluminium seal with an orange flip-off cap and silver crimping cap, containing 3.5 mg bortezomib.
The vial is contained in a carton. Each carton contains 1 single-use vial.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.
The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1- [[(2S)- 1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid.
The solubility of bortezomib, as the monomeric boronic acid, in water is: 3.3 - 3.8 mg/mL in a pH range of 2 - 6.5.

Chemical structure.

CAS number.

179324-69-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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