Stelara 130mg26ml concentrate for solution for infusion vials

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Ustekinumab
Available from:
Janssen-Cilag Ltd
ATC code:
L04AC05
INN (International Name):
Ustekinumab
Dosage:
5mg/1ml
Pharmaceutical form:
Solution for infusion
Administration route:
Intravenous
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: ; GTIN: 5012674902967

Read the complete document

Package leaflet: Information for the user

STELARA 130 mg concentrate for solution for infusion

Ustekinumab

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

This leaflet has been written for the person taking the medicine.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Stelara is and what it is used for

What you need to know before you use Stelara

How Stelara will be given

Possible side effects

How to store Stelara

Contents of the pack and other information

1.

What Stelara is and what it is used for

What Stelara is

Stelara contains the active substance ‘ustekinumab’, a monoclonal antibody. Monoclonal antibodies

are proteins that recognise and bind specifically to certain proteins in the body.

Stelara belongs to a group of medicines called ‘immunosuppressants’. These medicines work by

weakening part of the immune system.

What Stelara is used for

Stelara is used to treat moderate to severe Crohn’s disease in adults.

Crohn’s disease

Crohn’s disease is an inflammatory disease of the bowel. If you have Crohn’s disease you will first be

given other medicines. If you do not respond well enough or are intolerant to these medicines, you

may be given Stelara to reduce the signs and symptoms of your disease.

2.

What you need to know before you use Stelara

Do not use Stelara:

If you are allergic to ustekinumab

or any of the other ingredients of this medicine (listed in

section 6).

If you have an active infection

which your doctor thinks is important.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using

Stelara.

Warnings and precautions

Talk to your doctor or pharmacist before using Stelara. Your doctor will check how well you are

before treatment. Make sure you tell your doctor about any illness you have before treatment. Also

tell your doctor if you have recently been near anyone who might have tuberculosis. Your doctor will

examine you and do a test for tuberculosis, before you have Stelara. If your doctor thinks you are at

risk of tuberculosis, you may be given medicines to treat it.

Look out for serious side effects

Stelara can cause serious side effects, including allergic reactions and infections. You must look out

for certain signs of illness while you are taking Stelara. See ‘Serious side effects’ in section 4 for a

full list of these side effects.

Before you use Stelara tell your doctor:

If you ever had an allergic reaction to Stelara

. Ask your doctor if you are not sure.

If you have ever had any type of cancer

– this is because immunosuppressants like Stelara

weaken part of the immune system. This may increase the risk of cancer.

If you have or have had a recent infection or if you have any abnormal skin openings

(fistulae)

If you have any new or changing lesions

within psoriasis areas or on normal skin.

If you are having any other treatment for psoriasis and/or psoriatic arthritis

– such as

another immunosuppressant or phototherapy (when your body is treated with a type of

ultraviolet (UV) light). These treatments may also weaken part of the immune system. Using

these therapies together with Stelara has not been studied. However it is possible it may

increase the chance of diseases related to a weaker immune system.

If you are having or have ever had injections to treat allergies

– it is not known if Stelara

may affect these.

If you are 65 years of age or over

– you may be more likely to get infections.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before using

Stelara.

Children and adolescents

Stelara is not recommended for use in children under 18 years of age with Crohn’s disease because it

has not been studied in this age group.

Other medicines, vaccines and Stelara

Tell your doctor or pharmacist:

If you are taking, have recently taken or might take any other medicines.

If you have recently had or are going to have a vaccination. Some types of vaccines (live

vaccines) should not be given while using Stelara.

Pregnancy and breast-feeding

It is preferable to avoid the use of Stelara in pregnancy. The effects of Stelara in pregnant

women are not known. If you are a woman of childbearing potential, you are advised to avoid

becoming pregnant and must use adequate contraception while using Stelara and for at least

15 weeks after the last Stelara treatment.

Talk to your doctor if you are pregnant, think you may be pregnant or are planning to have a

baby.

Talk to your doctor if you are breast-feeding or are planning to breast-feed. You and your

doctor should decide if you should breast-feed or use Stelara - do not do both.

Driving and using machines

Stelara has no or negligible influence on the ability to drive and use machines.

3.

How Stelara will be given

Stelara is intended for use under the guidance and supervision of a doctor experienced in the diagnosis

and treatment of Crohn’s disease.

Stelara 130 mg concentrate for solution for infusion will be given to you by your doctor, through a

drip in the vein of your arm (intravenous infusion) over at least one hour. Talk to your doctor about

when you will have your injections and follow-up appointments.

How much Stelara is given

Your doctor will decide how much Stelara you need to receive and for how long.

Adults aged 18

years or older

The doctor will work out the recommended intravenous infusion dose for you based on your

body weight.

Your body weigh

Dose

≤ 55 kg

260 mg

> 55 kg to ≤ 85 kg

390 mg

> 85 kg

520 mg

After the starting intravenous dose, you will have the next dose of 90 mg Stelara by an injection

under your skin (subcutaneous injection) 8 weeks later, and then every 12 weeks therafter.

How Stelara is given

The first dose of Stelara for treatment of Crohn’s disease is given by a doctor as a drip in the

vein of an arm (intravenous infuson).

Talk to your doctor if you have any questions about receiving Stelara.

If you forget to use Stelara

If you forget or miss the appointment for receiving the dose, contact your doctor to reschedule your

appointment.

If you stop using Stelara

It is not dangerous to stop using Stelara. However, if you stop, your symptoms may come back.

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

4.

Possible side effects

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

Serious side effects

Some patients may have serious side effects that may need urgent treatment.

Allergic reactions – these may need urgent treatment. Tell your doctor or get emergency

medical help straight away if you notice any of the following signs.

Serious allergic reactions (‘anaphylaxis’) are rare in people taking Stelara (may affect up

to 1 in 1,000 people). Signs include:

difficulty breathing or swallowing

low blood pressure, which can cause dizziness or light-headedness

swelling of the face, lips, mouth or throat.

Common signs of an allergic reaction include skin rash and hives (these may affect up to

1 in 100 people).

If you have a serious allergic reaction, your doctor may decide that you should not use Stelara

again.

Infections – these may need urgent treatment. Tell your doctor straight away if you notice

any of the following signs.

Infections of the nose or throat and common cold are common (may affect up to 1 in

10 people)

Infections of the chest are uncommon (may affect up to 1 in 100 people)

Inflammation of tissue under the skin (‘cellulitis’) is uncommon (may affect up to 1 in

100 people)

Shingles (a type of painful rash with blisters) are uncommon (may affect up to 1 in

100 people)

Stelara may make you less able to fight infections, and some infections could become serious.

You must look out for signs of infection while you are using Stelara. These include:

fever, flu-like symptoms, night sweats

feeling tired or short of breath; cough which will not go away

warm, red and painful skin, or a painful skin rash with blisters

burning when passing water

diarrhoea.

Tell your doctor straight away if you notice any of these signs of infection. These may be signs

of infections such as chest infections, or skin infections or shingles that could have serious

complications.

Tell your doctor if you have any kind of infection that will not go away or keeps

coming back. Your doctor may decide that you should not use Stelara until the infection goes

away. Also tell your doctor if you have any open cuts or sores as they might get infected.

Shedding of skin – increase in redness and shedding of skin over a larger area of the body

may be symptoms of erythrodermic psoriasis or exfoliative dermatitis, which are serious

skin conditions. You should tell your doctor straight away if you notice any of these signs.

Other side effects

Common side effects

(may affect up to 1 in 10 people):

Diarrhoea

Nausea

Vomiting

Feeling tired

Feeling dizzy

Headache

Itching (‘pruritus’)

Back, muscle or joint pain

Sore throat

Redness and pain where the injection is given

Uncommon side effects

(may affect up to 1 in 100 people)

:

Tooth infections

Vaginal yeast infection

Depression

Blocked or stuffy nose

Bleeding, bruising, hardness, swelling and itching where the injection is given

Feeling weak

Drooping eyelid and sagging muscles on one side of the face (‘facial palsy’ or ‘Bell’s

palsy’), which is usually temporary

A change in psoriasis with redness and new tiny, yellow or white skin blisters,

sometimes accompanied by fever (pustular psoriasis)

Peeling of the skin (skin exfoliation)

Acne

Rare side effects

(may affect up to 1 in 1000 people)

Redness and shedding of skin over a larger area of the body, which may be itchy or

painful (exfoliative dermatitis). Similar symptoms sometimes develop as a natural

change in the type of psoriasis symptoms (erythrodermic psoriasis)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet.

In the UK,

you can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App

Store.

In Ireland,

you can also report side effects directly via: HPRA Pharmacovigilance, Earlsfort Terrace,

IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail:

medsafety@hpra.ie

In Malta,

report side effects to: ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Stelara

Stelara 130 mg concentrate for solution for infusion is given in a hospital or clinic and patients

should not need to store or handle it.

Keep this medicine out of the sight and reach of children.

Store in a refrigerator (2°C–8°C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Do not shake the Stelara vials. Prolonged vigorous shaking may damage the medicine.

Do not use this medicine:

After the expiry date which is stated on the label and the carton after ‘EXP’. The expiry date

refers to the last day of that month.

If the liquid is discoloured, cloudy or you can see other foreign particles floating in it (see

section 6 ‘What Stelara looks like and contents of the pack’).

If you know, or think that it may have been exposed to extreme temperatures (such as

accidentally frozen or heated).

If the product has been shaken vigorously.

If the seal is broken.

Stelara is for single use only. Any diluted infusion solution or unused product remaining in the vial

and the syringe should be thrown away in accordance with local requirements.

6.

Contents of the pack and other information

What Stelara

contains

The active substance is ustekinumab. Each vial contains130 mg ustekinumab in 26 mL.

The other ingredients are EDTA disodium salt dihydrate, L-histidine, L-histidine

monohydrochloride monohydrate, L-methionine, polysorbate 80, sucrose and water for

injection.

What Stelara

looks like and contents of the pack

Stelara is a clear, colourless to light yellow concentrate for solution for infusion. It is supplied as a

carton pack containing 1 single-dose, glass 30 mL vial. Each vial contains 130 mg ustekinumab in

26 mL of concentrate for solution for infusion.

Marketing Authorisation Holder

Janssen-Cilag International NV

Turnhoutseweg 30

2340 Beerse

Belgium

Manufacturer

Janssen Biologics B.V.

Einsteinweg 101

2333 CB Leiden

The Netherlands

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

Ireland

JANSSEN-CILAG Ltd.

50 -100 Holmers Farm Way,

High Wycombe,

Buckinghamshire, HP12 4EG - UK

Tel: +44 1 494 567 444

Malta

A.M. Mangion Ltd.

Mangion Building, Triq ġdida fi triq Valletta

MT-Ħal-Luqa LQA 6000

Malta

Tel: +356 2397 6000

Κύπρος

Βαρνάβας Χατζηπαναγής Λτδ

Λεωφόρος Γιάννου Κρανιδιώτη 226

Λατσιά

CY-2234 Λευκωσία

Tηλ: +357 22 20 77 00

United Kingdom

JANSSEN-CILAG Ltd.

50 -100 Holmers Farm Way

High Wycombe

Buckinghamshire, HP12 4EG - UK

Tel: +44 1 494 567 444

This leaflet was last revised in February 2018.

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu/.

---------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Traceability:

In order to improve the traceability of biological medicinal products, the tradename and the batch

number of the administered product should be clearly recorded.

Instructions for dilution:

STELARA concentrate for solution for infusion must be diluted, prepared and infused by a healthcare

professional using aseptic technique.

Calculate the dose and the number of STELARA vials needed based on patient weight (see

section 3, Table 1). Each 26 mL vial of STELARA contains 130 mg of ustekinumab.

Withdraw and then discard a volume of the sodium chloride 9 mg/mL (0.9%) solution from the

250 mL infusion bag equal to the volume of STELARA to be added (discard 26 mL sodium

chloride for each vial of STELARA needed, for 2 vials- discard 52 mL, for 3 vials discard

78 mL, for 4 vials- discard 104 mL).

Withdraw 26 mL of STELARA from each vial needed and add it to the 250 mL infusion bag.

The final volume in the infusion bag should be 250 mL. Gently mix.

Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles,

discoloration or foreign particles are observed.

Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should

be completed within eight hours of the dilution in the infusion bag.

Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore

size 0.2 micrometer).

Each vial is for single use only and any unused medicinal product should be disposed of in

accordance with local requirements.

Storage

If necessary, the diluted infusion solution may be stored at room temperature. The infusion should be

completed within 8 hours of the dilution in the infusion bag. Do not freeze.

Read the complete document

Object 1

STELARA 130 mg concentrate for solution for

infusion

Summary of Product Characteristics Updated 22-Mar-2018 | Janssen-Cilag Ltd

1. Name of the medicinal product

STELARA 130 mg concentrate for solution for infusion

2. Qualitative and quantitative composition

Each vial contains 130 mg ustekinumab in 26 mL (5 mg/mL).

Ustekinumab is a fully human IgG1κ monoclonal antibody to interleukin (IL)-12/23 produced in a murine

myeloma cell line using recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion.

The solution is clear, colourless to light yellow.

4. Clinical particulars

4.1 Therapeutic indications

Crohn's Disease

STELARA is indicated for the treatment of adult patients with moderately to severely active Crohn's

disease who have had an inadequate response with, lost response to, or were intolerant to either

conventional therapy or a TNFα antagonist or have medical contraindications to such therapies.

4.2 Posology and method of administration

STELARA concentrate for solution for infusion is intended for use under the guidance and supervision of

physicians experienced in the diagnosis and treatment of Crohn's disease. STELARA concentrate for

solution for infusion should only be used for the intravenous induction dose.

Posology

Crohn's Disease

STELARA treatment is to be initiated with a single intravenous dose based on body weight. The infusion

solution is to be composed of the number of vials of STELARA 130 mg as specified in Table 1 (see

section 6.6 for preparation).

Table 1 Initial intravenous dosing of STELARA

Body weight of patient at the time of dosing

Recommended dose

Number of 130 mg

STELARA Vials

≤ 55 kg

260 mg

> 55 kg to ≤ 85 kg

390 mg

> 85 kg

520 mg

Approximately 6 mg/kg

The first subcutaneous dose should be given at week 8 following the intravenous dose. For the posology

of the subsequent subcutaneous dosing regimen, see section 4.2 of the STELARA solution for injection

(vial) and solution for injection in pre-filled syringe SmPC.

Elderly (≥ 65 years)

No dose adjustment is needed for elderly patients (see section 4.4).

Renal and hepatic impairment

STELARA has not been studied in these patient populations. No dose recommendations can be made.

Paediatric population

The safety and efficacy of STELARA for the treatment of Crohn's disease in children less than 18 years

have not yet been established. No data are available.

Method of administration

STELARA 130 mg is for intravenous use only. It should be administered over at least one hour.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important, active infection (e.g. active tuberculosis; see section 4.4).

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch number

of the administered product should be clearly recorded.

Infections

Ustekinumab may have the potential to increase the risk of infections and reactivate latent infections. In

clinical studies, serious bacterial, fungal, and viral infections have been observed in patients receiving

STELARA (see section 4.8).

Caution should be exercised when considering the use of STELARA in patients with a chronic infection

or a history of recurrent infection (see section 4.3).

Prior to initiating treatment with STELARA, patients should be evaluated for tuberculosis infection.

STELARA must not be given to patients with active tuberculosis (see section 4.3). Treatment of latent

tuberculosis infection should be initiated prior to administering STELARA. Anti-tuberculosis therapy

should also be considered prior to initiation of STELARA in patients with a history of latent or active

tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA

should be monitored closely for signs and symptoms of active tuberculosis during and after treatment.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection

occur. If a patient develops a serious infection, the patient should be closely monitored and STELARA

should not be administered until the infection resolves.

Malignancies

Immunosuppressants like ustekinumab have the potential to increase the risk of malignancy. Some

patients who received STELARA in clinical studies developed cutaneous and non-cutaneous

malignancies (see section 4.8).

No studies have been conducted that include patients with a history of malignancy or that continue

treatment in patients who develop malignancy while receiving STELARA. Thus, caution should be

exercised when considering the use of STELARA in these patients.

All patients, in particular those greater than 60 years of age, patients with a medical history of prolonged

immunosuppressant therapy or those with a history of PUVA treatment, should be monitored for the

appearance of non-melanoma skin cancer (see section 4.8).

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in the postmarketing setting, in some cases several

days after treatment. Anaphylaxis and angioedema have occurred. If an anaphylactic or other serious

hypersensitivity reaction occurs, appropriate therapy should be instituted and administration of

STELARA should be discontinued (see section 4.8).

Vaccinations

It is recommended that live viral or live bacterial vaccines (such as Bacillus of Calmette and Guérin

(BCG)) should not be given concurrently with STELARA. Specific studies have not been conducted in

patients who had recently received live viral or live bacterial vaccines. No data are available on the

secondary transmission of infection by live vaccines in patients receiving STELARA. Before live viral or

live bacterial vaccination, treatment with STELARA should be withheld for at least 15 weeks after the

last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the Summary

of Product Characteristics for the specific vaccine for additional information and guidance on

concomitant use of immunosuppressive agents post-vaccination.

Patients receiving STELARA may receive concurrent inactivated or non-live vaccinations.

Long term treatment with STELARA does not suppress the humoral immune response to pneumococcal

polysaccharide or tetanus vaccines (see section 5.1).

Concomitant immunosuppressive therapy

In psoriasis studies, the safety and efficacy of STELARA in combination with immunosuppressants,

including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant

MTX use did not appear to influence the safety or efficacy of STELARA. In Crohn's disease studies,

concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or

efficacy of STELARA. Caution should be exercised when considering concomitant use of other

immunosuppressants and STELARA or when transitioning from other immunosuppressive biologics (see

section 4.5).

Immunotherapy

STELARA has not been evaluated in patients who have undergone allergy immunotherapy. It is not

known whether STELARA may affect allergy immunotherapy.

Serious skin conditions

In patients with psoriasis, exfoliative dermatitis has been reported following ustekinumab treatment (see

section 4.8). Patients with plaque psoriasis may develop erythrodermic psoriasis, with symptoms that may

be clinically indistinguishable from exfoliative dermatitis, as part of the natural course of their disease. As

part of the monitoring of the patient's psoriasis, physicians should be alert for symptoms of erythrodermic

psoriasis or exfoliative dermatitis. If these symptoms occur, appropriate therapy should be instituted.

STELARA should be discontinued if a drug reaction is suspected.

Special populations

Elderly (≥ 65 years)

No overall differences in efficacy or safety in patients age 65 and older who received STELARA were

observed compared to younger patients, however the number of patients aged 65 and older is not

sufficient to determine whether they respond differently from younger patients. Because there is a higher

incidence of infections in the elderly population in general, caution should be used in treating the elderly.

4.5 Interaction with other medicinal products and other forms of interaction

Live vaccines should not be given concurrently with STELARA (see section 4.4).

No interaction studies have been performed in humans. In the population pharmacokinetic analyses of the

phase III studies, the effect of the most frequently used concomitant medicinal products in patients with

psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine)

on pharmacokinetics of ustekinumab was explored. There were no indications of an interaction with these

concomitantly administered medicinal products. The basis for this analysis was that at least 100 patients

(> 5% of the studied population) were treated concomitantly with these medicinal products for at least

90% of the study period. The pharmacokinetics of ustekinumab was not impacted by concomitant use of

MTX, NSAIDs, 6-mercaptopurine, azathioprine and oral corticosteroids, or prior exposure to anti-TNFα

agents, in patients with psoriatic arthritis or Crohn's disease.

The results of an in vitro study do not suggest the need for dose adjustments in patients who are receiving

concomitant CYP450 substrates (see section 5.2).

In psoriasis studies, the safety and efficacy of STELARA in combination with immunosuppressants,

including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant

MTX use did not appear to influence the safety or efficacy of STELARA. In Crohn's disease studies,

concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or

efficacy of STELARA. (see section 4.4).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective methods of contraception during treatment and for

at least 15 weeks after treatment.

Pregnancy

There are no adequate data from the use of ustekinumab in pregnant women. Animal studies do not

indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development,

parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to

avoid the use of STELARA in pregnancy.

Breast-feeding

It is unknown whether ustekinumab is excreted in human breast milk. Animal studies have shown

excretion of ustekinumab at low levels in breast milk. It is not known if ustekinumab is absorbed

systemically after ingestion. Because of the potential for adverse reactions in nursing infants from

ustekinumab, a decision on whether to discontinue breast-feeding during treatment and up to 15 weeks

after treatment or to discontinue therapy with STELARA must be made taking into account the benefit of

breast-feeding to the child and the benefit of STELARA therapy to the woman.

Fertility

The effect of ustekinumab on human fertility has not been evaluated (see section 5.3).

4.7 Effects on ability to drive and use machines

Stelara has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions (> 5%) in controlled periods of the adult psoriasis, psoriatic arthritis

and Crohn's disease clinical studies with ustekinumab were nasopharyngitis and headache. Most were

considered to be mild and did not necessitate discontinuation of study treatment. The most serious

adverse reaction that has been reported for STELARA is serious hypersensitivity reactions including

anaphylaxis (see section 4.4). The overall safety profile was similar for patients with psoriasis, psoriatic

arthritis and Crohn's disease. No new safety concerns were identified with up to 2 years of treatment in

patients with Crohn's Disease.

Tabulated list of adverse reactions

The safety data described below reflect exposure in adults to ustekinumab in 12 phase 2 and phase 3

studies in 5,884 patients (4,135 with psoriasis and/or psoriatic arthritis and 1,749 with Crohn's disease).

This includes exposure to STELARA in the controlled and non-controlled periods of the clinical studies

for at least 6 months or 1 year (4,105 and 2,846 patients respectively with psoriasis, psoriatic arthritis or

Crohn's disease) and exposure for at least 4 or 5 years (1,482 and 838 patients with psoriasis

respectively).

Table 2 provides a list of adverse reactions from adult psoriasis, psoriatic arthritis and Crohn's disease

clinical studies as well as adverse reactions reported from post-marketing experience. The adverse

reactions are classified by System Organ Class and frequency, using the following convention: Very

common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to

< 1/1,000), Very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each

frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 List of adverse reactions

System Organ Class

Frequency: Adverse reaction

Infections and infestations

Common: Upper respiratory tract infection, nasopharyngitis

Uncommon: Cellulitis, dental infections, herpes zoster, lower

respiratory tract infection, viral upper respiratory tract infection,

vulvovaginal mycotic infection

Immune system disorders

Uncommon: Hypersensitivity reactions (including rash, urticaria)

Rare: Serious hypersensitivity reactions (including anaphylaxis,

angioedema)

Psychiatric disorders

Uncommon: Depression

Nervous system disorders

Common: Dizziness, headache

Uncommon: Facial palsy

Respiratory, thoracic and

mediastinal disorders

Common: Oropharyngeal pain

Uncommon: Nasal congestion

Gastrointestinal disorders

Common: Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue

disorders

Common: Pruritus

Uncommon: Pustular psoriasis, skin exfoliation, acne

Rare: Exfoliative dermatitis

Musculoskeletal and connective

tissue disorders

Common: Back pain, myalgia, arthralgia

General disorders and

administration site conditions

Common: Fatigue, injection site erythema, injection site pain

Uncommon: Injection site reactions (including haemorrhage,

haematoma, induration, swelling and pruritus), asthenia

Description of selected adverse reactions

Infections

In the placebo-controlled studies of patients with psoriasis, psoriatic arthritis and Crohn's disease, the

rates of infection or serious infection were similar between ustekinumab-treated patients and those treated

with placebo. In the placebo-controlled period of clinical studies of patients with psoriasis, patients with

psoriatic arthritis and patients with Crohn's disease, the rate of infection was 1.38 per patient-year of

follow-up in ustekinumab-treated patients, and 1.35 in placebo-treated patients. Serious infections

occurred at the rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (27 serious

infections in 829 patient-years of follow-up) and 0.03 in placebo-treated patients (11 serious infections in

385 patient-years of follow-up) (see section 4.4).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn's disease clinical

studies, representing 10,953 patient-years of exposure in 5,884 patients, the median follow up was 0.99

years; 3.2 years for psoriasis studies, 1.0 year for psoriatic arthritis studies and 0.6 year for Crohn's

disease studies. The rate of infection was 0.91 per patient-year of follow-up in ustekinumab-treated

patients, and the rate of serious infections was 0.02 per patient-year of follow-up in ustekinumab-treated

patients (178 serious infections in 10,953 patient-years of follow-up) and serious infections reported

included anal abscess, cellulitis, pneumonia, diverticulitis, gastroenteritis and viral infections.

In clinical studies, patients with latent tuberculosis who were concurrently treated with isoniazid did not

develop tuberculosis.

Malignancies

In the placebo-controlled period of the psoriasis, psoriatic arthritis and Crohn's disease clinical studies,

the incidence of malignancies excluding non-melanoma skin cancer was 0.12 per 100 patient-years of

follow-up for ustekinumab-treated patients (1 patient in 829 patient-years of follow-up) compared with

0.26 for placebo-treated patients (1 patient in 385 patient-years of follow-up). The incidence of non-

melanoma skin cancer was 0.48 per 100 patient-years of follow-up for ustekinumab-treated patients (4

patients in 829 patient-years of follow-up) compared to 0.52 for placebo-treated patients (2 patients in

385 patient-years of follow-up).

In the controlled and non-controlled periods of psoriasis, psoriatic arthritis and Crohn's disease clinical

studies, representing 10,935 patient-years of exposure in 5,884 patients, the median follow-up was 1.0

years; 3.2 years for psoriasis studies, 1.0 year for psoriatic arthritis studies and 0.6 year for Crohn's

disease studies. Malignancies excluding non-melanoma skin cancers were reported in 58 patients in

10,935 patient-years of follow-up (incidence of 0.53 per 100 patient-years of follow-up for ustekinumab-

treated patients). The incidence of malignancies reported in ustekinumab-treated patients was comparable

to the incidence expected in the general population (standardised incidence ratio = 0.87 [95% confidence

interval: 0.66, 1.14], adjusted for age, gender and race). The most frequently observed malignancies, other

than non-melanoma skin cancer, were prostate, melanoma, colorectal and breast cancers. The incidence of

non-melanoma skin cancer was 0.49 per 100 patient-years of follow-up for ustekinumab-treated patients

(53 patients in 10,919 patient-years of follow-up). The ratio of patients with basal versus squamous cell

skin cancers (4:1) is comparable with the ratio expected in the general population (see section 4.4).

Hypersensitivity and infusion reactions

In Crohn's disease induction studies, no events of anaphylaxis or other serious infusion reactions were

reported following the single intravenous dose. In these studies, 2.4% of 466 placebo treated patients and

2.6% of 470 patients treated with the recommended dose of ustekinumab reported adverse events

occurring during or within an hour of the infusion.

Immunogenicity

In psoriasis and psoriatic arthritis clinical studies less than 8% of ustekinumab-treated patients developed

antibodies to ustekinumab. In Crohn's disease clinical studies, less than 3% of patients treated with

ustekinumab developed antibodies to ustekinumab. No apparent association between the development of

antibodies to ustekinumab and the development of injection site reactions was observed. The majority of

patients who were positive for antibodies to ustekinumab had neutralizing antibodies. Efficacy tended to

be lower in patients positive for antibodies to ustekinumab; however, antibody positivity did not preclude

a clinical response.

Paediatric population

Undesirable effects in paediatric patients 12 years and older with plaque psoriasis

The safety of ustekinumab has been studied in a phase 3 study of 110 patients from 12 to 17 years of age

for up to 60 weeks. In this study, the adverse events reported were similar to those seen in previous

studies in adults with plaque psoriasis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple

App Store.

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: [email

protected]

4.9 Overdose

Single doses up to 6 mg/kg have been administered intravenously in clinical studies without dose-limiting

toxicity. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms

of adverse reactions and appropriate symptomatic treatment be instituted immediately.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC05.

Mechanism of action

Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared p40

protein subunit of human cytokines interleukin (IL)-12 and IL-23. Ustekinumab inhibits the bioactivity of

human IL-12 and IL-23 by preventing p40 from binding to the IL-12Rβ1 receptor protein expressed on

the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that is already bound to IL-

12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute to complement- or antibody-

mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and IL-23 are heterodimeric

cytokines secreted by activated antigen presenting cells, such as macrophages and dendritic cells, and

both cytokines participate in immune functions; IL-12 stimulates natural killer (NK) cells and drives the

differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype, IL-23 induces the T helper 17

(Th17) pathway. However, abnormal regulation of IL 12 and IL 23 has been associated with immune

mediated diseases, such as psoriasis, psoriatic arthritis and Crohn's disease.

By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in

psoriasis, psoriatic arthritis and Crohn's disease through interruption of the Th1 and Th17 cytokine

pathways, which are central to the pathology of these diseases.

In patients with Crohn's disease, treatment with ustekinumab resulted in a decrease in inflammatory

markers including C-Reactive Protein (CRP) and fecal calprotectin during the induction phase, which

were then maintained throughout the maintenance phase.

Immunisation

During the long term extension of Psoriasis Study 2 (PHOENIX 2), adult patients treated with STELARA

for at least 3.5 years mounted similar antibody responses to both pneumococcal polysaccharide and

tetanus vaccines as a non-systemically treated psoriasis control group. Similar proportions of adult

patients developed protective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titers

were similar among STELARA-treated and control patients.

Clinical efficacy

Crohn's Disease

The safety and efficacy of ustekinumab was assessed in three randomized, double-blind, placebo-

controlled, multicenter studies in adult patients with moderately to severely active Crohn's disease

(Crohn's Disease Activity Index [CDAI] score of ≥ 220 and ≤ 450). The clinical development program

consisted of two 8-week intravenous induction studies (UNITI-1 and UNITI-2) followed by a 44 week

subcutaneous randomized withdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy.

The induction studies included 1409 (UNITI-1, n = 769; UNITI-2 n = 640) patients. The primary

endpoint for both induction studies was the proportion of subjects in clinical response (defined as a

reduction in CDAI score of ≥ 100 points) at week 6. Efficacy data were collected and analyzed through

week 8 for both studies. Concomitant doses of oral corticosteroids, immunomodulators, aminosalicylates

and antibiotics were permitted and 75% of patients continued to receive at least one of these medications.

In both studies, patients were randomised to receive a single intravenous administration of either the

recommended tiered dose of approximately 6 mg/kg (see Table 1, section 4.2), a fixed dose of 130 mg

ustekinumab, or placebo at week 0.

Patients in UNITI-1 had failed or were intolerant to prior anti-TNFα therapy. Approximately 48% of the

patients had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies. In this

study, 29.1% of the patients had an inadequate initial response (primary non-responders), 69.4%

responded but lost response (secondary non-responders), and 36.4% were intolerant to anti-TNFα

therapies.

Patients in UNITI-2 had failed at least one conventional therapy, including corticosteroids or

immunomodulators, and were either anti-TNF-α naïve (68.6%) or had previously received but not failed

anti-TNFα therapy (31.4%).

In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical response and

remission in the ustekinumab treated group compared to placebo (Table 3). Clinical response and

remission were significant as early as week 3 in ustekinumab treated patients and continued to improve

through week 8. In these induction studies, efficacy was higher and better sustained in the tiered dose

group compared to the 130 mg dose group, and tiered dosing is therefore the recommended intravenous

induction dose.

Table 3: Induction of Clinical Response and Remission in UNITI-1 and UNITI 2

UNITI-1*

UNITI-2**

Placebo

Recommended

dose of

ustekinumab

Placebo

Recommended

dose of

ustekinumab

N = 247

N = 249

N = 209

N = 209

Clinical Remission, week 8

18 (7.3%)

52 (20.9%)

41 (19.6%)

84 (40.2%)

Clinical Response (100 point), week 6

53 (21.5%)

84 (33.7%)

60 (28.7%)

116 (55.5%)

Clinical Response (100 point), week 8

50 (20.2%)

94 (37.8%)

67 (32.1%)

121 (57.9%)

70 Point Response, week 3

67 (27.1%)

101 (40.6%)

66 (31.6%)

106 (50.7%)

70 Point Response, week 6

75 (30.4%)

109 (43.8%)

81 (38.8%)

135 (64.6%)

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI

score by at least 100 points or being in clinical remission

70 point response is defined as reduction in CDAI score by at least 70 points

* Anti-TNFα failures

** Conventional therapy failures

p < 0.001

p < 0.01

The maintenance study (IM-UNITI), evaluated 388 patients who achieved 100 point clinical response at

week 8 of induction with ustekinumab in studies UNITI-1 and UNITI-2. Patients were randomized to

receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mg

ustekinumab every 12 weeks or placebo for 44 weeks (for recommended maintenance posology, see

section 4.2 of the STELARA Solution for injection (vial) and Solution for injection in pre filled syringe

SmPC).

Significantly higher proportions of patients maintained clinical remission and response in the

ustekinumab treated groups compared to the placebo group at week 44 (see Table 4).

Table 4: Maintenance of Clinical Response and Remission in IM-UNITI (week 44; 52 weeks from

initiation of the induction dose)

Placebo*

N = 131

90 mg

ustekinumab

every 8 weeks

N = 128

90 mg

ustekinumab

every 12 weeks

N = 129

Clinical Remission

Clinical Response

Corticosteroid-Free Clinical Remission

Clinical Remission in patients:

in remission at the start of maintenance therapy

46% (36/79)

67% (52/78)

56% (44/78)

who entered from study CRD3002

44% (31/70)

63% (45/72)

57% (41/72)

who are Anti-TNFα naïve

49% (25/51)

65% (34/52)

57% (30/53)

who entered from study CRD3001

26% (16/61)

41% (23/56)

39% (22/57)

Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at

least 100 points or being in clinical remission

* The placebo group consisted of patients who were in response to ustekinumab and were randomized to

receive placebo at the start of maintenance therapy.

† Patients who were in 100 point clinical response to ustekinumab at start of maintenance therapy

Patients who failed conventional therapy but not anti-TNFα therapy

Patients who are anti-TNFα refractory/intolerant

p < 0.01

p < 0.05

nominally significant (p < 0.05)

In IM-UNITI, 29 of 129 patients did not maintain response to ustekinumab when treated every 12 weeks

and were allowed to dose adjust to receive ustekinumab every 8 weeks. Loss of response was defined as a

CDAI score ≥ 220 points and a ≥ 100 point increase from the CDAI score at baseline. In these patients,

clinical remission was achieved in 41.4% of patients 16 weeks after dose adjustment.

Patients who were not in clinical response to ustekinumab induction at week 8 of the UNITI-1 and

UNITI-2 induction studies (476 patients) entered into the non-randomized portion of the maintenance

study (IM-UNITI) and received a 90 mg subcutaneous injection of ustekinumab at that time. Eight weeks

later, 50.5% of the patients achieved clinical response and continued to receive maintenance dosing every

8 weeks; among these patients with continued maintenance dosing, a majority maintained response

(68.1%) and achieved remission (50.2%) at week 44, at proportions that were similar to the patients who

initially responded to ustekinumab induction.

Of 131 patients who responded to ustekinumab induction, and were randomized to the placebo group at

the start of the maintenance study, 51 subsequently lost response and received 90 mg ustekinumab

subcutaneously every 8 weeks. The majority of patients who lost response and resumed ustekinumab did

so within 24 weeks of the induction infusion. Of these 51 patients, 70.6% achieved clinical response and

39.2% percent achieved clinical remission 16 weeks after receiving the first subcutaneous dose of

ustekinumab.

In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a

study extension. Among patients who entered the study extension, clinical remission and response were

generally maintained through week 92 for both patients who failed TNF-therapies and those who failed

conventional therapies.

Endoscopy

Endoscopic appearance of the mucosa was evaluated in 252 patients with eligible baseline endoscopic

disease activity in a substudy. The primary endpoint was change from baseline in Simplified Endoscopic

Disease Severity Score for Crohn's Disease (SES-CD), a composite score across 5 ileo-colonic segments

of presence/size of ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface

affected by any other lesions and presence/type of narrowing/strictures. At week 8, after a single

intravenous induction dose, the change in SES-CD score was greater in the ustekinumab group (n = 155,

mean change = -2.8) than in the placebo group (n = 97, mean change = -0.7, p = 0.012).

Fistula Response

In a subgroup of patients with draining fistulas at baseline (8.8%; n = 26), 12/15 (80%) of ustekinumab-

treated patients achieved a fistula response over 44 weeks (defined as ≥ 50% reduction from baseline of

the induction study in the number of draining fistulas) compared to 5/11 (45.5%) exposed to placebo.

Health-related quality of life

Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ) and

SF-36 questionnaires. At week 8, patients receiving ustekinumab showed statistically significantly greater

and clinically meaningful improvements on IBDQ total score and SF-36 Mental Component Summary

Score in both UNITI-1 and UNITI-2, and SF-36 Physical Component Summary Score in UNITI-2, when

compared to placebo. These improvements were generally better maintained in ustekinumab-treated

patients in the IM-UNITI study through week 44 when compared to placebo. Improvement in health-

related quality of life was generally maintained during the extension through week 92.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with

ustekinumab in one or more subsets of the paediatric population in Crohn's Disease (see section 4.2 for

information on paediatric use).

5.2 Pharmacokinetic properties

In patients with Crohn's disease, following the recommended intravenous induction dose, median peak

serum ustekinumab concentration, observed 1 hour after the infusion, was 126.1 μg/mL.

Distribution

Median volume of distribution during the terminal phase (Vz) following a single intravenous

administration to patients with psoriasis ranged from 57 to 83 mL/kg.

Biotransformation

The exact metabolic pathway for ustekinumab is unknown.

Elimination

Median systemic clearance (CL) following a single intravenous administration to patients with psoriasis

ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t

) of ustekinumab was approximately 3 weeks

in patients with Crohn's disease, psoriasis and/or psoriatic arthritis, ranging from 15 to 32 days across all

psoriasis and psoriatic arthritis studies.

Dose linearity

The systemic exposure of ustekinumab (C

and AUC) increased in an approximately dose-proportional

manner after a single intravenous administration at doses ranging from 0.09 mg/kg to 4.5 mg/kg.

Special populations

No pharmacokinetic data are available in patients with impaired renal or hepatic function.

No specific studies have been conducted with intravenous ustekinumab in elderly or paediatric patients.

In patients with Crohn's disease, variability in ustekinumab CL was affected by body weight, serum

albumin level, CRP, TNF antagonist failure status, sex, race (Asian versus non-Asian), and antibody to

ustekinumab status while body weight was the main covariate affecting the volume of distribution.

Concomitant use of immunomodulators did not have a significant impact on ustekinumab disposition.

The impact of these statistically significant covariates on the respective PK parameters was within ± 20%

when evaluated across a representative range of covariate values or categories in the data which is within

the overall variability observed in the PK of ustekinumab.

Regulation of CYP450 enzymes

The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study

using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter

human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4; see section 4.5).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard (e.g. organ toxicity) for humans based on studies of repeated-

dose toxicity and developmental and reproductive toxicity, including safety pharmacology evaluations. In

developmental and reproductive toxicity studies in cynomolgus monkeys, neither adverse effects on male

fertility indices nor birth defects or developmental toxicity were observed. No adverse effects on female

fertility indices were observed using an analogous antibody to IL-12/23 in mice.

Dose levels in animal studies were up to approximately 45-fold higher than the highest equivalent dose

intended to be administered to psoriasis patients and resulted in peak serum concentrations in monkeys

that were more than 100-fold higher than observed in humans.

Carcinogenicity studies were not performed with ustekinumab due to the lack of appropriate models for

an antibody with no cross-reactivity to rodent IL-12/23 p40.

6. Pharmaceutical particulars

6.1 List of excipients

EDTA disodium salt dihydrate

L-histidine

L-histidine monohydrochloride monohydrate

L-methionine

Polysorbate 80

Sucrose

Water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal

products. Stelara should only be diluted with sodium chloride 9 mg/mL (0.9%) solution. STELARA

should not be administered concomitantly in the same intravenous line with other medicinal products.

6.3 Shelf life

3 years.

Do not freeze.

Chemical and physical in-use stability has been demonstrated for 8 hours at 15-25°C.

From a microbiological point of view, unless the method of dilution precludes the risk of microbial

contamination, the product should be used immediately. If not used immediately, in-use storage times and

conditions are the responsibility of user.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3

6.5 Nature and contents of container

26 mL solution in a type I glass 30 mL vial closed with a coated butyl rubber stopper. STELARA is

available in a 1 vial pack.

6.6 Special precautions for disposal and other handling

The solution in the STELARA vial should not be shaken. The solution should be visually inspected for

particulate matter or discoloration prior to administration. The solution is clear, colourless to light yellow.

The medicinal product should not be used if the solution is discoloured or cloudy, or if foreign particulate

matter is present.

Dilution

STELARA concentrate for solution for infusion must be diluted and prepared by a healthcare professional

using aseptic technique.

1. Calculate the dose and the number of STELARA vials needed based on patient weight (see section 4.2,

Table 1). Each 26 mL vial of STELARA contains 130 mg of ustekinumab. Only use complete vials of

Stelara.

2. Withdraw and discard a volume of the sodium chloride 9 mg/mL (0.9%) solution from the 250 mL

infusion bag equal to the volume of STELARA to be added. (discard 26 mL sodium chloride for each vial

of STELARA needed, for 2 vials-discard 52 mL, for 3 vials- discard 78 mL, for 4 vials- discard 104 mL)

3. Withdraw 26 mL of STELARA from each vial needed and add it to the 250 mL infusion bag. The final

volume in the infusion bag should be 250 mL. Gently mix.

4. Visually inspect the diluted solution before administration. Do not use if visibly opaque particles,

discoloration or foreign particles are observed.

5. Administer the diluted solution over a period of at least one hour. Once diluted, the infusion should be

completed within eight hours of the dilution in the infusion bag.

6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2

micrometer).

7. Each vial is for single use only and any unused medicinal product should be disposed of in accordance

with local requirements.

7. Marketing authorisation holder

Janssen-Cilag International NV

Turnhoutseweg 30

2340 Beerse

Belgium

8. Marketing authorisation number(s)

EU/1/08/494/005

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 16 January 2009

Date of latest renewal: 19 September 2013

10. Date of revision of the text

21 February 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/

Company Contact Details

Janssen-Cilag Ltd

Address

50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG

Telephone

+44 (0)1494 567 567

Medical Information Direct Line

+44 (0)800 731 8450

Customer Care direct line

+44 (0)800 731 5550

http://www.janssen-cilag.co.uk

+44 (0)1494 567 568

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0) 1494 567 445

Similar products

Search alerts related to this product

View documents history

Share this information