BREXIN SACHETS

םיחקורה תונקתיפלןכרצלןולע ( םירישכת ) משתה " ו - 1986

ע עבקנהזןולעטמרופ " רשואו קדבנונכותותואירבה דרשמ י

אפור םשרמב תבייחוז הפורת

ארק / שמתשת םרטב ופוסדע ןולעהתאןויעב י / הפורתב י

ןיסקרב , היתשלהסימתתנכהל הקבא

םיקיקש

בכרה :

לכ קיקש ליכמ Piroxicam (as Beta-Cyclodextrin) 20mg

יתלב םירמוח םיליעפ :

Sorbitol, Citrus flavor, Aspartame,Silica, colloidal arhydrous.

ליכמ קיקשלכ :

מ " ןינלאלינפג .

ק תיטיופרת הצוב :

םידיאורטס םניאש תקלד ידגונ ( NSAIDs .)

תיאופר תוליעפ :

באכ דגונויתקלד יטנא רישכת תויטמואר תולחממ םיעבונהםימוטפמיס תלקהל , באכ ןוגכ , תוחיפנ

וישקו ן םיקרפמ .

רישכתב שמתשהלןיאיתמ ?

וןוירהב ךניהרשאכ הפורתב ישמתשת לא / הקינמ וא .

הפורתב שמתשהלןיא הפורתהיביכרממ דחאלתושיגר ךלהעודיםא .

הפורתב שמתשהלןיא ןיריפסאלתושיגר העודיםא , תרחא הפורת לכ וא םיטליצילס

םידיאורטס םניאש תקלד ידגונתחפשממ NSAIDs) .)

לטונךנהםא שמתשהלןיא / התחפשממתורחא תופורת ת NSAID ( התצובקמ ללוכ -

cox-2 תיליצילס ליטצא הצמוחו - ןיריפסא ).

לבוס ךניהםא הפורתב שמתשהלןיא / ת , תכרעמב הלחמ וא ילוכיעביכמ רבעב תלבס וא

לוכיעה ( ןוגכ : ורק ה נ ' ס , יעמב ןטרס ). לבוס ךנהםא / תכרעמב םימומידמ תלבס וא ת

לוכיעה .

לבוס ךניהםא וז הפורתב שמתשהלןיא / הרומחבלתקיפסיא וא תוילכתלחממ ת .

תופורת לטונךניהםא הפורתב שמתשהלןיא םד תשירק דגנ ( ןידמוק ).

ליג לעמךנהרשאכ 80 .

לופיטהתלחתהינפלאפורב ץעווהלילבמהפורתב שמתשהלןיא :

לבוס ךניהםא / דוקפיתב יוקילמרבעב תלבס וא ת : המישנהתכרעמ ( המטסאןוגכ ) , ובלה / ילכוא

םד ( םד ץחלרתי ) , דבכה , הילכה / ןתשהתכרעמ , לוכיעהתכרעמ ( סוקלוא ןוגכ ) , םדהתכרעמ ( ןוגכ

םד תשירק תויעב , הימנא ) , גוסמ תפורתב וא ןיריפסאב שומישמ האצותכ ףאב םיפילופ NSAIDs ,

םיחלמתכירצב הלבגה .

םישישקב שומישב םירבגומ תוריהזיעצמאטוקנלשי .

ךלשםוי םויהייחלעהפורתה עיפשתךיא ?

בכרב הגיהנב תוריהזבייחמןכ לעותונרעבםוגפללולעוז הפורתב שומישה , תונכוסמ תונוכמ תלעפהב

תונריעתבייחמהתוליעפלכבו . ליג לעמםירגבתמ 12 , םיקחשממ וא םיינפוא לעהביכרמ םריהזהלשי

המודכושיבכהתברקב .

תונייתותשלןיא הפורתהםעלופיטהתפוקתב םיפירחתואקשמ וא .

שמשלהפישח םעתדחוימ תושיגרלםורגלהלולעוז הפורת ( שמש ימתכ לש תרבגומ תורצוויהלו ) :

לע - המיאתמהנגהלגואדלושמשלהפישחמענמהלשיןכ ( םיכורא םידגב , עבוכ , הנגהתוחשמ , וכו ') .

תונייתייתש ןוכיסהתאריבגהלהלולעהפורתהםעלופיטהתפוקתב םיפירחתואקשמ וא

לוכיעהתכרעמב ביכ תורצוויהל . ךרוצ ךנהםא / שיםויב הלעמוםיילוהוכלאתואקשמ השולש ת

שומישה ינפלאפורב ץעוויהל .

תורהזא :

תואבהתוקידבהתאךורעלשיוז הפורתב ךשוממ לופיט ךלהמב : םד , ידוקפת דבכוהילכ , םייניע .

שיגר ךניהםא / יהשלכ הפורתלוא והשלכ ןוזמלה , לעעידוהלךילע - הפורתהתליטנינפלאפורלךכ .

הפורתהתליטנלעאפורלחוודלךילע , דמועךניהםא / חותינרובעלת ( ילטנד ללוכ ) .

דמועךניהםא אפורלחוודלךילע / עירפהללולעלופיטהורחאמ תויתדבעמ תוקידב רובעלת

הקידבהתואצותל .

תרכוס ילוחב , תובורק םיתיעלםדב םירכוס תומר קודבלץלמומ .

קיתממכםייטרפסא הליכמ הפורתה , הירונוטקלינפלש הרקמבשמתשהלןיא ןכל .

ליג לעמםילוחב 70 תופסונתומיוסמ תופורתב םילפוטמה ( םידיאורטסוקיטרוק , לופיטלתופורת

התחפשממןואכידב - SSRI ) הביקהתנגהלתפסונהפורתב שומיש לעץילמיאפורהוןכתי

םייעמהו .

תויתפורת ןיב תובוגת :

לטונךניהםא / תפסונהפורת ת , תרחא הפורתב לופיטההתעהז תרמגםא וא אללתופורת ללוכ

םשרמ , ןיב תובוגתמםיעבונהתוליעייא וא םינוכיס עונמלידכ לפטמהאפורלחוודלךילע

תויתפורת , תואבהתוצובקהמ תופורת יבגלדחוימב : םד תשירק דגנתופורת , תונתשמ תופורת ,

פסא י ןיר , םידיאורטס םניאש תקלד ידגונוא םיטליצילס ( NSAIDs ) , םויתיל ( דל י ןואכ ) , תופורת

בללוםד ץחלתדרוהל ( ימסוחןוגכ 

לולונרפורפ ) , דיצנבורפ ( תואגתלחמל ) , טסקרטותמ ( לופיטל

סיסאירוספוןטרסב ) , הארוא לינופלוס תצובקמ תרכוסלתופורת , ןירופסולקיצ ( תולתשהל ) ,

ןיאוטינפ ( היספליפאל ) , צובקמתוקיטויבטנא ו ת םינולוניוקה , וםידיזוקילגונימא םידימאנופלוס ,

ןיסקוגיד ( בלבבצק תוערפהל ) , התצובקמ תופורת - SSRIs ( ןואכידל ) , םידיאורטסוקיטרוק .

יאוולתועפות :

הפורתהלש היוצרה תוליעפלףסונב , ןוגכיאוולתועפשה עיפוהלתולולע הב שומישה ןמזב :

תוריצע , תוליחב / תואקה , םונמנ , שאר באכ , תרוחרחס , הלק תברצ , לקןטב באכ , שמשלתושיגר .

האר / ב י " ךלשםויםויהייחלעהפורתהעיפשתךיא " ).

לוכיעהתכרעמב תועפותהתאתיחפהלתנמ לעלופיטהךלהמב הצמוחירתוסב שמתשהלןתינ .

אפורב ץעוויהלשיתורימחמ ולאתועפותוהדימב .

תדחוימ תוסחייתה תובייחמה תועפות :

םוח , הפירחתברצ , םינפהלש תקצב , םייתפש , םיידיוא םילגר , הביק ביכ , םיפירחןטב יבאכ ,

הזחב םיצחל , רתיתושיגר ( רועביוריג וא החירפ , םושנלישוקוא המישנרצוק , ביבסמ תוחיפנ

םיינעה , םינפבתוחיפנ ) , םינזואב םילוצליצ , תימד וא הרוחש האוצ , תימד האקה , ללחמ םימומיד

ףאה , ןתש ןתמב הדיריוא םיישק , הפב םיעצפ , היארב וא העימשב הדירי , ( רידנ ) : קספה / לופיטהי

הנפו / י אפורל .

שיגרמ ךניהובש הרקמ לכב / הזןולעב ונייוצ אלש יאוולתועפות ה , ךתשגרהב יוניש לחםא וא

דימ אפורהםעץעייתהלךילעתיללכה .

ןונימ :

דבלב אפורהתוארוהיפל , ץלמומהןונימהלערובעלןיא .

לתצלמומ הניאוז הפורת ו תוקונית םידלי .

שומישה ןפוא :

תומכהמ יצח קוידב ךורצל ןתינש ןפואב וזכרמב קלוחמקיקשה .

םימסוכ יצחב קיקשהןכותמ יצח וא קיקשהןכות תאסימהלשיאפורהתויחנהלםאתהב . בברעל

דימ תותשלוהסמהל .

ענמ / הלערה י !

וםידלילש םדיגשיהלץוחמרוגסםוקמב רומשלשיתרחא הפורת לכווז הפורת / לעותוקונית וא -

הלערהענמת ךכידי .

הפורתהןמ דליעלבתועטב םא וא רתיתנמ תלטנםא , הנפ / תיב לש ןוימ רדחלדימ י - םילוח ,

אבהו / ךתיא הפורתהתזירא י .

םורגתלא / האקהלי אפורמ תשרופמהארוהאלל !

ךתלחמב לופיטלהמשרנוז הפורת , רחא הלוחב / ת , קיזהלהלולעאיה . ןתת לא / וז הפורת י

ךיבורקל , ךירכמוא ךינכש .

ךשוחבתופורת לוטילןיא ! קודב / הנמהותיוותהי םעפלכב לטונךניהש / הפורת ת . בכרה / י

קוקז ךניהםא םייפקשמ / םהלה .

הנסחא :

לעהלועהניאש הרוטרפמטב ןסחאלשי 25ºC .

הזיראהיאנת יפלםג / םיצלמומההנסחא , דבלב תלבגומ הפוקתלתורמשנתופורת . בלםישל אנ

רישכתהלש הגופתהךיראתל ! קפס לש הרקמ לכב , הפורתהתאךלקפיסש חקורב ץעוויהלךילע .

הזירא התואב תונוש תופורת ןסחאלןיא .

סמ ' םושיר הפורתה : 136.62.29696

ןרצי : Chiesi Farmaceutici S.p.A., Parma, Italy

םושירה לעב : עבלנוישנרטניא ורת " מ , ת . ד 10347 הפיחץרפמ , 26110

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT:

BREXIN TABLETS

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION:

Tablets

Each tablet contains:

piroxicam β-cyclodextrin 191.2 mg, (equivalent to piroxicam 20 mg).

Excipient with known effect: lactose monohydrate, sodium

3.

PHARMACEUTICAL FORM

Tablets

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Piroxicam

indicated

symptomatic

relief

osteoarthritis

rheumatoid

arthritis or ankylosing spondylitis. When an NSAID is indicated piroxicam

should

considered

second

line

option.

decision

prescribe

piroxicam should be based on an assessment of the individual's patient overall

risk.

4.2

Posology and method of administration

Posology

The prescription of piroxicam should be initiated by physicians with experience

in the diagnostic evaluation and treatment of patients with inflammatory or

degenerative rheumatic diseases.

The maximum recommended daily dose is 20 mg.

Undesirable effects may be minimised by using the minimum effective dose for

the shortest duration necessary to control symptoms. The benefit and tolerability

of treatment should be reviewed within 14 days. If continued treatment is

considered necessary, this should be accompanied by frequent review.

Given that piroxicam has been shown to be associated with an increased risk of

gastrointestinal complications, the possible need for combination therapy with

gastro-protective agents (e.g. misoprostol or proton pump inhibitors) should be

carefully considered, in particular for elderly patients.

Paediatric population

Dosage and indications in children have not been established yet.

Elderly

In elderly patients, posology must be carefully established by the physician who

will have to consider a possible reduction of the dosage indicated above.

Method of administration

BREXIN should be administered once daily.

Brexin - SmPC final-03.2020

Tablets

1 tablet per day. Tablets are for oral use. The score line is intended to ease the

splitting and swallowing of the tablet and not to divide it into equal parts. To

divide the tablet, put it on a flat surface with the score upwards. Press gently

with your thumb to break the tablet into equal parts.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in

section 6.1.

History of gastrointestinal ulceration, bleeding or perforation.

Patient history of gastrointestinal disorders that predispose to bleeding disorders

such

ulcerative

colitis,

Crohn’s

disease,

gastrointestinal

cancer

diverticulitis.

Patients with active peptic ulcer, inflammatory gastrointestinal disorders or

gastrointestinal bleeding. Patients with gastritis, dyspepsia, severe hepatic or

renal disorders, moderate or

severe heart failure, severe hypertension, severe

blood changes or haemorrhagic diathesis. Concomitant use of other NSAIDs,

including COX-2 selective inhibitors and acetylsalicylic acid at analgesic doses.

Concomitant use of anticoagulants. History of previous severe allergic drug

reactions of any type, especially skin reactions such as erythema multiforme,

Stevens-Johnson syndrome, toxic epidermal necrolysis. Previous skin reactions

(regardless of severity) to piroxicam, other NSAIDs and other medications.

For known or suspected pregnancy, during lactation or the use in children (refer

to section 4.6).

There is a potential for cross-sensitivity with acetylsalicylic acid and other non-

steroidal anti-inflammatory drugs. This product should not be given to patients in

whom acetylsalicylic acid or other non-steroidal anti-inflammatory drugs have

induced symptoms of asthma, rhinitis, nasal polyposis, angioedema, urticaria.

4.4

Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the

shortest duration necessary to control symptoms.

The clinical benefit and tolerability of the treatment should be re-evaluated

periodically and treatment should be immediately discontinued at the first

appearance of skin reactions or significant gastrointestinal events.

Gastrointestinal (GI) effects, risk of gastrointestinal ulceration, bleeding, and

perforation.

NSAIDs,

including

piroxicam,

cause

serious

gastrointestinal

events

including bleeding, ulceration, and perforation of the stomach, small intestine or

colon, which can be fatal. These serious adverse events can occur at any time,

with or without warning symptoms, in patients treated with NSAIDs.

NSAID exposure of both short and long duration carries an increased risk of

severe gastrointestinal events. Evidence from observational studies suggests

that, compared to other NSAIDs, piroxicam may be associated with a high risk

of severe gastrointestinal toxicity.

Patients with significant risk factors for severe GI events should be treated with

piroxicam only after careful consideration (See below and section 4.3).

Brexin - SmPC final-03.2020

The possible need for combination therapy with gastro-protective agents (e.g.

misoprostol or proton pump inhibitors) should be carefully considered (see

section 4.2).

Severe gastrointestinal complications

Identification of at-risk subjects

The risk for developing serious gastrointestinal complications increases with

age. Being aged over 70 years is associated with a high risk of complications.

Administration to patients older than 80 years should be avoided.

Patients taking concomitant oral corticosteroids, selective serotonin reuptake

inhibitors (SSRIs), anticoagulants such as warfarin or platelet anti-aggregate

agents such as low-dose acetylsalicylic acid are at increased risk of severe

gastrointestinal

complications

(see

below

section

4.5).

with

other

NSAIDs, the use of piroxicam in combination with gastro-protectants agents

(e.g. misoprostol or proton pump inhibitors) must be considered for these at-risk

patients.

Patients

physicians

should

alert

signs

symptoms

gastrointestinal ulceration and/or bleeding during piroxicam treatment. Patients

should be asked to report any new or unusual abdominal symptom during

treatment.

If a

gastrointestinal complication is suspected during treatment,

piroxicam

should

discontinued

immediately

additional

clinical

evaluation and alternative treatment should be considered.

Cardiovascular and cerebrovascular effects

Suitable monitoring and instructions are necessary in patients with positive

anamnesis for hypertension and/or congestive heart failure, as water retention

and oedema have been reported in association with NSAIDs treatment.

Clinical studies and epidemiological data indicate that the use of some NSAIDs

(especially at high doses and for long-term treatment) may be associated with a

moderate increased risk of arterial thrombotic events (e.g. myocardial infarction

or stroke). There are not enough data to exclude such a risk for piroxicam.

Patients with uncontrolled hypertension, congestive heart failure, established

ischaemic

heart

disease,

peripheral

arterial

disease

and/or

cerebrovascular

disease should be treated with piroxicam only after careful evaluation. Similar

considerations should be made before starting long-term treatment in patients

with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia,

diabetes mellitus, smoking).

Piroxicam,

like

other

NSAIDs,

reduces

platelet

aggregation

prolongs

bleeding time; this characteristic must be taken into account when blood tests

are performed and when the patient is concomitantly treated with other platelet

aggregation inhibitors.

Patients with impaired renal function should be periodically monitored, as in

such patients the inhibition of prostaglandin synthesis caused by piroxicam may

result in a severe decrease in renal perfusion that may lead to acute renal failure.

In this regard, elderly patients and patients treated with diuretics should be

considered as at risk.

Dehydrated patients are at risk for impairment of renal function.

Brexin - SmPC final-03.2020

Caution should also be paid in patients with impaired hepatic function. It is

advisable

periodically

monitor

their

clinical

laboratory

parameters,

especially in case of prolonged treatment.

Due to its interaction with arachidonic acid metabolism, the drug may induce

bronchospasms and possibly shock and other allergic phenomena in asthmatic

and predisposed patients.

As some ocular changes have been observed during therapy with NSAIDs,

periodic

ophthalmological

examinations

advised

during

prolonged

treatment.

It is also advisable to frequently check blood glucose levels in diabetic patients

prothrombin

time

patients

concomitantly

receiving

anticoagulant

treatment with dicoumarol derivatives.

Skin reactions

Evidence from observational studies suggests that piroxicam may be associated

with a higher risk of serious skin reactions than other non-oxicam NSAIDs.

In association with the use of Brexin, serious skin reactions, potentially fatal,

have

been

reported

including:

Stevens-Johnson

syndrome

(SJS)

toxic

epidermal necrolysis (TEN).

Patients should be advised and closely monitored for any signs and symptoms

of skin reactions. Patients appear to be at highest risk of appearance of SJS and

TEN during initial weeks of treatment. Treatment with BREXIN should be

discontinued at the first appearance of symptoms and signs of SJS or TEN (i.e.

progressive skin rash, often with blisters and mucosal lesions).

The best results in management of SJS and TEN are achieved with early

diagnosis and the prompt discontinuation of therapy whatever the

suspect

medication. The early discontinuation is associated with a better prognosis.

Patients developing SJS or TEN due to a therapy with BREXIN, should never

be treated with BREXIN again.

The use of piroxicam, as of any other prostaglandin synthesis and cyclo-

oxygenase

inhibitors,

recommended

women

planning

start

pregnancy.

The administration of piroxicam should be discontinued in women with fertility

problems or undergoing fertility investigations.

The tablet contains lactose: patients with rare hereditary problems of galactose

intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should

not take this drug. This medicinal product contains less than 1 mmol (23 mg) of

sodium per tablet, and is basically sodium-free.

4.5

Interactions with other medicaments and other forms of interaction

Acetylsalicylic acid or other NSAIDs

: As with other NSAIDs, the use of

piroxicam together with acetylsalicylic acid or concomitant use with other

NSAIDs, including other piroxicam formulations, must be avoided, since data

are inadequate to show that such combinations produce greater improvement

Brexin - SmPC final-03.2020

than that achieved with piroxicam alone; moreover, the potential for adverse

reactions is increased (see section 4.4).

Human

studies

have

shown

that

concomitant

piroxicam

acetylsalicylic acid reduces the plasma piroxicam concentration to about 80% of

the usual value (see section 4.3).

Piroxicam interacts with acetylsalicylic acid, with other non-steroidal anti-

inflammatory drugs and with platelet aggregate inhibitors (see sections 4.3 and

4.4).

Corticosteroids

: increased risk of gastrointestinal ulceration or bleeding (see

section 4.4).

Anticoagulants

: NSAIDs, including piroxicam, may enhance the effects of

anticoagulants,

such

warfarin.

Therefore,

piroxicam

with

anticoagulants such as warfarin should be avoided (see section 4.3).

Platelet

anti-aggregate

agents

and

selective

serotonin

reuptake

inhibitors

(SSRIs):

increased risk of gastrointestinal bleeding (see section 4.4).

Diuretics, ACE-inhibitors and angiotensin II antagonists

: NSAIDs may reduce

the efficacy of diuretics and other anti-hypertensive drugs. In some patients with

impaired

renal

function

(e.g.

dehydrated

patients

elderly

patients

with

impaired renal

function), the

co-administration of

an ACE-inhibitor

or an

angiotensin II antagonist and agents that inhibit the cyclo-oxygenase system,

may further deteriorate renal function, with possible acute renal failure, which is

generally reversible. These interactions should be taken into consideration in

patients

taking

piroxicam

together

with

ACE-inhibitors

angiotensin

antagonists.

The combination should therefore be administered with caution, especially in

elderly patients.

Patients should be adequately hydrated and renal function monitoring should be

considered after starting concomitant therapy.

In case of concomitant intake of potassium-containing drugs, or diuretics that

cause

potassium

retention,

there

additional

risk

rise

serum

potassium concentration (hyperkalemia).

Lithium

: concomitant administration of lithium and NSAIDs, causes an increase

in plasma lithium levels; therefor these levels should be monitored at the

beginning, during and after the end of treatment with Piroxicam. Piroxicam is

highly protein bound and therefore displacement of other protein bound drugs

can be. Patients receiving piroxicam with other highly protein bound drugs must

be closely monitored by the doctor, in order to adjust dosage if necessary.

Piroxicam absorption was slightly increased after cimetidine administration.

However, this increase did not prove to be clinically significant.

Alcohol intake should be avoided.

Piroxicam may reduce the efficacy of intrauterine devices.

Concomitant use of non-steroidal anti-inflammatory drugs and quinolone drugs

is not recommended.

Brexin - SmPC final-03.2020

Cyclosporin

Tacrolimus:

administration

NSAIDs

together

with

cyclosporin or tacrolimus increases the risk of nephrotoxicity.

4.6

Fertility, Pregnancy and lactation

Piroxicam is contraindicated during ascertained or suspected pregnancy, and

during breast-feeding (see section 4.3).

Fertility

The use of piroxicam may impair female fertility and is not recommended in

women trying to become pregnant. Discontinuation of therapy with piroxicam

should be envisaged for women with difficulties in conceiving or those being

investigated for fertility.

Pregnancy

Inhibition of prostaglandin synthesis can adversely affect pregnancy and/or

embryo/foetal development.

Results from epidemiological studies suggest an increased risk of miscarriage,

cardiac malformation and gastroschisis after use of a prostaglandin synthesis

inhibitor during early pregnancy. The absolute risk of cardiac malformations

increased from less than 1% up to approximately 1.5%. It was considered that

the risk is dose-related and also increases with duration of therapy.

Studies on animals have shown reproductive toxicity (see section 5.3). In

animals, the administration of prostaglandin synthesis inhibitors has been shown

to cause an increase in pre- and post-implantation losses and in embryo-foetal

mortality.

Moreover, an increased incidence of various malformations, including

cardiovascular malformation, was reported in animals given prostaglandin

synthesis inhibitors during organogenesis.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors

can expose foetuses to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and

pulmonary hypertension);

- renal dysfunction, which may progress to renal failure with oligo-

hydroamniosis;

both mother and newborn child, at the end of pregnancy to:

- possible prolongation of bleeding time and anti-aggregating effect that can

even occur with very low doses;

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Lactation

Data show that piroxicam concentration in breast milk lies between 1% and 3%

of maternal plasma concentration. Piroxicam is contraindicated during

breastfeeding because safety in newborns has not yet been established (see

section 4.3).

4.7

Effects on ability to drive and use machines

Piroxicam can alter the state of alertness to the extent of compromising the

ability to drive vehicles or perform activities requiring quick reflexes.

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4.8

Undesirable effects

Oedema, hypertension and heart failure have been reported in association with

NSAID treatment.

Clinical studies and epidemiological data suggest that the use of some NSAIDs

(especially at high doses and for long-term treatment) may be associated with a

moderate increased risk of arterial thrombotic events (e.g. myocardial infarction

or stroke) (see section 4.4).

As for other substances with similar action, some patients showed increases in

blood urea nitrogen that do not exceed a certain level with prolonged treatment;

once therapy is discontinued values return to baseline.

Undesirable side effects are listed in the table below according to System Organ

Class and to the following frequency: very common (≥ 1/10); common (≥1/100

and <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).

According to MedDRA

System Organ Class

Adverse Reaction

Frequency

Hematopoetic tissue

Anaemia

Common

Aplastic anaemia, hemolitic

anaemia, thrombocytopenia,

leucopenia, eosinophilia,

pancytopenia

Rare

Immune system disorders

Serum disease, anaphylaxis,

allergic oedema (of hands and

face)

Rare

Hypersensitivity

Not known

Metabolism and nutrition

disorders

Fluid retention,

hypoglycaemia,

hyperglycaemia, abnormal

weight gain, loss of appetite,

anorexia

Not known

Psychiatric disorders

Depression, abnormal dreams,

hallucinations, insomnia,

confusion, mood swings,

nervousness, erethism

Not known

Nervous system disorders

Headache

Common

Dizziness, sleepiness

Uncommon

Eye disorders

Blurry vision

Uncommon

Sight impairment

Rare

Ear and labyrinth disorders

Vertigo, tinnitus

Common

Ear impairment

Not known

Brexin - SmPC final-03.2020

Vascular disorders

Vasculitis, shock (warning

symptoms)

Not known

Respiratory, thoracic and

mediastinal disorders

Bronchospasm, epistaxis

Not known

Gastrointestinal disorders

Abdominal distress, abdominal

pain, constipation, diarrhoea,

epigastric pain or distress,

flatulence, nausea, vomiting,

dyspepsia

Common

Ulcerative stomatitis

Uncommon

Gastritis, gastrointestinal

bleeding, gastrointestinal

perforation, melaena,

haematemesis, peptic ulcer

pancreatitis, mouth dryness

Not known

Hepatobiliary disorders

Jaundice

Rare

Hepatitis (rare cases of fatal

hepatitis)

Not known

Skin and subcutaneous

tissue disorders

Rash, pruritus

Common

Photosensitivity reaction,

urticaria, angioneurotic

oedema, non-

thrombocytopenic purpura,

Henoch-Schonlein purpura

Rare

Severe skin adverse reactions

(SCARs): Stevens-Johnson

syndrome (SJS), toxic

epidermal necrolysis (TEN)

(see section 4.4)

Very rare

Alopecia, skin desquamation,

erythema multiforme,

ecchymosis, sweating,

abnormal nail growth

Not known

Renal and urinary disorders

Interstitial nephritis, renal

papillary necrosis, nephrotic

syndrome, renal failure

Rare

Vesicular disorder

Very rare

Haematuria, dysuria

Not known

General Disorders and

Administration Site

Conditions

Oedema

Rare

Malaise, asthenia

Not known

Investigations

Liver function test abnormal

Rare

Increased transaminase levels,

positive antinuclear antibody,

abnormal haematology test,

Not known

Brexin - SmPC final-03.2020

decreased haemoglobin,

decreased haematocrit

The most commonly observed adverse events are gastrointestinal. Peptic ulcers,

gastrointestinal perforation or bleeding, sometimes fatal, may occur, especially

in the elderly (see section 4.4).

After piroxicam administration, exacerbation of colitis and Crohn's disease have

been observed (see section 4.4).

BREXIN has the prerequisites for being better tolerated than plain piroxicam in

the gastrointestinal tract; in fact, the shorter persistence of the active ingredient

in the gastrointestinal tract reduces the risk of contact irritation.

Piroxicam

therapy

should

however

discontinued

clinical

signs

symptoms of hepatic disturbances occur.

Some cases of haematuria, dysuria, acute renal failure, water retention, which

can occur as oedema especially in the declivous regions of the lower limbs or as

cardiovascular

disturbances

(hypertension,

decompensation)

have

been

reported.

Reporting of suspected adverse reactions

Reporting suspected adverse

reactions after

authorization of the medicinal

product is important. It allows continued monitoring of the benefit/risk balance

of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health

according

National

Regulation

using

online

form

https://sideeffects.health.gov.il/

4.9

Overdose

Symptoms: the most indicative overdose symptoms are headache, vomiting,

somnolence, dizziness and syncope.

In the event of overdose, supportive and symptomatic therapy is indicated.

Although no studies have been performed so far, haemodialysis is not likely to

be useful in helping to eliminate piroxicam, as the drug is highly bound to

plasma proteins.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic

group:

non-steroidal

anti-inflammatory/anti-rheumatic

drug.

ATC code: M01AC01.

Mechanism of action

Piroxicam,

belonging

class

benzothiazine-based

N-heterocyclic

carboxyamides, is the first compound of a new class of NSAIDs, the oxicams.

Piroxicam

anti-inflammatory,

analgesic

antipyretic

activity,

pharmacological

actions

similar

those

other

non-steroidal

anti-

inflammatory drugs.

Pharmacodynamic effects

Brexin - SmPC final-03.2020

Animal

studies

showed

piroxicam

affects

cell

migration

sites

inflammation.

Like other NSAIDs, piroxicam interferes with prostaglandin

synthesis by inhibiting cyclo-oxygenase.

Unlike

indomethacin,

piroxicam

reversible

inhibitor

prostaglandin

synthesis. In a study performed on 9 patients with active rheumatoid arthritis,

piroxicam

mg/day

days)

markedly

lowered

function

polymorphonuclear

(PMN)

cells,

production

superoxide

anions

peripheral blood and in synovial fluid, and the concentration of PMN and PMN-

elastase in synovial fluid. Modulation of PMN response may contribute to the

anti-inflammatory action of piroxicam.

BREXIN is a new formulation of piroxicam where the active compound is

complexed with ß-cyclodextrin.

ß-cyclodextrin is a cyclic oligosaccharide derived from enzymatic hydrolysis of

common starch. Due to its particular chemical structure, ß-cyclodextrin can

form inclusion complexes ('molecular encapsulation') with various drugs and so

improve their solubility, stability and bioavailability.

Piroxicam-ß-cyclodextrin was found to be very soluble in water and more

rapidly absorbed than piroxicam after oral and rectal administration.

The improved solubility results in a rapid increase in plasma levels of piroxicam

and means the peak value is reached sooner, which is clinically manifested with

a quicker onset and greater intensity of the analgesic and anti-inflammatory

effect.

As regards piroxicam, the extended plasma half-life in BREXIN is unchanged,

so allowing a once-a-day administration of the product.

The pharmacodynamic and pharmacokinetic properties of BREXIN make it

suitable for the treatment of markedly painful rheumatic and/or inflammatory

diseases,

which

seriously

compromise

patient's

general

condition

normal

activity,

where

necessary

obtain

rapid

intense

therapeutic effect.

Effectiveness and clinical safety

In the carrageenan-induced footpad oedema test, BREXIN produced an anti-

inflammatory activity more quickly than piroxicam; in the first hours after

administration, in fact, BREXIN was 2-3 times more active than piroxicam by

either oral or rectal route.

The analgesic activity was assessed in mice with the phenylquinone-induced

writhing test by oral route; 5 minutes after treatment, 99% of the maximum

inhibitory effect was obtained with BREXIN and 78% was obtained with

piroxicam. The activity of both drugs remained constant for two hours after

administration.

Therapeutic

index

values

BREXIN

piroxicam

were

calculated

comparing the anti-inflammatory effects, evaluated in rats with the carrageenan-

induced footpad oedema test, with the gastro-irritant effects in the same animal

species.

BREXIN by oral route had a therapeutic index 2.65 times higher than oral

piroxicam; the therapeutic index of BREXIN by rectal route was 2.31 times

higher than BREXIN by oral route.

The improved gastrointestinal tolerability of BREXIN was confirmed in man by

means of three double-blind controlled studies, in which the presence of blood

in the faeces was assessed using the

Cr-labelled red-cell method. In all these

Brexin - SmPC final-03.2020

studies, the treatment duration was 28 days. Two studies showed a significantly

lower faecal blood loss with BREXIN towards the end of the 4-week study

period, while in the third study a similar trend was seen.

further

study,

comparison

made

gastric

tolerability

BREXIN, piroxicam, indomethacin and placebo after administration over a 14-

day period; the gastric potential difference was also assessed (max GPD).

BREXIN

produced

lesser

effects

this

parameter

than

piroxicam

indomethacin, with a positive correlation between max GPD and endoscopic

results.

Therefore, BREXIN shows a more favourable ratio between pharmacodynamic

activity and gastrotoxicity than piroxicam.

5.2

Pharmacokinetic properties

Absorption

After oral administration of BREXIN, only the active ingredient (piroxicam) is

absorbed into the circulation, and not the complex as such.

Studies

healthy

volunteers

demonstrated

that,

equivalent

doses

piroxicam (20 mg), the piroxicam plasma peak is reached much earlier with

BREXIN (within 30-60 minutes, compared to an average of 2 hours with plain

piroxicam by oral route).

Biotransformation

ß-cyclodextrin is metabolized in the colon by bacterial microflora into linear

dextrin, maltose and glucose.

Distribution and elimination

The elimination parameters, Kel and half-life, do not differ from those of

piroxicam, as complexation with ß-cyclodextrin affects only absorption kinetics

and not elimination kinetics.

Urinary excretion of the active ingredient over 72 hours, for BREXIN and for

plain piroxicam, is about 10% of the administered dose.

After oral administration of the complex, no unchanged ß-cyclodextrin was

detected in plasma or urine.

5.3

Preclinical safety data

Non-clinical data show that there are no particular risks to humans, on the

basis of conventional studies on pharmacological safety, repeated dose

toxicity, genotoxicity, carcinogenic potential and reproduction toxicity.

As for other prostaglandin synthesis inhibitors, piroxicam, too, increases the

incidence of dystocia and post-term deliveries in animals when the drug is

administered throughout pregnancy. Administration of NSAIDs to pregnant

rats may cause constriction of the foetal ductus arteriosus. Moreover, in the

last trimester of pregnancy, gastro-duodenal toxicity is increased.

Non-clinical studies showed some effects such as gastrointestinal lesions and

Brexin - SmPC final-03.2020

renal papillary necrosis, at the highest dose used, which was about 60 times

higher than the suitable dose for humans.

Such exposure to piroxicam is therefore considered sufficiently in excess of

the maximum human exposure, indicating little relevance of these effects for

the clinical use of the drug.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose monohydrate, crospovidone, sodium carboxymethyl starch, colloidal

anhydrous silica, modified starch, magnesium stearate.

6.2

Incompatibilities

None known

6.3

Expiry date

The expiry date of the product is indicated on the packaging materials.

shelf-life period mentioned above refers to the product correctly stored in its

unopened package.

6.4.

Special precautions for storage

Store below 25°C.

6.5

Nature and contents of container

PVC/PVDC laminate blisters, sealed with Al/PVDC.

Pale yellow, hexagonal tablets with deep median score

Box of 4, 10, 20 or 30 tablets 20mg

Not all pack sizes may be marketed.

6.6.

Special precautions for disposal and handling

Any unused product or waste material deriving from it should be disposed of in

accordance with local requirements.

MANUFACTURER

Chiesi Farmaceutici S.p.A., Parma, Italy

8.

MARKETING AUTHORIZATION HOLDER

Taro International Ltd – 14 Hakitor st., Haifa Bay 2624761

9.

MARKETING AUTHORIZATION NUMBER

136-61-29695-00

Updated in March 2020.

Brexin - SmPC final-03.2020