1

Patient Information Leaflet

CALGEVAX, powder for suspension

(BCG for immunotherapy)

Please read this leaflet carefully before you start taking your medicine because it contains information,
which is important for you.
- Keep this leaflet; you may need to read it again.
- If you have further questions, please ask your doctor or pharmacist.
- This medicine has been prescribed for you personally and you should not pass it on to others.
It may harm them, even if their symptoms are the same as yours.
- If you notice any adverse reactions, please, tell your doctor or pharmacist. This includes all
possible adverse reactions, which are not pointed out in this leaflet. Please, refer to item 4.

In this leaflet:
1. What CALGEVAX is and what it is used for
2. What you should know before you take CALGEVAX
3. How to take CALGEVAX
4. Possible adverse reactions
5. Storing CALGEVAX
6. Content of the pack and additional information

1. What CALGEVAX is and what it is used for

CALGEVAX is BCG specially designed for cancer immunotherapy.
 Intravesically:
- for prophylaxis of the recurrences of the superficial tumors of the bladder after transurethral
resection;
- for treatment of carcinoma in situ of the bladder.
 Percutaneously:
- in the treatment of malignant melanoma;
- for nonspecific adjuvant immunostimulating therapy of other newly emerged malignant growths
(lung, breast cancer, acute leukemia, lymphosarcoma or osteosarcoma).

2. What should be known before CALGEVAX is given

Do not administer CALGEVAX if:

- there is allergy to the active substance or any of the other ingredients of this medicine (listed in
item 6).

Warnings and preventive measures

You should consult your doctor or pharmacyst before using CALGEVAX.

CALGEVAX IS NOT ADMINISTERED:

● in case of patients with immunosuppression;
 2

● in case of patients with inherent or acquired immune insufficiency caused by a disease or an

antitumor therapy;
● in case of HIV-positive persons and patients on immunosuppression doses of steroids or other
immunosuppresants;
● in febrile conditions;
● in case of infection of the urinary tracts or massive haematuria, as well as in a parallel anti-microbe
therapy;
 in active tuberculosis; a positive tuberculin Mantoux test is a contraindication only in case of
 certified active tuberculosis infection;
 In case of ongoing or previous systemic BCG reaction (i.e. a systemic granulomatous disease,
which can be revealed after the administration of BCG; it is determined on the basis of the
following symptoms: fever 39.5С for 12 hours; fever 38.5С for 48 hours, pneumonitis,
hepatitis or another organ disfunction outside the urinary-genital tract involving a granulomatous
inflammation, which is established through biopsy, or the classical symptoms of sepsis).

NECESSARY PRECAUTIONS FOR USE:

 Patients, who have had the medicine administered intravesically, should maintain adequate
 hydration.
 The intravesical administration of CALGEVAX may result in local inflammation of the urinary
bladder, accompanied by haematuria, dysuria, pollakiuria and flu-like symptoms. Patients with a
small capacity of the bladder are exposed to a higher risk of severe local reactions.
 In case of a doubt about a systemic BCG infection after the administration of CALGEVAX, which
may proceed with a fever above 390С, persisting temperature of over 38 0С or fatigue, a prompt
 antituberculosis treatment is carried out after consulting a specialist.
 CALGEVAX contains live bacteria and should be treated as infectious material. Persons with
 immunosuppression should not handle CALGEVAX.
 The catheterization of the bladder should be performed carefully avoiding traumatization of the
mucous membrane. If the doctor, performing the treatment, decides that the catheterization is
traumatic (for example, involves bleeding), the administration of the product should be postponed
 by at least 14 days.
 In case of serious overall adverse reactions, the intervals between the separate administrations are
extended. The treatment with CALGEVAX may be terminated at the discretion of the doctor,
performing the treatment. Antituberculosis treatment is recommended in case of disseminated
BCG infection.

Children and adolescents

CALGEVAX is not recommended for children due to the absence of sufficient data about the safety
and efficiency of the product regarding children.

Other medicines and CALGEVAX:

You should inform your doctor or pharmacyst if you have taken or can possibly take other medicines.
Taking of CALGEVAX may result in an increased sensitivity towards tuberculin, which would
complicate the interpretation of the skin reaction to tuberculin in a future testing for suspected
mycobacterial infections. In this context, it is recommended to determine the patient’s reaction to
tuberculin prior to the immunotherapy with CALGEVAX.
 3

Pregnancy, lactation and fertility

Do not take this medicine without first consulting your doctor, if you are pregnant or breast-
feeding, think that you might be pregnant or plan to become pregnant.
The risk/benefit balance is assessed carefully, when the medicinal product should be administered
during pregnancy and lactation due to the absence of clinical data about its administration in these
cases. It is known that a lactating woman with a systemic BCG infection may infect her child.

Driving and using machines

The effect of CALGEVAX on the ability to drive and operate machinery has not been studied.

3. How to administer CALGEVAX

You should take this medicine as described in this leaflet or as your doctor of pharmacyst has told
you. If you are uncertain about something, ask your doctor or pharmacyst.

INTRAVESICAL ADMINISTRATION:
CALGEVAX is administered at least 14 days after the performance of a biopsy, transurethral resection
or traumatic catheterization. The application of CALGEVAX should be done using aseptic equipment
and under the control of a urologist, having experience in the administration of the product. Three or
four ampoules of the product are used for each intravesical instillation at the discretion of the urologist
performing the treatment. The content of each ampoule is reconstituted into 1 ml of sterile saline (a
solution of sodium chloride with concentration of 9 g/l), carefully shaken until obtaining a
homogeneous suspension. The mixture is drawn by syringe and then returned to the ampoule three
times in order to ensure thorough mixing, which minimizes the clumping of the mycobacteria. The
content of the ampoules is transferred in a syringe of 50 ml. A supplementary volume of sterile saline
is added bringing the total volume to 50 ml. Light reduces considerably the efficiency of
CALGEVAX. Therefore, exposure to direct daylight should be avoided both before and after
preparing the suspension. The suspension should be used immediately.
After empting the bladder, the reconstituted CALGEVAX is instilled slowly into the bladder through
urethral catheter. The product remains in the urinary bladder in the course of two hours. While the
CALGEVAX is being retained in the bladder, every 15 minutes the patient alternates the following
positions: semi-left turning, semi-right turning, left side, right side.
The standard scheme of administration includes one intravesical instillation once a week in the course
of six weeks (inducing therapy). The maintenance therapy is determined on a case-by-case basis. The
following schemes can be used: monthly administration in the course of minimum 6-12 months or
three weekly instillations at the 3rd, 6th, 12th, 18th, 24th, 30th and 36th month of the date of the first
instillation.

PERCUTANEOUS ADMINISTRATION:
Ten horizontal and ten vertical lines are made by the syringe needle on an area of 5/5 сm. The
scarification should tear only the epidermal layer without causing extensive bleeding.
A multipuncture apparatus can also be used to regulate the depth of the scarification.
The scarification spot is treated by the following 0.5-ml suspension: the content of one ampoule is
mixed with 0.5 ml of sterile saline to obtain concentration of 75 mg/ml. One ampoule is used for one
scarification. Prior to the procedure, the area should be treated with acetone after which its full
 4

evaporation should be awaited. A new area is chosen for every following scarification. The frequency
and duration of administration are determined by the doctor, performing the treatment.

4. Possible undesirable reactions:

This medicine, like most other medicines, may cause adverse reaction, although this does not apply to
all people.
Intravesical administration
 Local reactions: transitory dysuria, pollakiuria, haematuria, bacterial infection of the urinary
 tract, granulomatous prostatitis, epididymitis, orchitis.
 General reactions: malaise, increased temperature, fever, sweating, sickness, vomiting,
headache, muscle pain, abdominal colic, diffuse rash, liver toxicity, disseminated BCG
infection, generalized hypersensitivity, erythema nodosium, conjunctivitis, uveitis, vitiligo,
arthritis, leucopenia or pancytopenia, splenomegaly.
In case of intravesical administration, adverse reactions (dysuria, pollakiuria, fever) emerge 3-4 hours
after the instillation and are transitory – they last 24-72 hours. A localized (epididymistis, orchitis,
prostatitis) or a systemic BCG infection occurs more rarely.

Percutaneous administration
 Local reactions: localized itching or rash, painful ulcer at the place of administration,
 regional adenopathy.
 General reactions: fatigue, increased temperature, fever, sweating, sickness, vomiting,
headache, muscle pain, abdominal colic, diffuse rash, liver toxicity, disseminated BCG
infection, generalized hypersensitivity, erythema nodosium, conjunctivitis, uveitis, vitiligo,
arthritis, leucopenia or pancytopenia, splenomegaly.

In case of serious adverse reactions, the intervals between the separate administrations are extended.
The treatment with CALGEVAX may be terminated at the discretion of the doctor, performing the
treatment. Antituberculosis treatment is recommended in case of disseminated BCG infection.
The patient must inform his doctor of any side effects, not pointed out in the leaflet.

Reporting adverse reactions

If you notice any adverse reactions, please, tell your doctor or pharmacist. This includes all possible
adverse reactions, which are not pointed out in this leaflet. You can also report adverse reactions
directly through the National Reporting System, pointed out below:
Bulgarian Drug Agency
8, Damyan Grouev St., 1303 Sofia,
tel.: + 359 28903417, website: www.bda.bg
By reporting adverse reactions you may contribute to ensuring more information about the safety
of this medicine.

5. Storage of CALGEVAX
Store at a temperature of +2 C to +8 С.
Store in a cardboard pack in order to avoid exposure to light.
Keep out of the reach of children.
After resuspending, avoid exposure to light and administer promptly.
 5

The product should not be used beyond its expiry date, pointed out on the
pack. The product is fit for use until the last day of the month indicated.

Special measures at disposal

Unused amounts of the suspension, needles, syringes and catheters are destroyed in accordance with
the rules for disposal of infectious materials. In case of a spill, the area is cleaned by a 70% solution of
ethyl alcohol.

6. Content of the package and additional information

Content of CALGEVAX
Active substance - Mycobacterium bovis BCG (Bacillus Calmette-Guérin) 11.25 mg (37.5 mg semi-
dry bacterial mass) 1,0 -3,0 x108 viable units
Excipients: Sodium glutamate 40 mg

What CALGEVAX looks like and what the package contains

Powder for suspension
White lyophilized compact mass
The cardboard box contains four or ten ampoules and a patient leaflet.

Marketing authorization holder and manufacturer

BB-NCIPD Ltd., 1504 Sofia, 26, Y. Sakazov
Blvd. tel. +359 2 944 61 91
fax: +359 2 943 34 55 e-
mail: bulbio@bulbio.com

Date of latest approval of the leaflet: March 2015

Uputu o lijeku

CALGEVAX, prašak za suspenziju

(BCG za imunoterapiju)

Molimo pročitajte ovu uputu pažljivo prije nego što počnete uzimati lijek jer sadrži informaciju, što je važno za
vas.

- Čuvajte ovu uputu o lijeku; možda ćete morati ponovno pročitati.

- Ako imate dodatnih pitanja, obratite se svom liječniku ili ljekarniku.

- Ovaj lijek propisan je vama osobno i ne smijete ga davati drugima. Može im naškoditi, čak i ako imaju
simptome jednake Vašima.

- Ako primijetite bilo kakve negativne reakcije, molim vas, obavijestite svog liječnika ili ljekarnika. To uključuje
sve moguće nuspojave koje nisu ukazao u ovoj uputi. Molimo pogledajte stavku 4.

U ovoj uputi:

1. Što CALGEVAX i za što se koristi za

2. Što morate znati prije nego što se CALGEVAX

3. Kako uzimati CALGEVAX

4. Moguće nuspojave

5. Čuvanje CALGEVAX

6. Sadržaj pakovanja i dodatne informacije

1. Što CALGEVAX i za što se koristi za

CALGEVAX je BCG posebno dizajniran za imunoterapiju raka.

 intravezikalno:

- Za prevenciju recidiva površinskim tumora mokraćnog mjehura nakon transuretralne resekcija;

- Za liječenje karcinoma in situ mjehura.

 perkutana:

- U tretmanu malignog melanoma;

- Za nespecifično adjuvantna imunostimulirajuća terapiju ostalih novonastalih maligne izrasline (pluća, raka
dojke, akutna leukemija, limfosarkom i osteosarcoma).

2. Što treba znati prije CALGEVAX je dano

Ne primjenjivati CALGEVAX ako:

- Postoji alergija na aktivnu tvar ili bilo koji drugi sastojak ovog lijeka (navedeni u točki 6.).

Upozorenja i preventivne mjere

Te bi trebao konzultirati svog liječnika ili pharmacyst prije korištenja CALGEVAX.

CALGEVAX NIJE primijeniti:

● u slučaju bolesnika s imunosupresija;

● u slučaju pacijenata s inherentne ili stečene imune insuficijencije uzrokovanih bolesti ili liječenju tumora;

● u slučaju HIV pozitivnih osoba i bolesnika na dozi imunosupresije steroida ili drugih immunosuppresants;
● u febrilnih stanja;

● u slučaju infekcije mokraćnih puteva ili masivnog hematurija, kao u paralelnom protiv mikroba terapije;

• aktivne tuberkuloze; pozitivan tuberkulinski Mantoux test kontraindikacija samo u slučaju ovlaštenog aktivne
infekcije tuberkulozom;

• U slučaju tekućeg ili prethodnog sistemska BCG reakcija (tj sistemska granulomatozna bolest, koja može biti
otkrivena nakon primjene BCG, ona se utvrđuje na temelju sljedećih simptoma: vrućica ≥39.5С za ≥12 sati;
groznica ≥ 38.5С za ≥48 sati, pneumonitis, hepatitis ili neku drugu organa disfunkcije izvan mokraćnog-
genitalnog trakta koji uključuje granulomatozna upala, koje se utvrđuje kroz biopsije ili klasične simptome
sepse).

Potrebne mjere opreza za upotrebu:

• Pacijenti koji su imali lijek primjenjuje intravezikalno, treba održavati adekvatnu hidrataciju.

• intravezikalnog uprava CALGEVAX može dovesti do lokalne upale mokraćnog mjehura, u pratnji hematurija
dizurija, polakiurije i simptome slične gripi. Bolesnici s malim kapacitetom mokraćnog mjehura su izloženi
većem riziku od teških lokalnih reakcija.
• U slučaju sumnje o sustavne BCG infekcije nakon primjene CALGEVAX, koja može nastaviti s vrućicom iznad
390С, uporan temperaturu iznad 38 0С ili umora, bit ćete upitani tretman antituberkuloticima se provodi nakon
konzultacija stručnjaka.

• CALGEVAX sadrži žive bakterije i treba biti tretirana kao infektivnog materijala. Osobe s imunosupresije ne bi
trebao nositi CALGEVAX.

• kateterizacijskom mjehura treba biti izvedena pažljivo izbjegavajući traumatizacije sluznice. Ako je liječnik,
izvodeći tretman, odluči da je kateterizacija traumatska (primjerice, uključuje krvarenje), davanje proizvoda
treba odgoditi za barem 14 dana.

• U slučaju ozbiljnih ukupnih nuspojava, intervali između pojedinačnih uprava se produžiti. Tretman s
CALGEVAX može prestati po nahođenju liječnika, koji obavlja tretman. Liječenje Antituberkulots se preporuča u
slučaju diseminirane BCG infekcije.

Djeca i adolescenti

CALGEVAX se ne preporučuje za djecu zbog nedostatka dovoljnih podataka o sigurnosti i učinkovitosti

proizvoda u vezi djece.

Ostali lijekovi i CALGEVAX:

Te bi trebao obavijestiti svog liječnika ili pharmacyst ako ste uzeli ili eventualno može uzimati druge lijekove.
Uzimanje CALGEVAX može dovesti do povećane osjetljivosti na tuberkulin koja će otežati tumačenje reakcije
kože na tuberkulin u budućem ispitivanju zbog sumnje mikobakterija infekcija. U tom kontekstu, preporuča se
odrediti reakciju pacijenta na tuberkulin prije imunoterapiju s CALGEVAX.

Trudnoća, dojenje i plodnost

Ne uzimajte ovaj lijek bez prethodnog savjetovanja s liječnikom, ako ste trudni ili dojite, mislite da biste mogli
biti trudni ili planirate zatrudnjeti.

Ravnoteža rizik / korist procjenjuje oprezno, kad se lijek treba davati tijekom trudnoće i dojenja zbog
nedostatka kliničkih podataka o njegovoj upravi u tim slučajevima. Poznato je da doji žena sa sistemskim BCG
infekcija može zaraziti dijete.
Upravljanje vozilima i strojevima

Učinak CALGEVAX na sposobnost upravljanja vozilima i rada na strojevima nije ispitivan.

3. Kako upravljati CALGEVAX

Te bi trebao uzeti ovaj lijek kao što je opisano u ovoj uputi ili kako je vaš liječnik pharmacyst ti je rekao. Ako
niste sigurni u nešto, obratite se liječniku ili pharmacyst.

Intravezikalnu UPRAVA:

CALGEVAX se daje najmanje 14 dana nakon obavljanja biopsije, transuretralne resekcija ili traumatske
kateterizacije. Primjena CALGEVAX treba učiniti sterilnom opremom i pod kontrolom urologu, ima iskustva u
primjene proizvoda. Tri ili četiri ampule proizvoda koriste se za svaku intravezikalnu ubacivanja po nahođenju
urolog koji obavlja tretman. Sadržaj svake bočice se pomiješa u 1 ml sterilne fiziološke otopine (otopina
natrijevog klorida s koncentracijom od 9 g / l), oprezno mućka dok se ne postigne homogena suspenzija. Smjesa
uvlači štrcaljkom a zatim su vraćene u ampuli tri puta kako bi se osiguralo potpuno miješanje, što smanjuje
gomilanje mikobakterijom. Sadržaj ampula se prenese u špricu od 50 ml. Doda se dodatni volumen sterilne
fiziološke otopine dovođenja do ukupnog volumena od 50 ml. Svjetlo znatno smanjuje učinkovitost CALGEVAX.
Stoga, u slučaju izravnog svjetlom treba izbjegavati kako prije tako i poslije pripreme suspenzije. Suspenzija se
mora odmah upotrijebiti.

Nakon anje mjehura, rekonstruirana CALGEVAX polako ubaci u mjehur kroz mokraćnu cijev katetera. Proizvod
ostaje u mokraćni mjehur u roku od dva sata. Dok CALGEVAX je zadržan u mjehuru, svakih 15 minuta pacijent
izmjenjuje slijedeće pozicije: polu-lijevo skretanje, polu-desno skretanje, lijeva strana, desna strana.

Standardna shema davanja uključuje jedan intravezikularnog ubacivanje jednom tjedno tijekom šest tjedana
(induciranim terapija). Terapija održavanja utvrđuje se od slučaja do slučaja. mogu se koristiti sljedeće sheme:
mjesečni upravu u toku minimalno 6-12 mjeseci ili tri tjedne ubacivanja u 3., 6., 12., 18., 24., 30. i 36. mjeseca
od datuma prvog ubacivanja.

Perkutana UPRAVA:

Deset horizontalna i deset okomite linije su izrađeni od igle štrcaljke na površini od 5/5 сm. Reckanje treba suza
samo epidermalni sloj bez uzrokovanja opsežna krvarenja.

Uređaj multipuncture također se mogu upotrijebiti za regulaciju dubinu skarifikacija.

Skarifikacija baza je tretirana sa slijedećom 0,5 ml suspenzije: sadržaj jedne ampule se pomiješa s 0,5 ml
sterilne fiziološke otopine, da bi se dobio koncentracija od 75 mg / ml. Jedna ampula se koristi za jednu
skarifikacija. Prije postupka, područje treba tretirati s acetonom nakon čega se puni

isparavanje treba čeka. Novi prostor je izabran za svaku sljedeću skarifikacija. Učestalost i trajanje davanja se
određuje liječnik, koji obavlja liječenje.

4. Moguće neželjene reakcije:

Ovaj lijek, kao i većina drugih lijekova, može izazvati nuspojavu, iako to ne vrijedi za sve ljude.

intravezikalnu uprava

• Lokalne reakcije: prolazna disurije, funkcionalne gastrointestinalne, hematurija, bakterijska infekcija

urinarnog trakta, granulomatozni prostatitis, epididimitis, orhitis.
• Opće reakcije: slabost, povećana temperatura, groznica, znojenje, mučnina, povraćanje,

glavobolju, bol u mišićima, bolovi kolike, difuzni osip hepatotoksičnosti, diseminirane BCG infekcija, općeg
preosjetljivost, erythema nodosium, konjunktivitis, uveitis, vitiligo, artritis, leukopenija ili pancitopenija,
slezene.

U slučaju intravezikalnu primjenu, nuspojave (dizurija, polakiurija, groznica) javljaju se 3-4 sata nakon
ukapavanja te su prolazne - traju 24-72 sati. Lokalizirana (epididymistis, orhitisa, prostatitis) ili sistemska
infekcija BCG javlja rjeđe.

Perkutana uprava

• lokalne reakcije: lokaliziran svrbež ili osip, bolan čir na mjestu primjene, regionalne adenopatiju.

• Opće reakcije: umor, povećana temperatura, groznica, znojenje, mučnina, povraćanje, glavobolja, bol u
mišićima, bolovi kolike, difuzni osip, toksičnost jetre, diseminirane BCG infekcije, opće preosjetljivosti, eritem
nodosium, konjunktivitis, uveitis, vitiligo, artritis, leukopenija ili pancitopenija, splenomegalija.

U slučaju ozbiljnih nuspojava, intervali između pojedinačnih uprava se produžiti. Tretman s CALGEVAX može
prestati po nahođenju liječnika, koji obavlja tretman. Liječenje Antituberkulots se preporuča u slučaju
diseminirane BCG infekcije.

Pacijent mora obavijestiti liječnika o bilo kakve nuspojave, a ne što je istaknuto u letku.

Prijavljivanje nuspojava

Ako primijetite bilo kakve negativne reakcije, molim vas, obavijestite svog liječnika ili ljekarnika. To uključuje
sve moguće nuspojave koje nisu ukazao u ovoj uputi. Također možete prijaviti nuspojave izravno putem
Nacionalnog izvještajnog sustava, istaknuo je u nastavku:

Bugarski Agencija za lijekove

8, Damyan Grouev St., 1303 Sofia,

tel .: + 359 28903417, web: www.bda.bg

Po izvještavanja nuspojava možete doprinijeti osiguravanju više informacija o sigurnosti ovog lijeka.

5. Skladištenje CALGEVAX

Pohraniti na temperaturi od +2 do +8 C С.

Pohranite u kartonskoj paket kako bi se izbjegla izloženost svjetlu.

Čuvati izvan dohvata djece.

Nakon suspendiranjem, izbjegavati izloženost svjetlosti i administraciju odmah.

Proizvod se ne smije koristiti istekao rok trajanja, istaknuo je na pakiranju. Proizvod je prikladan za upotrebu,
sve do posljednjeg dana u mjesecu naznačeno.

Posebne mjere na raspolaganju

Neiskorišteni iznos obustave, igala, šprica i kateteri su uništeni u skladu s pravilima za odlaganje infektivnog
materijala. U slučaju izlijevanja, područje se čisti 70% otopina etilnog alkohola.
6. Sadržaj paketa i dodatne informacije

Sadržaj CALGEVAX

Aktivna tvar - Mycobacterium bovis BCG (Bacillus Calmette-Guérin) 11,25 mg (37,5 mg polusuha bakterijska
masa) 1,0 -3,0 x108 održive jedinice

Pomoćne tvari: natrijev glutamat 40 mg

Što CALGEVAX izgleda i što paket sadrži

Prašak za suspenziju

Bijela liofilizirani kompaktna masa

Kartonskoj kutiji sadrži četiri ili deset ampule i letak pacijenta.

Nositelj odobrenja i proizvođač

BB-NCIPD doo, 1504 Sofija, 26, Y. Sakazov Blvd. tel. 359 2 944 61 91

fax: 359 2 943 34 55 e-mail: bulbio@bulbio.com

Datum najnovije odobrenja letka: ožujak 2015

Intravesical therapy for bladder cancer means putting liquid drugs directly into the bladder through a tube
called a catheter. The aim of this treatment is to treat the cancer and stop it from coming back or spreading
into the deeper layers of the bladder.Jun 26, 2015

Treatment into the bladder | Cancer Research UK

www.cancerresearchuk.org/about-cancer/type/.../treatment-into-the-bladder