CAMPTO

רזייפ יא ףא יפ מ"עב לארשי הקיטבצמרפ

רקנש 'חר

.ד.ת ,

12133

לארשי ,חותיפ הילצרה

46725

:לט

972-9-9700500

:סקפ

972-9-9700501

ינוי

2018

,ה/דבכנ ת/חקור ,ה/אפור

ולעב ןוכדע לע ךעידוהל וננוצרב

אפורל

לש

רישכתה

Campto

:ליעפה ביכרמה

Irinotecan hydrochloride 20mg/mL

Indicated for:

The treatment of patients with metastatic colorectal cancer:

In combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for metastatic

disease.

As a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

For the treatment of patients with small cell lung cancer.

For the treatment of patients with gastric cancer.

Irinotecan in combination with leucovorin, Oxaliplatin and 5-fluorouracil for the first-line treatment of patients

with metastatic pancreatic adenocarcinoma..

:אפורל ןולעב םיירקיעה םינוכדעה ןלהל

4.8.

Undesirable effects

....

POST-MARKETING SURVEILLANCE

MedDRA System Organ

Class

Preferred Term

Infections and infestations

Pseudomembranous colitis one of which has been

documented bacteriologically (Clostridium

difficile)

Sepsis

Fungal infections

Viral infections

....

....

e.g. Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candida.

enza, hepatitis B reactivation, cytomegalovirus colitis.

e.g. Herpes zoster, influ

....

.הרמחה םיווהמ בוהצ עקרב םישגדומה םייונישה ינוכדעו עדימ תטמשה ,עדימ תפסות םיללוכה םיפסונ םייוניש ועצוב ,ןכ ומכ .הרמחה םיווהמ םניאש חסונ

ולעה םינ

כדועמה םי

חלשנ

ךרוצל תואירבה דרשמל מוסרפ

:תואירבה דרשמ רתאבש תופורתה רגאמב

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=h

ולע תלבקל ,ןיפוליחל םינ

אלמ םי

ספדומ םי

חל תונפל ןתינ יא ףא יפ רזייפ תרב מ"עב לארשי הקיטבצמרפ

רקנש

.ד.ת ,

12133

,חותיפ הילצרה

46725

כרבב

ידובע לטרוא

הנוממ תחקור

Campto LPD WC 040618

2017-0034028 Page 1 of 20

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

CAMPTO

20 mg/ml, concentrate for solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

The concentrate contains 20 mg/ml irinotecan hydrochloride, trihydrate (equivalent to 17.33 mg/ml

irinotecan).

One vial of 2 ml contains 34.66 mg of irinotecan as 40 mg of irinotecan hydrochloride, trihydrate (40

mg/2 ml).

One vial of 5 ml contains 86.65 mg of irinotecan as 100 mg of irinotecan hydrochloride, trihydrate

(100 mg/5 ml).

One vial of 15 ml contains 259.95 mg of irinotecan as 300 mg of irinotecan hydrochloride, trihydrate

(300 mg/15 ml).

For the full list of excipients, see section 6.1.

Excipient(s) with known effect

Sorbitol

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indication

CAMPTO

is indicated for the treatment of patients with metastatic colorectal cancer:

In combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for

metastatic disease.

As a single agent in patients who have failed an established 5-fluorouracil containing treatment

regimen.

For the treatment of patients with small cell lung cancer.

For the treatment of patients with gastric cancer.

Irinotecan in

combination with leucovorin,

oxaliplatin

5-fluorouracil for

first-line

treatment of patients with metastatic pancreatic adenocarcinoma (based on NCCN guidelines,

version 2.2015).

4.2.

Posology and method of administration

For adults only. CAMPTO

solution for infusion should be infused into a peripheral or central vein.

Recommended dosage:

In monotherapy (for previously treated patient): The recommended dosage of CAMPTO

350 mg/m² administered as an intravenous infusion over a 30- to 90- minute period every three weeks

(see sections 4.4 and 6.6 ).

Campto LPD WC 040618

2017-0034028 Page 2 of 20

In combination therapy (for previously untreated patient): Safety and efficacy of CAMPTO

combination with 5-fluorouracil (5FU) and folinic acid (FA) have been assessed with the following

schedule (see section 5.1):

CAMPTO

plus 5FU/FA in every 2 weeks schedule

The recommended dose of CAMPTO

is 180 mg/m² administered once every 2 weeks as an

intravenous infusion over a 30- to 90-minute period, followed by infusion with folinic acid and 5-

fluorouracil.

Dosage adjustments:

CAMPTO

should be administered after appropriate recovery of all adverse events to Grade 0 or 1

NCI-CTC grading (National Cancer Institute Common Toxicity Criteria) and when treatment-related

diarrhoea is fully resolved.

At the start of a subsequent infusion of therapy, the dose of CAMPTO

, and 5FU when applicable,

should be decreased according to the worst grade of adverse events observed in the prior infusion.

Treatment should be delayed by 1 to 2 weeks to allow recovery from treatment-related adverse events.

With the following adverse events a dose reduction of 15 to 20% should be applied for CAMPTO

and/or 5FU when applicable:

haematological toxicity [neutropenia Grade 4, febrile neutropenia (neutropenia Grade 3-4 and fever

Grade 2-4), thrombocytopenia and leukopenia (Grade 4)],

non-haematological toxicity (Grade 3-4).

Treatment duration:

Treatment with CAMPTO

should be continued until there is an objective progression of the disease

or an unacceptable toxicity.

Special populations:

Patients with impaired hepatic function: In monotherapy: Blood bilirubin levels [up to 3 times the

upper limit of the normal range (ULN)] in patients with performance status

2, should determine the

starting dose of CAMPTO

. In these patients with hyperbilirubinemia and prothrombin time greater

than 50%, the clearance of irinotecan is decreased (see section 5.2) and therefore the risk of

hepatotoxicity is increased. Thus, weekly monitoring of complete blood counts should be conducted in

this patient population.

In patients with bilirubin up to 1.5 times the (ULN), the recommended dosage of CAMPTO

350 mg/m²,

In patients with bilirubin ranging from 1.5 to 3 times the ULN, the recommended dosage of

CAMPTO

is 200 mg/m².

Patients with bilirubin beyond to 3 times the ULN should not be treated with CAMPTO

(see

section 4.3 and 4.4).

No data are available in patients with hepatic impairment treated by CAMPTO

in combination.

Patients with impaired renal function: CAMPTO

is not recommended for use in patients with

impaired renal function, as studies in this population have not been conducted (see section 4.4 and

5.2).

Campto LPD WC 040618

2017-0034028 Page 3 of 20

Elderly: No specific pharmacokinetic studies have been performed in elderly. However, the dose

should be chosen carefully in this population due to their greater frequency of decreased biological

functions. This population should require more intense surveillance (see section 4.4).

4.3.

Contraindications

Chronic inflammatory bowel disease and/or bowel obstruction (see section 4.4).

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

Lactation (see section 4.6 and section 4.4).

Bilirubin > 3 times the upper limit of the normal range (see section 4.4).

Severe bone marrow failure.

WHO performance status > 2.

Concomitant use with St. John’s Wort

(see section 4.5).

Live attenuated vaccines (see section 4.5).

4.4.

Special warnings and precautions for use

The use of CAMPTO

should be confined to units specialised in the administration of cytotoxic

chemotherapy and it should only be administered under the supervision of a physician qualified in the

use of anticancer chemotherapy.

Given the nature and incidence of adverse events, CAMPTO

will only be prescribed in the following

cases after the expected benefits have been weighted against the possible therapeutic risks:

in patients presenting a risk factor, particularly those with a WHO performance status = 2.

in the few rare instances where patients are deemed unlikely to observe recommendations

regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment

combined with high fluid intake at onset of delayed diarrhoea). Strict hospital supervision is

recommended for such patients.

When CAMPTO

is used in monotherapy, it is usually prescribed with the every-3-weekdosage

schedule. However, the weekly-dosage schedule (see section 5) may be considered in patients who

may need a closer follow-up or who are at particular risk of severe neutropenia.

Delayed diarrhoea

Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the

administration of CAMPTO

and at any time before the next cycle. In monotherapy, the median time

of onset of the first liquid stool was on day 5 after the infusion of CAMPTO

. Patients should quickly

inform their physician of its occurrence and start appropriate therapy immediately.

Patients with an increased risk of diarrhoea are those who had a previous abdominal/pelvic

radiotherapy, those with baseline hyperleucocytosis, those with performance status

2 and women. If

not properly treated, diarrhoea can be life-threatening, especially if the patient is concomitantly

neutropenic.

As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages

containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This

antidiarrhoeal treatment will be prescribed by the department where CAMPTO

has been

administered. After discharge from the hospital, the patients should obtain the prescribed medicinal

products so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their

physician or the department administering CAMPTO

when/if diarrhoea is occurring.

Campto LPD WC 040618

2017-0034028 Page 4 of 20

The currently recommended antidiarrhoeal treatment consists of high doses of loperamide (4 mg for

the first intake and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last

liquid stool and should not be modified. In no instance should loperamide be administered for more

than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than

12 hours.

In addition to the antidiarrhoeal treatment, a prophylactic broad-spectrum antibiotic should be given,

when diarrhoea is associated with severe neutropenia (neutrophil count < 500 cells/mm³).

In addition to the antibiotic treatment, hospitalisation is recommended for management of the

diarrhoea, in the following cases:

- Diarrhoea associated with fever,

- Severe diarrhoea (requiring intravenous hydration),

- Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.

Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea

at previous cycles.

In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent

cycles (see section 4.2).

Haematology

In clinical studies, the frequency of NCI CTC Grade 3 and 4 neutropenia has been significantly higher

in patients who received previous pelvic/abdominal irradiation than in those who had not received

such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more have also had

a significantly greater likelihood of experiencing first-cycle Grade 3 or 4 neutropenia than those with

bilirubin levels that were less than 1.0 mg/dL.

Weekly monitoring of complete blood cell counts is recommended during CAMPTO

treatment.

Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia

(temperature > 38°C and neutrophil count

1,000 cells/mm³) should be urgently treated in the hospital

with broad-spectrum intravenous antibiotics.

In patients who experienced severe haematological events, a dose reduction is recommended for

subsequent administration (see section 4.2).

There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea.

In patients with severe diarrhoea, complete blood cell counts should be performed.

Liver impairment

Liver function tests should be performed at baseline and before each cycle.

Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging

from 1.5 to 3 times the ULN, due to decrease of the clearance of irinotecan (see section 5.2) and thus

increasing the risk of hematotoxicity in this population. For patients with a bilirubin > 3 times the

ULN (see section 4.3).

Nausea and vomiting

Campto LPD WC 040618

2017-0034028 Page 5 of 20

A prophylactic treatment with antiemetics is recommended before each treatment with CAMPTO

Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed

diarrhoea should be hospitalised as soon as possible for treatment.

Acute cholinergic syndrome

If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and

symptoms such as sweating, abdominal cramping, myosis and salivation), atropine sulphate (0.25 mg

subcutaneously) should be administered unless clinically contraindicated (see section 4.8).

These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be

related to the anticholinesterase activity of the irinotecan parent compound, and are expected to occur

more frequently with higher irinotecan doses.

Caution should be exercised in patients with asthma. In patients who experienced an acute and severe

cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent

doses of CAMPTO

Respiratory disorders

Interstitial lung disease presenting as lung infiltration is uncommon during irinotecan therapy.

Interstitial lung disease can be fatal. Risk factors possibly associated with the development of

interstitial lung disease include the use of pneumotoxic medicinal products, radiation therapy and

colony stimulating factors. Patients with risk factors should be closely monitored for respiratory

symptoms before and during irinotecan therapy.

Extravasation

While irinotecan is not a known vesicant, care should be taken to avoid extravasation and the infusion

site should be monitored for signs of inflammation. Should extravasation occur, flushing the site and

application of ice is recommended.

Elderly

Due to the greater frequency of decreased biological functions, in particular hepatic function, in

elderly patients, dose selection with CAMPTO

should be cautious in this population (see section 4.2).

Chronic inflammatory bowel disease and/or bowel obstruction

Patients must not be treated with CAMPTO

until resolution of the bowel obstruction (see section

4.3).

Renal function

Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of

acute renal failure. These events have generally been attributed to complications of infection or to

dehydration related to nausea, vomiting, or diarrhoea. Rare instances of renal dysfunction due to

tumour lysis syndrome have also been reported.

Irradiation therapy

Patients who have previously received pelvic/abdominal irradiation are at increased risk of

myelosuppression following the administration of irinotecan. Physicians should use caution in treating

patients with extensive prior irradiation (e.g.,>25% of bone marrow irradiated and within 6 weeks

Campto LPD WC 040618

2017-0034028 Page 6 of 20

prior to start of treatment with irinotecan). Dosing adjustment may apply to this population (see

section 4.2).

Cardiac disorders

Myocardial ischaemic events have been observed following irinotecan therapy predominately in

patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous

cytotoxic chemotherapy (see section 4.8).

Consequently, patients with known risk factors should be closely monitored, and action should be

taken to try to minimize all modifiable risk factors (e.g., smoking, hypertension, and hyperlipidaemia).

Vascular disorders

Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous

thrombosis, and arterial thromboembolism) in patients presenting with multiple risk factors in addition

to the underlying neoplasm.

Others

Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in

patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or

sepsis.

Women of childbearing potential and men have to use effective contraception during and up to 1

month and 3 months after treatment respectively.

Concomitant administration of irinotecan with a strong inhibitor (e.g., ketoconazole) or inducer (e.g.,

rifampicin, carbamazepine, phenobarbital,

phenytoin) of

CYP3A4

alter

metabolism of

irinotecan and should be avoided (see section 4.5).

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5.

Interaction with other medicinal products and other forms of interaction

Concomitant use contraindicated (see section 4.3)

Yellow fever vaccine: Risk of fatal generalised reaction to vaccines

Saint John’s Wort:

Decrease in the active metabolite of irinotecan, SN-38, plasma levels. In a small

pharmacokinetic study (n=5), in which irinotecan 350 mg/m

was co-administered with St. John's

Wort (Hypericum perforatum) 900 mg, a 42% decrease in the active metabolite of irinotecan, SN-38,

plasma concentrations was observed. As a result, St. John's Wort should not be administered with

irinotecan.

Live attenuated vaccines: Risk of generalised reaction to vaccines, possibly fatal. Concomitant use is

contraindicated during treatment with irinotecan and for 6 months following discontinuation of

chemotherapy. Killed or inactivated vaccines may be administered; however, the response to such

vaccines may be diminished.

Campto LPD WC 040618

2017-0034028 Page 7 of 20

Concomitant use not recommended (see section 4.4)

Concurrent administration of irinotecan with a strong inhibitors or inducers of cytochrome P450 3A4

(CYP3A4) may alter the metabolism of irinotecan and should be avoided (see section 4.4):

Strong CYP3A4 and/or UGT1A1 inducing medicinal products: (e.g. rifampicin, carbamazepine,

phenobarbital or phenytoin):

Risk of reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic

effects. Several studies have shown that concomitant administration of CYP3A4-inducing

anticonvulsant medicinal products leads to reduced exposure to irinotecan, SN-38 and SN-38

glucuronide and reduced pharmacodynamic effects. The effects of such anticonvulsant medicinal

products were reflected by a decrease in AUC of SN-38 and SN-38G by 50% or more. In addition to

induction of CYP3A4 enzymes, enhanced glucuronidation and enhanced biliary excretion may play a

role in reducing exposure to irinotecan and its metabolites. Additionally with phenytoin: Risk of

exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic

medicinal products.

Strong CYP3A4 inhibitors: (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease

inhibitors, clarithromycine, erythromycine, telithromycine):

A study has shown that the co-administration of ketoconazole resulted in a decrease in the AUC of

APC of 87% and in an increase in the AUC of SN-38 of 109% in comparison to irinotecan given

alone.

UGT1A1 inhibitors: (e.g. atazanavir, ketoconazole, regorafenib)

Risk to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should

take this into consideration if the combination is unavoidable.

Other CYP3A4 inhibitors: (e.g. crizotinib, idelalisib)

Risk of increase in irinotecan toxicity, due to a decrease in irinotecan metabolism by crizotinib or

idelalisib.

Caution for use

Vitamin K antagonists: Increased risk of haemorrhage and thrombotic events in tumoral diseases. If

vitamin K antagonist are indicated, an increased frequency in the monitoring of INR (International

Normalised Ratio) is required.

Concomitant use to take into consideration

Immunodepressant agents: (e.g. ciclosporine, tacrolimus): Excessive immunosuppression with risk

of lymphoproliferation.

Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking agents

cannot be ruled out. Since CAMPTO

has anticholinesterase activity, medicinal products with

anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the

neuromuscular blockade of non-depolarising medicinal products may be antagonised.

Other combinations

5-fluorouracil/folinic acid: Coadministration of 5-fluorouracil/folinic acid in the combination

regimen does not change the pharmacokinetics of irinotecan.

Campto LPD WC 040618

2017-0034028 Page 8 of 20

Bevacizumab: Results from a dedicated drug-drug interaction trial demonstrated no significant effect

of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this

does not preclude any increase of toxicities due to their pharmacological properties

Cetuximab: There is no evidence that the safety profile of irinotecan is influenced by cetuximab or

vice versa.

4.6.

Fertility, pregnancy and lactation

Women of childbearing potential/ Contraception in males and females

Women of childbearing potential and men have to use effective contraception during and up to 1

month and 3 months after treatment, respectively.

Pregnancy

There is no data from the use of irinotecan in pregnant women. Irinotecan has been shown to be

embryotoxic and teratogenic in animals. Therefore, based on results from animal studies and the

mechanism of action of irinotecan, CAMPTO

should not be used during pregnancy unless clearly

necessary.

Breast-feeding

In lactating rats,

C-irinotecan was detected in milk. It is not known whether irinotecan is excreted in

human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast-

feeding should be discontinued for the duration of CAMPTO

therapy (see section 4.3).

Fertility

There are no human data on the effect of irinotecan on fertility. In animals adverse effects of

irinotecan on the fertility of offspring have been documented (see section 5.3).

4.7.

Effects on ability to drive and use machines

CAMPTO

has moderate influence on the ability to drive and use machines. Patients should be

warned about the potential for dizziness or visual disturbances which may occur within 24 hours

following the administration of CAMPTO

, and advised not to drive or operate machinery if these

symptoms occur.

4.8.

Undesirable effects

CLINICAL STUDIES

Adverse reaction data have been extensively collected from studies in metastatic colorectal cancer; the

frequencies are presented below. The adverse reactions for other indications are expected to be similar

to those for colorectal cancer.

The most common (≥1/10), dose-limiting adverse reactions of irinotecan are delayed diarrhoea

(occurring more than 24 hours after administration) and blood disorders including neutropenia,

anaemia and thrombocytopenia.

Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median

day to nadir was 8 days whatever the use in monotherapy or in combination therapy.

Very commonly severe transient acute cholinergic syndrome was observed.

Campto LPD WC 040618

2017-0034028 Page 9 of 20

The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal

pain, sweating, myosis and increased salivation occurring during or within the first 24 hours after the

infusion of CAMPTO

. These symptoms disappear after atropine administration (see section 4.4).

MONOTHERAPY

The following adverse reactions considered to be possibly or probably related to the administration of

CAMPTO

have been reported from 765 patients at the recommended dose of 350 mg/m² in

monotherapy. Within each frequency grouping, adverse reactions are presented in order of decreasing

seriousness. Frequencies are defined as: 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), and very rare (<1/10,000).

Adverse Reactions Reported with CAMPTO

®

in Monotherapy (350 mg/m

2

every 3 weeks schedule)

MedDRA System Organ Class

Frequency Category

Preferred Term

Infections and infestations

Common

Infection

Blood and lymphatic system disorders

Very common

Neutropenia

Very common

Anaemia

Common

Thrombocytopenia

Common

Febrile neutropenia

Metabolism and nutrition disorders

Very common

Decreased appetite

Nervous system disorders

Very common

Cholinergic syndrome

Gastrointestinal disorders

Very common

Diarrhoea

Very common

Vomiting

Very common

Nausea

Very common

Abdominal pain

Common

Constipation

Skin and subcutaneous tissue disorders

Very common

Alopecia (reversible)

General disorders and administration site

conditions

Very common

Mucosal inflammation

Very common

Pyrexia

Very common

Asthenia

Investigations

Common

Blood creatinine increased

Common

Transaminases (ALT and AST)

increased

Common

Blood ilirubin increased

Common

Blood alkaline phosphatase increased

Description of selected adverse reactions (monotherapy)

Severe diarrhoea was observed in 20% of patients who follow recommendations for the management

of diarrhoea. Of the evaluable cycles, 14% have severe diarrhoea. The median time of onset of the first

liquid stool was on day 5 after the infusion of CAMPTO

Nausea and vomiting were severe in approximately 10% of patients treated with antiemetics.

Constipation has been observed in less than 10% of patients.

Neutropenia was observed in 78.7% of patients and was severe (neutrophil count < 500 cells/mm

) in

22.6% of patients. Of the evaluable cycles, 18 % had a neutrophil count below 1,000 cells/mm³

including 7.6% with a neutrophil count < 500 cells/mm³.

Total recovery was usually reached by day 22.

Febrile neutropenia was reported in 6.2% of patients and in 1.7% of cycles.

Infections occurred in about 10.3% of patients (2.5% of cycles) and were associated with severe

neutropenia in about 5.3% of patients (1.1% of cycles), and resulted in death in 2 cases.

Anaemia was reported in about 58.7% of patients (8% with haemoglobin < 8 g/dl and 0.9% with

haemoglobin < 6.5 g/dl).

Thrombocytopenia (< 100,000 cells/mm³) was observed in 7.4 % of patients and 1.8% of cycles with

0.9% with platelet count

50,000 cells/mm3 and 0.2% of cycles.

Nearly all the patients showed a recovery by day 22.

Campto LPD WC 040618

2017-0034028 Page 10 of 20

Acute cholinergic syndrome

Severe transient acute cholinergic syndrome was observed in 9 % of patients treated in monotherapy.

Asthenia was severe in less than 10 % of patients treated in monotherapy. The causal relationship to

CAMPTO

has not been clearly established.

Pyrexia in the absence of infection and without concomitant severe neutropenia, occurred in 12 % of

patients treated in monotherapy.

Laboratory tests

Transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase

or bilirubin were observed in 9.2 %, 8.1 % and 1.8 % of the patients, respectively, in the absence of

progressive liver metastasis.

Transient and mild to moderate increases of serum levels of creatinine have been observed in 7.3 % of

the patients.

COMBINATION THERAPY

Adverse reactions detailed in this section refer to irinotecan.

CAMPTO

has been studied in combination with 5FU and FA for metastatic colorectal cancer.

Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI

Grade 3 or 4 possibly or probably-related adverse events in the blood and the lymphatic system

disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders MedDRA System

Organ Classes.

The following adverse reactions considered to be possibly or probably related to the administration of

CAMPTO

have been reported from 145 patients treated by CAMPTO

in combination therapy with

5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m².

Adverse Reactions Reported with CAMPTO

®

in Combination Therapy (180 mg/m

2

every 2

weeks schedule)

MedDRA System Organ Class

Frequency Category

Preferred Term

Infections and infestations

Common

Infection

Blood and lymphatic system

disorders

Very common

Thrombocytopenia

Very common

Neutropenia

Very common

Anaemia

Common

Febrile neutropenia

Metabolism and nutrition

disorders

Very common

Decreased appetite

Nervous system disorders

Very common

Cholinergic syndrome

Gastrointestinal disorders

Very common

Diarrhoea

Very common

Vomiting

Very common

Nausea

Common

Abdominal pain

Common

Constipation

Skin and subcutaneous tissue

disorders

Very common

Alopecia (reversible)

General disorders and

administration site conditions

Very common

Mucosal inflammation

Very common

Asthenia

Common

Pyrexia

Investigations

Very common

Transaminases (ALT and AST)

increased

Very common

Blood bilirubin increased

Very common

Blood alkaline phosphatase

increased

Description of selected adverse reactions (combination therapy)

Campto LPD WC 040618

2017-0034028 Page 11 of 20

Severe diarrhoea was observed in 13.1 % of patients who follow recommendations for the

management of diarrhoea. Of the evaluable cycles, 3.9 % have a severe diarrhoea.

A lower incidence of severe nausea and vomiting was observed (2.1 % and 2.8 % of patients

respectively).

Constipation relative to CAMPTO

and/or loperamide has been observed in 3.4 % of patients.

Neutropenia was observed in 82.5% of patients and was severe (neutrophil count < 500 cells/mm

) in

9.8% of patients. Of the evaluable cycles, 67.3% had a neutrophil count below 1,000 cells/mm³

including 2.7% with a neutrophil count < 500 cells/mm³. Total recovery was usually reached within 7-

8 days.

Febrile neutropenia was reported in 3.4% of patients and in 0.9% of cycles.

Infections occurred in about 2% of patients (0.5% of cycles) and were associated with severe

neutropenia in about 2.1% of patients (0.5% of cycles), and resulted in death in 1 case.

Anaemia was reported in 97.2% of patients (2.1% with haemoglobin < 8 g/dl).

Thrombocytopenia (< 100,000 cells/mm³) was observed in 32.6% of patients and 21.8% of cycles.

No severe thrombocytopenia (< 50,000 cells/mm³) has been observed.

Acute cholinergic syndrome

Severe transient acute cholinergic syndrome was observed in 1.4 % of patients treated in combination

therapy.

Asthenia was severe in 6.2 % of patients treated in combination therapy. The causal relationship to

CAMPTO

has not been clearly established. Pyrexia in the absence of infection and without

concomitant severe neutropenia, occurred in 6.2 % of patients treated in combination therapy.

Laboratory tests

Transient serum levels (Grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were

observed in 15%, 11%, 11% and 10% of the patients, respectively, in the absence of progressive liver

metastasis. Transient Grade 3 were observed in 0%, 0%, 0% and 1% of the patients, respectively. No

Grade 4 was observed.

Increases of amylase and/or lipase have been very rarely reported.

Rare cases of hypokalaemia and hyponatremia mostly related with diarrhoea and vomiting have been

reported.

OTHER ADVERSE EVENTS REPORTED IN CLINICAL STUDIES WITH THE WEEKLY

REGIMEN FOR CAMPTO

®

The following additional drug-related events have been reported in clinical studies with irinotecan:

pain, sepsis, anorectal disorder, GI candida infection, hypomagnesamia, rash, skin signs, gait

disturbance, confusion, headache, syncope, flushing, bradycardia, urinary tract infection, breast pain,

gamma-glutamyltransferase increased, extravasation, and tumour lysis syndrome, cardiovascular

disorders (angina pectoris,cardiac arrest, myocardial infarction, myocardial ischaemia, peripheral

vascular disorder, vascular disorder), and thromboembolic events (arterial thrombosis, cerebral

infarction, cerebrovascular accident, deep vein thrombosis, peripheral embolism , pulmonary

embolism, thrombophlebitis, thrombosis, and sudden death) (see section 4.4.).

Campto LPD WC 040618

2017-0034028 Page 12 of 20

POST-MARKETING SURVEILLANCE

Frequencies from post-marketing surveillance are not known (cannot be estimated from available

data).

MedDRA System Organ Class

Preferred Term

Infections and infestations

Pseudomembranous colitis one of which has been

documented bacteriologically (Clostridium difficile)

Sepsis

Fungal infections

Viral infections

Blood and lymphatic system

disorders

Thrombocytopenia with antiplatelet antibodies

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Metabolism and nutrition disorders

Dehydration (due to diarrhoea and vomiting)

Hypovolaemia

Nervous system disorders

Speech disorder generally transient in nature, in some

cases, the event was attributed to the cholinergic

syndrome observed during or shortly after infusion of

irinotecan

Paraesthesia

Muscular contractions involuntary

Cardiac disorders

Hypertension (during or after infusion)

Cardio circulatory failure*

Vascular disorders

Hypotension*

Respiratory, thoracic and

mediastinal disorders

Interstitial lung disease presenting as lung infiltration is

uncommon during irinotecan therapy; early effects such

as dyspnoea have been reported (see section 4.4)

Dyspnoea (see section 4.4)

Hiccups

Gastrointestinal disorders

Intestinal obstruction

Ileus: cases of ileus without preceding colitis have also

been reported

Megacolon

Gastrointestinal haemorrhage

Colitis; in some cases, colitis was complicated by

ulceration, bleeding, ileus, or infection.

Typhlitis

Colitis ischaemic

Colitis ulcerative

Symptomatic or asymptomatic pancreatic enzymes

incraesed

Intestinal perforation

Hepatobiliary disorders

Steatohepatitis

Hepatic steatosis

Skin and subcutaneous tissue

disorders

Skin reaction

Musculoskeletal and connective

Cramps

Campto LPD WC 040618

2017-0034028 Page 13 of 20

tissue disorders

Renal and urinary disorders

Renal impairment and acute renal failure generally in

patients who become infected and/or volume depleted

from severe gastrointestinal toxicities.*

Renal insufficiency*

General disorders and

administration site conditions

Infusion site reaction

Investigations

Amylase increased

Lipase increased

Hypokalaemia

Hyponatraemia mostly related with diarrhoea and

vomiting

Transaminases increased(i.e., AST and ALT) in the

absence of progressive liver metastasis have been very

rarely reported

e.g. Pneumocystis jirovecii pneumonia, bronchopulmonary aspergillosis, systemic candida.

e.g. Herpes zoster, influenza, hepatitis B reactivation, cytomegalovirus colitis.

* Infrequent cases of renal insufficiency, hypotension or cardio circulatory failure have been observed in

patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.

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. Any suspected

adverse event should be reported to the Ministry of Health according to the National Regulation by

using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.he

alth.gov.il

4.9.

Overdose

Symptoms

There have been reports of overdosage at doses up to approximately twice the recommended

therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe

neutropenia and severe diarrhoea.

Management

There is no known antidote for CAMPTO

. Maximum supportive care should be instituted to prevent

dehydration due to diarrhoea and to treat any infectious complications.

Campto LPD WC 040618

2017-0034028 Page 14 of 20

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatic topoisomerase I inhibitor. ATC Code : L01XX19

Mechanism of action

Experimental data:

Irinotecan is a semi-synthetic derivative of camptothecin. It is an antineoplastic agent which acts as a

specific inhibitor of DNA topoisomerase I. It is metabolised by carboxylesterase in most tissues to SN-

38, which was found to be more active than irinotecan in purified topoisomerase I and more cytotoxic

than irinotecan against several murine and human tumour cell lines. The inhibition of DNA

topoisomerase I by irinotecan or SN-38 induces single-strand DNA lesions which blocks the DNA

replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time-

dependent and was specific to the S phase.

In vitro, irinotecan and SN-38 were not found to be significantly recognised by the P -glycoprotein

MDR, and display cytotoxic activities against doxorubicin-and vinblastine-resistant cell lines.

Furthermore, irinotecan has a broad antitumor activity in vivo against murine tumour models (P03

pancreatic ductal adenocarcinoma, MA16/C mammary adenocarcinoma, C38 and C51 colon

adenocarcinomas) and against human xenografts (Co-4 colon adenocarcinoma, Mx-1 mammary

adenocarcinoma, ST-15 and SC-16 gastric adenocarcinomas). Irinotecan is also active against tumours

expressing the P-glycoprotein MDR

(vincristine- and doxorubicin-resistant P388 leukaemias).

Beside the antitumor activity of CAMPTO

, the most relevant pharmacological effect of irinotecan is

the inhibition of acetylcholinesterase.

Clinical data:

In combination therapy for the first-line treatment of metastatic colorectal carcinoma

In combination therapy with Folinic Acid and 5-Fluorouracil

A phase III study was performed in 385 previously untreated metastatic colorectal cancer patients

treated with either every 2 weeks schedule (see section 4.2) or weekly schedule regimens. In the every

2 weeks schedule, on day 1, the administration of CAMPTO

at 180 mg/m² once every 2 weeks is

followed by infusion with folinic acid (200 mg/m² over a 2-hour intravenous infusion) and 5-

fluorouracil (400 mg/m² as an intravenous bolus, followed by 600 mg/m² over a 22-hour intravenous

infusion). On day 2, folinic acid and 5-fluorouracil are administered at the same doses and schedules.

In the weekly schedule, the administration of CAMPTO

at 80 mg/m² is followed by infusion with

folinic acid (500 mg/m² over a 2-hour intravenous infusion) and then by 5-fluorouracil (2300 mg/m²

over a 24-hour intravenous infusion) over 6 weeks.

In the combination therapy trial with the 2 regimens described above, the efficacy of CAMPTO

evaluated in 198 treated patients:

Campto LPD WC 040618

2017-0034028 Page 15 of 20

Combined regimens

(n=198)

Weekly schedule

(n=50)

Every 2 weeks schedule

(n=148)

CAMPTO

+5FU/FA

5FU/FA

CAMPTO

+5FU/FA

5FU/FA

CAMPTO

+5FU/FA

5FU/FA

Response rate

40.8 *

23.1 *

51.2 *

28.6 *

37.5 *

21.6 *

p value

p<0.001

p=0.045

p=0.005

Median time to

progression

(months)

p value

p<0.001

p=0.001

Median duration

of response

(months)

p value

p=0.043

Median duration

of response and

stabilisation

(months)

p value

p<0.001

p=0.003

Median time to

treatment failure

(months)

p value

p=0.0014

p<0.001

Median survival

(months)

16.8

14.0

19.2

14.1

15.6

13.0

p value

p=0.028

p=0.041

5FU : 5-fluorouracil

FA : folinic acid

NS : Non Significant

*: As per protocol population analysis

In the weekly schedule, the incidence of severe diarrhoea was 44.4% in patients treated by CAMPTO

in combination with 5FU/FA and 25.6% in patients treated by 5FU/FA alone. The incidence of severe

neutropenia (neutrophil count < 500 cells/mm

) was 5.8% in patients treated by CAMPTO

combination with 5FU/FA and in 2.4% in patients treated by 5FU/FA alone.

Additionally, median time to definitive performance status deterioration was significantly longer in

CAMPTO

combination group than in 5FU/FA alone group (p=0.046).

Quality of life was assessed in this phase III study using the EORTC QLQ-C30 questionnaire. Time to

definitive deterioration constantly occurred later in the CAMPTO

groups. The evolution of the

Global Health Status/Quality of life was slightly better in CAMPTO

combination group although not

significant, showing that efficacy of CAMPTO

in combination could be reached without affecting

the quality of life.

In monotherapy for the second-line treatment of metastatic colorectal carcinoma:

Clinical phase II/III studies were performed in more than 980 patients in the every-3-week dosage

schedule with metastatic colorectal cancer who failed a previous 5FU regimen. The efficacy of

CAMPTO

was evaluated in 765 patients with documented progression on 5FU at study entry.

Campto LPD WC 040618

2017-0034028 Page 16 of 20

Phase III

CAMPTO

versus supportive care

CAMPTO

versus 5FU

CAMPTO

n=183

Supportive

care

n=90

p values

CAMPTO

n=127

n=129

p values

Progression Free

Survival

at 6 months (%)

33.5 *

26.7

p=0.03

Survival

at 12 months (%)

36.2 *

13.8

p=0.0001

44.8 *

32.4

p=0.0351

Median survival

(months)

9.2*

p=0.0001

10.8*

p=0.0351

NA = Non Applicable

* : Statistically significant difference

In phase II studies, performed on 455 patients in the every-3-week dosage schedule, the progression

free survival at 6 months was 30 % and the median survival was 9 months. The median time to

progression was 18 weeks.

Additionally, non-comparative phase II studies were performed in 304 patients treated with a weekly

schedule regimen, at a dose of 125 mg/m² administered as an intravenous infusion over 90 minutes for

4 consecutive weeks followed by 2 weeks rest. In these studies, the median time to progression was 17

weeks and median survival was 10 months. A similar safety profile has been observed in the weekly-

dosage schedule in 193 patients at the starting dose of 125 mg/m², compared to the every-3-week-

dosage schedule. The median time of onset of the first liquid stool was on day 11.

Patients with Reduced UGT1A1 Activity:

Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) is involved in the metabolic

deactivation of SN-38, the active metabolite of irinotecan to inactive SN-38 glucuronide (SN-38G).

The UGT1A1 gene is highly polymorphic, resulting in variable metabolic capacities among

individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter

region known as the UGT1A1*28 variant. This variant and other congenital deficiencies in UGT1A1

expression (such as Crigler-Najjar and Gilbert's syndrome) are associated with reduced activity of this

enzyme. Data from a meta analysis indicate that individuals with Crigler-Najjar syndrome (types 1 and

2) or those who are homozygous for the UGT1A1*28 allele (Gilbert’s syndrome) are at increased risk

of haematological toxicity (Grades 3 and 4) following administration of irinotecan at moderate or high

doses (>150 mg/m

). A relationship between UGT1A1 genotype and the occurrence of irinotecan

induced diarrhoea was not established.

Patients known to be homozygous for UGT1A1*28 should be administered the normally indicated

irinotecan starting dose. However, these patients should be monitored for haematologic toxicities. A

reduced irinotecan starting dose should be considered for patients who have experienced prior

haematologic toxicity with previous treatment. The exact reduction in starting dose in this patient

population has not been established and any subsequent dose modifications should be based on a

patient's tolerance of the treatment (see sections 4.2 and 4.4).

There is at present insufficient data to conclude on clinical utility of UGT1A1 genotyping.

Campto LPD WC 040618

2017-0034028 Page 17 of 20

5.2.

Pharmacokinetic properties

Absorption

At the end of the infusion, at the recommended dose of 350 mg/m², the mean peak plasma

concentrations of irinotecan and SN-38 were 7.7 µg/ml and 56 ng/ml, respectively, and the mean area

under the curve (AUC) values were 34 µg.h/ml and 451 ng.h/ml, respectively. A large interindividual

variability in pharmacokinetic parameters is generally observed for SN-38.

Distribution

The phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to

750 mg/m² every three weeks, the volume of distribution at steady state (Vss): 157 L/m².

In vitro, plasma protein binding for irinotecan and SN-38 was approximately 65% and 95%,

respectively.

Biotransformation

Mass balance and metabolism studies with 14C-labelled drug have shown that more than 50% of an

intravenously administered dose of irinotecan is excreted as unchanged drug, with 33% in the faeces

mainly via the bile and 22% in urine.

Two metabolic pathways account each for at least 12% of the dose:

Hydrolysis by carboxylesterase into active metabolite SN-38, SN-38 is mainly eliminated by

glucuronidation, and further by biliary and renal excretion (less than 0.5% of the irinotecan dose) The

SN-38 glucuronite is subsequently probably hydrolysed in the intestine.

Cytochrome P450 3A enzymes-dependent oxidations resulting in opening of the outer piperidine

ring with formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate) (see

section 4.5).

Unchanged irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN-38.

Only SN-38 has significant cytotoxic activity.

Elimination

In a phase I study in 60 patients with a dosage regimen of a 30-minute intravenous infusion of 100 to

750 mg/m² every three weeks, irinotecan showed a biphasic or triphasic elimination profile. The mean

plasma clearance was 15 L/h/m². The mean plasma half-life of the first phase of the triphasic model

was 12 minutes, of the second phase 2.5 hours, and the terminal phase half-life was 14.2 hours. SN-38

showed a biphasic elimination profile with a mean terminal elimination half-life of 13.8 hours.

Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times

the upper normal limit. In these patients a 200 mg/m² irinotecan dose leads to plasma drug exposure

comparable to that observed at 350 mg/m² in cancer patients with normal liver parameters.

Linearity/non-linearity

A population pharmacokinetic analysis of irinotecan has been performed in 148 patients with

metastatic colorectal cancer, treated with various schedules and at different doses in phase II trials.

Pharmacokinetic parameters estimated with a three compartment model were similar to those observed

in phase I studies. All studies have shown that irinotecan (CPT-11) and SN-38 exposure increase

Campto LPD WC 040618

2017-0034028 Page 18 of 20

proportionally with CPT-11 administered dose; their pharmacokinetics are independent of the number

of previous cycles and of the administration schedule.

Pharmacokinetic/Pharmacodynamic relationship(s)

The intensity of the major toxicities encountered with CAMPTO

(e.g. leukoneutropenia and

diarrhoea) are related to the exposure (AUC) to parent drug and metabolite SN-38. Significant

correlations were observed between haematological toxicity (decrease in white blood cells and

neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN-38 AUC values in

monotherapy.

5.3.

Preclinical safety data

Irinotecan and SN-38 have been shown to be mutagenic in vitro in the chromosomal aberration test on

CHO-cells as well as in the in vivo micronucleus test in mice.

However, they have been shown to be devoid of any mutagenic potential in the Ames test.

In rats treated once a week during 13 weeks at the maximum dose of 150 mg/m² (which is less than

half the human recommended dose), no treatment-related tumours were reported 91 weeks after the

end of treatment.

Single- and repeated-dose toxicity studies with CAMPTO

have been carried out in mice, rats and

dogs. The main toxic effects were seen in the haematopoietic and lymphatic systems. In dogs, delayed

diarrhoea associated with atrophy and focal necrosis of the intestinal mucosa was reported. Alopecia

was also observed in the dog.

The severity of these effects was dose-related and reversible.

Reproduction

Irinotecan was teratogenic in rats and rabbits at doses below the human therapeutic dose. In rats, pups

born to treated animals with external abnormalities showed a decrease in fertility. This was not seen in

morphologically normal pups. In pregnant rats there was a decrease in placental weight and in the

offspring, a decrease in fetal viability and increase in behavioural abnormalities.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Sorbitol,

lactic acid,

sodium hydroxide (to adjust to pH 3.5),

hydrochloride acid (to adjust to pH 3.5) ,

water for injections.

6.2.

Incompatibilities

Campto LPD WC 040618

2017-0034028 Page 19 of 20

None known.

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

products.

6.3.

Shelf life

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

CAMPTO

solution is physically and chemically stable with infusion solutions (0.9% (w/v) sodium

chloride solution and 5% (w/v) glucose solution) for up to 28 days when stored in LDPE or PVC

containers at 5°C or at 30°C and protected from light. When exposed to light, physico-chemical

stability has been demonstrated for up to 3 days.

It is recommended, however, that in order to reduce microbiological hazard, the infusion solutions

should be prepared immediately prior to use and infusion commenced as soon as practicable after

preparation. If not used immediately, in-use storage times and conditions prior to use are the

responsibility of the user and should not be longer than 24 hours at 2°C to 8°C, unless dilution has

taken place in controlled and validated aseptic conditions.

6.4.

Special precautions for storage

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

- Store below 30°C.

- Store in the original package in order to protect from light.

6.5.

Nature and contents of container

Single amber-coloured medical-grade polypropylene vial closed with halobutyl rubber stopper. Vials

contain 40 mg/ 2ml; 100 mg/5 ml or 300 mg/15 ml of solution.

Not all pack sizes may be marketed.

6.6.

Special precautions for disposal and other handling

As with other antineoplastic agents, CAMPTO

must be prepared and handled with caution. The use

of glasses, mask and gloves is required.

If CAMPTO

solution or infusion solution should come into contact with the skin, wash immediately

and thoroughly with soap and water. If CAMPTO

solution or infusion solution should come into

contact with the mucous membranes, wash immediately with water.

Preparation for the intravenous infusion administration:

As with any other injectable medicinal product, the CAMPTO

solution must be prepared aseptically

(see section 6.3)

If any precipitate is observed in the vials or after dilution, the product should be discarded according to

standard procedures for cytotoxic agents.

Aseptically withdraw the required amount of CAMPTO

solution from the vial with a calibrated

syringe and inject into a 250 ml infusion bag or bottle containing either 0.9% sodium chloride solution

or 5%

glucose

solution. The infusion should then be thoroughly mixed by manual rotation.

Disposal:

Campto LPD WC 040618

2017-0034028 Page 20 of 20

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

requirements.

All materials used for dilution and administration should be disposed of according to hospital standard

procedures applicable to cytotoxic agents.

7.

Manufacturer: Pfizer (Perth) PTY Limited, Australia

8.

License Holder: Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya

Pituach, Israel 46725

9. License number: 106-12-29047

The content of this leaflet was approved by the Ministry of Health in July 2017 and updated according

to the guidelines of the Ministry of Health in June 2018