CONTROLOC I.V.

1

| P a g e

Takeda Israel Ltd. IL/PANV/0919/0004

25 Efal st., P.O.B 4140, Petach-Tikva 4951125

Tel:+972-

3- 33733140 Fax (local): + 972-3-3733150

וטקוא רב

2019

אפור

ה/דבכנ

חקור

דבכנ

:ןודנה

CONTROLOC

®

I.V. 40 mg/Vial

קולורטנוק

™

.

V

.

I

0

4

/ג"מ ) ןוקובקב לאיו

(

ןכדעתה ,ןודנבש רישכתה לש אפורל ןולעה יכ םכעידוהל תשקבמ מ"עב לארשי הדקט תרבח

רבמטפס

2019

וכדעה

הז בתכמב עיפומ הטמ ,

עדימל

ףסונ

שי

ןייעל

רגאמב

תופורתה

רתאבש

דרשמ

תואירבה

,ןכ ומכ לבקל ןתינ

קתעה

ספדומ

ןולעה לש

ינכדעה

ידי

:םושירה לעבל היינפ

לעפא 'חר ,מ"עב לארשי הדקט

חתפ ,

קת

,הו

:'לט

03-3733140

:לארשיב רישכתל תרשואמה היוותהה

Controloc I.V. is indicated for the treatment of duodenal ulcer, gastric ulcer, moderate and severe forms of

reflux oesophagitis, Zollinger Ellison Syndrome.

ביכרמ

ליעפ

:

Pantoprazole (as sodium) 40 mg/Vial

הכרבב

ידרו בהי

תחקור

הנוממ

הדקט

לארשי

עב

"

2

| P a g e

Takeda Israel Ltd. IL/PANV/0919/0004

25 Efal st., P.O.B 4140, Petach-Tikva 4951125

Tel:+972-

3- 33733140 Fax (local): + 972-3-3733150

פורל ןולעב ןוכדעה וניה א

טסקט

ףסונש

ןמוסמ

לוחכ טסקט ,

הרמחה הווהמה בוהצב שגדומ

:

4.8

Undesirable effects

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency

System

Organ Class

Common

Uncommon

Rare

Very rare

Not known

Gastrointestinal

disorders

Fundic gland

polyps

(benign)

Diarrhoea;

Nausea/

vomiting;

Abdominal

distension and

bloating;

Constipation;

Dry mouth;

abdominal pain

and discomfort

Microscopic colitis

This leaflet format was determined by the Israeli Ministry of Health (MOH) and its content was checked

and approved by the Israeli MOH in October 2016 and was updated according to the guidelines of the

Ministry of Health (MOH) in September 2019

PRESCRIBING INFORMATION

CONTROLOC

®

I.V.

1. NAME OF THE MEDICINAL PRODUCT

Controloc

I.V.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains pantoprazole sodium 42.3 mg (corresponding to pantoprazole 40 mg)

Excipients with known effect:

Each vial contains 1 mg disodium edetate and 0.24 mg sodium hydroxide.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially

‘sodium-free’.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injection.

White to off-white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

- duodenal ulcer

- gastric ulcer

- moderate and severe reflux oesophagitis

- Zollinger-Ellison-Syndrome

4.2 Posology and method of administration

This medicine should be administered by a healthcare professional and under appropriate medical

supervision.

Intravenous administration of Controloc

I. V. is recommended only if oral administration is not

appropriate. Data are available on intravenous use for up to 7 days.

Therefore, as soon as oral therapy is possible, treatment with Controloc

I.V. should be

discontinued and 40 mg pantoprazole p.o. should be administered instead.

Posology

Duodenal ulcer, gastric ulcer, moderate and severe reflux oesophagitis

The recommended intravenous dose is one vial of Controloc

I.V. (40 mg pantoprazole) per day.

Zollinger-Ellison-Syndrome

For the long-term management of Zollinger-Ellison-Syndrome patients should start their treatment with a

daily dose of 80 mg Controloc I.V. Thereafter, the dose can be titrated up or down as needed using

measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided

and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but

should not be applied longer than required for adequate acid control.

In case a rapid acid control is required, a starting dose of 2 x 80 mg Controloc

I.V. is sufficient to

manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of

patients.

Patients with hepatic impairment

A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in

patients with severe liver impairment (see section 4.4).

Patients with renal impairment

No dose adjustment is necessary in patients with impaired renal function (see section 5.2).

Older people

No dose adjustment is necessary in older patients (see section 5.2).

Paediatric population

The safety and efficacy of Controloc

I.V. in children aged under 18 years have not been

established. Therefore, Controloc

I.V. is not recommended for use in patients below 18 years of age.

Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

A ready-to-use solution is prepared in 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

For instructions for preparation see section 6.6. The prepared solution may be administered directly or

may be administered after mixing it with 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection,

or glucose 55 mg/ml (5%) solution for injection.

After preparation the solution must be used within 12 hours.

The medicinal product should be administered intravenously over 2 – 15 minutes.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles, or to any of the excipients listed in

section 6.1.

4.4 Special warnings and precautions for use

Gastric malignancy

Symptomatic response to pantoprazole may mask the symptoms of gastric malignancy and may delay

diagnosis. In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent

vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or

present, malignancy should be excluded.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Hepatic impairment

In patients with severe liver impairment, the liver enzymes should be monitored during therapy. In the case

of a rise of the liver enzymes, the treatment should be discontinued (see section 4.2).

Co-administration with HIV protease

inhibitors

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption

is dependent on acidic intragastric pH such as atazanavir, due to significant reduction in their

bioavailability (see section 4.5).

Gastrointestinal infections caused by bacteria

Treatment with Controloc

I.V.

may lead to a slightly increased risk of gastrointestinal infections caused

by bacteria such as

Salmonella

Campylobacter

C. difficile.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially ‘sodium-free’.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with PPIs like pantoprazole for at least

three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue,

tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin

insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium

replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or medicinal

products that may cause hypomagnesaemia (e.g., diuretics), health care professionals should consider

measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fractures

Proton pump inhibitors, especially if used in high doses and over long durations (>1 year), may modestly

increase the risk of hip, wrist and spine fracture, predominantly in older people or in the presence of other

recognized risk factors. Observational studies suggest that proton pump inhibitors may increase the

overall risk of fracture by 10–40%. Some of this increase may be due to other risk factors. Patients at risk

of osteoporosis should receive care according to current clinical guidelines and they should have an

adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in

sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help

promptly and the healthcare professional should consider stopping Controloc

I.V. SCLE after previous

treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Interference with Laboratory Tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To

avoid this interference, Controloc® I.V. treatment should be stopped for at least 5 days before CgA

measurements (see section 5.1). If CgA and gastrin levels have not returned to reference range after

initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor

treatment.

4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products with pH Dependent Absorption Pharmacokinetics

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with

the absorption of other medicinal products where gastric pH is an important determinant of oral

bioavailability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other

medicine such as erlotinib.

HIV protease inhibitors

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption

dependent

acidic

intragastric

such

atazanavir

significant

reduction

their

bioavailability (see section 4.4).

If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close

clinical monitoring (e.g. virus load) is recommended. A pantoprazole dose of 20 mg per day should not be

exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Coumarin anticoagulants (phenprocoumon or warfarin)

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics

of warfarin, phenoprocoumon or INR. However, there have been reports of increased INR and

prothrombin time in patients receiving PPIs and warfarin or phenoprocoumon concomitantly. Increases in

INR and prothrombin time may lead to abnormal bleeding, and even death.

Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase

in INR and prothrombin time.

Methotrexate

Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported

to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is

used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be

considered.

Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main

metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by

CYP3A4.

Interaction studies with medicinal products also metabolized with these pathways, like carbamazepine,

diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl

oestradiol did not reveal clinically significant interactions.

An interaction of pantoprazole with other medicinal products or compounds, which are metabolized using

the same enzyme system, cannot be excluded.

Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of

active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam,

diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with

p-glycoprotein related absorption of digoxin.

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed administering pantoprazole concomitantly with the

respective antibiotics (clarithromycin, metronidazole, amoxicillin).No clinically relevant interactions

were found.

Medicinal products that inhibit or induce CYP2C19:

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose

reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with

hepatic impairment.

Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John´s wort (Hypericum

perforatum) may reduce the plasma concentrations of PPIs that are metabolized through these enzyme

systems.

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no

malformative or feto/ neonatal toxicity of Controloc

I.V.

Animal studies have shown reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Controloc

I.V. during pregnancy.

Breast-feeding

Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on

the excretion of pantoprazole in human milk but excretion into human milk has been reported. A risk to the

newborns/infants cannot be excluded. Therefore a decision on whether to discontinue breast-feeding or to

discontinue/abstain from

Controloc

I.V.

therapy should take into account the benefit of breast-feeding for

the child, and the benefit of

Controloc

I.V.

therapy for the woman.

Fertility

There was no evidence of impaired fertility following the administration of pantoprazole in animal studies

(see section 5.3).

4.7 Effects on ability to drive and use of machines

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

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If

affected, patients should not drive or operate machines.

4.8 Undesirable effects

Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs). The

most commonly reported ADR is injection site thrombophlebitis. Diarrhoea and headache occurred

in approximately 1 % of patients.

The table below lists adverse reactions reported with pantoprazole, ranked under the following

frequency classification:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare

(≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available

data).

For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse

Reaction frequency and therefore they are mentioned with a “not known”

frequency.

Within

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

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency

System

Organ Class

Common

Uncommon

Rare

Very rare

Not known

Blood and

lymphatic system

disorders

Agranulocytosis

Thrombocytopenia;

Leukopenia;

Pancytopenia

Immune system

disorders

Hypersensitivity

(including

anaphylactic

reactions and

anaphylactic

shock)

Metabolism and

nutrition

disorders

Hyperlipidaemia

and lipid increases

(triglycerides,

cholesterol); Weight

changes

Hyponatraemia;

Hypomagnesaem-

(see section 4.4);

Hypocalcaemia

Hypokalaemia

Psychiatric

disorders

Sleep disorders

Depression (and

all aggravations)

Disorientation

(and all

aggravations)

Hallucination;

Confusion

(especially in

pre-disposed

patients, as well

as the

aggravation

of these

symptoms in

case of pre-

existence)

Nervous system

disorders

Headache;

Dizziness

Taste disorders

Paraesthesia

Eye disorders

Disturbances in

vision/ blurred

vision

Frequency

System

Organ Class

Common

Uncommon

Rare

Very rare

Not known

Gastrointestinal

disorders

Fundic gland

polyps

(benign)

Diarrhoea;

Nausea/

vomiting;

Abdominal

distension and

bloating;

Constipation;

Dry mouth;

abdominal pain

and discomfort

Microscopic colitis

Hepatobiliary

disorders

Liver enzymes

increased

(transaminases,

γ -GT);

Bilirubin

increased

Hepatocellular

injury; Jaundice;

Hepatocellular

failure

Skin and

subcutaneous tissue

disorders

Rash

/exanthema/

eruption;

Pruritus

Urticaria;

Angioedema

Stevens-Johnson

syndrome, Lyell

syndrome;

Erythema

multiforme;

Photosensitivity;

Subacute cutaneous

lupus

erythematosus (see

section 4.4)

Musculoskeletal

and connective

tissue disorders

Fracture of the

hip, wrist or

spine (see

section 4.4)

Arthralgia;

Myalgia

Muscle spasm

Renal and

urinary disorders

Interstitial

nephritis

(with possible

progression to

renal failure)

Reproductive

system and

breast disorders

Gynaecomastia

General

disorders and

administration site

conditions

Injection

site thrombo-

phlebitis

Asthenia,

fatigue and

malaise

Body temperature

increased;

Oedema

peripheral

Hypocalcaemia in association with hypomagnesemia

Muscle spasm as a consequence of electrolyte disturbance

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 events should be reported to the Ministry of Health according to the

National Regulation by using an online form

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

4.9 Overdose

There are no known symptoms of overdose in man.

Systemic exposure with up to 240 mg administered intravenously over 2 minutes, were well

tolerated. As pantoprazole is extensively protein bound, it is not readily dialysable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and

supportive treatment, no specific therapeutic recommendations can be made.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC

code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of

hydrochloric acid in the stomach by specific blockade of the proton pumps of the

parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells

where it inhibits the H

-ATPase enzyme, i.e. the final stage in the production of

hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and

stimulated acid secretion.

n most patients, freedom from symptoms is achieved within 2

weeks. As with other proton pump inhibitors and H2

receptor inhibitors, treatment with

pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the

reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the

enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently

of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same

whether the product is given orally or intravenously.

Pharmacodynamic effects

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they

do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in

most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild

to moderate increase in the number of specific endocrine (ECL) cells in the stomach is

observed in a minority of cases during long-term treatment (simple to adenomatoid

hyperplasia). However, according to the studies conducted so far, the formation of carcinoid

precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments

(see section 5.3) have not been observed in humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be

completely ruled out on endocrine parameters of the thyroid according to results in animal

studies.

During treatment with antisecretory medicinal products, serum gastrin increases in response to

the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The

increased CgA level may interfere with investigations for neuroendocrine tumours.

Available published evidence suggests that proton pump inhibitors should be discontinued

between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that

might be spuriously elevated following PPI treatment to return to reference range.

5.2 Pharmacokinetic properties

General pharmacokinetics

Pharmacokinetics does not vary after single or repeated administration. In the dose range of 10

to 80 mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous

administration.

Distribution

Pantoprazole's serum protein binding is about 98%.Volume of distribution is about 0.15 l/kg.

Biotransformation

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is

demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway

includes oxidation by CYP3A4.

Elimination

Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a few cases

of subjects with delayed elimination. Because of the specific binding of pantoprazole to the

proton pumps of the parietal cell the elimination half-life does not correlate with the much

longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80%) for the metabolites of

pantoprazole; the rest is excreted with the faeces. The main metabolite in both the serum and

urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main

metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Special populations

Poor metabolisers

Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are

called poor metabolisers. In these individuals the metabolism of pantoprazole is probably

mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the

mean area under the plasma concentration-time curve was approximately 6 times higher in

poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive

metabolisers). Mean peak plasma concentrations were increased by about 60 %. These

findings have no implications for the posology of pantoprazole.

Renal impairment

No dose reduction is recommended when pantoprazole is administered to patients with

impaired renal function (incl. dialysis patients). As with healthy subjects, pantoprazole's

half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main

metabolite has a moderately delayed half-life (2 – 3 h), excretion is still rapid and thus

accumulation does not occur.

Hepatic impairment

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life

values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the

maximum serum concentration only increased slightly by a factor of 1.5 compared with

healthy subjects.

Older people

A slight increase in AUC and C

in elderly volunteers compared with younger counterparts

is also not clinically relevant.

Paediatric population

Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to

children aged 2 - 16 years there was no significant association between pantoprazole

clearance and age or weight. AUC and volume of distribution were in accordance with data

from adults.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard to humans based on conventional studies

of safety pharmacology, repeated dose toxicity and genotoxicity.

In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In

addition, squamous cell papillomas were found in the forestomach of rats. The mechanism

leading to the formation of gastric carcinoids by substituted benzimidazoles has been

carefully investigated and allows the conclusion that it is a secondary reaction to the

massively elevated serum gastrin levels occurring in the rat during chronic high-dose

treatment. In the two-year rodent studies an increased number of liver tumors was observed

in rats and in female mice and was interpreted as being due to pantoprazole's high metabolic

rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats

receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated

with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As

the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.

In a peri-postnatal rat reproduction study designed to assess bone development, signs of

offspring toxicity (mortality, lower mean body weight, lower mean body weight gain and

reduced bone growth) were observed at exposures (C

) approximately 2x the human

clinical exposure. By the end of the recovery phase, bone parameters were similar across

groups and body weights were also trending toward reversibility after a drug-free recovery

period. The increased mortality has only been reported in pre-weaning rat pups (up to 21

days age) which is estimated to correspond to infants up to the age of 2 years old. The

relevance of this finding to the paediatric population is unclear. A previous peri-postnatal

study in rats at slightly lower doses found no adverse effects at 3 mg/kg compared with a

low dose of 5 mg/kg in this study.

Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with

advanced gestation. As a result, concentration of pantoprazole in the foetus is increased

shortly before birth.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium edetate

Sodium hydroxide

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

6.3 Shelf life

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

After reconstitution, or reconstitution and dilution, chemical and physical in-use stability has

been demonstrated for 12 hours at 25 °C.

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25°C.

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

For storage conditions of the reconstituted and diluted medicinal product see section 6.3.

6.5 Nature and contents of container

10 ml clear glass (type 1) vial with aluminum cap and grey rubber stopper containing 40 mg

powder for solution for injection.

Pack size of 1 vial with powder for solution for injection.

6.6 Special precautions for disposal

A ready-to-use solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9%)

solution for injection into the vial containing the powder. The appearance of the product after

reconstitution is a clear yellowish solution. This solution may be administered directly or may

be administered after mixing with 100 ml sodium chloride 9 mg/ml (0.9%) solution for

injection or glucose 55 mg/ml (5%) solution for injection. Glass or plastic containers should

be used for dilution.

After reconstitution, or reconstitution and dilution, chemical and physical in use stability has

been demonstrated for 12 hours at 25 °C.

From a microbiological point of view, the product should be used immediately.

Controloc

I.V. must not be prepared or mixed with solvents other than those stated.

The medicine should be administered intravenously over 2 -15 minutes.

The contents of the vial are for single use only. Any product that has remained in the

container or the visual appearance of which has changed (e.g. if cloudiness or

precipitation is observed) should be disposed of in accordance with local requirements.

7. MANUFACTURER:

Takeda GmbH

Byk-Gulden-Str. 2, D-78467 Konstanz

Germany

8. LICENSE HOLDER

Takeda Israel Ltd.

25 Efal st., P.O.B 4140, Petach Tikva

4951125

9. LICENSE NO.

129-41-30772-00