Provingo

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Provingo 40 mg/5 ml, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Indigotin ................................................................................. 40 mg
In 5 ml of solution for injection.
A full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.
Blue to blue-purple, solution for injection.
pH: 3.6 to 6.5
Osmolality: 0.025-0.030 osmol/l

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

The medicinal product is intended for diagnostic purposes only.
The Provingo medicinal product is indicated for the intraoperative detection of ureteral injuries, if such suspicion arises during abdominal and pelvic surgery.

4.2 Dosage and Administration

Dosage
This medicinal product should be administered intravenously. The recommended initial dose is 5 ml (1 ampoule) in slow intravenous injection.
If necessary, the contents of a second ampoule (5 ml) can be injected 20-30 minutes after the first injection.
Children and Adolescents
The safety and efficacy of the Provingo medicinal product in children have not been established.
Patients with Renal Impairment
Provingo may be used in patients with a creatinine clearance of ≥ 10 ml/min.
However, the Provingo medicinal product should not be used in patients with a creatinine clearance of <10 ml min (see section 4.4).
Patients with Hepatic Impairment
Indigotin is mainly excreted by the kidneys. Although there are no data on patients with hepatic impairment, dose adjustment is not necessary.
Elderly
Dose adjustment is not necessary.
Administration
Slow intravenous injection with control of arterial pressure and heart rate.
Precautions to be taken before administration of this medicinal product
Since the Provingo medicinal product has an intense blue color, it is recommended to use a filter when administering intravenously (e.g., 0.45 μm filter, with a filtration area of at least 2.8 cm², in a hydrophilic polyethersulfone membrane).

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Special warnings
Indigotin may cause transient hypertension and reflex bradycardia, especially in patients under general or spinal anesthesia. Rare idiosyncratic reactions with bradycardia and hypotension have also been reported. Therefore, it is necessary to monitor heart rate and blood pressure during and for several minutes after injection.
Intravenous administration should be discontinued if the following symptoms occur: bradycardia, tachycardia, hypotension, hypertension, rash, or respiratory symptoms such as dyspnea or bronchospasm.
In patients with a creatinine clearance of <10 ml min, the time to appearance of indigotin in urine may be delayed by several minutes. therefore, it should not used patients with a creatinine clearance < 10 min (see section 4.4).
Indigotin may interfere with pulse oximetry readings.
After administration of indigotin, a change in urine color should occur.
Precautions for use
Indigotin should be used with caution in the following cases:

• concomitant use of drugs that cause bradycardia,
• cardiac rhythm and conduction disorders,
• hypertension,
• low heart rate,
• coronary artery disease, due to the vasoconstrictive effect. It is recommended to avoid the use of indigotin in patients with:
• uncontrolled heart failure,
• history of allergic reactions,
• hemodynamic instability.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

No interaction studies have been performed.

4.6 Fertility, Pregnancy, and Lactation

Pregnancy
There are no data or only limited data on the use of indigotin in pregnant women.
Animal studies on reproductive toxicity are insufficient (see section 5.3).
The Provingo product is not recommended for use during pregnancy and in women of childbearing potential not using effective contraception.
Breast-feeding
It is not known whether indigotin or its metabolites pass into human milk.
A risk to newborns/infants cannot be excluded.
A decision must be made to either discontinue breast-feeding or discontinue/withhold indigotin administration, taking into account the benefit of breast-feeding to the child and the benefit of treatment to the mother.

4.7 Effects on Ability to Drive and Use Machines

Not applicable.

4.8 Undesirable Effects

The most common undesirable effects of indigotin are mainly related to its alpha-adrenergic activity and concern the cardiovascular system.
Other idiosyncratic reactions, such as changes in blood pressure, acceleration of heart rate, or anaphylactoid reactions, have also been reported. Serious undesirable effects of indigotin occur very rarely.
Undesirable effects are listed below by system organ class and frequency of occurrence, using the following convention: very common (≥ 1/10); common (≥ 1/100 to <1>

• 000); not known (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Reporting of Suspected Undesirable Effects
After authorization of the medicinal product, it is important to report any suspected undesirable effects. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected undesirable effects via the national reporting system:
Department of Monitoring of Adverse Reactions to Medicinal Products, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, PL-02 222 Warsaw, Tel.: + 48 22 49 21 301, Fax: + 48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl.
Undesirable effects can also be reported to the marketing authorization holder.

4.9 Overdose

No cases of overdose with intravenously administered doses of up to 80 mg of indigotin have been reported in the literature.
Symptoms
Overdose may cause a hypertensive crisis and severe bradycardia.
Management
In the event of overdose, the use of a vasodilator may be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Therapeutic Group: Diagnostic Agents, ATC Code: V04CH02
Indigotin is a dye used clinically for diagnostic purposes. After intravenous administration, it causes a dark blue discoloration of the urine within 4-9 minutes of injection. The intense discoloration allows for the detection of any pathological changes in the urinary tract.
Indigotin, due to its alpha-adrenergic properties, causes an increase in peripheral vascular resistance, resulting in a moderate and transient increase in blood pressure and probably a reactive, moderate decrease in heart rate.
To evaluate the diagnostic efficacy of indigotin in detecting ureteral injuries during abdominal and pelvic surgery, a meta-analysis of published studies was used.
The meta-analysis showed high sensitivity and specificity of the indigotin test (89.2% and 99.7%, respectively), as well as its impact on the diagnostic process (positive predictive value 86.7% and negative predictive value 99.7% in a population with a ureteral injury rate of 2.3%). The likelihood ratio also confirms that the indigotin diagnostic test is useful for confirming both the presence (positive likelihood ratio 285) and absence (negative likelihood ratio 0.111) of ureteral injury during abdominal and pelvic surgery.
The safety and efficacy of indigotin were also evaluated in a randomized, controlled, intra-individual, multicenter study with an unknown dose of indigotin (Provingo) in 118 adult patients undergoing urological or gynecological surgical procedures.
Patients were randomly assigned in a 1:1 ratio to receive either 2.5 ml or 5 ml of indigotin intravenously before the end of the surgical procedure. Each patient underwent cystoscopy and received an injection of 5 ml of 0.9% sodium chloride, followed by a random dose of indigotin to visualize the flow of urine from the ureteral orifices. The 2.5 ml dose is not approved for marketing (see section 4.2).
Visualization of urine flow was significantly better after indigotin injection (at doses of 5 ml and/or 2.5 ml) than after sodium chloride injection.

5.2 Pharmacokinetic Properties

Indigotin is extensively and reversibly bound to plasma proteins after intravenous administration.
It is rapidly eliminated from the plasma and largely excreted by the kidneys. A small amount is excreted in the bile.
The pharmacokinetic profile of indigotin was evaluated in a pharmacokinetic study in healthy volunteers; in this study, the half-life of indigotin in plasma was 12 minutes.
In the case of renal impairment, the mean elimination time may be prolonged by several minutes.

5.3 Preclinical Safety Data

Data on the acute toxicity of indigotin are available from studies in rats and mice. In rats, the LD50 (median lethal dose) is 93 mg/kg body weight after intravenous administration, and in mice, the LD50 is 405 mg/kg body weight after subcutaneous administration.
No carcinogenicity studies have been performed with intravenously administered indigotin. However, long-term studies in rats (oral administration) and mice (subcutaneous administration) did not show any carcinogenic effects.
In studies conducted in rats and rabbits using orally administered doses of up to 250 mg/kg body weight/day, no teratogenic effects were observed. However, the bioavailability after oral administration is approximately 3%, so the risk associated with intravenous administration of indigotin during pregnancy cannot be assessed based on the available data.

6. PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Water for injections.
Citric acid monohydrate (for pH adjustment).
Sodium citrate (for pH adjustment).

6.2 Incompatibilities

Since compatibility studies have not been performed, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years
After opening: from a microbiological point of view, the product should be used immediately. If the product is not used immediately, the in-use storage times and conditions are the responsibility of the user.

6.4 Special Precautions for Storage

Do not store in a refrigerator or freeze.

6.5 Nature and Contents of Container

Ampoules of type I brown glass with a capacity of 5 ml, pack containing 5 ampoules.

6.6 Special Precautions for Disposal and Administration

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

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

PROVEPHARM SAS
22, rue Marc Donadille
13013 Marseille
France

8. MARKETING AUTHORIZATION NUMBER(S)

227725

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

Date of first authorization: 21/03/2023
Date of last renewal:

10. DATE OF REVISION OF THE TEXT

Summary of Product Characteristics

04/10/2023

LABELING OF OUTER PACKAGING

INFORMATION TO APPEAR ON THE OUTER PACKAGING

Carton

1. NAME OF THE MEDICINAL PRODUCT

Provingo, 40 mg/5 ml, solution for injection
Indigotin

2. CONTENTS OF THE ACTIVE SUBSTANCE(S)

Each ml of solution contains 8 mg of indigotin.
Each 5 ml ampoule contains 40 mg of indigotin.

3. LIST OF EXCIPIENTS

Excipients: water for injections, citric acid monohydrate (for pH adjustment), sodium citrate (for pH adjustment).

4. PHARMACEUTICAL FORM AND CONTENTS OF THE PACKAGING

Solution for injection.
5 ampoules of 5 ml each
Code: 3760237160683

5. METHOD AND ROUTE OF ADMINISTRATION

Read the package leaflet before use.
For intravenous use only.
For slow intravenous injection.

6. SPECIAL WARNING FOR STORAGE OF THE MEDICINAL PRODUCT

OUT OF THE SIGHT AND REACH OF CHILDREN

Keep the medicinal product out of the sight and reach of children.

7. OTHER SPECIAL WARNINGS, IF NECESSARY

8. EXPIRY DATE

EXP
The medicinal product should be used immediately after opening.

9. SPECIAL STORAGE CONDITIONS

Do not store in a refrigerator or freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS, IF APPROPRIATE

For single use only.
Any remaining solution in opened ampoules should be discarded.

11. NAME AND ADDRESS OF THE MARKETING AUTHORIZATION HOLDER

Marketing Authorization Holder:
PROVEPHARM SAS
22, rue Marc Donadille
13013 Marseille
France
To obtain more information on this medicinal product, please contact the local representative of the Marketing Authorization Holder:

12. MARKETING AUTHORIZATION NUMBER(S)

Marketing Authorization Number:

13. BATCH NUMBER

Batch Number (Lot)

14. GENERAL CATEGORY OF DISPENSING

Lz – Medicinal product for hospital use

15. INSTRUCTIONS FOR USE

16. INFORMATION IN BRAILLE

Justification for the absence of Braille information has been accepted.

17. UNIQUE IDENTIFIER – 2D BAR CODE

Includes a 2D bar code that is a carrier of the unique identifier.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

MINIMUM INFORMATION TO APPEAR ON SMALL OUTER PACKAGING

Ampoule

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION

Provingo 40 mg/5 ml, solution for injection
Indigotin
For intravenous use only

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS OF THE PACKAGING WITH DOSE, VOLUME, OR NUMBER OF UNITS

40 mg/5 ml

6. OTHER

PATIENT INFORMATION LEAFLET

Patient Information Leaflet: Information for the User

Provingo 40 mg/5 ml, solution for injection

Indigotin

Read the package leaflet carefully before using the medicinal product, as it contains important information for the patient.

• Keep this package leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this package leaflet, please inform your doctor, pharmacist, or nurse. See section 4.

Table of Contents

• 1. What is Provingo and what is it used for
• 2. Important information before using Provingo
• 3. How to use Provingo
• 4. Possible side effects
• 5. How to store Provingo
• 6. Contents of the packaging and other information

1. What is Provingo and what is it used for?

Therapeutic Group: Diagnostic Agents, ATC Code: V04CH02
Provingo contains the active substance indigotin.
This medicinal product is intended for diagnostic purposes only.
It is a blue dye used by surgeons and anesthesiologists during abdominal surgery. It discolors the urine (to a dark blue color) within 4 to 9 minutes of injection.
This discoloration allows for the detection of the ureters (tubes that carry urine from the kidneys to the bladder) and verification that they have not been damaged during surgery.

2. Important information before using Provingo

When not to use Provingo

• if you are allergic to indigotin or any of the other ingredients of this medicinal product (listed in section 6).

Warnings and precautions

Before using Provingo, you should discuss with your doctor, pharmacist, or nurse:

• if you are taking medications that slow down your heart rate,
• if you have cardiac rhythm or conduction disorders,
• if you have high blood pressure,
• if you have a low heart rate,
• if you have coronary artery disease, due to the vasoconstrictive effect. It is recommended to avoid the use of indigotin in patients with:
• uncontrolled heart failure,
• a history of allergic reactions,
• hemodynamic instability.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicinal product.
As a precautionary measure, it is recommended not to use this medicinal product during pregnancy or breast-feeding.

Driving and using machines

Not applicable.

3. How to use Provingo

The medicinal product will be administered by a qualified healthcare professional through slow intravenous injection.
The recommended dose is 5 ml (1 ampoule) in slow intravenous injection. If necessary, the contents of a second ampoule (5 ml) can be injected 20-30 minutes after the first injection.
Overdose
Your doctor will monitor your blood pressure and heart rate.
Overdose may cause a hypertensive crisis and severe bradycardia.
Vasodilator therapy may be considered.

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

4. Possible side effects

Like all medicinal products, Provingo can cause side effects, although not everybody gets them.

• Changes in blood pressure
• Changes in heart rate
• Conduction disorders in the heart
• Respiratory difficulties
• Rash or skin discoloration

Reporting of side effects

If you experience any side effects, including those not listed in this package leaflet, please inform your doctor, pharmacist, or nurse. Side effects can be reported to the Department of Monitoring of Adverse Reactions to Medicinal Products, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, PL-02 222 Warsaw, Tel.: + 48 22 49 21 301, Fax: + 48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl.
By reporting side effects, you can help provide more information on the safety of this medicinal product.
Side effects can also be reported to the marketing authorization holder.

5. How to store Provingo

Keep the medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the ampoule label and carton after the words "EXP". The expiry date refers to the last day of the month.
Do not store in a refrigerator or freeze.
After opening the ampoule: the medicinal product should be used immediately.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.
For the batch number, the abbreviation "Lot" is used.

6. Contents of the packaging and other information

What Provingo contains

• The active substance is indigotin. Each ml of solution contains 8 mg of indigotin. Each 5 ml ampoule contains 40 mg of indigotin.
• The other excipients are: water for injections, citric acid monohydrate, and sodium citrate (for pH adjustment).

What Provingo looks like and contents of the packaging

This medicinal product is a solution for injection, blue to blue-purple in color, packaged in brown glass ampoules. Each carton contains a tray of 5 ampoules of 5 ml each.

Marketing Authorization Holder

PROVEPHARM SAS
22, rue Marc Donadille
13013 Marseille
France

Manufacturer

Cenexi
52, rue Marcel et Jacques Gaucher
94120 Fontenay-sous-Bois
France

To obtain more information on this medicinal product, please contact the local representative of the Marketing Authorization Holder:

Apfel Pharm Sp. z o.o.
Ul. Marszałka Józefa Piłsudskiego 6
59-850 Świeradów-Zdrój
Tel: +48 694 775 205
Email: [email protected]
Date of last revision of the package leaflet:04/10/2023
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The following information is intended for healthcare professionals only:

Dosage

This medicinal product is intended for intravenous administration. The recommended initial dose is 1 ampoule of 5 ml in slow intravenous injection.
If necessary, a second ampoule can be injected 20-30 minutes after the first injection.
Children
The safety and efficacy of the Provingo medicinal product in children have not been established.
Patients with Renal Impairment
Provingo may be used in patients with a creatinine clearance of ≥ 10 ml/min.
Provingo should not be used in patients with a creatinine clearance of <10 ml min.
Patients with Hepatic Impairment
Indigotin is mainly excreted by the kidneys. Although there are no data on patients with hepatic impairment, dose adjustment is not necessary.
Elderly
Dose adjustment is not necessary.

Storage

Before opening: no special storage precautions are necessary.
After opening the ampoule: the medicinal product should be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.