Provingo

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Provingo 40 mg/5 ml, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Indigo carmine ........................................................................... 40 mg
In 5 ml of injection solution.
For a complete 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
Medicinal product intended for diagnostic use only.
The medicinal product Provingo is indicated for intraoperative detection of ureteral injuries when such suspicion arises during abdominal or pelvic surgery.

4.2 Dosage and method of administration

Dosage
This medicinal product must be administered intravenously. The recommended initial dose is 5 ml (1 ampoule) given as a slow intravenous injection.
If necessary, the contents of a second ampoule (5 ml) may be administered 20–30 minutes after the first injection.

Children and adolescents
The safety and efficacy of the medicinal product Provingo in children have not been established.

Patients with renal impairment
Provingo may be used in patients with creatinine clearance ≥ 10 ml/min.
However, the medicinal product Provingo must not be used in patients with creatinine clearance < 10 ml/min. (see section 4.4).

Patients with hepatic impairment
Excretion of indigo carmine occurs mainly via the kidneys. There are no data available in patients with hepatic impairment; however, dosage adjustment is not required.

Elderly
Dosage adjustment is not required.

Method of administration
Slow intravenous injection with monitoring of arterial blood pressure and heart rate.

Precautions to be taken before administration of this medicinal product
Because the medicinal product Provingo is intensely blue in color, the use of a filter is recommended during intravenous administration (e.g., a 0.45 μm filter, with a filtration area of at least 2.8 cm², with 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
Indocyanine green may cause transient increases in blood pressure and reflex bradycardia, especially in patients under general or spinal anesthesia. Rare idiosyncratic reactions with bradycardia and hypotension have also been reported. Therefore, monitoring of heart rate and arterial blood pressure is required during and for several minutes after injection. Intravenous administration must be discontinued if the following symptoms occur: bradycardia, tachycardia, hypotension, hypertension, rash or flushing, or respiratory symptoms such as dyspnea or bronchospasm.
In patients with creatinine clearance < 10 ml/min, the time to appearance of indocyanine green in urine may be delayed by several minutes. Therefore, it should not be used in patients with creatinine clearance < 10 ml/min.
Indocyanine green may interfere with pulse oximeter readings.
Following administration of indocyanine green, a change in urine color should occur.

Precautions for use
Indocyanine green should be used with caution in the following cases:

• concomitant use of drugs causing bradycardia,
• cardiac rhythm and conduction disorders,
• high blood pressure,
• low heart rate,
• coronary artery disease, due to its peripheral vasoconstrictive effect.

Indocyanine green should be avoided in patients with:

• uncontrolled heart failure,
• history of allergic reactions,
• hemodynamic instability.

4.5 Interactions with other medicinal products and other forms of interaction

No interaction studies have been conducted.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no data or only limited data on the use of indigotine in pregnant women.
Animal studies on reproductive toxicity are insufficient (see section 5.3).
Provingo should not be used during pregnancy or in women of childbearing potential who are not using effective contraception.

Breastfeeding
It is unknown whether indigotine or its metabolites are excreted in human milk.
A risk to newborns/infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from indigotine administration, taking into account the benefits of breastfeeding for the child and the benefits of treatment for the mother.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

The most common undesirable effects of indygotine are mainly related to its alpha-adrenergic activity and concern the cardiovascular system. Other idiosyncratic reactions have also been reported, such as changes in blood pressure, increased heart rate, or anaphylactoid reactions. Serious undesirable effects of indygotine 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 < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (frequency cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in descending order of severity, from the most severe to the least severe.

Reporting suspected adverse reactions
It is important to report suspected adverse reactions after the medicinal product has been authorised. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system:
Department for Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C,
02 222 Warsaw, Phone: +48 22 49 21 301, Fax: +48 22 49 21 309, Website:
https://smz.ezdrowie.gov.pl.
Adverse reactions may also be reported to the marketing authorisation holder.

4.9 Overdose

There have been no reported cases in the literature of overdose with intravenous doses of indigo carmine up to 80 mg.
Symptoms
Overdose may cause hypertensive crisis and severe bradycardia.
Management
In the event of overdose, treatment with peripheral vasodilators may be considered.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: DIAGNOSTIC AGENTS, ATC code: V04CH02
Indigo carmine is a dye used clinically for diagnostic purposes. After intravenous administration, it causes dark blue discoloration of urine within 4–9 minutes after injection. The intense coloration enables detection of any pathological changes in the urinary tract.
Due to its alpha-adrenergic properties, indigo carmine increases peripheral vascular resistance, resulting in a moderate and transient increase in blood pressure and probably a reactive, moderate decrease in heart rate.
To assess the diagnostic efficacy of indigo carmine in detecting ureteral injuries during abdominal and pelvic surgery, a meta-analysis of published studies was performed.
The meta-analysis demonstrated high sensitivity and specificity of the indigo carmine 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 prevalence of 2.3%). The resulting likelihood ratio further confirms that the diagnostic test with indigo carmine 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 indigo carmine were also evaluated in a randomized, within-patient, controlled, multicenter study with blinded assessment of indigo carmine (Provingo) involving 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 indigo carmine intravenously before completion of the surgical procedure. Each patient underwent cystoscopy and received an injection of 5 ml of 0.9% sodium chloride followed by a randomized dose of indigo carmine to visualize urine flow from the ureteral orifices. The 2.5 ml dose is not authorized for marketing (see section 4.2).
Visualization of urine efflux was significantly better after administration of indigo carmine (at doses of 5 ml and/or 2.5 ml) compared to saline.

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

Data on acute toxicity of indigotine are available from studies in rats and mice. In rats, the LD50 (median lethal single dose) is 93 mg/kg body weight following intravenous administration, while in mice the LD50 is 405 mg/kg body weight following subcutaneous administration.
Carcinogenicity studies with intravenously administered indigotine have not been conducted. However, long-term studies in rats (oral administration) and mice (subcutaneous administration) showed no carcinogenic effects.
Studies in rats and rabbits using orally administered doses of indigotine up to 250 mg/kg body weight/day did not reveal any teratogenic effects. However, oral bioavailability is approximately 3%. Therefore, based on available data, the risk associated with intravenous administration of indigotine during pregnancy cannot be assessed.
6. PHARMACEUTICAL DATA
6.1 List of excipients
Water for injections.
Citric acid monohydrate (for pH adjustment).
Sodium citrate (for pH adjustment).

6.2 Pharmaceutical incompatibilities

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

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 user is responsible for the duration and storage conditions prior to administration.

6.4 Special precautions during storage

Do not store in the refrigerator or freeze.

6.5 Type and contents of the container

5 ml amber glass type I ampoules, pack containing 5 ampoules.

6.6 Special precautions for disposal and preparation of the medicinal product for administration

Any unused residues of the medicinal product or its waste must be disposed of in accordance with local regulations.

7. MARKETING AUTHORISATION HOLDER

PROVEPHARM SAS
22, rue Marc Donadille
13013 Marseille
France

8. MARKETING AUTHORISATION NUMBER(S)

FOR SALE

9. DATE OF FIRST AUTHORISATION OR RENEWAL OF THE AUTHORISATION

DATE OF FIRST AUTHORISATION OR RENEWAL OF THE AUTHORISATION
Date of first authorisation: 21/03/2023
Date of latest renewal:

10. DATE OF ADOPTION OR PARTIAL CHANGE OF THE TEXT

SUMMARY OF PRODUCT CHARACTERISTICS
04/10/2023
PACKAGING LABELS
INFORMATION ON OUTER PACKAGING
Cardboard box

1. NAME OF THE MEDICINAL PRODUCT

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

2. COMPOSITION OF ACTIVE SUBSTANCE(S)

Each ml of solution contains 8 mg of indigo carmine.
Each 5 ml ampoule contains 40 mg of indigo carmine.

3. LIST OF EXCIPIENTS

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

4. PHARMACEUTICAL FORM AND PACKAGING CONTENTS

Injection solution.
5 vials of 5 ml each: code 3760237160683

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the instruction leaflet before using the medicine.
For intravenous use only.
For slow intravenous injection.

6. WARNING ON STORAGE OF THE MEDICINAL PRODUCT

KEEP OUT OF SIGHT AND REACH OF CHILDREN
Keep the medicine in a place out of sight and reach of children.
7. OTHER SPECIAL WARNINGS, IF NECESSARY
8. EXPIRY DATE
EXP
The medicine should be used immediately after opening.

9. SPECIAL STORAGE CONDITIONS

Do not store in the refrigerator or freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED

MEDICINAL PRODUCT OR WASTE DERIVING FROM IT, IF
APPLICABLE
For single use only.
Any residue solution remaining in opened ampoules must be discarded.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Marketing authorisation holder:
Provepharm SAS
22, rue Marc Donadille
13013 Marseille
France
For further information regarding this medicinal product, please contact the local representative of the marketing authorisation holder:
Apfel Pharm Sp. z o.o.
Ul. Marszałka Józefa Piłsudskiego 6
59-850 Świeradów-Zdrój
Tel: +48 694 775 205

12. MARKETING AUTHORISATION NUMBER(S)

Marketing authorisation number:

13. LOT NUMBER

Lot number (Lot)

14. GENERAL CATEGORY OF AVAILABILITY

Lz – Medicinal product used in inpatient care
15. INSTRUCTIONS FOR USE
16. INFORMATION PROVIDED IN BRAILLE SYSTEM
Justification for the absence of information in Braille accepted.

17. UNIQUE IDENTIFIER – 2D CODE

Includes a 2D code serving as a carrier of the unique identifier.

18. UNIQUE IDENTIFIER – HUMAN-READABLE DATA

PC:
SN:
NN:
MINIMUM INFORMATION TO BE INDICATED ON SMALL IMMEDIATE PACKAGING
IMMEDIATE PACKAGING
AMPULLE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Provingo 40 mg/5 ml, solution for injection
Indygotyna
For intravenous use only
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP

4. BATCH NUMBER

Lot

5. CONTENTS OF THE PACKAGE WITH INDICATION OF MASS, VOLUME OR NUMBER OF UNITS

40 mg/5 ml

6. OTHER

Package leaflet: Information for the user

Provingo 40 mg/5 ml, solution for injection
Indigotin
Please read all of this leaflet carefully before use, as it contains important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Leaflet contents

1. What Provingo is and what it is 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 pack and other information

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

Pharmacotherapeutic group: diagnostic agents, ATC code: V04CH02
Provingo contains the active substance indigotin.
This medicine is intended for diagnostic use only.
It is a blue dye used by surgeons and anaesthetists during abdominal surgery. It causes urine to turn blue within 4 to 9 minutes after injection.
This colouration helps identify the ureters (tubes carrying urine from the kidneys to the bladder) and verify whether they have been damaged during surgery.

2. Important information before using Provingo

When not to use Provingo

• if the patient is allergic to indigotin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Before using Provingo, discuss with your doctor, pharmacist, or nurse:

• if the patient is taking medicines that slow the heart rate,
• if the patient has heart rhythm disorders (too fast, too slow, or irregular heartbeat) or conduction disorders in the heart,
• if the patient has hypertension (excessively high blood pressure in the arteries),
• if the patient has heart failure (impaired heart function) or angina pectoris (heart disease characterized by acute chest pain that may radiate to adjacent areas),
• if the patient has had allergic reactions in the past,
• if the patient is pregnant,
• if the patient is breastfeeding. After administration of this medicine, blue discoloration of urine should occur.

Children and adolescents
Not applicable.
Provingo and other medicines
Inform your doctor, pharmacist, or nurse about all medicines the patient is currently using or has recently used, as well as any medicines the patient plans to use.
Provingo with food, drink, and alcohol
Not applicable.
Pregnancy, breastfeeding, and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.
As a precautionary measure, it is recommended to avoid using this medicine during pregnancy or breastfeeding.
Driving and operating machinery
Not applicable.

3. How to use Provingo

The medicine will be administered by a qualified healthcare professional via slow intravenous injection.
The recommended dose is 5 ml (1 vial) given as a slow intravenous injection. If necessary, the contents of a second vial (5 ml) may be administered 20–30 minutes after the first injection.
Use of a higher than recommended dose of Provingo
The doctor will monitor blood pressure and heart rate.
Overdose may cause hypertensive crisis (sudden increase in arterial blood pressure) and bradycardia (slowed heart rate).
Treatment with peripheral vasodilators (to help lower blood pressure) may be considered.
If you have any further questions about the use of this medicine, please consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.

• Increase or decrease in blood pressure
• Slowing or speeding of the heart rate
• Conduction disorders in the heart
• Breathing difficulties
• Rash or skin discoloration

Reporting of adverse reactions
If any adverse reactions occur, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the 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.
Reporting adverse reactions helps to provide more information on the safety of the medicine.
Adverse reactions can also be reported to the marketing authorization holder.

5. How to store Provingo

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and carton after the word “EXP”. The expiry date refers to the last day of the stated month.
Do not store in the refrigerator or freeze.
After opening the vial: the medicine must be used immediately.
Medicines must not be disposed of via wastewater. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.
The batch number is indicated by the abbreviation “Lot”.

6. Contents of the pack and other information

What Provingo contains

• The active substance is indigotin. Each ml of solution contains 8 mg of indigotin. Each 5 ml vial contains 40 mg of indigotin.
• The other ingredients are: water for injections, monohydrate citric acid and/or sodium citrate (to adjust pH).

What Provingo looks like and contents of the pack
This medicine is a solution for injection ranging in colour from blue to blue-violet, supplied in vials made of brown glass. Each carton contains a tray with 5 vials of 5 ml.
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
For further information about this medicine, 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]

The following information is intended for healthcare professionals only:
Dosage
This medicine is intended for intravenous injection. The recommended initial dose is 1 vial of 5 ml administered as a slow intravenous injection.
If necessary, a second vial may be injected 20–30 minutes after the first injection.
Children
The efficacy and safety of Provingo in children have not been established.
Patients with renal impairment
Provingo may be administered to patients with a creatinine clearance ≥ 10 ml/min.
Provingo should not be administered to patients with a creatinine clearance < 10 ml/min.
Patients with hepatic impairment
Elimination of Provingo occurs primarily via the kidneys. Although data in patients with hepatic impairment are lacking, dose adjustment is not necessary.
Elderly patients
Dose adjustment is not required.
Storage
Before opening: no special storage conditions required.
After opening the vial: the medicine must be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.