Dotagraf multidose

Package leaflet: Information for the user

Dotagraf multidose, 0.5 mmol/ml
Injection solution
Gadoterinic acid
Please read all of this leaflet carefully before this medicine is administered, because it contains
important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• If you have any further questions, please ask your doctor or radiologist.
• If you experience any side effects, including any not listed in this leaflet, please inform your doctor or radiologist. See section 4.

Leaflet contents

1. What Dotagraf multidose is and what it is used for
2. What you need to know before receiving Dotagraf multidose
3. How to use Dotagraf multidose
4. Possible side effects
5. How to store Dotagraf multidose
6. Contents of the pack and other information

1. What Dotagraf multidose is and what it is used for

Dotagraf multidose is a contrast agent containing gadoterinic acid. It is intended for diagnostic use only.
Dotagraf multidose is used to enhance image contrast in magnetic resonance imaging (MRI) scans. This contrast enhancement improves the visibility and differentiation of images:
Adults, children and adolescents (0–18 years)

• in MRI of the central nervous system, including abnormalities (pathological changes) in the brain, spinal cord and surrounding tissues;
• in whole-body MRI diagnostics, including abnormalities (pathological changes) in the liver, kidneys, pancreas, pelvis, lungs, heart, breast and musculoskeletal system.

Adults

• in MR angiography, including abnormalities (pathological changes) and narrowing (stenosis) of arteries, except coronary arteries.

2. Important information before using Dotagraf multidose

When NOT to use Dotagraf multidose

• if the patient is allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6.).
• if the patient is allergic to gadolinium-containing medicines (such as other contrast agents used in magnetic resonance imaging).

Warnings and precautions
Before starting Dotagraf multidose, inform your doctor or radiologist if any of the following apply to the patient:

• the patient previously experienced a reaction to a contrast agent during an examination.
• the patient has asthma.
• the patient has had allergies in the past (e.g. allergy to seafood, hives, hay fever).
• the patient is being treated with beta-blockers (medicines used to treat heart disorders and high blood pressure, such as metoprolol).
• the patient's kidneys are not working properly.
• the patient recently underwent or is scheduled to undergo a liver transplant.
• the patient suffers from heart or blood vessel disease.
• the patient has had seizures or is being treated for epilepsy.

In all these cases, the doctor or radiologist will evaluate the benefit-risk ratio and decide whether Dotagraf multidose can be administered to the patient. If Dotagraf multidose is administered, the doctor or radiologist will take necessary precautions and the administration of Dotagraf multidose will be closely monitored.
The doctor or radiologist may decide to perform a blood test to check the patient's kidney function before deciding to administer Dotagraf multidose, especially in patients aged 65 years and older.
Newborns and infants
Due to immature kidney function in newborns up to 4 weeks of age and infants up to 1 year of age, Dotagraf multidose will be used in these patients only after careful consideration by the doctor.
Before the examination, all metallic objects the patient may be wearing should be removed. Inform the doctor or radiologist if the patient has any of the following implanted devices:

• cardiac pacemaker,
• vascular clip,
• infusion pump,
• nerve stimulator,
• cochlear implant (inner ear implant),
• or if there is suspicion of any metallic foreign body, especially in the eye. This is very important because magnetic resonance imaging systems use very strong magnetic fields, which may cause serious problems.

Dotagraf multidose and other medicines
Tell the doctor or radiologist if the patient is taking, has recently taken, or might have taken any other medicines. In particular, inform the doctor, radiologist, or pharmacist if the patient is currently taking or has recently taken medicines for heart disorders or high blood pressure, such as beta-blockers, vasoactive agents, angiotensin-converting enzyme inhibitors, or angiotensin II receptor antagonists.
Dotagraf multidose with food and drink
No interactions between Dotagraf multidose and food or beverages are known. However, ask your doctor, radiologist, or pharmacist whether fasting or abstaining from drinking is required before the examination.
Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she might be pregnant, or is planning to have a child, she should consult her doctor or radiologist before using this medicine.
Pregnancy
Gadoterate acid may cross the placenta. It is not known whether this affects the unborn child. Dotagraf multidose should not be used during pregnancy unless absolutely necessary.
Breastfeeding
The treating doctor or radiologist will discuss with the patient and explain whether she can continue breastfeeding or should interrupt it for 24 hours after administration of Dotagraf multidose.
Driving and operating machinery
There are no available data on the effect of Dotagraf multidose on the ability to drive. If the patient feels unwell after the examination, he/she should not drive or operate machinery.

3. How to use Dotagraf multidose

Dotagraf multidose will be administered as an intravenous injection.
During the examination, the patient will be under close supervision of a physician or radiologist. A needle will remain in the patient's vein so that, if necessary, the physician or radiologist can quickly administer life-saving medications. If the patient experiences an allergic reaction, administration of Dotagraf multidose will be stopped immediately.
Dotagraf multidose may be administered manually or using an automated injector.
In newborns and infants, this medicine will be administered manually only.
This procedure may be performed in a hospital, outpatient clinic, or private practice. The personnel involved in the examination are aware of the precautions necessary during the procedure and are familiar with potential complications that may occur.

Dosage
The physician or radiologist will determine the appropriate dose for the patient and will supervise the injection of the medicine.

Dosage in special patient groups
Dotagraf multidose is not recommended for patients with severe renal function impairment or for patients who have recently undergone or are about to undergo liver transplantation. However, if Dotagraf multidose is required during an MRI examination, the patient should receive only a single dose of the medicine and should not receive another dose within at least 7 days.

Newborns, infants, children, and adolescents
Due to immature kidney function in newborns up to 4 weeks of age and infants up to 1 year of age, Dotagraf multidose should be used in these patients only after careful consideration by the physician. Newborns and infants should receive only a single dose of Dotagraf multidose during the examination and should not receive another dose within at least 7 days.
Angiography is not recommended in children under 18 years of age.

Elderly patients
There is no need to adjust the dose in patients aged 65 years and older; however, blood tests to assess kidney function may be necessary.

Administration of a higher than recommended dose of Dotagraf multidose
It is highly unlikely that a patient would receive an excessive dose of the medicine. Dotagraf multidose will be administered in a medical facility by trained personnel. In the event of actual overdose, Dotagraf multidose can be removed from the body by hemodialysis (blood purification).

Additional information on the use and handling of this medicine by medical personnel is provided at the end of this leaflet.
If you have any further questions regarding the use of this medicine, please consult your physician or radiologist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
After administration of the medicine, the patient will be monitored for at least half an hour. Most
adverse reactions occur immediately or shortly after administration of the medicine. Some adverse
reactions may occur up to seven days after injection of Dotagraf multidose.
There is a small risk of an allergic reaction to Dotagraf multidose. Such reactions can be severe and may
lead to anaphylactic shock (a type of allergic reaction which may be life-threatening). The following
symptoms may be the first signs of shock. If the patient notices any of the symptoms listed below, they
should immediately inform the doctor, radiologist or other medical personnel:

• swelling of the face, lips or throat, which may cause difficulty in swallowing or breathing,
• swelling of hands or feet,
• dizziness (low blood pressure),
• difficulty breathing,
• wheezing,
• cough,
• itching,
• runny nose,
• sneezing,
• eye irritation,
• hives,
• skin rash.

Uncommon adverse reactions (may occur in no more than 1 in 100 patients):

• hypersensitivity (allergic reaction),
• headache,
• unusual taste in the mouth,
• dizziness,
• somnolence (drowsiness),
• tingling sensation, feeling of warmth / burning, cold and (or) pain,
• low or high blood pressure,
• nausea,
• abdominal pain,
• rash,
• feeling of warmth, feeling of cold,
• asthenia (loss of energy, weakness),
• discomfort at injection site, reactions at injection site, feeling of cold at injection site, swelling at injection site, extravasation of the medicine (leakage from blood vessels), which may lead to inflammation (redness and local pain).

Rare adverse reactions (may occur in no more than 1 in 1,000 patients):

• anxiety, collapse (dizziness and feeling of impending fainting),
• eyelid swelling,
• palpitations,
• sneezing,
• vomiting,
• diarrhoea,
• increased salivation,
• urticaria, itching, excessive sweating,
• chest pain, chills.

Very rare adverse reactions (may occur in no more than 1 in 10,000 patients):

• anaphylactic or anaphylactoid reactions (severe, potentially life-threatening allergic reactions),
• excitation,
• coma, convulsions, fainting (short-term loss of consciousness), disturbances of smell (perception of often unpleasant odours), muscle tremor,
• conjunctivitis, red eyes, blurred vision, excessive tearing,
• circulatory arrest, rapid or slow heartbeat, irregular heartbeat, vasodilation, pallor,
• respiratory arrest, pulmonary oedema, breathing difficulties, wheezing, nasal congestion, cough, dry throat, throat spasm with sensation of suffocation, respiratory spasms, throat oedema,
• rash, skin redness, swelling of lips and inside the mouth,
• muscle spasms, muscle weakness, back pain,
• malaise, chest discomfort, fever, facial oedema, extravasation of the medicine which may lead to tissue necrosis at the injection site, phlebitis,
• decreased oxygen level in blood.

There have been reports of systemic nephrogenic fibrosing dermopathy (which causes hardening of the skin and may also affect soft tissues and internal organs), which usually occurred in patients receiving Dotagraf multidose together with other contrast agents containing gadolinium. If, in the weeks following an MRI examination, the patient notices changes in colour and (or) thickness of the skin anywhere on the body, they should inform the radiologist who performed the examination.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, the patient should inform their doctor or radiologist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, telephone: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl.
Adverse reactions can also be reported to the marketing authorisation holder. Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Dotagraf multidose

Keep this medicine out of the sight and reach of children.
No special storage conditions are required.
Chemical and physical stability of the prepared medicine has been demonstrated for at least 72 hours
at room temperature. From a microbiological standpoint, the medicine should be used immediately. If
the medicine is not used immediately, the user is responsible for ensuring appropriate storage conditions and duration prior to administration, which should not exceed 24 hours
at 2°C – 8°C, unless the medicine was opened under controlled and validated aseptic conditions.
Do not use this medicine after the expiry date stated on the vial and carton, following the abbreviation "Exp". The expiry date refers to the last day of the specified month.

6. Contents of the pack and other information

What Dotagraf multidose contains

• The active substance is gadoteric acid. One millilitre of injection solution contains 279.32 mg of gadoteric acid (as meglumine salt), equivalent to 0.5 mmol of gadoteric acid (as meglumine salt).
• The other components are meglumine, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and water for injections.

What Dotagraf multidose looks like and contents of the pack
Dotagraf multidose is a colourless to yellow, clear, transparent solution for intravenous injection. The Dotagraf multidose pack contains one or ten vials with 60 ml or 100 ml of injection solution. Not all pack sizes may be marketed.

Marketing Authorisation Holder
Bayer AG
Kaiser-Wilhelm-Allee 1
51373 Leverkusen
Germany

Manufacturer
Sanochemia Pharmazeutika GmbH
Landegger Straße 7
2491 Neufeld/Leitha
Austria

This medicinal product is authorised for marketing in the EEA countries under the following names:

Information intended exclusively for medical professionals:

Dosage
The lowest dose providing sufficient contrast enhancement for diagnostic purposes should be used. The dose must be calculated based on the patient's body weight and must not exceed the recommended dose per kilogram of body weight specified in this section.

• Brain and spinal cord MRI: In neurological imaging, doses range from 0.1 to 0.3 mmol/kg body weight, corresponding to 0.2 to 0.6 ml/kg body weight. After administering 0.1 mmol/kg body weight to patients with brain tumors, an additional dose of 0.2 mmol/kg body weight may facilitate characterization of the tumor and assist in making treatment decisions.

• Whole-body MRI and angiography: The recommended intravenous dose providing contrast adequate for diagnosis is 0.1 mmol/kg body weight (i.e., 0.2 ml/kg body weight). Angiography: In exceptional circumstances (e.g., when satisfactory image quality covering a large vascular area has not been achieved), administration of a second, sequential dose of 0.1 mmol/kg body weight (corresponding to 0.2 ml/kg body weight) may be justified. However, if two sequential doses of Dotagraf multidose are anticipated before initiating angiography, it may be beneficial to administer 0.05 mmol/kg body weight (i.e., 0.1 ml/kg body weight) per dose, depending on the available imaging equipment.

• Children and adolescents: Brain and spine MRI / Whole-body MRI: The recommended and maximum dose of Dotagraf multidose is 0.1 mmol/kg body weight. More than one dose should not be administered during a single examination. Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Dotagraf multidose should be used in these patients only after careful consideration and at a dose not exceeding 0.1 mmol/kg body weight.
  More than one dose should not be administered during a single examination. Due to lack of data on repeated administration, injections of Dotagraf multidose should not be repeated at intervals shorter than 7 days. Dotagraf multidose is not recommended for use in pediatric angiography in patients under 18 years of age due to insufficient data on efficacy and safety for this indication.

• Patients with renal impairment: In patients with mild to moderate renal impairment (GFR ≥30 ml/min/1.73 m²), the standard adult doses are used. See also section "Renal function impairment" below.

• Patients with hepatic impairment: In such patients, standard adult doses are used. Caution is advised, particularly in the perioperative period related to liver transplantation.

Route of administration
Dotagraf multidose is indicated for intravenous use only. Do not administer intrathecally. Intravenous administration only: extravasation may cause local intolerance reactions requiring local treatment.
Infusion rate: 3–5 ml/min (during angiographic procedures, higher infusion rates may be used—up to 120 ml/min, i.e., 2 ml/s).
Optimal imaging window: within 45 minutes after injection.
Optimal imaging sequence: T1-weighted images.
Whenever possible, the contrast agent should be administered intravenously to the patient in a supine position. After administration, the patient should remain under observation for at least 30 minutes, as clinical experience shows that most adverse reactions occur during this period.
The rubber stopper must be punctured only once, using an appropriate withdrawal device (spike).
Generally, the withdrawal device should contain the following components: spike, sterile air filter, Luer connector, and a protective sterile cap.
The product may be used with a sterile, single-use syringe for single administration of the medicinal product or for bolus injection of a second contrast dose if clinically indicated.
An automated injection system may be used for multiple administrations of the medicinal product, but only for a single patient.
Any residual volume of the medicinal product remaining in the vial and in single-use devices after completion of the procedure must be discarded within 24 hours of piercing the rubber stopper. Instructions provided by the manufacturer of the device must be strictly followed.
The injectable solution should be visually inspected before use. Only clear, particle-free solutions should be used.

Children and adolescents
Depending on the amount of Dotagraf multidose to be administered to a child, use of vials of Dotagraf multidose with a single-use syringe of appropriate capacity is recommended to ensure greater accuracy of the injected volume.
In neonates and infants, the required dose should be administered manually.

Renal function impairment
It is recommended that all patients undergo screening laboratory tests for renal function impairment prior to administration of Dotagraf multidose:
Cases of nephrogenic systemic fibrosis (NSF) associated with the use of gadolinium-containing contrast agents have been reported in patients with acute or chronic severe renal impairment (GFR < 30 ml/min/1.73 m²). Patients undergoing liver transplantation are particularly at risk of this complication, as this group has a high risk of developing acute renal failure. Because of the risk of NSF following administration of Dotagraf multidose, the product should be used in patients with severe renal impairment and in patients in the perioperative period of liver transplantation only after careful benefit-risk assessment and only when diagnostic information is essential and cannot be obtained by non-contrast MRI. If use of Dotagraf multidose is necessary, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be administered during a single examination. Due to lack of data on repeated administration, injections of Dotagraf multidose should not be repeated at intervals shorter than 7 days.
Hemodialysis performed shortly after administration of Dotagraf multidose may facilitate elimination of the agent from the body. There is no evidence supporting initiation of hemodialysis to prevent or treat NSF in patients not already undergoing hemodialysis.

Elderly patients
Since renal clearance of gadoterate acid may be reduced in elderly patients, prior assessment of renal function is particularly important in patients aged 65 years and older.

Neonates and infants
See Dosage and Administration, Children and adolescents.

Pregnancy and lactation
Dotagraf multidose should not be used during pregnancy unless the clinical condition of the woman necessitates the use of gadoterate acid.
The decision whether to continue or interrupt breastfeeding for 24 hours after administration of Dotagraf multidose should be made jointly by the physician and the nursing mother.

Instructions for handling Dotagraf multidose
The detachable identification label from the vial should be attached to the patient's medical record to allow accurate documentation of the gadolinium-containing contrast agent used. The administered dose should also be recorded. If the patient's record is maintained electronically, the name of the medicinal product, batch number, and administered dose should be entered into the electronic record.