Gadovist 1.0

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GADOVIST 1.0 (GADOVIST® 1.0)

Composition:

Active substance: gadobutrol;

1 ml of injection solution contains 604.72 mg of gadobutrol (equivalent to 1 mmol/ml);

Excipients: calcium sodium butrol, trometamol, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear solution free of particles.

Pharmacotherapeutic group. Paramagnetic contrast agents.

ATC code V08CA09.

Pharmacological Properties

Pharmacodynamics.

The contrast enhancement effect is achieved due to the neutral (non-ionic) complex composed of gadolinium (III) and the macrocyclic ligand dihydroxymethylpropyltetraazacyclododecanetriacetic acid (butrol).

The relaxivity of gadobutrol, measured in vitro in human blood/plasma under physiological conditions and at clinically relevant magnetic field strengths (1.5 and 3.0 T), ranges from 3.47 to 4.97 L/mmol/sec.

At clinical doses, the pronounced relaxivity of gadobutrol results in shortening of the proton relaxation time of water in tissues.

The stability of the gadobutrol complex was studied in vitro under physiological conditions (in native human serum at pH 7.4 and 37 °C) over 15 days. The amount of free gadolinium ions released from gadobutrol was below the limit of quantitative detection (0.1 mol.% of total gadolinium), indicating high complex stability of gadobutrol under the tested conditions.

Clinical Efficacy

In one Phase III clinical study evaluating the diagnostic use of Gadovist 1.0 for liver diseases (using combined magnetic resonance imaging (MRI) before and after contrast agent administration), the mean sensitivity was 79%. Specificity for detection and verification of liver lesions suspected of malignancy was 81% (analysis based on objective patient data).

In one Phase III kidney study, sensitivity for differential diagnosis of benign and malignant kidney lesions was on average 91% (analysis based on objective patient data) and 85% (analysis based on lesion-based assessment). Specificity was on average 52% in the patient-based analysis and 82% in the lesion-based analysis.

When using Gadovist 1.0, the increase in MRI sensitivity before contrast administration versus combined MRI before and after contrast administration was 33% in liver imaging (analysis based on objective patient data) and 18% in kidney imaging (analysis based on both objective patient data and lesion-based assessment). The increase in MRI specificity before contrast administration versus combined MRI before and after contrast administration was 9% in liver imaging (analysis based on objective patient data), while no increase in specificity was observed in kidney imaging (analysis based on both objective patient data and lesion-based assessment).

Results were averaged based on anonymous evaluation by independent radiologists.

In one intra-individual crossover comparative study involving 132 patients, Gadovist 1.0 was compared with meglumine gadoterate (both at 0.1 mmol/kg) during visualization of brain neoplastic lesions.

The primary endpoint was overall preference for either Gadovist 1.0 or meglumine gadoterate, determined by mean ratings from independent experts. Preference for Gadovist 1.0 was statistically significant (p = 0.0004). Specifically, preference for Gadovist 1.0 was observed in 42 patients (32%) compared to overall preference for meglumine gadoterate in 16 patients (12%). In 74 patients (56%), no preference was given to either contrast agent.

For the secondary endpoint used in the analysis—the ratio of MRI signal intensity in the tumor to signal intensity in normal tissue—Gadovist 1.0 demonstrated statistically significantly higher efficacy (p < 0.0003). The percentage of signal enhancement was higher with Gadovist 1.0 (p < 0.0003) compared to meglumine gadoterate, with statistically significant differences noted by independent experts.

Gadovist 1.0 (129) showed a higher mean contrast-to-noise ratio compared to meglumine gadoterate (98). The difference was not statistically significant.

In a crossover-comparison designed study, gadobutrol at a reduced dose of 0.075 mmol/kg was compared with meglumine gadoterate at its standard dose of 0.1 mmol/kg for contrast-enhanced CNS MRI in 141 patients with CNS lesions. Primary endpoints included lesion contrast enhancement, lesion morphology, and lesion border delineation. Images were analyzed by three independent, blinded readers. Non-inferiority of meglumine gadoterate compared to unenhanced imaging was demonstrated for all three primary endpoints (at least 80% of the effect preserved) based on mean reader assessment. The mean number of lesions detected was similar with gadobutrol (2.14) and gadoterate (2.06).

Pediatric Population

Two Phase I/III studies were conducted using a single dose in 138 pediatric patients scheduled for contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS), liver, and kidneys or contrast-enhanced magnetic resonance angiography (MRA), and in 44 subjects aged from birth to 2 years (including full-term neonates) scheduled for standard contrast-enhanced MRI of any body region. Diagnostic efficacy and improved diagnostic confidence for all evaluated parameters were observed, with no differences between pediatric patients and adults. Study results demonstrated excellent tolerability of Gadovist 1.0 with a safety profile of gadobutrol similar to that in adults.

Clinical Safety

The type and frequency of adverse reactions following administration of Gadovist 1.0 across various indications were evaluated in a large international prospective non-interventional study (GARDIAN). The safety population included 23,708 patients of all age groups, including children (n = 1,142; 4.8%) and elderly individuals (n = 4,330; 18.3% aged 65 to < 80 years and n = 526; 2.2% aged ≥ 80 years). The mean age was 51.9 years.

Two hundred two patients (0.9%) reported a total of 251 adverse events, and 170 (0.7%) reported 215 events classified as adverse reactions, the majority of which (97.7%) were mild or moderate in intensity. The most frequently reported adverse reactions were nausea (0.3%), vomiting (0.1%), and dizziness (0.1%). The rate of adverse reactions was 0.9% in women and 0.6% in men. There were no differences in adverse reaction rates related to the dose of gadobutrol. Of the 170 patients who experienced adverse reactions (0.02%), 4 patients had serious adverse reactions, one of which (anaphylactic shock) resulted in a fatal outcome. Adverse events were recorded in 8 of 1,142 (0.7%) pediatric patients. In six children, these adverse events were classified as adverse reactions (0.5%).

Renal Impairment

In a prospective pharmacoepidemiological study (GRIP) assessing the potential risk of nephrogenic systemic fibrosis (NSF) in patients with impaired renal function, 908 patients with varying degrees of renal dysfunction received Gadovist 1.0 at the standard approved dose for contrast MRI. All patients, including 234 patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²) who did not receive other gadolinium-containing contrast agents, were monitored over two years for signs and symptoms of NSF. No patient included in the study developed NSF.

Preclinical Data.

Based on standard safety pharmacology, repeated-dose toxicity, or genotoxicity studies, no specific risk for humans was identified.

In reproductive toxicity studies, repeated dosing (intravenous) caused delayed embryonic development in rats and rabbits, increased embryolethality in rats, rabbits, and monkeys at doses 8–16 times (based on body surface area) or 25–50 times (based on body weight) higher than diagnostic doses in humans. It is unknown whether these effects could also be induced by single-dose administration. Studies of single and repeated dose toxicity in neonatal and sexually immature rats did not indicate a specific risk for use in children of all age groups, including full-term neonates and infants.

Less than 0.1% of the administered dose of radiolabeled gadobutrol was excreted into milk in lactating rats. After oral administration in rats, absorption was very low, approximately 5% (calculated from urinary excretion levels).

According to preclinical safety studies, transient dose-dependent increases in blood pressure and myocardial contractility were observed in the cardiovascular system. These effects were not observed in humans.

Environmental studies indicate that the persistence and mobility of gadolinium-containing contrast agents suggest potential spread in surface water and possibly groundwater.

Pharmacokinetics.

Distribution

After intravenous administration, gadobutrol rapidly distributes into the extracellular space. Protein binding is negligible. The pharmacokinetic parameters of gadobutrol in humans are dose-proportional. After administration of gadobutrol at doses up to 0.4 mmol/kg body weight, plasma levels declined biexponentially. Following administration of 0.1 mmol/kg body weight, mean plasma concentrations were 0.59 mmol/L at 2 minutes and 0.3 mmol/L at 60 minutes post-injection.

Biotransformation

No metabolites were detected in plasma or urine.

Elimination

Gadobutrol is eliminated from plasma with a mean terminal half-life of 1.81 hours (range: 1.3–2.1 hours). More than 50% of the intravenously administered dose is excreted in urine within two hours, and over 90% within 12 hours. After a dose of 0.1 mmol/kg body weight, a mean of 100.3±2.6% of the administered dose was excreted in urine within 72 hours post-injection. Renal clearance of gadobutrol ranges from 1.1 to 1.7 mL/min/kg in healthy subjects, similar to the renal clearance of inulin, indicating elimination via glomerular filtration. Less than 0.1% is excreted in feces.

Pediatric Patients

The overall pharmacokinetic profile of gadobutrol in pediatric patients (< 18 years) is similar to that in adults (see section "Dosage and Administration").

Two Phase I/III studies were conducted in pediatric patients (< 18 years). Pharmacokinetic profiles were assessed in 130 pediatric patients aged 2 to < 18 years and in 43 pediatric patients aged < 2 years (including full-term neonates).

The pharmacokinetic profile of gadobutrol in children of all age groups is similar to that in adults, resulting in comparable values for area under the curve (AUC), total clearance (CLtot), volume of distribution (Vss), half-life, and excretion rate.

Approximately 99% (mean value) of the dose was excreted in urine within 6 hours (in the age group 2 to < 18 years).

Elderly Patients (≥ 65 years)

Due to age-related physiological changes in renal function, systemic exposure in healthy elderly volunteers (≥ 65 years) increases by 33% in men and 54% in women, terminal half-life increases by 33% in men and 58% in women, and plasma clearance decreases by 25% (men) and 35% (women). Renal excretion of the administered dose is complete within 24 hours in all patients, with no differences observed between healthy elderly and younger patients.

Renal Impairment

In patients with impaired renal function, the plasma half-life of the substance is prolonged due to reduced glomerular filtration. The mean terminal half-life is 5.8 hours in patients with moderate renal impairment (creatinine clearance 80 > 30 mL/min) and up to 17.6 hours in patients with severe renal impairment not on dialysis (creatinine clearance < 30 mL/min). Mean plasma clearance decreases to 0.49 mL/min/kg in patients with moderate renal impairment (creatinine clearance 80 > 30 mL/min) and to 0.16 mL/min/kg in patients with severe renal impairment not on dialysis (creatinine clearance < 30 mL/min).

Complete urinary excretion was observed within 72 hours in patients with mild or moderate renal impairment. In patients with severe renal impairment, at least 80% of the administered dose was excreted in urine within 5 days (see sections "Dosage and Administration", "Special Warnings and Precautions for Use"). In patients undergoing dialysis, gadobutrol is almost completely eliminated from plasma after the third dialysis session.

Clinical characteristics.

Indications.

The medicinal product is used for diagnostic purposes. Gadovist 1.0 is indicated in adults and children of all age groups (including full-term newborns) for:

• Enhancement of image contrast during cranial and spinal MRI.
• Enhancement of image contrast during MRI of the liver or kidneys in patients with suspected or confirmed focal lesions, for classification of these lesions as benign or malignant.
• Enhancement of image contrast during magnetic resonance angiography (MRA).

Gadovist 1.0 may also be used during magnetic resonance imaging of pathological lesions throughout the body.

Gadovist 1.0 facilitates visualization of abnormal formations or lesions and enables differentiation between healthy and pathological tissues.

Gadovist 1.0 should be used only when diagnostic information is essential and cannot be obtained by magnetic resonance imaging (MRI) without the use of a contrast agent.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the product.

Special safety precautions.

The product is intended for single use only (for one examination).

This medicinal product should be carefully inspected visually prior to administration. Gadovist 1.0 must not be used if significant discoloration, presence of particulate matter, or damage to the integrity of the plastic container is observed.

Any unused portion of the contrast agent remaining after the examination must not be reused and should be discarded.

Syringes should be removed from the plastic container immediately before use.

The cap should be removed from the syringe only immediately before administration.

Gadovist 1.0 should be drawn into a syringe from the vial only immediately before administration. The rubber stopper of the vial should not be punctured more than once.

If this medicinal product is to be administered using an automated injection system, the suitability of its use with such equipment must be demonstrated by the manufacturer of the device/medical product. Any additional instructions provided by the manufacturer of the equipment/medical device must be followed.

Interaction with other medicinal products and other forms of interaction.

Studies on interactions with other medicinal products have not been conducted.

Special precautions for use.

Gadobutrol must not be administered intrathecally. Serious, life-threatening, and fatal cases, predominantly with neurological reactions (e.g., coma, encephalopathy, seizures), have been reported following intrathecal administration.

When administering Gadovist 1.0 into small veins, adverse reactions such as redness and swelling may occur.

General safety rules applicable during MRI procedures, especially the exclusion of ferromagnetic implants, also apply to the use of Gadovist 1.0.

• Hypersensitivity or other idiosyncratic reactions

Administration of Gadovist 1.0, as with other intravenous contrast agents, may be associated with anaphylactoid/hypersensitivity reactions or other idiosyncratic reactions (e.g., acute respiratory distress syndrome/pulmonary edema with or without hypersensitivity reactions), manifesting as cardiovascular, respiratory, or cutaneous symptoms, up to severe reactions including shock. Patients with cardiovascular disease are at greater risk of serious or even fatal outcomes from severe hypersensitivity reactions.

The risk of hypersensitivity reactions is increased in the presence of the following conditions or diseases:

• previous reaction to contrast agent administration;
• history of bronchial asthma;
• history of allergic reactions.

The decision to administer Gadovist 1.0 to patients with a predisposition to allergies should be made only after careful assessment of the risk-benefit ratio.

Most of these reactions occur within 30 minutes after administration. Therefore, it is recommended to observe the patient after the procedure.

Appropriate medications for treating hypersensitivity or other idiosyncratic reactions, as well as emergency equipment, must always be readily available (see section "Method and route of administration").

Delayed reactions (occurring several hours or days after administration) have been observed in isolated cases (see section "Adverse reactions").

• Renal function impairment

All patients should be screened for renal dysfunction based on laboratory results prior to administration of Gadovist 1.0.

Cases of nephrogenic systemic fibrosis (NSF) associated with the use of gadolinium-containing contrast agents have been observed in patients with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m²). A particular risk exists in patients undergoing liver transplantation, as the incidence of acute renal failure in this group is high.

Because of the risk of NSF with Gadovist 1.0, the decision to administer the agent to patients with severe renal insufficiency or in the perioperative period of liver transplantation should be made only after careful risk-benefit assessment and only when diagnostic information is essential and cannot be obtained by non-contrast MRI.

Hemodialysis performed shortly after administration of Gadovist 1.0 may be beneficial in eliminating the agent from the body. However, data on the use of hemodialysis for prevention or treatment of NSF in patients not previously on dialysis are lacking.

• Neonates and infants

Due to immature renal function, Gadovist 1.0 should be used with caution in neonates up to 4 weeks of age and infants up to 1 year of age, and only after careful evaluation of the necessity of use.

• Elderly patients

Since renal clearance of gadobutrol may be impaired in elderly patients, it is particularly important to assess for renal dysfunction in patients aged 65 years and older.

• Seizures

As with other gadolinium-containing contrast agents, particular caution should be exercised when administering Gadovist 1.0 to patients with a low seizure threshold.

• Excipients

Gadovist 1.0 contains less than 1 mmol sodium (23 mg) per dose (calculated based on the average dose for a patient weighing 70 kg), i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of gadolinium-based contrast agents, including gadobutrol, in pregnant women are limited. Gadolinium may cross the placenta. It is unknown whether gadolinium exposure is associated with adverse fetal effects.

Reproductive toxicity was observed in animal studies following repeated high doses of the drug (see section "Pharmacological properties").

Gadovist 1.0 is not recommended during pregnancy unless absolutely necessary.

Lactation. Gadolinium-containing contrast agents are excreted into breast milk in very small amounts (see section "Pharmacological properties"). With clinical doses, no effect on the infant is expected due to the minimal amount of active substance excreted in breast milk and poor gastrointestinal absorption. The decision whether to continue or interrupt breastfeeding for 24 hours after administration of Gadovist 1.0 should be made jointly by the physician and the breastfeeding woman.

Fertility. Animal studies did not indicate impaired fertility.

Ability to affect reaction speed when driving or operating machinery.

Unknown.

Administration and Dosage

Gadovist 1.0 must be administered only by qualified medical personnel experienced in clinical MRI practice.

The product is indicated for diagnostic use only by intravenous administration.

The required dose should be administered intravenously as a bolus injection. Magnetic resonance imaging may begin immediately (after a short interval following injection, depending on the pulse sequence and imaging protocol). Optimal contrast enhancement is observed during the first pass through the arteries for MRA, as well as for approximately 15 minutes after injection of Gadovist 1.0 when used for CNS imaging (this duration depends on the type of lesion/tissue).

T1-weighted imaging sequences are particularly suitable for contrast-enhanced examinations.

Intravascular administration of the contrast agent should be performed, whenever possible, with the patient in a supine position. After administration, the patient must remain under medical supervision for at least 30 minutes, as clinical experience with contrast agents indicates that most adverse reactions occur during this period (see section "Special Warnings and Precautions for Use").

Dosage

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

Adults

Recommendations for MRI of the Brain and Spinal Cord

The recommended dose for adults is 0.1 mmol of Gadovist 1.0 per kg of body weight (mmol/kg), corresponding to 0.1 mL per kg of body weight of the 1.0-M solution.

If there is still suspicion of a lesion (based on clinical findings) despite normal MRI results, or if more precise information may influence patient management, a second dose of up to 0.2 mL per kg of body weight may be administered within 30 minutes after the first injection.

A dose of 0.075 mmol gadobutrol per kg of body weight (equivalent to 0.075 mL of Gadovist 1.0 per kg of body weight) may be administered as a minimum for CNS visualization (see section "Pharmacological Properties").

MRI of the Whole Body (excluding MRA)

In general, administration of Gadovist 1.0 at a dose of 0.1 mL/kg body weight is sufficient for addressing most clinical questions.

Contrast Enhancement in Magnetic Resonance Angiography (CE-MRA)

Imaging of a single field of view:

7.5 mL if body weight is less than 75 kg;

10 mL if body weight is 75 kg or more (corresponding to 0.1 – 0.15 mmol/kg body weight).

Imaging of more than one field of view:

15 mL if body weight is less than 75 kg;

20 mL if body weight is 75 kg or more (corresponding to 0.2 – 0.3 mmol/kg body weight).

Special Patient Populations

Children

For children of all age groups (including term newborns), the recommended dose is 0.1 mmol of Gadovist 1.0 per kg of body weight (equivalent to 0.1 mL/kg body weight) for all indications.

Newborns (up to 4 weeks of age) and Infants (up to 1 year of age)

Due to immature renal function observed in newborns (up to 4 weeks of age) and infants (up to 1 year of age), Gadovist 1.0 should be administered to these patients only after careful assessment of benefit-risk balance and at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be administered during a single scanning session. Due to insufficient data on repeated administration, the interval between repeated injections of Gadovist 1.0 should be at least 7 days.

Elderly Patients (aged 65 years and older)

No dose adjustment is required for elderly patients. However, special caution is necessary when administering the product to elderly patients (see section "Special Warnings and Precautions for Use").

Renal Impairment

The decision to administer Gadovist 1.0 to patients with severe renal impairment (glomerular filtration rate < 30 mL/min/1.73m²) and to patients in the perioperative period of liver transplantation should be made only after careful assessment of the risk-benefit ratio and only when diagnostic information is essential and cannot be obtained by non-contrast MRI (see section "Special Warnings and Precautions for Use"). If administration of Gadovist 1.0 is necessary, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be administered during a single scanning session. Because data on repeated administration are limited, repeated injection with Gadovist 1.0 should not be performed unless the interval between injections is at least 7 days.

Children

Gadovist 1.0 is indicated for use in children of all age groups (including term newborns).

Overdose

The maximum single dose of gadobutrol administered in humans is 1.5 mmol per kg of body weight. To date, no signs of intoxication due to overdose have been observed during clinical use of the product.

In case of accidental overdose, monitoring of the cardiovascular system (including ECG) and renal function is recommended.

In cases of overdose in patients with renal impairment, Gadovist 1.0 can be eliminated from the body by hemodialysis. Approximately 98% of the active substance is removed from the body after 3 dialysis sessions. However, there are no data indicating that hemodialysis can be used to prevent the development of nephrogenic systemic fibrosis.

Adverse reactions

The safety profile of Gadovist 1.0 is based on results from clinical trials involving over 6,300 patients and post-marketing surveillance. The most frequently observed adverse reactions (≥0.5%) in patients receiving Gadovist 1.0 were headache, nausea, and dizziness.

The most serious adverse reactions reported in patients receiving Gadovist 1.0 included cardiac arrest, acute respiratory distress syndrome/pulmonary edema, and severe anaphylactoid reactions (including respiratory arrest and anaphylactic shock).

Delayed anaphylactoid or other idiosyncratic reactions (occurring from several hours to several days after administration) have been observed rarely (see section "Special precautions").

Most adverse effects were of mild or moderate severity.

Adverse reactions observed with administration of Gadovist 1.0 are listed in the table below and classified by MedDRA System Organ Classes (SOC).

Appropriate MedDRA terms were used to describe specific reactions, their symptoms, and symptomatically similar conditions.

The adverse reactions listed below were recorded during clinical trials with Gadovist 1.0 and are categorized by frequency of occurrence: common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000). Adverse reactions identified only during the post-marketing period, for which the frequency cannot be estimated, are labeled as "frequency not known." Within each category, adverse reactions are listed in order of decreasing severity.

Adverse reactions identified during clinical trials and post-marketing surveillance in patients receiving Gadovist 1.0.

1 The adverse reactions were reported including and excluding hypersensitivity reactions.

#Apart from urticaria, none of the adverse reaction symptoms listed in the section "Hypersensitivity/anaphylactoid reactions" were reported in clinical trials with a frequency greater than "rare".

• Adverse reactions that may be life-threatening or have a fatal outcome.

§ Hypersensitivity/anaphylactoid reactions were observed only during post-marketing surveillance (frequency unknown).

º Reactions at the injection site (of various types), including the following clinical variants: local extravasation, local feeling of heat, local feeling of cold, local feeling of warmth, local erythema or rash, local pain, post-injection hematoma.

Patients with a predisposition to allergic reactions are more likely to experience hypersensitivity reactions.

Isolated cases of NSF development have been reported in association with the use of Gadovist 1.0 (see section "Special precautions for use").

After administration of Gadovist 1.0, changes in renal function parameters have been observed, including increased creatinine levels.

Children

Data from two phase I/III studies involving administration of a single dose to 138 subjects aged 2–17 years and 44 subjects under 2 years of age (see section "Pharmacological properties") indicate that the frequency, type, and severity of adverse reactions in children of all age groups (including full-term newborns) do not differ from the adverse reaction profile observed in adults. This conclusion was confirmed by the results of a phase IV study involving over 1100 pediatric patients and post-marketing surveillance data.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Shelf life after first opening: Unused portions of the injection solution should be discarded after use. Chemical, physical, and microbiological stability during use may be demonstrated for a period of 24 hours at 20–25 °C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the responsibility lies with the user.

Storage conditions.

No special storage conditions required.

Incompatibilities.

Due to lack of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Packaging.

5 ml, 7.5 ml, or 10 ml in a glass syringe, placed in a transparent plastic box sealed with paper; 5 syringes per cardboard box;

5 ml, 7.5 ml, or 10 ml in a plastic syringe, placed in a transparent plastic box sealed with polyethylene; 5 syringes per cardboard box;

7.5 ml or 15 ml in a glass vial; 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Bayer AG / Bayer AG.

Manufacturer's address and place of business.

Müllerstrasse 178, 13353, Berlin, Germany / Mullerstrasse 178, 13353, Berlin, Germany.