Ginipral

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GYNIPRAL® (GYNIPRAL®)

Composition:

Active substance: hexoprenaline;

One 5 ml ampoule contains 0.025 mg of hexoprenaline sulfate;

Excipients: sodium metabisulfite (E 223); disodium edetate; sodium chloride; sulfuric acid, diluted (for pH adjustment); water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Drugs affecting the genitourinary system and sex hormones. Other drugs used in gynecology. Sympathomimetics inhibiting uterine contractility. ATC code G02CA.

Pharmacological properties.

Pharmacodynamics.

Ginipral is a selective beta-2 sympathomimetic agent that relaxes uterine muscles. Under the influence of Ginipral, the frequency and intensity of uterine contractions are reduced or suppressed. The drug inhibits both spontaneous and oxytocin-induced preterm labor contractions. The tocolytic effect develops within 3–15 minutes after intravenous administration of the drug and lasts approximately 30 minutes. Maximum effect is achieved within 12–18 minutes.

Pharmacokinetics.

Distribution. There are no data regarding the distribution of the drug in the human body. According to preclinical studies, high concentrations of hexoprenaline after intravenous administration are observed in the liver, kidneys, and skeletal muscles; lower concentrations are found in the brain and myocardium.

Metabolism. Hexoprenaline is metabolized by catechol-O-methyltransferase into mono-3-O-methyl-hexoprenaline and di-3-O-methyl-hexoprenaline.

Elimination. After intravenous administration, approximately 44% of the drug is excreted in urine and 5% in feces within 24 hours, and 54% and 15.5%, respectively, within 8 days. At the initial stage, free hexoprenaline, two methylated metabolites, as well as their sulfate and glucuronide conjugates are not excreted in urine. Within 48 hours after drug administration, only the metabolite di-3-O-methyl-hexoprenaline is detected in urine. A small amount of the drug (about 10%) is excreted in bile, usually in the form of O-methylated metabolite conjugates. Since a lower dose of the drug is excreted in feces than is secreted in bile, some portion of the drug is reabsorbed.

Clinical characteristics.

Indications.

• Short-term treatment of uncomplicated preterm labor:

suppression of uterine contractile activity in patients with a gestational age from 22 to 37 weeks in the absence of medical or gynecological contraindications to tocolytic therapy.

• Prior to external cephalic version.
• As an emergency measure in preterm labor prior to transporting the pregnant woman to hospital.

Contraindications.

• Hypersensitivity to hexoprenaline or to any component of the medicinal product.
• Presence of any condition before 22 weeks of gestation.
• Use of the medicinal product as a tocolytic agent in patients with a history of ischemic heart disease or in patients with significant risk factors for developing ischemic heart disease.
• Threatened abortion during the I and II trimesters of pregnancy.
• Any maternal or fetal condition where continuation of pregnancy is hazardous, e.g., severe preeclampsia, intrauterine infection, vaginal bleeding due to placenta previa, eclampsia or severe preeclampsia, placental abruption, or umbilical cord compression.
• Intrauterine fetal death, lethal congenital anomalies in history, or lethal chromosomal abnormalities.
• Bronchial asthma with hypersensitivity to sulfates.
• Cardiovascular disorders, particularly tachyarrhythmia, myocarditis, mitral valve insufficiency.
• Hyperthyroidism.
• Severe hepatic and renal diseases.
• Closed-angle glaucoma.

Use of Ginipral is contraindicated in patients with conditions where administration of beta-mimetics may have undesirable effects, for example, pulmonary hypertension, cardiovascular disorders (hypertrophic obstructive cardiomyopathy or obstruction to blood flow from the left ventricle, such as aortic stenosis).

Interaction with other medicinal products and other forms of interaction.

Halogenated anesthetics. Due to additional antihypertensive effects, the risk of uterine inertia with subsequent hemorrhage is increased. Serious ventricular arrhythmias have been reported due to increased cardiac excitability when the medicinal product is used concomitantly with halogenated anesthetics.

Treatment with the medicinal product must be discontinued at least 6 hours before any planned anesthesia using halogenated anesthetics.

Corticosteroids. Systemic corticosteroids are frequently administered in preterm labor to accelerate fetal lung maturation. Pulmonary edema has been reported in women receiving concomitant beta-agonists and corticosteroids.

Corticosteroids increase blood glucose levels and may lead to decreased serum potassium levels. Concomitant therapy with corticosteroids should be administered under constant monitoring due to the increased risk of hyperglycemia and hypokalemia (see section "Special precautions for use").

Antidiabetic agents. Administration of beta-agonists increases blood glucose levels, which may be interpreted as reduced efficacy of antidiabetic therapy. In such cases, antidiabetic treatment should be adjusted (see section "Special precautions for use").

Agents that reduce potassium levels. Administration of beta-agonists is associated with decreased serum potassium levels. Concomitant therapy with other agents that increase the risk of hypokalemia (such as diuretics, digoxin, methylxanthines, corticosteroids) should be prescribed with caution and only after careful assessment of the risk/benefit ratio of treatment, with particular attention to the increased risk of cardiac arrhythmias due to hypokalemia (see section "Special precautions for use").

Other interactions. Non-selective beta-adrenoblockers reduce or abolish the effect of Ginipral.

The intensity of glycogen accumulation in the liver induced by glucocorticosteroids is reduced under the influence of Ginipral.

Concomitant treatment with sympathomimetics (cardiovascular and antiasthmatic agents) should not be performed, as this enhances the effects on the cardiovascular system and increases the risk of adverse reactions due to overdose.

Ginipral should not be used concomitantly with medicinal products containing ergot alkaloids, or with preparations containing calcium, vitamin D, dihydrotachysterol, and mineralocorticoids.

Special precautions for use.

The decision to initiate therapy with Ginipral should be made only after a careful assessment of the risk/benefit ratio of its use.

Treatment must be conducted exclusively in properly equipped facilities to ensure continuous monitoring of the health status of both mother and fetus.

Tocolysis with beta-agonists is not recommended in cases of ruptured fetal membranes or cervical dilation exceeding 4 cm.

Ginipral should be used with caution during tocolysis. Throughout the entire treatment period, cardiac and respiratory function must be monitored, including continuous electrocardiographic (ECG) monitoring.

The following continuous monitoring of the mother and, whenever possible or necessary, the fetus should be performed:

• Measurement of blood pressure and heart rate;
• ECG monitoring;
• Assessment of fluid and electrolyte balance to detect potential development of pulmonary edema;
• Monitoring of blood glucose and lactate levels, especially in patients with diabetes mellitus;
• Monitoring of serum potassium levels, as beta-agonists may cause a decrease in serum potassium, increasing the risk of arrhythmias (see section "Interaction with other medicinal products and other forms of interaction"). Patients with hypokalemia should receive potassium supplementation with oral potassium preparations prior to initiating tocolytic therapy.

Treatment should be discontinued if symptoms of myocardial ischemia occur (e.g., chest pain or ECG changes).

Ginipral should not be used as a tocolytic agent in patients with significant risk factors or suspected history of any cardiovascular disease (e.g., tachyarrhythmia, heart failure, or valvular heart disease; see section "Contraindications"). In cases of preterm labor in patients with established or suspected cardiovascular disease, a physician experienced in managing such patients should evaluate the appropriateness of Ginipral therapy prior to initiating infusion.

Pulmonary edema. Due to the potential risk of developing pulmonary edema and myocardial ischemia in the mother during or after beta-agonist therapy for preterm labor, careful monitoring of fluid and electrolyte balance, cardiac, and respiratory function is essential. Patients with conditions that impair physiological defense mechanisms—including multiple pregnancy, hypervolemia, infection, and pre-eclampsia—are at increased risk of developing pulmonary edema. Use of an infusion pump for drug administration, rather than standard intravenous infusion, minimizes the risk of hypervolemia. If symptoms of pulmonary edema or myocardial ischemia occur, particularly during concomitant corticosteroid therapy or in the presence of comorbid conditions (e.g., renal disease, pre-eclampsia), discontinuation of Ginipral is recommended. Sodium intake should be restricted.

Blood pressure and heart rate. Infusion of beta-agonists typically increases maternal heart rate by 20–50 beats per minute. Maternal pulse rate should be monitored, and in each individual case, consideration should be given to whether dose reduction or discontinuation of the drug is necessary to control this tachycardia. Generally, the maternal resting pulse should not exceed 120 beats per minute.

Maternal blood pressure may slightly decrease during infusion, with diastolic pressure decreasing more than systolic. The drop in diastolic pressure usually ranges from 10 to 20 mm Hg. The effect of infusion on fetal heart rate is less pronounced, but an increase of up to 20 beats per minute may occur.

To minimize the risk of arterial hypotension associated with tocolytic therapy, special precautions should be taken to avoid compression of the vena cava superior; the patient should be positioned alternately on her left and right side during infusion.

Diabetes mellitus. Beta-agonist administration may increase blood glucose levels. Therefore, blood glucose and lactate levels should be monitored in pregnant women with diabetes mellitus, and diabetes treatment should be adjusted as needed during tocolysis (see section "Interaction with other medicinal products and other forms of interaction").

Other precautions. During tocolytic therapy with beta-agonists, symptoms of concomitant myotonic dystrophy may be exacerbated. In such cases, phenytoin is recommended.

Ginipral should be administered in low, individually adjusted doses under continuous medical supervision in patients with increased sensitivity to sympathomimetics.

Since Ginipral therapy may suppress intestinal peristalsis (intestinal atony has been rarely observed), regular bowel movements should be monitored throughout tocolytic treatment.

Use during pregnancy or breastfeeding.

Pregnancy. Ginipral is indicated for use during pregnancy (see section "Indications").

Breastfeeding. Ginipral is not recommended for use during breastfeeding; therefore, appropriate data are lacking.

Ability to affect reaction speed when driving or operating machinery.

Ginipral has no or negligible effect on the ability to drive or operate machinery.

Method of administration and dosage.

For intravenous bolus administration or infusion.

The dosage indicated below is intended as a guideline only, as tocolysis requires an individualized approach to each patient.

Initiation of treatment with Ginipral must be performed only by obstetricians/doctors experienced in the use of tocolytic agents. Treatment must be carried out exclusively in adequately equipped medical facilities enabling continuous monitoring of maternal and fetal status.
Ginipral should be administered as early as possible after diagnosis of preterm labor and after exclusion of any contraindications to the use of hexoprenaline (see section "Contraindications").

During therapy, appropriate assessment of the cardiovascular system must be performed using continuous ECG monitoring (see section "Special precautions for use").

Dosage.

Prior to fetal version from transverse lie or as an emergency measure in preterm labor before transporting the pregnant woman to hospital.

Recommended dose: 10 mcg (1 ampoule of 2 ml) of Ginipral injection solution diluted in 10 ml of 0.9 % sodium chloride solution or 5 % glucose solution, administered intravenously over 5–10 minutes. If continued treatment with Ginipral is required, proceed with Ginipral concentrate for infusion solution.

Short-term treatment of preterm labor in the presence of cervical shortening and/or dilation.

At the beginning of treatment, initiate with a bolus dose of 10 mcg (1 ampoule of 2 ml) (dilution method as described above), followed by continuous infusion of Ginipral at a rate of 0.3 mcg/min.

As an alternative, treatment may consist solely of Ginipral infusion at a rate of 0.3 mcg/min without prior bolus administration.

Administer intravenously by drip infusion (when calculating infusion rate using standard infusion sets, note that 20 drops = 1 ml). Dissolve the required number of ampoules of concentrate for infusion solution in 500 ml of 0.9 % sodium chloride solution or 5 % glucose solution.

Infusion rate of 0.3 mcg/min:

Single cases of hexoprenaline use at a dose of 430 mcg per day have been registered.

Short-term treatment of preterm labor without shortening or dilation of the cervix.

Recommended dose: continuous infusion of 0.075 mcg/min. Administer intravenously by drip infusion (when calculating the infusion rate using standard infusion systems, note that 20 drops = 1 ml). Dissolve the required number of vials of concentrate for infusion in 500 ml of 0.9% sodium chloride solution or 5% glucose solution.

Infusion rate of 0.075 mcg/min:

Duration of treatment.

The duration of tocolytic therapy depends on the existing degree of risk of interruption of pregnancy (tendency to reduce the interval between contractions, condition of the cervix) and on the severity of adverse effects (e.g., increased heart rate). Adverse effects should be minimized as much as possible.

The duration of treatment with the drug should not exceed 48 hours, as clinical data indicate that tocolytic therapy can delay delivery by up to 48 hours. In randomized controlled trials, no statistically significant effect of treatment with Ginipral on perinatal mortality or morbidity was observed. Delaying delivery using Ginipral may allow time for the implementation of other interventions that significantly improve perinatal outcomes.

Safety precautions for infusion administration.

The drug dosage should be individually adjusted according to limiting factors: suppression of uterine contractions, increased pulse rate, changes in arterial pressure. These parameters should be carefully monitored during treatment. The maternal heart rate should not exceed 120 beats per minute.

Continuous assessment of maternal hydration status should be performed to avoid potential development of pulmonary edema (see section "Special precautions"). The volume of fluid used for drug administration should be minimized. The drug should be administered using a controlled infusion device, preferably an infusion pump.

Children.

The drug is not intended for use in children.

Overdose.

Symptoms of overdose may include: marked increase in maternal heart rate, tremor, palpitations, headache, and sweating.

Usually, reducing the dose of the drug is sufficient to alleviate these symptoms. For management of severe overdose symptoms, non-selective beta-adrenoblockers, which competitively inhibit the action of Ginipral, are recommended.

Adverse Reactions

The most common adverse effects of Ginipral are associated with the pharmacological properties of beta-mimetics. To prevent or minimize the occurrence of adverse effects, careful monitoring of hemodynamic parameters such as arterial pressure, heart rate, and appropriate dose adjustment are required. These effects usually resolve after discontinuation of the drug.

Adverse reactions are classified by frequency of occurrence as follows:

Very common (≥ 1:10), common (≥ 1:100, < 1:10), uncommon (≥ 1:1,000, < 1:100), rare (≥ 1:10,000, < 1:1,000), very rare (< 1:10,000), not known (frequency cannot be determined from available data).

Endocrine system.

Not known: lipolysis.

Metabolic disturbances.

Common: hypokalaemia.*

Rare: hyperglycaemia (more pronounced in patients with diabetes mellitus).*

Nervous system.

Very common: tremor.

Not known: headache, dizziness, anxiety.

Cardiovascular system.

Very common: tachycardia.*

Common: palpitations*, decrease in diastolic pressure*, arterial hypotension (see section "Special precautions").*

Rare: cardiac arrhythmias, e.g. atrial fibrillation, myocardial ischaemia (see section "Special precautions")*, peripheral vasodilation*, ventricular extrasystoles.

Not known: increased cardiac output, rise in systolic pressure, minor fluctuations in fetal heart rate.

Respiratory system.

Uncommon: pulmonary oedema.*

Gastrointestinal tract.

Rare: nausea.

Not known: vomiting, inhibition of intestinal peristalsis, intestinal atony.

Hepatic system.

Not known: (transient) increase in serum transaminase concentrations.

Skin and subcutaneous tissue.

Common: sweating.

Not known: skin flushing.

Renal and urinary system.

Not known: decreased diuresis (especially in the initial phase of treatment), oedema.

* These reactions have been reported with the use of short-acting beta-agonists in obstetric practice and are considered class-specific effects (see section "Special precautions").

In isolated cases, particularly in patients with bronchial asthma, sulfites contained in the preparation may provoke hypersensitivity reactions with possible symptoms: nausea, diarrhoea, wheezing, acute asthmatic attack, impaired consciousness, or shock. The severity of these symptoms depends on individual patient characteristics and may lead to life-threatening consequences.

Diabetes mellitus. If delivery occurs shortly after short-term treatment with the drug, the newborn should be monitored for signs of hypoglycaemia, as hexoprenaline may increase glucose and insulin levels in maternal blood. Also, the possibility of acidosis in newborns should be considered due to potential placental transfer of acidic metabolites (lactate, ketone bodies).

Rarely, sodium metabisulfite contained in the preparation may cause severe hypersensitivity reactions and bronchospasm.

Shelf life.

3 years.

Reconstituted solution: chemical and physical stability of the reconstituted solution after dilution (with 0.9% sodium chloride solution or 5% glucose solution) has been demonstrated for 24 hours at 15–25 °C. From a microbiological standpoint, the solution should be used immediately. If not used immediately, the storage period and conditions prior to use are the responsibility of the user.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children!

Incompatibilities.

Sulfite is a highly reactive component; therefore, mixing Ginipral with other solutions should be avoided except for 0.9% sodium chloride solution and 5% glucose solution.

Packaging.

5 ml in a vial; 5 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Takeda Austria GmbH, Austria.

Manufacturer's address.

St. Peter-Strasse 25, 4020 Linz, Austria.