Document: Oxygrindeks solution for injection and infusion ENG SmPC change

• Oxygrindeks solution for injection and infusion SmPC
• Oxygrindeks solution for injection and infusion ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Oxygrindeks 8.3 microgram/ml solution for injection and infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 8.3 microgram oxytocin (5 IU).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection and infusion (Injection and Infusion).

Colourless, clear liquid with characteristic odour.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

• Labour induction in the case of delayed parturition.

• Premature rupture of membranes, eclampsia, pre-eclampsia, intrauterine foetal death.

• Primary and secondary uterine inertia.

• Induced abortion and at spontaneous abortion in early stages of pregnancy as an adjunctive therapy for the management of evacuation of the uterus and to advance the subsequent course.

• At the placental separation (e.g. placental haemorrhage, subinvolutio uteri).

4.2 Posology and method of administration

Posology

Induction of labourand at uterine inertia

The major advantage of intravenous drip infusion is that the uterine contractions can be carefully monitored in order to use the lowest dose of Oxygrindeks for an adequate effect. Oxygrindeks should be administered as an intravenous (i.v.) drip infusion given as 0.2 ml Oxygrindeks 8.3 microgram/ml per 100 ml 5.5 % dextrose solution or physiological sodium chloride solution.

The initial infusion rate should be set at 2‑8 drops/min (0.1‑0.4 ml/min). During careful monitoring of the frequency, strength, and duration of contractions as well as the foetal heart rate the infusion rate (maximum infusion rate is 40 drops/min (2 ml/min)) may be gradually increased at intervals of at least 20 min, until an adequate level of uterine activity is attained. In the event of uterine hyperactivity and/or foetal distress, the infusion must be discontinued immediately.

If regular contractions are not established after the infusion of a total amount of 1 ml Oxygrindeks 8.3 microgram/ml, the attempt to induce labour should be ceased. It may be repeated on the following day.

Oxygrindeks is well tolerated by the tissues why an inadvertent extravascular infusion is not harmful.

Caesarean section

1 ml Oxygrindeks 8.3 microgram/ml as i.v. infusion (1.0 ml diluted in physiological sodium chloride solution and administered via i.v. drip infusion or preferably by means of a variable-speed infusion pump over 5 minutes) after delivery.

At abortion (vacuum aspiration)

1 ml Oxygrindeks 8.3 microgram/ml as i.v. infusion (1.0 ml diluted in physiological sodium chloride solution and administered as an i.v. drip infusion or preferably by means of a variable-speed infusion pump over 5 minutes).

I.v. infusion of 6 ml Oxygrindeks 8.3 microgram/ml in 500 ml 5.5 % dextrose solution during evacuation of the uterus, with a start when cervix is dilated to Hegar No. 8. During surgery a maximal infusion rate is applied, i.e. about 300 drops/min (15 ml/min). After the surgery the drop rate is reduced to about 120 drops/min (6 ml/min). This drop rate should be maintained until the whole amount has been infused. If painful uterus contractions occur, the drop rate should be decreased or the infusion temporarily stopped.

In placental separation (e.g. placental (post partum) haemorrhage, subinvolutio uteri) Oxygrindeks may be administered i.v. (0.6-2.0 ml Oxygrindeks 8.3 microgram/ml).

1.0 ml Oxygrindeks 8.3 microgram/ml may be administered as i.v. infusion (1.0 ml diluted in physiological sodium chloride solutionand administered via i.v. drip infusion or preferably by means of a variable-speed infusion pump over 5 minutes).

Hepatic and renal impairment

Patients with hepatic and renal impairment may require dose reduction or longer intervals between doses (see section 5.2).

Older people

There are no indications for use of Oxygrindeks in elderly patients.

Paediatric population

There are no indications for use of Oxygrindeks in children or adolescents.

4.3 Contraindications

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

• Mechanical obstruction to delivery (e.g. significant cephalopelvic disproportion, foetal malpresentation).

• Hypertonic uterine contractions.

4.4 Special warnings and precautions for use

Precaution should be observed in patients with a history of ceasarean section or other surgical uterus interventions.

The induction of labour by means of oxytocin should be attempted only when strictly indicated for medical reasons. Administration should only be under hospital conditions and qualified medical supervision.

Oxygrindeks (oxytocin) given for induction and enhancement of labour, must only be administered as an intravenous drip infusion.

Oxytocin should not be used for prolonged periods in patients with oxytocin-resistant uterine inertia, severe pre-eclamptic toxaemia or severe cardiovascular disorders.

Oxygrindeks should never be administered by intravenous bolus injection as it may cause a short-lasting hypotension accompanied with flushing and reflex tachycardia.

Oxytocin should be used with caution in patients who have a pre-disposition to myocardial ischaemia due to pre-existing cardiovascular disease (such as hypertrophic cardiomyopathy, valvular heart disease and/or ischaemic heart disease including coronary artery vasospasm), to avoid significant changes in blood pressure and heart rate in these patients.

Oxytocinshould be given with caution to patients with known “long QT syndrome” or related symptoms and to patients taking drugs that are known to prolong QT interval.

Administration of oxytocin at excessive doses can be hazardous to both mother and foetus, resulting in uterine overstimulation which may cause foetal distress (foetal bradycardia, meconium-stained amniotic fluid, foetal asphyxia and death) and hypertonicity, tetanic contractions or rupture of the uterus. Careful monitoring of foetal heart rate (if possible cardiotocography (CTG)), uterine motility and blood pressure is essential, so that the dosage may be adjusted to individual response. For patients with cardiovascular disease, the volume of infused fluid should be kept low by infusing oxytocin at a higher concentration.

In rare circumstances, the pharmacological induction of labour using uterotonic agents increases the risk of postpartum disseminated intravascular coagulation (DIC). The pharmacological induction itself and not a particular agent linked to such risk. This risk is increased in particular if the woman has additional risk factors for DIC such as being 35 years of age or over, complications (such as gestational diabetes, hypertension, hypothyroidism) during pregnancy and gestational age more than 40 weeks. In these women, oxytocin or any other alternative medicine should be used with caution, and the practitioner should be alerted by signs of DIC. Women with the above mentioned risk factors should be examined concerning fibrinolysis immediately after labour.

Since oxytocin possesses slight antidiuretic activity, its prolonged i.v. administration at high doses in conjunction with large volumes of fluid, as may be the case in the treatment of inevitable or missed abortion or in the management of postpartum haemorrhage, may cause water intoxication associated with hyponatraemia (see section 4.8). The combined antidiuretic effect and the intravenous fluid administration may cause fluid overload leading to a haemodynamic form of acute pulmonary oedema without hyponatraemia.

Parenteral oxytocin must not be given simultaneously with oxytocin‑containing nasal spray.

Prostaglandins may potentiate the oxytocin effect of uterine contractions and vice versa. If used in sequence, the patient's uterine activity should be carefully monitored.

Some inhalation anaesthetics, e.g., cyclopropane or halothane, may enhance the hypotensive effect of oxytocin and reduce its oxytocic action. Their concurrent use with oxytocin has also been reported to cause cardiac rhythm disturbances.

Oxytocin should be given with caution to patients taking medicines that are known to prolong the QT interval.

When given during or after caudal block anaesthesia, oxytocin may potentiate the pressor effect of sympathomimetic vasoconstrictor agents.

4.6 Fertility, pregnancy and lactation

Pregnancy

Animal reproduction studies have not been conducted with oxytocin. Based on the wide experience with this medicine and its chemical structure and pharmacological properties, it is not expected to present a risk of foetal abnormalities when used as indicated.Oxytocin is contraindicated in pregnancy with exception of use for strictly medical reasons such as induction or enhancement of labour or at spontaneous or induced abortion.

Breastfeeding

Oxytocin may be found in small quantities in mother's breast milk. However, oxytocin is not expected to cause harmful effects in the newborn because it passes into the alimentary tract where it undergoes rapid inactivation.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed, but since oxytocin actuate the labour, the patient should not drive or use machines during treatment with oxytocin.

Adverse reactions are presented according to the MedDRA system organ classes and MedDRA frequency 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), not known (cannot be estimated from the available data).

Immune system disorders

Rare: Anaphylactoid reactions associated with dyspnoea, hypotension or shock

Metabolism and nutrition disorders

Uncommon: Antidiuretic effect that can cause water intoxication with headache and nausea

Nervous system disorders

Common: Headache

Cardiac disorders

Common: Tachycardia, bradycardia

Rare: Arrhythmia

Respiratory, thoracic and mediastinal disorders

Rare: Laryngeal oedema

Gastrointestinal disorders

Common: Nausea, vomiting

Skin and subcutaneous tissue disorders

Rare: Rash, urticaria

In rare circumstances the pharmacological induction of labour using uterotonic agents, including oxytocin, increases the risk of postpartum DIC (see section 4.4) (may affect less than 1 in 1000 patients).

Prolonged i.v. administration or rapid infusion may cause adverse effects.

Rapid i.v. bolus injection of oxytocin at doses more than 3.34 micrograms may result in acute short-lasting hypotension accompanied with flushing and reflex tachycardia (see section 4.4). These rapid haemodynamic changes may result in myocardial ischaemia, particularly in patients with pre-existing cardiovascular disease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

[To be completed nationally]

4.9 Overdose

Overdosage may cause the following complications: foetal distress (foetal bradycardia, meconium-stained amniotic fluid, asphyxia), hypertonicity, tetanic contractions, rupture of the uterus,water intoxication.

Toxicity: no symptoms were seen when 2‑3 and 10 IU respectively was given i.m. to newborns and 8 IU was given by nasal administration to children of ½‑1½years of age.

Serious intoxication was seen in adults after infusion of 80 IU in a solution of isotonic glucose during 35 hours, infusion of 488 IU during 40 hours and infusion of 800 IU during 60 hours.

(1 IU corresponds to 1.67 microgram).

Symptoms: antidiuretic effect – risk for water intoxication (hyponatraemia, hypo-osmolality, cerebral oedema).Vascular spasm, hypertension.

Treatment: in the case of fluid retention observation is necessary. In the event of water intoxication, diuretics (mannitol or furosemide), infusion of sodium and cerebral oedema therapy should be administered. Other symptomatic treatment may be used.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Oxytocin and analogues, ATC code: H01BB02

Oxytocin stimulates contractions (frequency and strength) during labour, accelerates the involution of the uterus and pulls together the myoepithelial cells of the mammary gland, thereby making the emptying process easier.

Being synthetic, Oxygrindeks does not contain vasopressin and is therefore not blood pressure‑raising with the recommended doses, and may therefore be used at pre-eclampsia.

5.2 Pharmacokinetic properties

When intravenous infusion is used the effect occurs gradually, with steady state usually after 20‑40 min.

After intravenous or intramuscular (i.m.) injection, oxytocin acts rapidly; in approx. 1 min after i.v. injection and 2‑4 min after i.m. injection. The effect remains for 30‑60 min after i.m. injection and probably for a somewhat shorter period after i.v. injection.

Distribution

At steady state the distribution volume is approx. 170 ml/kg in men. Plasma protein binding is low.

Metabolism

The enzyme oxytocinase, a glycoprotein aminopeptidase, is produced during pregnancy. The enzyme is found in plasma and can metabolise oxytocin. The enzymatic activity increases gradually until labour begins it then increases rapidly, and decreases again after delivery. The enzyme activity is also high in the placental and uterine tissues during this period. There is no or very little metabolism of oxytocin in the plasma in men or non-pregnant women.

Elimination

The half‑life is short, 3‑20 min. Oxytocin is excreted mainly via the liver and kidneys. Metabolic clearance is approx. 20 ml/kg/min in both men or non-pregnant women. Less than 1 % of the given dose is excreted unchanged in the urine.

The degree to which the pharmacokinetics of oxytocin are affected by renal or hepatic function impairment has not been investigated. As it has been shown indirectly that the liver and kidneys play an important role in the excretion of oxytocin, impairment of renal or hepatic function would be expected to have a significant effect on the pharmacokinetics of oxytocin.

5.3 Preclinical safety data

There is no additional preclinical information appraised to be of relevance for the clinical safety other than already included in other parts of the Summary of Products Characteristics.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Chlorobutanol hemihydrate

Acetic acid (pH-adjustment)

Water for injections

6.2 Incompatibilities

For mixture as an additive to infusion fluids, see section 6.6.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

1 ml transparentglass ampoules. Pack size: 10 ampoules.

6.6 Special precautions for disposal and other handling

Oxygrindeks 8.3 microgram/ml solution for injection and infusion is compatible with infusion fluids. An appropriate diluent is physiological sodium chloride or 5.5 % dextrose solution. A proper concentration is 1.7 microgram per 100 ml infusion fluid.

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

7. MARKETING AUTHORISATION HOLDER

AS GRINDEKS.

Krustpils iela 53, Rīga, LV‑1057, Latvia

Tel: +371 67083205

Fax: +371 67083505

E‑mail: grindeks@grindeks.lv

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

2015-06-24