VARIQUEL Solution for injection Ref.[8893] Active ingredients: Terlipressin

Variquel should only be used with caution and under strict monitoring of the patients in the following cases:

• septic shock
• bronchial asthma, respiratory deficiencies
• uncontrolled hypertension
• cerebral, coronary and peripheral vascular diseases (e.g. advanced arteriosclerosis)
• pre-existing seizures (seizures)
• cardiac arrhythmias
• history of ischemic cardiovascular disease because terlipressin can induce ischemia
• coronary deficiencies or previous myocardial infarction
• chronic renal insufficiency
• elderly patients over 70 years of age as experience is limited in this group
• pregnancy (see section 4.6).

Hypovolaemic patients often react with an increased vasoconstriction and atypical cardiac reactions.

Terlipressin has a weak antidiuretic effect (only 3% of the antidiuretic effect of native vasopressin) therefore patients with a history of disturbed electrolyte metabolism should be monitored for a possible hyponatraemia and hypokalaemia.

In principle the use of the product should be confined to specialist supervision. Regular checks of blood pressure, ECG, heart rate, sodium and potassium serum levels and fluid balance are required during treatment.

In emergency situations which require immediate treatment before sending the patient to a hospital, symptoms of hypovolaemia must be considered.

Terlipressin has no effect on arterial bleeding.

To avoid local necrosis at the injection site, the injection must be administered intravenously.

Skin Necrosis

During post-marketing experience several cases of cutaneous ischemia and necrosis unrelated to the injection site (see section 4.8) have been reported. Patients with peripheral venous hypertension or morbid obesity seem to have a greater tendency to this reaction. Therefore, extreme caution should be exercised when administering terlipressin in these patients.

Torsade de pointes

During clinical trials and post-marketing experience, several cases of QT interval prolongation and ventricular arrhythmias including “Torsade de pointes” have been reported (see section 4.8). In most cases, patients had predisposing factors such as basal prolongation of the QT interval, electrolyte abnormalities (hypokalemia, hypomagnesemia) or medications with concomitant effect on QT prolongation. Therefore, extreme caution should be exercised in the use of terlipressin in patients with a history of QT interval prolongation, electrolytic abnormalities, concomitant medications that can prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that can cause hypokalaemia or hypomagnesemia (e.g. some diuretics) (see section 4.5).

This medicinal product contains less than 1mmol (23 mg) of sodium per 5 ml, i.e. essentially “sodium-free”.

Special populations

Particular caution should be exercised in the treatment of children, adolescents and elderly patients, as experience is limited and there are no safety and efficacy data available regarding dosage recommendation in this population.

Terlipressin increases the hypotensive effect of non-selective β-blockers on the portal vein. The reduction in heart rate and cardiac output caused by the treatment can be attributed to the inhibition of the reflexogenic activity of the heart through the vagus nerve as a result of increased blood pressure. Concomitant treatment with drugs known to induce bradycardia (e.g. propofol, sufentanil) can cause severe bradycardia.

Terlipressin can trigger ventricular arrhythmias including “Torsade de pointes” (see sections 4.4 and 4.8). Therefore, extreme caution should be exercised in the use of terlipressin in patients with concomitant medications that can prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that may cause hypokalaemia or hypomagnesemia (e.g. some diuretics).

Pregnancy

The use of terlipressin is not recommended during pregnancy as it has been shown to cause uterine contractions and increased intrauterine pressure in early pregnancy and may decrease uterine blood flow. Terlipressin may have harmful effects on pregnancy and foetus. Spontaneous abortion and malformation has been shown in rabbits after treatment with terlipressin (see section 5.3).

Variquel should therefore only be used at vital indication on a case by case decision especially in the first trimester, when bleeding cannot be controlled with endoscopic therapy.

Breastfeeding

It is not known whether terlipressin is excreted in human breast milk. The excretion of terlipressin in milk has not been studied in animals. A risk to the breastfed child cannot be excluded.

A decision should be made on whether to discontinue breast-feeding or to discontinue/abstain from terlipressin therapy taking into account the benefit of breast-feeding to the child and the benefit of therapy for the woman.

No studies on the effect on the ability to drive and use machines have been performed.

Summary of the safety profile

The most common side effects reported in clinical studies (frequency 1-10%) are paleness, high blood pressure, abdominal pain, nausea, diarrhoea and headache.

The antidiuretic effects of terlipressin can cause hyponatremia if the fluid balance is not controlled.

Tabulated list of adverse reactions

The following frequencies are used to evaluate side effects: 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 (frequency cannot be estimated from the available data).

Description of selected adverse reactions

During clinical trials and post-marketing experience, several cases of QT interval prolongation and ventricular arrhythmias including “Torsade de pointes” have been reported (see sections 4.4 and 4.5).

During post-marketing experience, several cases of cutaneous ischemia and necrosis unrelated to the injection site have been reported (see section 4.4).

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.