Terlipressin acetate injection 1mg/10ml Taj Pharma

  1. Name of the medicinal product

Terlipressin acetate injection 1mg/5ml Taj Pharma
Terlipressin acetate injection 1mg/10ml Taj Pharma

2. Qualitative and quantitative composition

a) Terlipressin acetate injection 1mg/5ml
Each ml contains:
Terlipressin acetate                           0.2mg
Water for injection                            q.s

b) Terlipressin acetate injection 1mg/10ml
Each ml contains:
Terlipressin acetate                           0.1mg
Water for injection                            q.s

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Solution for injection.

Clear colourless solution, with pH between 3.7 and 4.2, and osmolality between 290 and 360 mOsm/kg.

  1. Clinical particulars

4.1 Therapeutic indications

Terlipressin is indicated in the treatment of bleeding oesophageal varices.

4.2 Posology and method of administration

The administration of terlipressin serves the emergency care for acute bleeding oesophageal varices until endoscopic therapy is available. Afterwards the administration of terlipressin for the treatment of oesophageal varices is usually an adjuvant therapy to the endoscopic haemostasis.

Adults

The recommended initial dose is 1 to 2 mg terlipressin acetate(equivalent to 8.5 to 17 ml of solution), administered by intravenous injection over a period of time.

Depending on the patient’s body weight the dose can be adjusted as follows:

– weight less than 50 kg: 1 mg terlipressin acetate (8.5 ml)

– weight 50 kg to 70 kg: 1.5 mg terlipressin acetate (12.75 ml)

– weight exceeding 70 kg: 2 mg terlipressin acetate (17 ml).

After the initial injection, the dose can be reduced to 1 mg terlipressin acetate every 4 to 6 hours.

The approximate value for the maximum daily dose of Terlipressin acetate SUN 0.12 mg/ml solution for injection is 120 μg terlipressin acetate per kg body weight.

The therapy is to be limited to 2 – 3 days in adaptation to the course of the disease.

1 to 2 mg terlipressin acetate corresponding to 0.85 to 1.7 mg terlipressin.

Elderly

Terlipressin should only be used with caution in patients over 70 years (see section 4.4).

Paediatric population

Terlipressin is not recommended in children and adolescents due to insufficient experience on safety and efficacy (see section 4.4).

Renal insufficiency

Terlipressin should only be used with caution in patients with chronic renal failure (see section 4.4).

Hepatic insufficiency

A dose adjustment is not required in patients with liver failure.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Terlipressin 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 or peripheral vascular diseases

– cardiac arrhythmias

– acute coronary syndrome, coronary deficiencies or previous myocardial infarction

– chronic renal insufficiency

– elderly patients> 70 years as experience is limited in this group

– pregnancy (see section 4.6).

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

Due to the weak antidiuretic effect of terlipressin (only 3% of the antidiuretic effect of native vasopressin) especially patients with already 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 in units with facilities for regular monitoring of the cardiovascular system, haematology and electrolytes.

In emergency situations which require an immediate treatment before sending the patient to a hospital symptoms of hypovolaemia have to 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 anormalities, 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).

Particular caution should be exercised in the treatment of children, adolescents and elderly patients, as experience is limited and there is no data available regarding dosage recommendation in these special patient categories.

This medicinal product contains 15.7 mmol (or 361 mg) of sodium in its single maximum dose. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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).

4.6 Fertility, pregnancy and lactation

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).

Terlipressin 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 suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with terlipressin should be made taking into account the benefit of breast-feeding to the child and the benefit of terlipressin therapy to the woman.

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.

4.8 Undesirable effects

The assessment of undesirable effects is based on the following frequencies:

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).

Treatment of bleeding oesophageal varices with terlipressin (1 mg intravenously and more) may be accompanied by the following adverse reactions:

Metabolism and nutrition disorders
Uncommon: hyponatraemia if fluid not monitored
Very rare: hyperglycaemia
Nervous system disorders
Common: headache
Uncommon: triggering of a convulsive disorder
Very rare: stroke
Cardiac disorders
Common: ventricular and supra-ventricular arrhythmia, bradycardia, signs of ischaemia in the ECG
Uncommon: angina pectoris, acute hypertension rise, in particular in patients already suffering from hypertension (generally, it decreases spontaneously), atrial fibrillation, ventricular extrasystoles, tachycardia, chest pain, myocardial infarction, fluid overload with pulmonary oedema, cardiac failure, Torsade de Pointes
Very rare: myocardial ischemia
Vascular disorders
Common: hypertension, hypotension, peripheral ischaemia, peripheral vasoconstriction, facial pallor
Uncommon: intestinal ischaemia, peripheral cyanosis, hot flushes
Respiratory, thoracic and mediastinal disorders
Uncommon: pain in the chest, bronchospasm, respiratory distress, respiratory failure
Rare: dyspnoea
Gastrointestinal disorders
Common: transient abdominal cramps, transient diarrhoea
Uncommon: transient nausea, transient vomiting
Skin and subcutaneous tissue disorders
Common: paleness
Uncommon: lymphangitis, skin necrosis unrelated to the site of administration
Reproductive system and breast disorders
Common: abdominal cramps (in women)
Pregnancy, puerperium and perinatal conditions
Uncommon: uterine hypertonus, uterine ischemia
Not known: uterine constriction, decreased uterine blood flow
General disorders and administration site conditions
Uncommon: local cutaneous necrosis.

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.

4.9 Overdose

The recommended dose should not be exceeded in any case, since the risk of severe circulatory adverse effects is dose-dependent.

An acute hypertensive crisis, especially in patients with recognized hypertension can be controlled with a vasodilator-type alpha-blocker, e.g. 150 microgram clonidine intravenously.

Bradycardia requiring treatment should be treated with atropine.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Systemic hormonal preparations, posterior pituitary lobe hormones, vasopressin and analogues.

Terlipressin inhibits portal hypertension with simultaneous reduction of blood circulation in portal vessels. Terlipressin contracts smooth oesophageal muscle with consecutive compression of oesophageal varices.

The inactive pre-hormone terlipressin slowly releases bioactive lysinevasopressin . Metabolic elimination takes place concomitantly and within a period of 4-6 hours. Therefore, concentrations remain continuously above the minimal effective dose and below toxic concentrations.

Specific effects of terlipressin are assessed as follows:

Gastrointestinal system

Terlipressin increases the tone of vascular and extravascular smooth muscle cells. The increase in arterial vascular resistance leads to decrease of splanchnic hypervolemia. The decrease of the arterial blood supply leads to reduction of pressure in the portal circulation. Intestinal muscles contract concomitantly which increases intestinal motility. The muscular wall of the esophagus also contracts which leads to closure of experimentally induced varices.

Kidneys

Terlipressin has only 3% antidiuretic effect of the native vasopressin. This residual activity is of no clinical significance. Renal blood circulation is not significantly effected in normovolemic condition. Renal blood circulation is increased, however, under hypovolemic condition.

Blood pressure

Terlipressin induces a slow haemodynamic effect which lasts 2-4 hours. Systolic and diastolic blood pressure increase mildly. More intense blood pressure increase has been observed in patients with renal hypertension and general blood vessel sclerosis.

Heart

All studies reported that no cardio-toxic effects were observed, not even under the highest dose of terlipressin. Influences on the heart, such as bradycardia, arrhythmia, coronary insufficiency, occur possibly because of reflex or direct vascular constrictive effects of terlipressin.

Uterus

Terlipressin causes significant decrease in myometrial and endometric blood flow.

Skin

The vasoconstrictive effect of terlipressin causes significant decrease in blood circulation of the skin. All studies reported obvious paleness on face and body.

In conclusion, the main pharmacological properties of terlipressin are its haemodynamic effects and its effects on smooth muscle. The centralization effect under hypovolemic condition is a desired side effect in patients with bleeding oesophageal varices.

5.2 Pharmacokinetic properties

After bolus intravenous injection terlipressin elimination follows second order kinetics. Plasma half-life was calculated as 8-12 minutes during the distribution phase (0-40 minutes) and 50-80 minutes during the elimination phase (40-180 minutes). The release of lysine-vasopressine is maintained for at least 180 minutes. Due to cleavage of the glycyl groups from terlipressin lysine-vasopressin is slowly released and reaches maximal concentrations after 120 minutes. Urine contains only 1% of the injected terlipressin, which indicates almost complete metabolism by endo- and exopeptidases of liver and kidneys.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single- and repeat-dose toxicity, and genotoxicity. At doses relevant to humans, the only effects observed in animals were those attributed to the pharmacological activity of terlipressin.

Adverse reactions observed in animal studies with possible relevance to clinical use were as follows:

Due to its pharmacological effect on smooth muscles terlipressin may induce abortion in the first trimester.

An embryo-fetal study in rats demonstrated no adverse effects of terlipressin. In rabbits abortions occurred, probably related to maternal toxicity, and there were ossification anomalies in a small number of fetuses and a single isolated case of cleft palate.

No carcinogenicity studies have been performed with terlipressin.

  1. Pharmaceutical particulars

6.1 List of excipients

Sodium acetate trihydrate

Sodium chloride

Acetic acid, glacial (for pH adjustment)

Water for injection.

6.2 Incompatibilities

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

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store in a refrigerator (2-8°C).

6.5 Nature and contents of container

Terlipressin acetate SUN 0.12 mg/ml solution for injection is packed in 10 ml clear type-I treated glass OPC (one point cut) ampoule with blue dot green band.

Pack size: 5 x 8.5ml.

6.6 Special precautions for disposal and other handling

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

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Terlipressin Injection 1mg/5ml, 1mg/10ml Taj Pharma

Package leaflet: Information for the user

terlipressin (as acetate)

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or nurse.
  • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Terlipressin acetate Injection is and what it is used for
    2. What you need to know before you are given Terlipressin acetate Injection
    3. How to use Terlipressin acetate Injection
    4. Possible side effects
    5. How to store Terlipressin acetate Injection
    6. Contents of the pack and other information
  2. What Terlipressin acetate Injection is and what it is used for

Terlipressin acetate Injection is a synthetic pituitary hormone.

Terlipressin acetate Injection is used for treatment of bleeding from dilated veins in the food pipe leading to your stomach (bleeding oesophageal varices).

  1. What you need to know before you are given Terlipressin acetate Injection

You should not be given Terlipressin acetate Injection

  • if you are allergic to terlipressin or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

This medicine will be given to you if you have severe or life-threatening bleeding in your food pipe (oesophagus). It is used under continuous monitoring of your heart and blood circulation.

If you are able to, tell your doctor if you suffer from the conditions shown below:

  • if you are suffering from a severe infection known as septic shock
  • if you suffer from bronchial asthma or other conditions that affect your breathing
  • if you suffer from acute coronary syndrome (ACS describes symptoms related to poor blood flow to the heart muscle leading to a heart attack. This results in chest pain, or angina pectoris.)
  • if you suffer from uncontrolled high blood pressure, insufficient blood circulation in the heart vessels (e.g. angina), have previously had a heart attack (myocardial infarction), or you have hardening of your arteries (arteriosclerosis)
  • if you suffer from irregular heartbeats (cardiac arrhythmias)
  • if you have poor blood circulation to your brain (e.g. you have had a stroke) or to your limbs (peripheral vascular disease)
  • if you suffer from impaired kidney function (renal insufficiency)
  • if you suffer from disturbances in the level of salt (electrolytes) in your blood
  • if you are suffering from reduced amount of fluid in your circulation or have already lost a large amount of blood
  • if you are over the age of 70 years
  • if you are pregnant.

Children and adolescents

Terlipressin acetate Injection is not recommended for use in children and adolescents due to insufficient experience.

Other medicines and Terlipressin acetate Injection

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.

Please inform your doctor immediately if you use the following medicines:

  • drugs that have an effect on your heart rate (e.g. beta-blockers or propofol)
  • drugs that can trigger irregular beating of the heart (arrhythmia) such as the following:
  • anti-arrhythmic drugs known as Class IA (quinidine, procainamide, disopyramide) and Class III (amiodarone, sotalol, ibutilide, dofetilide)
  • an antibiotic called erythromycin
  • antihistamines (mainly used to treat allergies but also found in certain cough and cold remedies)
  • medicines used to treat depression called tricyclic antidepressants
  • medicines that may alter the level of salt or electrolytes in your blood, particularly diuretics (used to treat high blood pressure and heart failure).

Pregnancy and breast-feeding

Terlipressin acetate Injection should only be used during pregnancy if it is vital to treat your condition. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before you are given this medicine.

It is not known if Terlipressin acetate Injection is present in breast milk. Therefore the possible effects on your baby are unknown. You should discuss the potential risk to your baby with your doctor.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed. However, if you feel unwell after receiving the injection, do not drive or operate machinery.

Terlipressin acetate Injection contains sodium

This medicinal product contains 15.7 mmol (or 361 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

  1. How Terlipressin acetate Injection is used

This medicine will always be administered to you by your doctor. Please ask your doctor for further information regarding its use.

How much Terlipressin acetate Injection is given

Adults

Initially 1-2 mg terlipressin acetate (equivalent to 8.5-17 ml of injection solution) is given by injection into your vein. Your dose will depend on your body weight.

After the initial injection, your dose may be reduced to 1 mg terlipressin acetate (equivalent to 8.5 ml of solution), every 4 to 6 hours.

The maximum dose you can receive each day is approximately 120 micrograms/kg body weight.

Elderly

If you are over 70 years of age speak with your doctor before you receive Terlipressin acetate Injection .

How Terlipressin acetate Injection is given

Terlipressin acetate Injection should be slowly injected intravenously.

How often you will be given Terlipressin acetate Injection

The use is limited to 2 – 3 days, depending on the course of your condition.

If you are given more Terlipressin acetate Injection than you should be

You must not have more Terlipressin acetate Injection than the recommended dose. If you are given too much then you may have a rapid increase in your blood pressure, especially if you already suffer with high blood pressure. If this happens then you need another medicine called an alpha blocker (e.g. clonidine) to control your blood pressure.

If you experience lightheadedness, dizziness, or feeling faint, tell your doctor as these could be signs of a low heart rate. This can be treated with a medicine called atropine.

If you forget to use Terlipressin acetate Injection

You will be given Terlipressin acetate Injection in hospital under the supervision of your doctor.

If you stop using Terlipressin acetate Injection

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Important side effects or signs you should pay attention to, and measures to be taken if you are affected

In very rare cases severe side effects are possible when you are given terlipressin. If you are affected by one of the following side effects, please tell your doctor immediately if you are able to. Your doctor should not give you any more terlipressin.

Severe shortness of breath due to an asthma attack, severe difficulty with or stopping breathing, severe pain in the chest (angina), severe and persistent irregular heartbeats, locally dead skin (necrosis), convulsions (seizure), kidney failure.

Other possible side effects

Common (may affect up to 1 in 10 people)

  • headache
  • too slow heart rate
  • signs of insufficient blood circulation in the heart vessels shown in the ECG
  • high blood pressure
  • low blood pressure
  • insufficient blood circulation in arms, legs and skin, pale skin
  • abdominal cramps

Uncommon (may affect up to 1 in 100 people)

  • too little sodium in the blood (hyponatraemia) if not monitored
  • dead skin (necrosis) not related to the injection site
  • rapid increase in blood pressure
  • too fast heart rate (palpitations)
  • swelling of the tissues in the body or fluid on the lungs
  • chest pain
  • heart attack
  • excess fluid on the lungs
  • heart failure (Torsade de Pointes)
  • insufficient blood flow to the intestines
  • uterine cramps
  • decreased blood flow to the uterus
  • bluish colouration of the skin or lips
  • hot flushes
  • temporary nausea (feeling sick)
  • temporary vomiting
  • inflammation of the lymph vessels (fine red streaks under your skin extending from the affected area to the armpit or groin and by fever, chills, headache, and muscle pain).

Rare (may affect up to 1 in 1,000 people)

  • shortness of breath.

Very rare (may affect up to 1 in 10,000 people)

  • too much sugar in the blood (hyperglycaemia)

Not known (frequency cannot be estimated from the available data)

  • uterine cramps (cramps in the womb)
  • decreased blood flow to the uterus.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Terlipressin acetate Injection

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the ampoule after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator at 2-8°C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Terlipressin acetate Injection contains

  • The active substance is terlipressin (as acetate). Each ampoule contains 1 mg of terlipressin acetate in 8.5 ml solution for injection, corresponding to 0.85 mg terlipressin. This is equivalent to 0.12 mg terlipressin acetate per ml, corresponding to 0.1 mg terlipressin per ml.
  • The other ingredients are sodium acetate trihydrate, sodium chloride, acetic acid, glacial (for pH adjustment) and water for injection.

What Terlipressin acetate Injection looks like and contents of the pack

Terlipressin acetate Injection is a clear, colourless solution for injection without visible particles.

Terlipressin acetate Injection is packed into one carton with 5 ampoules.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

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