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Endocrine - Metabolic

TRINITRINA

1. NAME OF THE MEDICINAL PRODUCT

TRINITRINE 5 mg/1.5 ml concentrate for infusion solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Every 1.5 ml ampoule contains:

active substance: nitroglycerin 5 mg

For excipients see 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Unstable angina, variant angina, Prinzmetal’s.angina.  Acute left ventricular failure either subsequent or not to acute myocardial infarction, especially with high filling pressure and low output per minute. Acute pulmonary oedema and pulmonary pre-oedema. Hypertensive crisis.

4.2 Posology and method of administration

Posology must be established to suit individual patient requirements and depending on the response to monitored parameters. Experience recommends a dose of 0.5-6 mg/hour of nitroglycerine for continuous intravenous infusion.

These doses rarely need to be exceeded, reaching 6 mg/hour. The solution for intravenous infusion is prepared by appropriately diluting nitroglycerine as specified in the table below and infusing it with either an automatic device or drop by drop, as indicated in the infusion table (1 ml corresponds to approx. 20 drops of a normal infusion).

 

Dilution Table

 

Number of ampoules

(quantity of active substance)   

1

(5 mg)

2

(10 mg)

Solution in ampoules

1.5 ml

3 ml

Diluent solution (ml)

250

500

 

Final volume of the ready solution

(ml)

 

251.5

503

Final nitroglycerin concentration (mg/ml)

[corresponds to 20 drops of a normal infusion]

                  0.02

 

 

 

 

                                                                             

           

Infusion Table

 

Desired quantity of

NTG per hour 

No. of drops

 a minute

 

0.50 mg

0.75 mg

1.00 mg

1.25 mg

1.50 mg

2.00 mg

2.50 mg

3.00 mg

3.50 mg

4.00 mg

4.50 mg

5.00 mg

5.50 mg

6.00 mg

 

6-7

10

13-14

17

20-21

26-27

34

41

47-48

53

59-60

68

74-75

82

 

                                                                                                  

4.3 Contraindications

  • Shock.

  • Cardiogenic shock, unless appropriate diastolic aortic pressure is maintained.

  • Hypotension during acute myocardial infarction with low filling pressure.

  • Acute hypotension (<90 mmHg systolic pressure).

  • Severe hypovolaemia.

  • Increased intracranial pressure, brain injury and brain haemorrhage.

  • Myocardial failure due to obstruction (i.e. either with aortic or mitral stenosis or constrictive pericarditis).

  • Hypertrophic obstructive cardiomiopathy.

  • Toxic pulmonary oedema.

  • Severe anaemia.

  • Angle-closure glaucoma.

  • Generally contraindicated in children and during pregnancy and breast-feeding.

  • In combination with sildenafil (see “Interactions”).

  • Hypersensitivity to organic nitrates and/or to an excipient.

4.4 Special warnings and precautions for use

The product must be administered with extreme caution to patients with brain injuries and cerebral haemorrhage.

Treatment with nitroglycerine for intravenous infusion must only be administered in a hospital environment, monitoring arterial pressure, cardiac rate and the patient’s clinical condition. Severe patients require central venous pressure and/or pulmonary pressure, cardiac output and ECG monitoring.

4.5 Interaction with other medicinal products and other forms of interaction

Ethanol can block metabolic processes, subsequently enhancing the action of nitroglycerine. Vasodilators, antihypertensives and diuretics can enhance the hypotensive effect of nitroglycerine. The peripheral vasodilation produced by nitroglycerine is hindered by the concomitant administration of indomethacin, probably through a prostaglandin-inhibiting mechanism. The intravenous administration of nitroglycerine reduces the thrombolytic effect of alteplase and the anticoagulant effects of heparin. Sildenafil enhances the hypotensive effects of nitrates; hence, its co-administration with organic nitrates (i.e. nitroglycerine) is contraindicated (see “Contraindications”).

Interactions with laboratory tests

Nitrates can interfere with the Zlatkis/Zak colourimetric assay by producing a false low plasma cholesterol result.

4.6 Pregnancy and lactation

There is no adequate clinical and epidemiological data concerning the use of nitroglycerine in pregnancy. Trials conducted on animals do not suffice to establish the effects of nitroglycerine during pregnancy, on the development of the foetus and/or on post-natal development and delivery (see “Preclinical Safety Data”). The potential risk in man is not known.

Trinitrina concentrate for solution for infusion should not be administered during pregnancy, especially in the first three months, unless it is strictly necessary.

It has not been ascertained whether nitroglycerine is excreted with breast milk. Since this possibility cannot be ruled out, special caution is required when nitroglycerine is prescribed to a breast-feeding patient.

4.7 Effects on ability to drive and use machines

Though it is unlikely that a patient who needs Trinitrina vials will either drive or use machinery due to certain side-effects (orthostatic hypotension, nausea, vertigo), the drug can considerably influence the ability to drive or use machinery. These undesirable effects can slow down the subject’s reactions. 

4.8 Undesirable effects

Acute and persistent headache caused by cerebral vasodilation can set in soon after the administration of nitroglycerine.

Vertigo, confusion, weakness, increased heart rate and other signs of hypotension, like nausea, vomiting, diaphoresis, pallor and lipothymia are generally related to drug overdose.  Nitroglycerine may rarely induce bradycardia and signs of hypervagotony. Moreover, skin reddening and exfoliative dermatitis can be observed in patients under treatment with nitrates. 

Rare cases of methemoglobinemia that rapidly cleared by reducing infusion velocity and administering methylene blue have been reported.

Undesirable effects, such as hot flushes, headache and postural hypotension, can be a limit, especially during the initial phases of treatment, when angina is severe or when patients are hypersensitive to the effects of nitrates. Headache generally passes during treatment.

Reported adverse events are listed below in categories organised by system.

– Blood and lymphatic system disorders

            Rare: methemoglobinemia

– Nervous system disorders

            vertigo, headache

– Ophthalmological disorders

            blurred vision

– Cardiac disorders

            tachycardia, palpitations, paradoxical bradycardia, syncope

– Vascular disorders

            postural hypotension

– Gastrointestinal disorders

            nausea, digestive disorders

  • Skin and subcutaneous disorders

rash

– General disorders and alterations at the site of administration

            General disorders: hot flushes with rash, asthenia and perspiration.

            Very rare: cyanosis

            Alterations at the site of administration: burning sensation and rash.

Methemoglobinemia has been associated with prolonged treatment and high doses.

4.9 Overdose

Signs and symptoms are especially caused by enhanced vasodilation and methemoglobinemia. Symptoms: hypotension and reflex tachycardia, cold pale skin, headache, vertigo, confusion, sight disorders, nausea and vomiting with colic-like abdominal pain that can be associated with watery diarrhoea, palpitations, syncope and cardiocirculatory failure.

Symptoms related with severe generalised hypotension require an instant reduction in infusion velocity, while the intoxicated patient must be placed in the Trendelenburg position (stretched out with the application of passive limb movements) and administered IV fluids. Administer alpha-adrenergic agonists (i.e. methoxamine or phenylephrine), if necessary. Adrenaline and similar substances are ineffective on significant overdose-related hypotension.

Treatment of cyanosis caused by methemoglobinemia: starting when methemoglobin levels are 0.8 g/100 ml, the treatment envisages one IV administration of 1% methylene blue (1-2 mg/kg).  A dose of 50 mg/kg should be administered orally to less severe cases. Treatment should be administered in a specialised centre.

5. PHARMACOLOGICAL PROPERTIES

  1. Pharmacodynamic properties

Pharmacotherapy group: vasodilator used in cardiac diseases, organic nitrates; ATC code: C01DA02.

Nitroglycerine has a relaxing effect on the smooth muscles of the human body. In the vascular system, it is effective on the large coronary arteries and, especially, on the venous system.

In angina, nitroglycerine’s main action mode lies in increasing venous capacity, thus reducing blood flow to the heart. This brings down end-diastolic left ventricular pressure (pre-load) and atrial filling volume, thus reducing the myocardium’s demand for oxygen. Low oxygen consumption is accompanied by improved myocardial perfusion due to the antispastic action on the epicardial coronary arteries and flow redistribution to benefit the cardiac muscle’s subepicardial layers.

Moreover, nitroglycerine dilates atherosclerotic stenoses in case of eccentric atheroma and relaxes both spontaneous vasospasm and vasospasm induced by ergonovine.

Nitroglycerine has a systemic dilating dose-dependent effect on arteries; this reduces peripheral vascular resistance (post-load) and systolic pressure in the left ventricular wall. Both events reduce the myocardium’s oxygen consumption.

Action mode

Nitroglycerine produces the free radical NO (nitric oxide), which activates guanylate cyclase and increases cyclic GMP levels in smooth muscle and other tissues. This leads to the dephosphorylation of the light chains of myosin, thus regulating smooth muscle contraction and, then, causing vasodilation.

  1. Pharmacokinetic properties

Absorption

The intravenous administration of nitroglycerine enables to rapidly reach drug plasma concentration levels and start therapeutic activities.

Distribution

The distribution volume (Vd) of nitroglycerine after intravenous administration is 3.3 l/kg.

At plasma concentrations of 50-500 ng/ml, the bond between nitroglycerine and plasma proteins is approx. 60%, while that of 1,2- and 1,3-dinitroglycerine (the two main metabolites of nitroglycerine) is 60% and 30%, respectively.

Metabolism

The active substance is rapidly metabolised in the liver by a glutathione-dependent organic nitrate reductase, generating pharmacologically inactive metabolites. Moreover, in vitro trials conducted on human erythrocytes have proved that even red blood cells are a site of nitroglycerine biotransformation by means of a sulphydryl-dependent enzymic process and interaction with reduced haemoglobin.

Trials conducted on animals have proved that even extrahepatic vascular tissues (femoral vein, inferior vena cava, aorta) play an important role in the metabolism of nitroglycerine, which explains the high systemic clearance of nitrates. In vitro trials have also observed that the biotransformation of nitroglycerine occurs concurrently with the release of smooth vascular muscle; this is consistent with the theory that drug-induced vasodilation is the process that transforms nitroglycerine into NO.

Elimination

Plasma concentrations of nitroglycerine rapidly drop with a mean half-life of 2-3 minutes after intake. Clearance (13.8 l/min) considerably exceeds hepatic blood flow.

5.3 Preclinical safety data

Preclinical data reveals the absence of risks for humans on the basis of conventional trials on drug safety, the toxicity of repeated administration, genotoxicity, carcinogenic potential and reproductive toxicity.

Individual administration-related toxicity: the LD50 of intravenously administered nitroglycerine is 23 mg/kg in rats and 10 mg/kg in mice.

Repeated administration-related toxicity: in chronic toxicity trials conducted on growing albino rats, a dose of 300 mg/kg administered for 6 months epicutaneously caused neither significant changes in body growth nor blood crasis nor other biological parameters. Moreover, no histological alterations were observed in the examined organs. The intraperitoneal administration of 825 mg/kg in rats for 33 days witnessed a loss of body weight. In dogs, nitroglycerine administered by slow infusion at a dose of 1 mg/h for 5 hours for 14 consecutive days caused neither variations in biochemical, haematological and urinary parameters nor histological alterations in the main organs.

Mutagenesis: though the Ames test has proved that nitroglycerine is a weak mutagen, in vivo assays (dominant lethal assay) conducted on male rats treated with max. oral doses of 363 mg/kg and ex vivo cytogenetic tests performed on murine and canine tissue provide no evidence of genotoxicity.

Carcinogenesis: rats treated with very high doses of nitroglycerine (363 mg/kg/day in males and 434 mg/kg/day in females) for 2 years presented the onset of hepatocellular carcinomas and interstitial cell tumours in the testis. Mice treated with 1022 (males) or 1058 (females) mg/kg/day and rats treated with 31.5 (males) and 38.1 (females) mg/kg/day for the same period presented no treatment-related tumours. Administration of 1058 mg/kg/day of nitroglycerine with the diet for the entire life cycle caused no increase in the incidence of tumours.

Reproductive toxicity: no trials have been conducted on the reproductive toxicity and teratogenicity of sublingual nitroglycerine. However, teratogenicity trials conducted on rats and rabbits with maximum topical nitroglycerine doses of 80 mg/kg/day and 240 mg/kg/day, respectively, highlighted no foetal damage.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Alcohol, water for preparations for injection.

6.2 Incompatibilities

Nitroglycerine is compatible with solutions for infusion for clinical use as, for instance, isotonic saline solution, 4-30% glucose solution, Ringer’s solution and protein solutions. No incompatibilities have so far been reported with other solutions for infusion. The drug must only be diluted in glass containers for phleboclysis.

Nitroglycerine tends to rapidly migrate to many plastic materials. Nitroglycerine for injection must only be diluted in glass containers for phleboclysis to obtain the solution for venous infusion.

Nitroglycerine contained in the final solution for infusion can be absorbed by the PVC of normal out-flow tubes in quantities amounting to 40-80% of the total with an absorption velocity that is inversely proportional to infusion velocity. Hence, the use of small polyethylene tubes that considerably reduce the loss of nitroglycerine is recommended.

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product requires no special storage conditions.

6.5 Nature and contents of container

Neutral yellow glass ampoule.

Package: with 10 ampoules, 5 mg/1.5 ml each.

6.6 Special precautions for disposal

None.

7. MARKETING AUTHORISATION HOLDER

Acarpia Farmaceutici S.r.l.

Via Vivaio 17 – 20122 Milan, Italy

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