Hypopress 0.1 mg/m or 10 mg/ml Solution for injection or infusion

HYPOPRESS is indicated for increasing blood pressure in adults with clinically significant hypotension resulting primarily from vasodilation in such settings as septic shock and anaesthesia. The duration of action is short-lived (minutes) and repeat injections are frequently required.

HYPOPRESS 10 mg/ml can only be administered via IV after dilution. HYPOPRESS should only be administered by healthcare professionals with appropriate training and relevant experience in the safe administration of phenylephrine preparations. HYPOPRESS should be administered in the lowest effective dosage for the shortest possible time. When possible, small doses should be injected initially and subsequent doses determined by pressor response.

Patients receiving HYPOPRESS should be closely monitored. Treatment with HYPOPRESS is not a substitute for replacement of blood, plasma, fluids and/or electrolytes. Prior to administration of therapy, hypovolaemia should be corrected. Acidosis may reduce the effectiveness of phenylephrine.

Posology

Adults

HYPOPRESS 0,1 mg/ml:

Intravenous bolus injection:

Dosing for Perioperative Setting

In adult patients undergoing surgical procedures with either neuraxial anaesthesia or general anaesthesia: 50 u03bcg to 250 u03bcg by intravenous bolus administration. The most frequently reported initial bolus dose is 50 u03bcg or 100 u03bcg.

Continuous infusion:

• Dosing for Perioperative Setting
• In adult patients undergoing surgical procedures with either neuraxial anaesthesia or general anaesthesia: 0,5 u03bcg/kg/min to 1,4 u03bcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal.
• Dosing for septic shock
• In adult patients with septic shock: 0,5 u03bcg/kg/min to 6 u03bcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal. Doses above 6 u03bcg/kg/min do not show significant incremental increase in blood pressure.

HYPOPRESS 10 mg/ml:

Intravenous bolus injection:

10 mg of phenylephrine (1 ml of HYPOPRESS 10 mg/ml) must be diluted to 200 ml of glucose 5 % injection or sodium chloride 0,9 % injection prior to bolus intravenous injection. This dilution yields a final concentration of 50 u03bcg/ml. Withdraw an appropriate dose from the 50 u03bcg/ml solution prior to bolus intravenous administration of the diluted solution.

Continuous infusion:

10 mg of phenylephrine (1 ml of HYPOPRESS 10 mg/ml) must be diluted in 500 ml of glucose 5 % injection or sodium chloride 0,9 % injection prior to administration via intravenous infusion:

• Dosing for Perioperative Setting
• In adult patients undergoing surgical procedures with either neuraxial anaesthesia or general anaesthesia: 0,5 u03bcg/kg/min to 1,4 u03bcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal.
• Dosing for septic shock
• In adult patients with septic shock: 0,5 u03bcg/kg/min to 6 u03bcg/kg/min by intravenous continuous infusion, titrated to blood pressure goal. Doses above 6 u03bcg/kg/min do not show significant incremental increase in blood pressure.

Special populations

Patients with renal impairment: Lower doses of HYPOPRESS may be required in patients with renal impairment.

Patients with hepatic impairment: Higher doses of HYPOPRESS may be needed in patients with liver cirrhosis.

Elderly patients: Treatment of the elderly should be made with caution.

Paediatric population: The safety and efficacy of HYPOPRESS in children have not been established. No data are available.

Method of administration: HYPOPRESS 0,1 mg/ml should be administered by slow intravenous bolus injection or continuous intravenous infusion. HYPOPRESS 10 mg/ml should be administered by slow intravenous bolus injection or continuous intravenous infusion, after dilution. When discontinuing therapy, the dosage should be reduced gradually, since sudden cessation of therapy may result in severe hypotension, intravascular fluid should be administered if necessary to avoid hypotension.

• Hypersensitivity to phenylephrine hydrochloride, or to any of the excipients (see section 6.1).
• Patients with severe hypertension.
• Patients with peripheral vascular disease, as it can lead to ischaemia with a risk of gangrene or vascular thrombosis.
• Patients with heart-block with or without bradycardia, uncontrolled cardiac failure, bradycardia less than 50 bpm or seriously impaired coronary arterial circulation.
• In combination with indirectly acting sympathomimetic medicines (ephedrine, methylphenidate, pseudoephedrine): risk of vasoconstriction and / or hypertensive crisis.
• In combination with alpha-sympathomimetic medicines (oral and / or nasal use) (etilefrine, midodrine, naphazoline, oxymetazoline, synephrine, tetryzoline, tuaminoheptane, tymazoline): risk of vasoconstriction and / or hypertensive crisis.
• In combination with non-selective monoamine oxidase inhibitors (MAOs) (or within 2 weeks of their withdrawal), due to risk of paroxysmal arterial hypertension and possibly fatal hyperthermia (see section 4.5).
• Patients with severe hyperthyroidism.

Arterial blood pressure should be monitored during treatment. HYPOPRESS should be given with caution to patients with:

• Diabetes.
• Arterial hypertension.
• Aneurysm.
• Uncontrolled hyperthyroidism.
• Coronary heart disease and chronic heart disease.
• Bradycardia.
• Heart block.
• Tachycardia.
• Dysrhythmia.
• Angina pectoris (phenylephrine can precipitate or exacerbate angina in patients with coronary artery disease and history of angina).
• Non-severe peripheral vascular insufficiency.
• Peripheral vascular diseases e.g. Raynaudu2019s phenomenon.
• Closed angle glaucoma.

HYPOPRESS may induce a decrease in cardiac output. Therefore, it should be administered with extreme caution in patients with atherosclerosis in the elderly and in patients with impaired cerebral or coronary arterial circulation. In patients with severe heart failure or cardiogenic shock, HYPOPRESS may cause a worsening of heart failure as a result of the induced vasoconstriction (increased afterload). Patients with medical conditions such as decreased cardiac output or peripheral or coronary artery disease should have frequent monitoring of vital body functions and lower systemic blood pressure boundary should be considered as a criterion for dose reduction or discontinuation of HYPOPRESS. Particular attention should be paid during injection to avoid extravasation, since this may cause tissue necrosis. Lower doses may be required in patients with renal impairment. Higher doses may be required in patients with liver cirrhosis. Allergic reactions, including anaphylactic shock, may occur in patients with sulphite-sensitivity.

Blood pressure response to HYPOPRESS may be increased in patients with autonomic dysfunction. The administration of HYPOPRESS simultaneously with the following medicines is not recommended, because of the risk of vasoconstriction and / or hypertensive crisis associated with its indirect sympathomimetic effect (see section 4.5):

• dopaminergic ergot alkaloids (bromocriptine, carbergoline, lisuride or pergolide) or vasoconstrictors (dihydroergotamine, ergotamine, or methysergide, methylergometrine).
• in combination with linezolid. Concurrent use may prolong and intensify cardiac stimulation and vasopressor effects because of the release of catecholamines, which accumulate in intraneuronal storage sites during MAO inhibitor therapy; this may result in headache, cardiac dysrhythmias, vomiting or sudden and severe hypertensive or hyper-pyretic crises.

For patients who have been receiving MAO inhibitors 2 to 3 weeks prior to administration of sympathomimetic medicines, the initial dosage should be reduced to be no more than one-tenth of the usual dose.

HYPOPRESS 0,1 mg/ml contains 3,54 mg sodium per ml, equivalent to 0,2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. HYPOPRESS 10 mg/ml contains 2,36 mg sodium per ml, equivalent to 0,1 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Combinations that are contraindicated (see section 4.3):

• Non-selective monoamine oxidase inhibitors (MAOIs) (iproniazid, nialamide, phenelzine): increased risk of paroxysmal hypertension, hyperthermia possibly fatal. Due to the long duration of action of MAOIs, this interaction is still possible 15 days after discontinuation of the MAOIs.
• Indirect sympathomimetics medicines (ephedrine, methylphenidate, pseudoephedrine): increased risk of vasoconstriction and / or hypertensive crisis.
• Alpha sympathomimetic medicines (oral and/or nasal use) (etilefrine, midodrine, naphazoline, oxymetazoline, synephrine, tetryzoline, tuaminoheptane, tymazoline): increased risk of vasoconstriction and / or hypertensive crisis.

Combinations not recommended (see section 4.4):

• Dopaminergic ergot alkaloids (bromocriptine, cabergoline, lisuride and pergolide): increased risk of vasoconstriction and/or hypertensive crisis.
• Vasoconstrictor ergot alkaloids (dihydroergotamine, ergotamine, methylergometrine, methysergide): increased risk of vasoconstriction and/or hypertensive crisis.
• Linezolid: increased risk of vasoconstriction and/or hypertensive crisis.
• Tricyclic antidepressants (desipramine, imipramine, nortriptyline): increased risk of paroxysmal hypertension with possibility of dysrhythmia (inhibition of adrenaline or noradrenaline entry in sympathetic fibres).
• Noradrenergic-serotoninergic antidepressants (venlafaxine): increased risk of paroxysmal arterial hypertension with possibility of dysrhythmias (inhibition of adrenaline or noradrenaline entry in sympathetic fibres).
• Selective monoamine oxidase inhibitors (MAOs) (moclobemide, pargyline, selegiline, toloxatan): risk of vasoconstriction and/or hypertensive crisis.
• Guanethidine and related products: substantial increase in blood pressure (hyperreactivity linked to the reduction in sympathetic tone and / or to the inhibition of adrenaline or noradrenaline entry in sympathetic fibres). If the combination cannot be avoided, use with caution lower doses of sympathomimetic medicines.
• Digoxin, quinidine: increased risk of dysrhythmias.
• Halogenated volatile anaesthetics (desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane): risk of perioperative hypertensive crisis and dysrhythmia.
• The effect of antihypertensive and diuretic medicines used as antihypertensives may be reduced when used concurrently with HYPOPRESS; the patient should be carefully monitored to confirm the desired effect is obtained.
• Beta-adrenoceptor-blocking medicines, systemic or ophthalmic - concurrent use of HYPOPRESS may result in an exaggeration of the vasoconstriction effects and profound bradycardia.
• Reserpine and other sympatholytic medicines - concomitant use with HYPOPRESS causes a substantial increase in blood pressure. If the combination cannot be avoided, use with caution.
• The pressor effect of HYPOPRESS is increased in patients receiving atropine sulphate.

Combinations requiring caution:

• Oxytocic medicines: The effect of presso-active sympathomimetic amines is potentiated. Thus, some oxytocic medicines may cause severe persistent hypertension and strokes can occur during post-partum period.
• Digoxin: HYPOPRESS may be used with digoxin for therapeutic advantage; caution and close electrocardiographic monitoring are recommended during concurrent use.
• Alpha-adrenoceptor-blocking medicines (doxazosin, labetalol, prazosin, haloperidol, phenothiazines): concurrent use may antagonise the peripheral vasoconstriction effect of HYPOPRESS.

Fertility

There are no data available regarding fertility, following treatment with HYPOPRESS (see section 5.3).

Pregnancy

The safety of HYPOPRESS during pregnancy has not been established. Animal studies are insufficient with respect to effects on pregnancy, embryonal / foetal development, parturition or postnatal development. The potential risk for humans is unknown.

Breastfeeding

The safety of HYPOPRESS during breastfeeding has not been established. Small amounts of phenylephrine are excreted in human milk. The administration of vasoconstrictors to the mother puts the child at risk for cardiovascular and neurological effects. HYPOPRESS should not be used during lactation.

No studies done.

Most of the adverse events of phenylephrine are dose-dependent and a consequence of the expected pharmacodynamic profile. HYPOPRESS may cause a transient tingling and coolness of the skin and a temporary sensation of fullness in the head. Extravasation of the injection may cause local necrosis (see section 4.4). Peripheral vasoconstriction, possibly leading to necrosis or gangrene, may occur with prolonged use of HYPOPRESS in high doses or low doses in the presence of peripheral vascular disease.

System Organ Class

Undesirable effects

Frequency

• Immune system disorders
• Hypersensivity
• Less frequent
• Metabolism and nutrition disorders
• Glucose metabolism abnormal
• Not known*
• Psychiatric disorders
• Euphoria, agitation, anxiety, psychotic states, confusion
• Less frequent
• Nervous system disorders
• Headache
• Frequent
• Tingling, fullness head, nervousness or restlessness, insomnia, paraesthesia, tremor
• Less frequent
• Eye disorders
• Mydriasis, aggravation of pre-existing angle-closure glaucoma
• Less frequent
• Cardiac disorders
• Anginal pain, reflex bradycardia, tachycardia, ventricular dysrhythmias
• Less frequent
• Dysrhythmia, cardiac arrest, palpitations, myocardial ischemia
• Not known*
• Vascular disorders
• Cerebral haemorrhage, hypertension, hypotension with dizziness, hypertensive crisis, pallor
• Less frequent
• Fainting, flushing, coldness of skin
• Not known*
• Respiratory, thoracic and mediastinal disorders
• Dyspnoea, pulmonary oedema
• Less frequent
• Gastrointestinal disorders
• Vomiting, nausea
• Less frequent
• Hypersalivation
• Not known*
• Skin and subcutaneous tissue disorders
• Piloerection, sweating, skin blanching
• Less frequent
• Diaphoresis
• Not known*
• Musculoskeletal and connective tissue disorders
• Muscular weakness
• Less frequent
• Renal and urinary disorders
• Difficulty in micturition, urinary retention
• Less frequent
• General disorders and administration site conditions
• Extravasation necrosis at injection site
• Less frequent

* Frequency cannot be estimated from available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms of overdosage include headache, nausea, vomiting, hypertension (which may be severe), palpitations and reflex bradycardia and other cardiac dysrhythmias (ventricular extra systoles and short paroxysms of ventricular tachycardia). Treatment should consist of symptomatic and supportive measures. Should an excessive elevation of blood pressure occur, the administration of HYPOPRESS should be reduced or temporarily discontinued until blood pressure is decreased. If these measures fail to lower the blood pressure, a short acting alpha adrenoceptor blocking medicine (e.g. phentolamine, 5 to 60 mg i.v. over 10 u2013 30 minutes, repeated as necessary) may be administered. Reflex bradycardia may be expected with a significant increase in blood pressure.