4.1. Therapeutic indications

Treatment of hypotension during spinal, epidural and general anaesthesia.

4.2. Posology and method of administration

Posology

To be administered by intravenous injection or infusion. Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.

This product should be administered after appropriate dilution. See section 6.6 for Instructions on dilution.

Adults

Intravenous bolus injections:

Initially repeated bolus doses of 50 to 100 micrograms (1-2 ml of the 50 micrograms/ml diluted solution or 0,5-1 ml of the 100 micrograms/ml diluted solution) are given until the desired effect is attained and before the continuous infusion is started. See instructions on dilution in section 6.6)

Continuous infusion:

Large dose variations occur. Initial dose is commonly in the range of 25 to 50 micrograms/min. The doses may subsequently be increased or decreased to maintain the systolic blood pressure close to the normal (target) value. Doses between 25 to 100 micrograms/min have been assessed to be effective.

If doses higher than 50 micrograms/min are required or there is a tendency to reflex bradycardia a switch to another vasopressor drug should be done.

The blood pressure must be monitored regularly.

Renal impairment:

Lower doses of phenylephrine may be needed in patients with impaired renal function.

Hepatic impairment:

Higher doses of phenylephrine may be needed in patients with cirrhosis of the liver.

Older people:

Treatment of the elderly should be carried out with care.

Paediatric population:

The safety and efficacy of phenylephrine in children have not been established. No data are available.

Method of administration:

Parenteral administration.

10 mg/ml: concentrate for dilution to injections or infusion.

Phenylephrine, 10 mg/ml, should only be administered by health care professionals with appropriate training and relevant experience.

Ensure that the needle is correctly inserted and avoid extravasation because of the risk of tissue damage/ ischemia.

For instructions on dilution of the product before administration, see section 6.6.

4.3. Contraindications

Phenylephrine should not be used

- in patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1;

- in patients with severe hypertension or peripheral vascular disease due to the risk of ischemic gangrene or vascular thrombosis;

- in combination with non-selective monoamine oxidase inhibitors (MAOs) (or within 2 weeks of their withdrawal) due to the risk of paroxysmal hypertension and possibly fatal hyperthermia (see section 4.5);

- in patients with severe hyperthyroidism.

4.4. Special warnings and precautions for use

The arterial blood pressure should be monitored during treatment.

Phenylephrine should be administered with care to patients with:

• diabetes mellitus;

• arterial hypertension;

• uncontrolled hyperthyroidism;

• coronary heart disease and chronic heart conditions;

• non-severe pheripheral vascular insufficiency;

• bradycardia;

• partial heart block;

• tachycardia;

• arrhythmias;

• angina pectoris (phenylephrine can precipitate or exacerbate angina in patients with coronary artery disease and history of angina);

• aneurysma;

• closed angle glaucoma;

Phenylephrine can induce a reduction in cardiac output. Therefore, care should be exercised in administering to patients with arteriosclerosis, the elderly and to patients with impaired cerebral or coronary circulation. In patients with reduced cardiac output or coronary vascular disease, vital organ functions should be closely monitored and dose reduction should be considered when systemic blood pressure is near the lower end of the target range.

In patients with serious heart failure or cardiogenic shock, phenylephrine may cause deterioration in the heart failure as a consequence of the induced vasoconstriction (increase in afterload).

Particular attention should be paid to phenylephrine injection to avoid extravasation, since this may cause tissue necrosis.

Each 2 ml ampoule (containing 1 ml solution) contains 0,2 mmol (3,7 mg) sodium per ampoule, i.e. is essentially sodium-free.

4.5. Interaction with other medicinal products and other forms of interaction

Contraindicated combinations (see section 4.3):

- Non-selective monoamine oxidase inhibitors (MAOs) (iproniazid, nialamide):

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 MAOI.

Inadvisable combinations:

- Dopaminergic ergot alkaloids (bromocriptine, carbergoline, lisuride, pergolide):

Risk of vasoconstriction and/or hypertensive crisis.

-Vasoconstrictor ergot alkaloids (dihydroergotamine, ergotamine, methylergometrine, methylsergide):

Risk of vasoconstriction and/or hypertensive crisis.

- Tricyclic antidepressants (e.g. imipramine):

Paroxysmal hypertension with possibility of arrhythmias (inhibition of adrenaline or noradrenaline entry in sympathetic fibres).

- Noradrenergic-serotoninergic antidepressants (minalcipram, venlafaxine):

Paroxysmal hypertension with possibility of arrhythmias (inhibition of adrenaline or noradrenaline entry in sympathetic fibres).

- Selective type A monoamine oxidase inhibitors (MAOs) (moclobemide, toloxatone):

Risk of vasoconstriction and/or hypertensive crisis.

- Linezolid:

Risk of vasoconstriction and/or hypertensive crisis.

- Guanethidine and related products:

Substantial increase in blood pressure (hyper reactivity linked to the reduction in sympathetic tone and /or to the inhibition of adrenaline or noradrenaline entry in sympathetic fibers). If the combination cannot be avoided, use with caution lower doses of sympathomimetic agents.

- Cardiac glycosides, quinidine:

Increased risk of arrhythmias.

- Halogenated volatile anaesthetics (desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane):

Risk of perioperative hypertensive crisis and arrhythmia.

Combinations requiring precautions for use:

- Oxytocic agents:

The effect of presso-active sympathomimetic amines may be potentiated. Thus, some oxytocic agents may cause severe persistent hypertension and strokes can occur during post-partum period.

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal studies are insufficient with respect to reproductive toxicity and teratogenicity (see section 5.3). Administration of phenylephrine in late pregnancy or labour may potentially cause fetal hypoxia and bradycardia. Phenylephrine Unimedic is not recommended during pregnancy..

The combination with some oxytocic agents can cause severe hypertension (see section 4.5).

Breastfeeding

Small quantities of phenylephrine are excreted into human breast milk and oral bioavalability may be low. Administering vasoconstricors to the mother exposes the infant to a theroretical risk of cardiovascular and neurological effects. However, in the event of a single bolus administration during childbirth, breast-feeding is possible.

Fertility

There is no available data concerning fertility after exposure to phenylephrine (se section 5.3).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Summary of the safety profile

The most common adverse events of phenylephrine reported in literature are bradycardia, hypertensive episodes, nausea and vomiting. Most undesired effects of phenylephrine are dose dependent.

Tabulated summary of adverse reactions

The adverse reactions listed by system organ class and frequency. Frequencies: not known (cannot be estimated from the available data)

Table 1 Tabulated list of Adverse reactions

Immune system disorders

Not known

Hypersensitivity

Psychiatric disorders

Not Known

Anxiety, excitability, agitation, psychotic states, confusion

Nervous system disorders

Not Known

Headache, nervousness, insomnia, paresthesia, tremor

Eye disorders

Not Known

Mydriasis, aggravation of pre-existing angle-closure glaucoma

Cardiac disorders

Not Known

Reflex bradycardia, tachycardia, palpitations, hypertension, arrhythmia, angina pectoris, myocardial ischemia

Vascular disorders

Not Known

Cerebral haemorrhage, hypertensive crisis

Respiratory, thoracic and mediastinal disorders

Not Known

Dyspnoea, pulmonary oedema

Gastrointestinal disorders

Not known:

Nausea, vomiting

Skin and subcutaneous tissue disorders

Not known

Sweating, pallor or skin blanching, piloerection, skin necrosis with extravasation

Musculoskeletal and connective tissue disorders

Not known

Muscular weakness

Renal and urinary disorders Renal and urinary disorders:

Not Known

Difficulty in micturition and urinary retention

Description of selected adverse reactions

As phenylephrine has been frequently used in the critical care setting in patients with hypotension and shock, some of the reported serious adverse events and deaths are probably related to the underlying disease and not related to the use of phenylephrine.

Other special population(s)

Elderly: risk for phenylephrine toxicity is increased in elderly patients (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 the national reporting system listed in Appendix V.

4.9. Overdose

Symptoms of overdose include headache, nausea, vomiting, paranoid psychosis, hallucinations, hypertension and reflex bradycardia. Cardiac arrhythmia such as ventricular extra-systoles and short paroxysmal episodes of ventricular tachycardia may occur.

Treatment should consist of symptomatic and supportive measures. The hypertensive effects may be treated with an alpha-adrenoceptor blocking drug, such as phentolamine.