Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Synchrony Pharma Ltd., Business Technology Centre, Bessemer Drive, Stevenage, Hertfordshire, SG1 2DX, United Kingdom
There have been rare reports of severe hepatocellular injury with labetalol therapy. The hepatic injury is usually reversible and has occurred after both short and long term treatment. There have been reports of fatal hepatic necrosis. Appropriate laboratory testing should be done at the first sign or symptom of liver dysfunction. If there is laboratory evidence of liver injury or the patient is jaundiced, labetalol therapy should be stopped and not re-started.
Extra caution needs to be taken when labetalol is used in patients with liver dysfunction, as these patients metabolize labetalol slower than patients without liver dysfunction.
Caution needs to be taken when Labetalol is used in patients with severe renal impairment (GFR = 15–29 ml/min/1,73 m²).
Labetalol should be used with great caution in patients with peripheral circulatory disorders as aggravation of these disorders may occur. Great caution is advised in patients with peripheral arterial diseases (Raynaud’s disease or syndrome, intermittent claudication), as aggravation of these disorders may occur. Alpha blockers may counteract the adverse effects of beta blockers.
If the patient experiences symptoms related to bradycardia, the dosage of Labetalol should be reduced.
Due to the negative effect of beta-adrenergic blocking agents on the atrioventricular conduction time, labetalol needs to be administered with caution to patients with first degree atrioventricular block
Great caution needs to be taken with untreated or uncontrolled diabetes mellitus. As with other beta-adrenergic blocking agents, labetalol can mask the symptoms of hypoglycemia (tachycardia and tremor) in diabetic patients. The hypoglycemic effect of insulin and oral hypoglycemic agents can be higher when beta-adrenergic blocking agents are used.
Beta-blockers can mask the symptoms of thyrotoxicosis, but will not change the thyroid function.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
If patients who are treated with labetalol need adrenaline, a lower dose of adrenaline needs to be used since the use of both adrenaline and labetalol at the same time may cause bradycardia and hypertension (see section 4.5 “interactions with other medicinal products and other forms of interaction”)
When adrenaline has a serious influence, as is the case with phaeochromocytoma, labetalol can lead to a paradoxical blood pressure increase.
There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when the treatment was withdrawn. Gradual discontinuation of the drug should be considered if any such reaction is not otherwise explicable.
The occurrence of intraoperative floppy iris syndrome (IFIS, a variation of Horner’s syndrome) has been observed during cataract surgeries in some patients who were being treated with tamsulosine, or have been treated with tamsulosine in the past. IFIS has also been reported when other alpha-1-blockers were being used, and the possibility of a class effect cannot be excluded. Since IFIS can lead to a higher chance of complications during cataract surgeries, the ophthalmologist needs to be informed if alpha-1-blockers are currently being used, or have been used in the past.
Extra caution needs to be taken in patients who suffer from heart failure or decreased left ventricular function. Labetalol is contraindicated for uncontrolled heart failure, but may be used with caution in patients whose heart failure is under control and who are free of symptoms. Heart failure needs to be controlled with an appropriate treatment before labetalol should be used.
The use of beta-blockers may induce or aggravate heart failure or obstructive pulmonary disease. In the case of heart failure, the myocardial contractility needs to be maintained and the failure needs to be compensated. Patients with reduced contractility , especially elderly patients, need to be checked regularly on the development of heart failure.
It is strongly recommended not to interrupt or discontinue labetalol therapy abruptly, especially patients with heart failure and patients with angina pectoris (to prevent exacerbation of angina pectoris, myocardial infarction and ventricular fibrillation).
Caution needs to be taken when inhalation anaesthetics are used concurrently (see section 4.5 “interactions with other medicinal products and other forms of interaction”).
It is not necessary to discontinue labetalol therapy in patients requiring anaesthesia, but the anaesthetist must be informed and the patient should be given intravenous atropine prior to induction. Labetalol can increase the hypotensive effect of inhalational anaesthetics.
Caution needs to be taken with cases of metabolic acidosis and phaeochromocytoma. In patients with phaeochromocytoma, labetalol may only be used after adequate alpha-blockage has been reached.
Caution needs to be taken when labetalol is used at the same time as calcium antagonists, and especially calcium entry-blockers, which negatively influence the contractility and the atrioventricular conductions.
Caution needs to be take when adrenaline, verapamil or class I antiarrhythmic agents are administered at the same time as labetalol (see section 4.5 “interactions with other medicinal products and other forms of interaction”). Beta-blockers have a negative inotropic effect, but will not influence the positive inotropic effect of digoxin.
During anaesthesia labetalol may mask the compensatory physiological responses to sudden haemorrhage (tachycardia and vasoconstriction). Close attention must therefore be paid to blood loss, and the blood volume maintained.
It is desirable to check the blood pressure and the heart rate after injection and during infusion. In most patients, the heart rate will decrease slightly.
Severe bradycardia is not usual, but can be controlled by injecting 1 to 2mg of atropine intravenously.
Breathing should be carefully checked in patients with a known airway disease.
As soon as blood pressure is reduced by bolus injection or infusion, the treatment should be maintained with labetalol tablets, with a starting dose of 100mg two times a day.
Labetalol-injection is administered to patients who suffer from an uncontrolled hypotension and who have been given other hypotensive substances, including beta- blockers, without suffering from side effects.
The hypotensive effect of Labetalol may be reduced when used in combination with prostaglandin synthetase inhibiting drugs (NSAID’s, nonsteroidal anti-inflammatory drugs). Dose adjustments may be necessary. The combination with other antihypertensives may lead to additive synergism.
Labetalol is fluorescent in alkaline solution with an excitation wavelength of 334 nanometer and a fluorescent wavelength of 412 nanometer, and may therefore interfere with the tests of some fluorescent substances, including catecholamines.
The presence of labetalol metabolites in the urine can lead to false high levels of catecholamines, metanephrines, normetanephrines, and vanillylmandelic acid (VMA) in the urine when measured with fluorimetric or photometric methods. When patients who are suspected to suffer from phaeochromocytoma are screened, and are treated with labetalol hydrochloride, a specific method such as HPLC-assay with solid phase extraction will need to be used to determine the level of catecholamines.
Labetalol has been shown to reduce the uptake of radioisotopes of metaiodobenzylguanidine (MIBG). Care should therefore be taken in interpreting results from MIBG scintigraphy.
The use of both adrenaline and labetalol at the same time may cause bradycardia and hypertension (see section 4.4 “special warnings and precautions for use.”).
Extra care should be taken if labetalol is used at the same time as either class I antiarrhythmic agents or calcium antagonists of the Verapamil class.
Class I antiarrhytmic agents (e.g. disopyramide, quinidine) and amiodarone (antiarrhytmic Class II) may have potentiating effects on atrial conduction and induce negative inotropic effect.
If labetalol is used simultaneously with calcium antagonists with a negative inotropic effect (e.g. verapamil, diltiazem), the risk of bradycardia and hypotension may increase, especially in patients with atrioventricular conduction disease or contractility disease. If the patient is switched from calcium antagonists to beta blockers, or the other way around, a new intravenous treatment should not be started until at least 48 hours after the previous treatment has ended.
Simultaneous use of labetalol with calcium antagonists belonging to the dihydropyridine derivates (e.g. nifedipine), may increase the risk of hypotension and may lead to cardiac failure in patients with latent cardiac insufficiency. Digitalis glycosides used in association with beta-blockers may increase atrioventricular conduction time. Labetalol can heighten the effect of digoxin on the reduction of ventricular flow.
Beta-blockers, especially non-selective beta-blockers, can increase the risk of hypoglycemia in diabetic patients and may prevent the appearance of signs of hypoglycemia, such as tachycardia and tremors, and may delay the normalization of glucose levels after insulin induced hypoglycemia. Changes of the dose of oral anti diabetics may be necessary.
Extra caution needs to be taken when general anesthesia is used on patients who are treated with beta-blockers. Beta-blockers reduce the risk of arrhythmia during anesthesia, but can lead to a reduction of the reflex tachycardia and a higher risk of hypotension during anesthesia. An anesthetic with the lowest possible negative inotropic effect should be used. Heart function needs to be monitored closely and bradycardia due to vagal dominance needs to be corrected by administrating 1-2 mg atropine intravenously (stopping before surgery, see section 4.2 “posology and method of administration”).
When treatment is discontinued in patients who use both beta-blockers and clonidine, the beta-blocker should be phased out a couple of days before the treatment with clonidine is discontinued. This needs to be done to avoid a recurrence of hypertensive crisis as a result of the discontinuance of the clonidine treatment. For the same reasons it is also important to phase out the clonidine when a switch to beta-blockers is being made, and to start the treatment with the beta-blocker some time before the clonidine is discontinued.
Concomitant use of labetalol and cholinesterase inhibitors can increase the risk on bradycardia.
Concomitant use with alpha adrenergic agonists (e.g. phenylpropanolamine and adrenalin) can increase the risk of high blood pressure, while concomitant use with beta adrenergic agonists may counteract the beta adrenergic agonists (antidotum- effect).
Concomitant use of ergot derivatives may increase the risk of peripheral vasoconstriction in some patients.
It has been demonstrated that labetalol increased the biological availability of imipramine by more than 50% through the inhibition of 2-hydroxylation. Labetalol in combination with imipramine can increase the effect of imipramine and the concurrent use of tricyclic antidepressants. Concomitant use of tricyclic antidepressants may increase tremors.
Labetalol may increase the hypotensive effect of volatile anaesthetics.
An increase in blood pressure reduction may occur during concomitant use of, for example, nitrates, anti-psychotics (phenothiazine derivatives like chloropromazine) and other anti-psychotics and anti-depressants.
There is no information available on the effect labetalol has on the fertility.
On the basis of experience during human pregnancy, it is unexpected that labetalol increases the risk of birth defects. Animal studies have not demonstrated reproductive toxicity. However, toxicity has been demonstrated in embryo-foetal development (see section 5.3). Labetalol crosses the placenta barrier and because of the pharmacological activity of alpha- and beta- adreneceptor blockade, side effects in the foetus and neonate should be borne in mind (bradycardia, hypotension, respiratory depression, hypoglycemia, hypothermia). Close observation up to 24 to 48 hours after birth is required. Beta-blockers may reduce placental perfusion.
Labetalol should only be used during the pregnancy if the potential benefit for the mother outweighs the potential risk for the foetus.
Labetalol is excreted in breast milk in small amounts (approximately 0.004-0.07% of the dose administered to the mother). No side-effects have been reported. Monitoring is needed if Labetalol is used in lactating mothers.
No general information.
The most frequently reported undesirable effects during the use of labetalol injection and those reported in post-marketing studies include: congestive heart failure, postural hypotension, hypersensitivity, drug fever, increased liver functions, nasal congestion and erectile dysfunctions.
Very common ≥1/10
Common ≥1/100 <1/10
Sometimes ≥1/1000 <1/100
Rarely ≥1/10,000 <1/1000
Very rarely <1/10,000
Undesirable effects marked with a hash sign (#), are usually transient in nature and occur in the first weeks of treatment.
Common: Sensitivity, drug fever
Common: Congestive heart failure
Rarely: Bradycardia
Very rarely: Heart block
Common: #Postural hypotension
Very rarely: Worsening of the symptoms of Raynaud’s syndrome
Common: #Nasal congestion
Rarely: Bronchospasm
Common: Raised liver function tests
Very rarely: Hepatitis, hepatocellular jaundice, cholestatic jaundice, hepatic necrosis
Common: Erectile dysfunction
Reports of hypersensitivity include rash, pruritus, angioedema and dyspnea, and very rarely drug fever and angioedema.
Excessive postural hypotension may occur if patients are allowed to assume an upright position within three hours of receiving Labetalol injection.
The signs and symptoms of hepato-biliary disorders are usually reversible after discontinuing the treatment.
Reporting suspected adverse reactions after authorization 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 through the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Labetalol Injection has been shown to be incompatible with sodium bicarbonate injection 4.2% w/v.
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