Lorazepam Macure 4 mg/ml solution for injection

Each ampoule contains 4 mg/ml lorazepam (4 mg per 1 ml ampoule).

Excipients with known effect: benzyl alcohol, propylene glycol.

Each ml contains 21 mg benzyl alcohol.

Each ml contains 840 mg propylene glycol.

For the full list of excipients, see section 6.1

Solution for injection

A clear, colourless or almost colourless hypertonic solution, free from visible particles.

As pre-operative medication or premedication for uncomfortable or prolonged investigations, e.g. bronchoscopy, arteriography, endoscopy.

For the treatment of acute anxiety states, acute excitement or acute mania.

For the control of status epilepticus.

Posology

Dosage and duration of therapy should be individualised. The lowest effective dose should be prescribed for the shortest time possible.

Treatment in all patients should be withdrawn gradually to minimise possible withdrawal symptoms (see section 4.4).

Premedication

Adults: 0.05 mg/kg (3.5 mg for an average 70 kg man).

By the intravenous route the injection should be given 30-45 minutes before surgery when sedation will be evident after 5-10 minutes and maximal loss of recall will occur after 30-45 minutes.

By the intramuscular route the injection should be given 1-1½ hours before surgery when sedation will be evident after 30-45 minutes and maximal loss of recall will occur after 60-90 minutes.

Paediatric population: Lorazepam Macure 4 mg/ml solution for injection is not recommended in children under 12.

Acute anxiety

Adults: 0.025-0.03 mg/kg (1.75-2.1 mg for an average 70 kg man). Repeat 6 hourly.

Paediatric population: Lorazepam Macure 4 mg/ml solution for injection is not recommended in children under 12.

Status epilepticus

Adults: 4 mg intravenously.

Paediatric population: 2 mg intravenously.

Elderly: The elderly may respond to lower doses and half the normal adult dose may be sufficient.

Patients with renal or hepatic impairment

Lower doses may be sufficient in these patients (See section 4.4). Use in patients with severe hepatic insufficiency is contraindicated.

Elderly and debilitated patients

For elderly and debilitated patients reduce the initial dose by approximately 50% and adjust the dosage as needed and tolerated (see section 4.4).

Method of administration

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

Lorazepam Macure 4 mg/ml solution for injection can be given intravenously or intramuscularly. However, the intravenous route is to be preferred. Care should be taken to avoid injection into small veins and intra-arterial injection.

Absorption from the injection site is considerably slower if the intramuscular route is used and as rapid an effect may be obtained by oral administration of lorazepam.

Lorazepam Macure should not be used for long-term chronic treatment.

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

Acute pulmonary insufficiency.

Sleep apnoea syndrome.

Myasthenia gravis.

Severe hepatic insufficiency.

Lorazepam Macure 4 mg/ml solution for injection is not recommended for out-patient use unless the patient is accompanied.

Prior to use

Lorazepam Macure 4 mg/ml solution for injection may be diluted for IM administration and should always be diluted for IV administration with equal amounts of compatible diluent (see section 4.2).

Intravenous injection should be administered slowly except in the control of status epilepticus where rapid injection is required.

After use

It is recommended that patients receiving lorazepam should remain under observation for at least eight hours and preferably overnight. When lorazepam is used for short procedures on an outpatient basis, the patient should be accompanied when discharged.

Respiratory distress

The possibility that respiratory arrest may occur or that the patient may have partial airway obstruction should be considered. Therefore, equipment necessary to maintain a patent airway and to support respiration/ventilation should be available and used where necessary.

Use of benzodiazepines, including lorazepam, may lead to potentially fatal respiratory depression. Extreme care must be taken in administering lorazepam to elderly or very ill patients and to those with limited pulmonary reserve or compromised respiratory function (e.g. chronic obstructive pulmonary disease [COPD]), because of the possibility that apnoea and/or cardiac arrest may occur. Care should also be exercised when administering lorazepam to a patient with status epilepticus, especially when the patient has received other central nervous system depressants.

Severe anaphylactic/anaphylactoid reactions have been reported with the use of benzodiazepines.

Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of benzodiazepines. Some patients taking benzodiazepines have had additional symptoms such as dyspnoea, throat closing, or nausea and vomiting. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with a benzodiazepine should not be rechallenged with the drug.

Drug abuse and dependence

The use of benzodiazepines, including lorazepam, may lead to physical and psychological dependence.

There are no clinical data available for lorazepam with regard to abuse or dependence. However, based upon experience with oral benzodiazepines, doctors should be aware that repeated doses of lorazepam over a prolonged period of time may lead to physical and psychological dependence. The risk of dependence on lorazepam is low when used at the recommended dose and duration, but increases with higher doses and longer term use. The risk of dependence is further increased in patients with a history of alcoholism or drug abuse, or in patients with significant personality disorders. Therefore, use in individuals with a history of alcoholism or drug abuse should be avoided.

Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. Therefore, the drug should always be discontinued gradually - using the oral preparation if necessary.

Symptoms reported following discontinuation of oral benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of "rebound" phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

In severe cases the following symptoms may occur: derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; vomiting; hallucinations; convulsions. Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold, such as antidepressants.

It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of "rebound" phenomena to minimise anxiety should they occur.

Withdrawal symptoms (e.g. rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy.

There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.

When benzodiazepines with a long duration of action are being used, it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Abuse of benzodiazepines has been reported.

Psychiatric illness

Lorazepam is not intended for the primary treatment of psychotic illness or depressive disorders, and should not be used alone to treat depressed patients. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients.

Pre-existing depression may emerge during benzodiazepine use.

Anxiety or insomnia may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is more specific treatment.

Alcohol

Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished in the presence of lorazepam. Alcoholic beverages should not be consumed for at least 24 to 48 hours after receiving lorazepam.

Risk from concomitant use of opioids

Concomitant use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death.

Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as lorazepam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe lorazepam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).

Coma/shock

There is no evidence to support the use of lorazepam in coma or shock.

Narrow-angle glaucoma

Caution should be used in the treatment of patients with acute narrow-angle glaucoma.

Renal or hepatic impaired function

As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy.

As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.

Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.

Blood tests

Some patients taking benzodiazepines have developed a blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematologic and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary.

Anterograde amnesia

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This effect may be advantageous when lorazepam is used as a premedicant.

Paradoxical reactions

Paradoxical reactions have been occasionally reported during benzodiazepine use (see section 4.8). Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued.

Hypotension

Although hypotension has occurred only rarely, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.

Elderly patients

Lorazepam should be used with caution in elderly due to the risk of sedation and/or musculoskeletal weakness that can increase the risk of falls, with serious consequences in this population. Elderly patients should be given a reduced dose (see section 4.2).

Benzyl alcohol

This medicine contains 21 mg benzyl alcohol in each 1 ml of solution for injection.

Benzyl alcohol may cause allergic reactions.

High volumes should be used with caution and only if necessary, especially pregnant or breast-feeding women or in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in neonates (“gasping syndrome”). The minimum amount of benzyl alcohol at which toxicity may occur is not known.

Propylene glycol

This medicine contains 840 mg propylene glycol in each 1 ml of solution for injection.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates and in children less than 5 years old.

Medical monitoring is required in paediatric patients with impaired renal or hepatic functions who receive ≥ 50 mg/kg/day of propylene glycol because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

Alcohol

Concomitant intake with alcohol is not recommended.

The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Benzodiazepines, including lorazepam, produce additive CNS depressant effects including respiratory depression, when co-administered with other medications which themselves produce CNS depression, e.g. opioids, barbiturates, antipsychotics, sedatives/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants and anaesthetics (see section 4.4).

Opioids

The concomitant use of sedative medicines such as benzodiazepines or related drugs such as lorazepam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).

Valproate

Concurrent administration of lorazepam with sodium valproate may result in reduced clearance (20 to 40%) and increased concentrations of lorazepam. Therefore clinical monitoring is advised and lorazepam dosage should be reduced when appropriate.

Probenecid

Concurrent administration of lorazepam with probenecid may result in reduced clearance, increased elimination half-life and increased concentrations of lorazepam. Therefore clinical monitoring is advised and lorazepam dosage should be reduced when appropriate.

Narcotic analgesics

An enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychic dependence.

Cytochrome P450 inhibitor

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines which are metabolised only by conjugation.

Scopolamine

The addition of scopolamine to lorazepam is not recommended, since their combination has been observed to cause an increased incidence of sedation, hallucination and irrational behaviour.

Clozapine

Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, and ataxia.

Theophylline or aminophylline

Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

Haloperidol

There have been reports of apnoea, coma, bradycardia, heart arrest and death with the concomitant use of lorazepam injection solution and haloperidol.

Pregnancy

Lorazepam should not be used during pregnancy, especially during the first and last trimesters, unless in the judgement of the physician such administration is clinically justifiable. Benzodiazepines may cause foetal damage when administered to pregnant women.

If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the drug if she intends to become, or suspects that she is, pregnant.

Use of lorazepam during the late phase of pregnancy may require ventilation of the infant at birth.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period.

Symptoms such as hypotonia, hypothermia, respiratory depression, apnoea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.

There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in caesarean section. Such use, therefore, is not recommended.

Benzyl alcohol can cross the placenta, see section 4.4.

Breastfeeding

Since benzodiazepines are found in breast milk, lorazepam should not be given to breast-feeding mothers unless the expected benefit to the woman outweighs the potential risk to the infant.

Fertility

A study in rats showed no impairment of fertility, see section 5.3.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988.

When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or use machines. Therefore, patients should not drive or operate machinery within 24-48 hours of administration of lorazepam and should be advised not to take alcohol (see section 4.5).

± Benzodiazepine effects on the CNS are dose-dependent, with more severe CNS depression occurring with high doses.

β The extent of respiratory depression with benzodiazepines is dose-dependent, with more severe depression occurring with high doses.

Tolerance at the injection site is generally good although, rarely, pain and redness have been reported after lorazepam.

Transient anterograde amnesia or memory impairment may occur using therapeutic doses, the risk increasing at higher doses (see section 4.4).

Paediatric population

Paradoxical reactions may be more likely to occur in children and the elderly (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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

In the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.

Overdosage of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, and especially when other CNS-depressant drugs or alcohol are ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, cardiovascular depression, coma and, very rarely, death.

Propylene glycol toxicity have been reported following higher than recommended doses of lorazepam (see section 4.4).

Treatment

Treatment of overdosage is mainly supportive including monitoring of vital signs and close observation of the patient. An adequate airway should be maintained and assisted respiration used as needed. Hypotension, though unlikely, may be controlled with noradrenaline. Lorazepam is poorly dialysable.

The benzodiazepine antagonist, flumazenil, may be useful in hospitalised patients for the management of benzodiazepine overdosage. Flumazenil product information should be consulted prior to use. The physician should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in tricyclic antidepressant overdose.

Pharmacotherapeutic group: benzodiazepine derivatives, ATC code: N05BA06.

Lorazepam is a benzodiazepine with anxiolytic, sedative, hypnotic, anticonvulsant and muscle relaxant properties.

Absorption

Lorazepam is readily absorbed when given intramuscularly. Peak plasma concentrations occur approximately 60-90 minutes following intramuscular administration.

Biotransformation

Lorazepam is metabolised by a simple one-step process to a pharmacologically inactive glucuronide. There is minimal risk of accumulation after repeated doses, giving a wide margin of safety.

There are no major active metabolites.

Elimination

The elimination half-life is about 12-16 hours when given intramuscularly or intravenously.

Lorazepam glucuronide, the major metabolite of lorazepam, has no demonstrable CNS activity in animals.

Carcinogenicity

No evidence of carcinogenic potential emerged in rats and mice during an 18-month study with oral lorazepam.

Mutagenicity

A study of the mutagenic activity of lorazepam on Drosophila melanogaster indicated that this agent was mutationally inactive.

Impairment of fertility

A pre-implantation study in rats was performed with oral lorazepam at a 20 mg/kg dose that showed no impairment of fertility.

Macrogol

Benzyl alcohol

Propylene glycol

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products other than those mentioned in section 6.6.

Unopened: 24 months.

Stability after dilution:

Chemical and physical in-use stability has been demonstrated for 1 hour at 2-8°C. From a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store and transport refrigerated (2°C – 8°C). Keep in the outer carton to protect from light.

For storage conditions after dilution/first opening of the medicinal product, see section 6.3.

1ml solution in a Type I glass ampoule (2ml capacity) with a one-point-cut opening.

Box of 5 or 10 ampoules.

Not all pack sizes may be marketed.

Lorazepam injection is slightly viscous when cool. It must be inspected visually for the presence of particles or discolouration prior to administration. It should not be mixed with other drugs in the same syringe.

Intramuscular administration

Dilution with an equal volume of diluent is recommended. The diluent should be 0.9% sodium chloride, 5% glucose or water for injections.

Intravenous administration

Lorazepam injection should always be diluted with an equal volume of one of the following diluents: 0.9% sodium chloride, 5% glucose or water for injection.

Do not use if solution has developed a colour or a precipitate.

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

Macure Pharma ApS

Hejrevej 39

2400 Copenhagen NV

Denmark

PL 53749/0002

22/12/2020

01/03/2021