Consumer medicine information

Lorazepam SXP

Lorazepam

BRAND INFORMATION

Brand name

Lorazepam SXP

Active ingredient

Lorazepam

Schedule

SUMMARY CMI

LORAZEPAM SXP

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I being given LORAZEPAM SXP?

LORAZEPAM SXP contains the active ingredient lorazepam. It is used in adults to treat epilepsy, for the short-term relief of excessive anxiety or agitation and also to relax a patient before surgery or sedation for prolonged procedures. This medicine may be given to your child to treat epilepsy.

For more information, see Section 1. Why am I being given LORAZEPAM SXP? in the full CMI.

2. What should I know before I am given LORAZEPAM SXP?

Do not use if you have ever had an allergic reaction to lorazepam or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given LORAZEPAM SXP? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with LORAZEPAM SXP and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given LORAZEPAM SXP?

Your doctor will decide what dose of LORAZEPAM SXP injection you will receive and how long you will receive it. This depends on your medical condition and other factors, such as weight.
LORAZEPAM SXP injection must be diluted with an equal amount of diluent prior to intravenous injection into a vein. The injection should be made slowly.

More instructions can be found in Section 4. How am I given LORAZEPAM SXP? in the full CMI.

5. What should I know while being given LORAZEPAM SXP?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are being given LORAZEPAM SXP. Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do	You may need assistance to get out of bed after you have been given this medicine. If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Avoid consuming alcohol for at least 48 hours after being given this medicine.
Driving or using machines	Do not drive or operate machinery until 48 hours after you have been given LORAZEPAM SXP.
Looking after your medicine	LORAZEPAM SXP will be stored in the refrigerator at the surgery, pharmacy or ward of the medical facility where the temperature stays below 8°C.

For more information, see Section 5. What should I know while I am being given LORAZEPAM SXP? in the full CMI.

6. Are there any side effects?

All medicines have side effects, likewise this medicine may have unwanted side effects. Sometimes these are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Common side effects are confusion, depression, dizziness, drowsiness, sleepiness, insomnia, unsteadiness or lack of balance or co-ordination, disorientation, slurred speech, muscle weakness, dry mouth, increased saliva, cough, or lack of energy. Serious side effects include difficulty breathing, excessive sleepiness or loss of consciousness, convulsions, fits or seizures, depression, anxiety, suicidal thoughts, tremor, slurred speech, impaired concentration, visual disturbances, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin. Tell your doctor immediately if you notice any of the serious symptoms above.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring due to approval of an extension of indications. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FOR ACUTE USE ONLY. CONTAINS BENZYL ALCOHOL AND PROPYLENE GLYCOL. CHRONIC USE OR EXCESSIVE DOSAGE RISKS TOXICITY. NOT FOR USE IN NEONATES.

FULL CMI

LORAZEPAM SXP

Active ingredient(s): Lorazepam (law-raz-uh-pam)

Consumer Medicine Information (CMI)

This leaflet provides important information about using LORAZEPAM SXP. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using LORAZEPAM SXP.

Where to find information in this leaflet:

1. Why am I being given LORAZEPAM SXP?
2. What should I know before I am given LORAZEPAM SXP?
3. What if I am taking other medicines?
4. How am I given LORAZEPAM SXP?
5. What should I know while being given LORAZEPAM SXP?
6. Are there any side effects?
7. Product details

1. Why am I being given LORAZEPAM SXP?

LORAZEPAM SXP contains the active ingredient lorazepam. LORAZEPAM SXP is a benzodiazepine which are thought to work by action on the brain chemicals.

LORAZEPAM SXP is used to treat epilepsy. Epilepsy is a condition which causes different types of seizures. Lorazepam injection is used to treat epilepsy where there are a number of rapidly repeated seizures.

LORAZEPAM SXP is also used for the short-term relief of excessive anxiety in patients. It is also used for the short-term relief of excessive agitation.

It is also used to relax a patient before surgery or for sedation for prolonged investigations.

2. What should I know before I am given LORAZEPAM SXP?

Warnings

You should not be given LORAZEPAM SXP if you:

are allergic to benzodiazapines, lorazepam, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
have severe and chronic lung disease or severe breathing difficulties
have a condition where you temporarily stop breathing while you sleep
have severe liver disease
have a condition of the nerves and muscles
have recently consumed alcohol

Check with your doctor if you:

Have any other medical conditions such as
- acute narrow-angle glaucoma, a high pressure in the eye
- breathing difficulties
- liver problems
- kidney problems
- depression or psychosis
- have benzodiazepine, opioid or alcohol dependence
- or are over 65 years or less than 18 years of age
Take any medicines for any other condition
Are unsure whether you should be given this medicine.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

LORAZEPAM SXP contains benzyl alcohol and propylene glycol. This medicine contains 21 mg benzyl alcohol in each 1 ml of solution for injection.

Benzyl alcohol may cause allergic reactions.

Ask your doctor for advice if you are pregnant or breast-feeding or if you have a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).

Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in young children

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

If your child is less than 5 years old, talk to your doctor or pharmacist before giving them this medicine, in particular if they use other medicines that contain propylene glycol or alcohol. If they suffer from a liver or kidney disease, your doctor may carry out extra checks while they are taking this medicine

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not recommended that lorazepam is given to pregnant or breastfeeding women.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Medicines that may interact with Lorazepam injection may interfere with each other:

Opioids, medicines used to treat anxiety or pain, such as morphine or oxycodone
Probenecid, a medicine used to treat gout
Valproate, a medicine used to treat epilepsy
Other sleeping tablets, sedatives or tranquilisers
Scopolamine, a medicine used to treat nausea
Medicines used to treat mental illness and depression, such as clozapine.
Haloperidol, an antipsychotic medication.

These medicines may be affected by LORAZEPAM SXP injection or may affect how well it works. You may need different amounts of your medicines or may need to take different medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect LORAZEPAM SXP.

4. How am I given LORAZEPAM SXP?

How much you will be given

Your doctor will decide what dose or LORAZEPAM SXP Injection you will receive and how long you will receive it. This depends on your medical condition and other factors, such as weight.

When you are given LORAZEPAM SXP

LORAZEPAM SXP injection must only be given by a doctor or nurse on the ward or at the surgery.

Your doctor will decide when you should be given LORAZEPAM SXP.

How LORAZEPAM SXP is injected

LORAZEPAM SXP is given as a slow injection into the muscle or vein.

If you forget to be given LORAZEPAM SXP

Your doctor will decide the correct time for you to be given LORAZEPAM SXP injection as necessary for your condition. You must keep all of your appointments.

If you are given too much LORAZEPAM SXP

Your doctor will decide how much you will be given based on a range of factors including weight, and other conditions.

If you think that you have been given too much LORAZEPAM SXP, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while being given LORAZEPAM SXP?

Things you should do

Call your doctor straight away if you:

Experience symptoms of drowsiness, mental confusion and lethargy.
If you experience poor coordination, decreased muscle tone, low blood pressure, hypnosis or coma, seek medical attention.

Remind any doctor, dentist or pharmacist you visit that you are being given LORAZEPAM SXP.

Things you should not do

You may need assistance to get out of bed for at least 8 hours after you have been given this medicine. Getting out of bed without help may result in a fall or injury. Elderly patients have a greater risk of a fall.
If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from chairs, will help your body get used to change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Driving or using machines

Do not drive or operate machinery until 48 hours after use.

Be careful before you drive or use any machines or tools until you know how LORAZEPAM SXP affects you.

LORAZEPAM SXP may cause dizziness, and drowsiness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol is not to be consumed for at least 48 hours after this medicine is given.

Looking after your medicine

Your medicine will be stored in the surgery, pharmacy or ward of a hospital. The injection should be stored in the refrigerator where the temperature stays below 8°C and protected from light.

When to discard your medicine

As this medicine is stored in the surgery, pharmacy or ward, the pharmacist will dispose of any unused medicine.

LORAZEPAM SXP Injection will be opened for use on you. It will be used only once and then it will be discarded

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
Dizziness Drowsiness Sleepiness Unsteadiness Forgetfulness Insomnia Lack of balance or co-ordination Disorientation Cough Dry mouth or increased saliva	Speak to your doctor if you have any of these less serious side effects and they worry you.

Moderately serious side effects

Moderately serious side effects	What to do
Headache Slow or fast breathing Apnoea Weakness Chills Nausea, vomiting, constipation Agitation, confusion, abnormal thinking, hallucinations Worsened asthma Sore muscles	Speak to your doctor if you have any of these moderately serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Difficulty breathing
Excessive sleepiness or loss of consciousness
Convulsions, fits or seizures
Depression, anxiety, suicidal thoughts, tremor, slurred speech, impaired concentration and visual disturbances.
Allergic reactions. Symptoms may include: shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What LORAZEPAM SXP contains

Active ingredient (main ingredient)	lorazepam
Other ingredients (inactive ingredients)	polyethylene glycol macrogol 400 benzyl alcohol

You should not be given this medicine if you are allergic to any of these ingredients.

What LORAZEPAM SXP looks like

LORAZEPAM SXP is a clear colourless or almost colourless solution.

AUST R 352550.

Who distributes LORAZEPAM SXP

Southern XP Pty Ltd
Unit 5, 118 Church Street
Hawthorn VIC 3122
Australia

Sponsor:

Southern XP IP Pty Ltd
Unit 5/118 Church Street
Hawthorn, 3122, Victoria
Australia

This leaflet was prepared on 18 March 2022.

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Lorazepam SXP

Active ingredient

Lorazepam

Schedule

Notes

Distributed by Southern XP Pty Ltd

1 Name of Medicine

Lorazepam.

2 Qualitative and Quantitative Composition

This product contains 4 mg lorazepam per 1 mL ampoule.

Excipients with known effect.

Propylene glycol (840 mg/ampoule), benzyl alcohol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Clear, colourless solution supplied in clear glass ampoules.

Administer 0.05 - 0.1 mg/kg (maximum 2 mg) of the diluted injection intravenously as a slow bolus injection over 1-2 minutes. The dose may be repeated after 5-10 minutes if seizures continue. Maximum dose: 4 mg.

Adults.

Administer a 4 mg dose of the diluted injection intravenously as a slow bolus injection over 1-2 minutes. The dose may be repeated after 5 - 10 minutes if seizures continue. Maximum dose: 8 mg.
Patients with renal or hepatic impairment. Lower doses may be sufficient in these patients (see Section 4.4 Special Warnings and Precautions for Use).
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 Special Warnings and Precautions for Use).

4.3 Contraindications

Pulmonary insufficiency.
Hypersensitivity to benzodiazepines, including lorazepam or to any of the excipients listed in Section 6.1.
Sleep apnoea syndrome.
Myasthenia gravis.
Severe hepatic insufficiency.

4.4 Special Warnings and Precautions for Use

Severe anaphylactic/anaphylactoid reactions.

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.

Impaired respiratory function.

Caution in the use of lorazepam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased arterial oxygen tension.

Amnesia.

Transient amnesia or memory impairment has been reported in association with the use of lorazepam.

Dependence and abuse.

There are no clinical data available for lorazepam injection with regard to abuse or dependence. Continuous long-term use of lorazepam is not recommended.

Depression, psychosis and schizophrenia.

Lorazepam is not recommended as primary therapy in patients with depression and psychosis. In such conditions, psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients, and may contribute to deterioration in severely disturbed schizophrenics with confusion and withdrawal. Suicidal tendencies may be present or uncovered and protective measures may be required. Therefore, benzodiazepines should be used with caution in patients with signs and symptoms of a depressive disorder or suicidal tendencies.

CNS and/or paradoxical reactions.

As with other benzodiazepines and CNS active drugs, three idiosyncratic symptom clusters, which may overlap, have been described.

Amnestic symptoms.

Anterograde amnesia with appropriate or inappropriate behaviour.

Confusional states.

Disorientation, derealisation, depersonalization and/or clouding of consciousness.

Agitational states.

Sleep disturbances, restlessness, irritability, aggression and excitation.
Lorazepam should be discontinued if confusion or agitation occurs.
Paradoxical reactions such as acute rage, stimulation or excitement may occur. Should such reactions occur, lorazepam 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.
There is no evidence to support the use of lorazepam injection in coma or shock.

Glaucoma.

Caution should be used in the treatment of patients with acute narrow-angle glaucoma (because of atropine-like side effects).

Myasthenia gravis.

Lorazepam could increase the muscle weakness in myasthenia gravis and should be used with caution in this condition.

Concomitant use with alcohol/CNS depressants including opiates.

The concomitant use of lorazepam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of lorazepam which may include severe sedation, clinically relevant respiratory and/or cardio-vascular depression (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death.

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 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.

Use in hepatic and renal impairment.

Patients with impaired renal or hepatic function should use benzodiazepine medication with caution and dosage reduction may be advisable.
As with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy.
Patients with hepatic or renal impairment may be prone to propylene glycol accumulation and toxicity. Also see Section 4.4 Special Warnings and Precautions for Use above.

Blood dyscrasias.

Use benzodiazepine medication with caution and dosage reduction may be advisable.

Use in the elderly or debilitated patients.

Such patients may be particularly susceptible to the sedative effects of benzodiazepines and associated giddiness, ataxia and confusion which may increase the possibility of a fall.
Lower doses should be used in elderly patients (see Section 4.2 Dose and Method of Administration).
Paradoxical reactions may be more likely to occur in the elderly (see Section 4.4 Special Warnings and Precautions for Use).

Monitoring.

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.

Paediatric use.

Paradoxical reactions may be more likely to occur in children (see Section 4.4 Special Warnings and Precautions for Use).
Lorazepam is not recommended for use in the treatment of anxiety, agitation or as a pre-surgical medication in children.
Lorazepam injection contains propylene glycol. Paediatric patients may be prone to propylene glycol accumulation and toxicity. The recommended maximum daily dose is 50 mg/kg in children ≥ 5 years. Also see Section 4.4 Special Warnings and Precautions for Use above.
Benzyl alcohol has been associated with serious adverse events, and death in paediatric patients including neonates. Benzyl alcohol containing products should not be used in pre-term or full-term neonates and in young children under 3 years. Also see Section 4.4 Special Warnings and Precautions for Use above.

Paediatric neurotoxicity.

Some published studies in children have observed cognitive deficits after repeated or prolonged exposures to anaesthetic agents early in life. These studies have substantial limitations, and it is not clear if the observed effects are due to the anaesthetic/analgesic/sedation drug administration or other factors such as the surgery or underlying illness.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy. The clinical significance of these nonclinical finding is yet to be determined.
Depending on the drug and patient characteristics, as well as dosage, the elimination phase may be prolonged relative to the period of administration resulting in longer exposure to the drug.

Effects on laboratory tests.

No interference with laboratory tests has been identified or reported with the use of lorazepam.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Sedation.

Not recommended: concomitant intake with alcohol.

The sedative effects may be enhanced when the product is used in combination with alcohol.
Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished in the presence of lorazepam injection. Alcoholic beverages should not be consumed for at least 24 to 48 hours after receiving lorazepam injection.
The benzodiazepines, including lorazepam injection, produce additive CNS depressant effects including respiratory depression, when co-administered with other medications which themselves produce CNS depression, e.g. opioids, and narcotic analgesics, barbiturates, sedatives/hypnotics, anxiolytics, antidepressants, non-selective MAO inhibitors, phenothiazines and other antipsychotics, sedative antihistamines, scopolamine and anaesthetics.
The addition of scopolamine to lorazepam injection is not recommended, since their combination has been observed to cause an increased incidence of sedation, hallucination and irrational behaviour.
Concomitant use of clozapine and lorazepam may produce marked sedation, excessive salivation, and ataxia.
There have been reports of apnoea, coma, bradycardia, heart arrest and death with the concomitant use of lorazepam injection solution and haloperidol.

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 Special Warnings and Precautions for Use).
Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lorazepam.

Skeletal muscle relaxants.

The action of skeletal muscle relaxants may be enhanced.
Anticholinergic effects. The anticholinergic effects of other drugs including atropine and similar drugs, antihistamines and antidepressants may be potentiated.

Pharmacokinetic interactions.

The cytochrome P450 system has not been shown to be involved in the disposition of lorazepam and, unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with lorazepam.
Interactions have been reported between some benzodiazepines and anticonvulsants, with changes in the serum concentration of the benzodiazepine or anticonvulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anticonvulsants are prescribed together, and that serum level monitoring of the anticonvulsant be performed more frequently.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A pre-implantation study in rats was performed with oral lorazepam at a 20 mg/kg dose which showed no impairment of fertility.
(Category C)
Lorazepam is not recommended for use in pregnant women. Benzodiazepines may cause foetal damage when administered during first trimester. The use of lorazepam during the first trimester of pregnancy should be avoided. Continuous treatment during pregnancy and administration of high doses in connection with delivery should also be avoided. The use of benzodiazepines during the late phase of pregnancy or at delivery may require ventilation of the infant at birth.
If the drug is prescribed to a woman of child-bearing potential, she should be warned to contact her physician regarding discontinuation of the drug if she intends to become or suspects that she is pregnant.
Withdrawal symptoms in newborn infants have been reported with this class of drugs.
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.
Benzodiazepines cross the placenta and it is considered as the mechanism of action.
Neonates appear to conjugate lorazepam slowly, the glucuronide being detectable in the urine for more than seven days. Glucuronidation of lorazepam may competitively inhibit the conjugation of bilirubin, leading to hyperbilirubinaemia in the newborn.
There are insufficient data regarding obstetrical safety of parenteral lorazepam, including use in caesarean section. Following caesarean section, 36% of the lorazepam patients had severe symptoms of delirium, including hallucinations, confusion, agitation, restlessness, inappropriate weeping and repetitive hand movements. Use of intravenous lorazepam in caesarean section is not recommended.
IV or IM lorazepam administered during pregnancy was associated with significantly low Apgar scores, need for ventilation, hypothermia, and poor suckling in neonates.
The effects of lorazepam on neonates indicate that its use at any stage in pregnancy should be restricted to hospitals with facilities for neonatal intensive care.
Published animal studies of some anaesthetic/analgesic/sedation drugs have reported adverse effects on brain development in early life and late pregnancy.
Published studies in pregnant and juvenile animals demonstrate that the use of anaesthetic/analgesic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of rapid brain growth or synaptogenesis may result in neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis when used for longer than 3 hours. These studies included anaesthetic agents from a variety of drug classes.
Caution should be exercised when lorazepam is given to breast feeding women. Lorazepam is excreted in human breast milk and may cause drowsiness and feeding difficulties in the infant.
Paediatric patients may be prone to propylene glycol accumulation and toxicity (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

This medicine can impair cognitive function and can affect a patient's ability to drive safely. As with all patients taking CNS-depressant medications, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from lorazepam therapy. Abilities may be impaired on the day following use.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.
See Table 1.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
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 involved, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, cardiovascular depression, coma and, very rarely, proves fatal.
Propylene glycol toxicity have been reported following higher than recommended doses of lorazepam.
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 an agonist, flumazenil, may be useful in hospitalised patients for the management of benzodiazepine overdosage. Please consult the flumazenil product information prior to usage.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

The exact mechanism of action of benzodiazepines has not yet been elucidated; however, benzodiazepines appear to work through several mechanisms. Benzodiazepines presumably exert their effects by binding to specific receptors at several sites within the central nervous system either by potentiating the effects of synaptic or pre-synaptic inhibition mediated by gamma-aminobutyric acid or by directly affecting the action potential generating mechanisms.

Clinical trials.

No in-house clinical trials have been conducted for lorazepam injection.
Minor EEG changes, usually low voltage fast activity, of no known clinical significance, have been reported with benzodiazepine administration.

5.2 Pharmacokinetic Properties

Absorption.

Lorazepam Injection is readily absorbed when given intramuscularly. Peak plasma concentrations occur approximately 1-3 hours following intramuscular administration.

Distribution.

At clinically relevant concentrations, lorazepam is approximately 90% bound to plasma proteins.

Metabolism.

Lorazepam is metabolised in the liver, mainly to the inactive glucuronide. Seventy to seventy-five percent of the dose is excreted as the glucuronide in the urine. The glucuronides of lorazepam have no demonstrable CNS activities in animals, and there are no active metabolites of lorazepam.
The plasma levels of lorazepam are proportional to the dose given.
Lorazepam is not a substrate for N-dealkylating enzymes of the cytochrome P450 system nor is it hydroxylated to any significant extent.

Excretion.

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

Special patient groups.

Studies comparing young and elderly subjects have shown that the pharmacokinetics of lorazepam remain unaltered with advancing age. No changes in absorption, distribution, metabolism and excretion were reported in patients with hepatic disease (hepatitis, alcoholic cirrhosis). As with other benzodiazepines, the pharmacokinetics of lorazepam may change in patients with impaired renal function and the medication should be used with caution.

Pharmacokinetics in paediatric patients.

Children (2 years to 12 years).

In children with acute lymphocytic leukaemia in complete remission (2 to 12 years, n = 37), total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalised to body-weight) and a 35% longer mean half-life compared to normal adults (n = 10). Unbound lorazepam clearance normalised to body-weight was 15% higher in children than in adults.

Adolescents (12 years to 18 years).

In adolescents with acute lymphocytic leukemia in complete remission (12 to 18 years, n = 13) total (bound and unbound) lorazepam had a 50% higher mean volume of distribution (normalized to body-weight) and a mean half-life that was almost two-fold greater compared to normal adults (n = 10). Unbound lorazepam clearance normalised to body-weight was comparable in adolescents and adults.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Propylene glycol, macrogol 400, benzyl alcohol.

6.2 Incompatibilities

Lorazepam SXP may be mixed 1:1 with normal saline or sterile water for injection. It should not be mixed with other drugs in the same syringe (see Section 4.2 Dose and Method of Administration).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
To reduce microbiological hazard, this product should be used as soon as practicable after opening the ampoule. If storage is necessary, hold at 2-8°C for not more than 1 hour.

6.4 Special Precautions for Storage

Store in original package at refrigerated temperatures of between 2°C to 8°C. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

Lorazepam SXP is supplied in 2 mL clear glass ampoules containing 4 mg lorazepam in 1 mL.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Chemical name: 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.
Molecular formula: C₁₅H₁₀Cl₂N₂O₂.
Molecular weight: 321.2.

CAS number.

846-49-1.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

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