17th Expert Committee on the Selection and Use of Essential Medicines Geneva, March 2009

1. Summary statement of the proposal for inclusion, change or deletion

Parenteral lorazepam and parenteral midazolam are proposed for inclusion in the WHO Model List of

Essential Medicines. Parenteral lorazepam is proposed for the intravenous treatment of prolonged

convulsive seizures and status epilepticus in children and adults. Parenteral midazolam is proposed for

buccal administration for the treatment of acute repetitive convulsive seizures and prolonged

convulsive seizures, including status epilepticus where an intravenous access is unavailable, in both

children and adults.

In developed countries, intravenous lorazepam is the drug of choice for the treatment of status

epilepticus by medical personnel. Buccal midazolam is a most valuable treatment for acute repetitive

convulsive seizures, prolonged convulsive seizures and status epilepticus when medical personnel is

not readily available. Lorazepam and midazolam are out of patent and relatively inexpensive, and

therefore also suitable for use in resource-poor countries.

Intravenous lorazepam, given as a slow bolus, is safe and effective at controlling ongoing epileptic

seizures and, compared with diazepam, it is longer acting, thereby reducing the risk of re-emergence

of seizure activity. Buccal midazolam, administered as a liquid formulation, has been reported to be

more effective than rectal diazepam (the most appropriate comparator in this indication) in the

emergency management of convulsive seizures when an intravenous line is not available, e,g, in the

absence of medical personnel, or difficult to access, e.g. in a convulsing small child.

Intravenous lorazepam is the gold standard for the initial treatment of status epilepticus, whereas

buccal midazolam is indicated to treat acute repetitive convulsive seizures, and prolonged convulsive

seizures, including status epilepticus when an intravenous access is unavailable. Both agents are life-

saving, because a delay in starting effective treatment in these conditions can lead to lead to serious

morbidity and even death.

2. Name of the focal point in WHO supporting the application:

Dr Tarun Dua

Programme for Neurological Diseases and Neuroscience

Evidence, Research and Action on Mental and Brain Disorders (MER)

Department of Mental Health and Substance Abuse, WHO, Geneva

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3. Name of the organization submitting the application:

Professor Emilio Perucca, M.D, Ph.D., Head, Clinical Trial Center, Institute of Neurology IRCCS C

Mondino Foundation, Via Mondino, 27100 Pavia, Italy, and Professor of Medical Pharmacology,

Department of Internal Medicine and therapeutics, University of Pavia, Piazza Botta 10, 27100 Pavia,

Italy

4. International Non-proprietary names:

4a. Lorazepam

4b. Midazolam

5. Formulations proposed for inclusion:

5a. Lorazepam: 2 and 4 mg/mL

5b. Midazolam: 5 mg/mL

6. International availability

6a. Lorazepam

Baxter Healthcare Corporation, Deerfield, IL 60015, manufacture lorazepam injection USP1 in

the United States. It is available in 1 and 10 mL vials containing 2 mg/mL and 4 mg/mL.

6b. Midazolam

A midazolam maleate preparation specifically indicated for buccal administration for the treatment

of status epilepticus as an alternative to rectal diazepam is marketed in the United Kingdom as an

Unlicensed Prescription Only Medicine (POM) under the trade name Epistatus2 by Special

Products Ltd, Trade City, Avro Way, Brooklands Business Park, Weybridge, Surrey KT13 0YF. It

is available as a sugar-free buccal liquid (10 mg/mL, content expressed as midazolam base, 4 x 10

mg doses in each bottle). Midazolam injection is an alternative liquid formulation of midazolam

available throughout the world. In the United Kingdom, midazolam injection BP3 is marketed by

CP Pharmaceuticals Ltd, Ash Road North, Wrexham, LL13 9UF. It is available in 2 mL

ampoules containing 5 mg/mL and in 5 mL ampoules containing 2 mg/mL. Although

recommended by NHS institutions in the United Kingdom for buccal use in acute seizure

disorders, particularly in children4, midazolam injection is licensed for intramuscular use for

sedation and for intravenous use for sedation and anesthesia. Baxter Healthcare Corporation,

2

Deerfield, IL 60015, also manufacture midazolam hydrochloride injection5 in the United States. It

is available as 1 mL, 2 mL, 5 mL and 10 mL vials containing 5 mg/mL, and in 2 mL, 5 mL and 10

mL vials containing 1 mg/mL (content expressed as midazolam base).

7. Listing type required

7a. Lorazepam

Listing is requested as an individual medicine and formulation (parenteral formulation, for

intravenous use).

7b. Midazolam

Listing is requested as an individual medicine and formulation (parenteral formulation, for use by

the buccal route).

8. Information supporting the public health relevance

8a. Epidemiology of status epilepticus

Status epilepticus is a medical and neurological emergency consisting of prolonged seizure activity

without full recovery of consciousness between seizures. There is no universal agreement on the

duration of seizure activity required to meet the definition of status epilepticus. Since some

studies indicated that spontaneous cessation of generalised convulsive seizures is unlikely to occur

after 5 min6,7, an operational definition of status based on a seizure duration of 5 min has been

proposed8. Most authors, however, seem to agree on a definition of convulsive status as a

condition characterized by seizure activity lasting at least 30 minutes, or two or more seizures

without full recovery of consciousness between seizures9, a definition which was also adopted by

the recent Cochrane review of the drug management of convulsive status epilepticus in children10.

The annual incidence of status epilepticus worldwide is estimated at 10 to 61 per 100,000 people

(or from 17 to 23 per 100,000 in children), with the highest incidence in populations with low

socioeconomic living standards and quality of health care11. Treiman11 estimated that worldwide

there are about 3 million cases of status epilepticus each year, of which 70% are cases of

generalised convulsive status epilepticus, which is associated with the highest morbidity and

mortality. There are some differences in incidence across regions, with estimates in the order 1012

to 1713 per 100,000 people in Europe, and between 1814 and 4115 per 100,000 people in America.

The incidence is thought to be higher in resource-poor countries, although evidence for this is

limited.16 A study conducted between 2001 and 2004 in a hospital in Queensland, Australia,

which provides the only specialist neurological services for the region, looked at the patterns of

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epilepsy in indigenous and non-indigenous people presenting to hospital17. The health status of the

indigenous population is thought to be typical of that in resource-poor countries. Of those

admitted in status epilepticus, 44% were indigenous, compared with 13% indigenous in the

population. The difference was more pronounced in the adults presenting with status epilepticus,

of whom 53% were indigenous. A prospective study conducted in Richmond, USA, around 1990,

found the annual incident rate to be 20 per 100,000 in whites, and 57 per 100,000 in non-whites15,

but it is difficult to extrapolate this to other countries. There are few studies of the incidence of

status epilepticus in resource-poor countries. Prolonged seizures, which are prone to develop into

status epilepticus and represent by themselves a major medical emergency, are estimated to

account for about 15% of visits to pediatric emergency services in sub-Saharan Africa18,19. In a

recent study from Kenya, the incidence of convulsive status epilepticus (including non-confirmed

cases) was 268 and 227 per 100,000 per year in children aged 1-11 months and 12-59 months,

respectively20. In another study from Kenya, the reported incidence of status epilepticus among

children was 46 per 100,000 per year, but this is likely to be a gross underestimate because

children with epilepsy were excluded and only cases referred to hospital care were surveyed21.

The incidence of status epilepticus varies with age, having a bimodal distribution with peaks in

early childhood and in the elderly. Not all people presenting in status epilepticus have a history of

epilepsy. Indeed, studies of people in status have shown a previous history of epilepsy in 68%

(children 0 to 12 years in Saudi Arabia22), 57% (patients 12 years and over in Hong Kong23), 50%

(adults in Germany13), 47% (children up to ten years in India24), 42% (USA, all ages15) and 27%

(children in Finland – almost one third had an episode of either febrile or acute symptomatic status

epilepticus prior to the onset of epilepsy21).

People with convulsive status epilepticus have a high risk of dying, particularly if status is not

adequately and urgently treated. One study showed the mortality rate to be 31% in white people

with status epilepticus, but only 17% in non-white people15. Some other studies have shown the

mortality to be lowest in children (short-term mortality approximately 3% to 9%, long-term

mortality in short-term survivors 7%) and highest in the elderly (short-term mortality 22 to 38%,

long-term mortality 82%)26. A study conducted in the 1980s set out to find predictors of mortality

in adults with status epilepticus27. Overall mortality was 23%, although only 2% died during the

status. Those with prolonged status (an hour or more) had a one-month mortality rate of 32%

whereas those with status lasting 30 to 59 minutes had one-month mortality of 3%. Mortality

increased with increasing age, and non-black people had a higher mortality rate (31%) than black

people (19%). Those with status probably alcohol related, or due to discontinuation of

antiepileptic drugs (AEDs) had low mortality rates, while those with anoxia or haemorrhage had

high mortality rates. A study of status epilepticus in 184 subjects with a first non-febrile episode of

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status in Rochester, Minnesota, found a fatality rate at 30 days to be 21%28. Most deaths occurred

in the group with acute symptomatic aetiology, where the fatality rate was 34% (mostly due to

cerebrovascular disease or hypoxic insults), and fatality rates were overall highest in those aged

over 65 years. Mortality appears to be higher in resource poor countries, probably due to longer

duration of seizures prior to admission to hospital and onset of treatment and, possibly, suboptimal

treatment facilities. In a retrospective study from India, 9 of 30 children admitted to a paediatric

intensive care unit with status epilepticus died either during seizure activity or before discharge

from hospital24. The risk of death was increased in those with seizure activity for more than 45

minutes and septic shock. A retrospective study of children in Pakistan found the mortality to be

25%29. In this small study mortality was higher in those under one year, those with abnormal

imaging and those with longer duration of status. Central nervous system (CNS) infections are a

common cause of status, particularly in resource poor countries. In a recent survey from India, 37

of 93 adult patients (39.8%) with status epilepticus had CNS infections and 11 of these patients

(29.7%) died, with mortality being higher when status failed to respond to treatment30. CNS

infections were also the most common determinant of status epilepticus among 119 cases reported

from Ethiopia, with AED withdrawal being the most common cause in the subgroup of people

known to have epilepsy27. In the latter study, mortality was 20.2%. In a survey of 388 children

with convulsive status in Kenya, 59 (15%) died in hospital, 81 (21%) died during long-term

follow-up, and 46 (12%) developed neurological sequelae18.

The fact that mortality and morbidity rates, including subsequent development of epilepsy and

neurodevelopmental disorders in children, correlate directly with the duration of convulsive

seizures is of major importance, because a delay in instituting effective treatment is associated

with a higher probability of persistence of status11,32,. In a recent population-based study from

London, United Kingdom, for each minute delay in the interval between status onset and arrival at

the accident and emergency unit, there was a 5% added cumulative risk that the convulsive

episode would last more than 60 min32. The Saudi Arabian study, looking at 47 children with

status epilepticus (59 episodes) found that in only 18 (31%) of the episodes was appropriate AED

treatment initiated22. In many cases there was delay in administration of second- or third-line

drugs, or delayed treatment of underlying metabolic disturbances. The Hong Kong study also

found delay in treatment in 29%, and found that poor outcome (defined as death or functional

deterioration) was predicted by increased age, status due to cerebrovascular disease, CNS infection

and delay in treatment23.

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8b. Assessment of current use of intravenous lorazepam

Lorazepam is currently regarded by most authorities as the first choice treatment for status

epilepticus. This view is reflected in many national and international guidelines.

The evidence-based guidelines published in 2006 by the European Federation of Neurological

Societies (EFNS) for the management of status epilepticus in adults conclude that “the preferred

treatment pathway is intravenous administration of 4 mg of lorazepam – this dose is repeared if

seizures continue for more than 10 min after the first injection” 34.

The evidence-based guidelines of the Royal College of General Practitioners, London, United

Kingdom, for the diagnosis and management in adults and children in primary and secondary care,

in the section dealing with the treatment of convulsive status epilepticus state that “lorazepam

should be used as a first line treatment in status epilepticus” 35.

The evidence-based guidelines of the Italian League against Epilepsy for the management of status

epilepticus consider benzodiazepines as “the first line antiepileptic agents, and intravenous

lorazepam is generally preferred because it is associated with a lower risk of early relapses” 36.

In the Finnish Evidence Based Guidelines for Prolonged Seizures and Status Epilepticus

lorazepam is mentioned together with diazepam as the first line option for the treatment of status

by medical personnel37.

In the U.S., a survey among 106 members of the Critical Care or Epilepsy sections of the

American Academy of Neurology showed that neurologists most often use lorazepam as first-line

therapy for convulsive status epilepticus” 38.

Lorazepam is also considered as the first choice drug in guidelines and expert opinions addressing

specifically the treatment of status epilepticus in childhood. In the United Kingdom, intravenous

lorazepam is indicated by the Status Epilepticus Working Party guidelines as the drug of choice

for the treatment of convulsive status epilepticus in children39. Likewise, a survey made among

41 U.S. physicians specializing in pediatric epilepsy showed that for “initial therapy for all types

of pediatric status epilepticus, lorazepam was treatment of choice”40.

A parenteral formulation of lorazepam is available in most developed countries and in some

resource-poor countries, but it is not available in Japan, where diazepam is recommended as first

line treatment for status41, or in Australia, where intravenous diazepam, clonazepam or midazolam

are used42. When both lorazepam and diazepam are available, however, lorazepam is generally

preferred because it appears to be superior to diazepam in achieving sustained cessation of seizures

and to have a lower risk for continuation of status epilepticus requiring a different drug or general

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anesthesia43 or admission to an intensive care unit10. Studies have also shown a trend for

lorazepam being less likely than diazepam to cause adverse effects, including respiratory

depression requiring ventilatory support43. Other alternatives to lorazepam include parenteral

phenobarbital and phenytoin. Parenteral phenobarbital is frequently used to control status

epilepticus in resource-poor countries, but it has the potential to cause severe respiratory and

cardiovascular depression and most guidelines classify it as a second- or third-choice drug.

Phenytoin can cause serious reactions at the injection site, should be administered slowly through

a large vein, and cardiac monitoring is required (which is frequently not available in resource-poor

countries) and has been found to be inferior to lorazepam in controlling the status (see section

10b). The prodrug of phenytoin, fosphenytoin, whilst reducing some of the complications of

phenytoin treatment, is significantly more expensive. Intramuscular paraldehyde is sometimes

used to treat convulsive emergencies in resource-poor countries, but its efficacy is less well

documented than that of benzodiazepines and it carries a risk of causing sterile abscesses44.

No specific diagnostic or treatment facilities or skills are required when using lorazepam, other

than the standard monitoring and facilities to deal with potentially serious adverse effects, i.e.

respiratory depression and hypotension. On the other hand, a disadvantage of lorazepam when

used in resource-poor countries is the need for storage in a refrigerator1.

The impact of not having parenteral lorazepam for the treatment of status epilepticus would be

lack of early seizure control and prolonged seizures resulting in increased mortality rates and

increased rates of sequelae from brain damage and systemic complications. Increased numbers of

patients will require admission to intensive care units in centres lacking such facilities, and centres

with such facilities will be unable to cope with the higher load of patients due to lack of safe

transport systems and bed space.

8c. Assessment of current use of buccal midazolam

There is general consensus that prolonged (<5 min) or rapidly recurring convulsive seizures (acute

repetitive seizures) should be treated promptly and aggressively, to prevent irreversible sequelae

and progression to status epilepticus11,32. In a representative statement, the evidence-based

guidelines of the Royal College of General Practitioners, London, United Kingdom, for the

diagnosis and management in adults and children in primary and secondary care state that “an

individual who has prolonged convulsive (lasting 5 min or more) or serial seizures (three or more

seizures in an hour) in the community should receive urgent medical care an treatment” 35. Both in

developed and in resource-poor countries, interventions at community level to ensure prompt out-

of-hospital treatment are essential to prevent serious complications, including the development of

established status epilepticus and drug-refractory status11.

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The treatment most commonly used around the world to abort prolonged or rapidly recurring

seizures is rectal diazepam, partly because in some countries it is the only treatment option or the

only licensed medication for this indication32,45. In 2004, the evidence-based guidelines of the

Royal College of General Practitioners, London, already recognized that “for many individuals

and in many circumstances, buccal midazolam is more acceptable than rectal diazepam and is

easier to administer” 35. Since then, further evidence has accumulated indicating that buccal

midazolam represents a preferable choice to rectal diazepam, both in developed and in resource-

poor countries.

In 2005, a randomized trial in the United Kingdom demonstrated that buccal midazolam is

superior to rectal diazepam in providing sustained efficacy in the emergency management of

convulsive seizures46. A superiority of buccal midazolam over rectal diazepam was also confirmed

by a more recent randomized trial in Uganda, although benefits were limited to children without

malaria47. In 2008, a Cochrane review concluded that the “evidence supports the use of buccal

midazolam as the first line treatment of acute tonic-clonic seizures in childhood including

convulsive status epilepticus where intravenous access is unavailable” 10.

There is extensive evidence that prolonged or rapidly recurring seizures are not readily recognized

and treated11. Early treatment is especially critical in resource-poor countries, where facilities for

rapid access to hospital and intensive care treatment are unavailable to the majority of the

population. In view of the evidence that buccal midazolam is not only safe but also more

effective, easier to administer and socially more acceptable than rectal diazepam, it is important

that its availability is ensured worldwide.

Buccal midazolam is suitable for administration by non-medical personnel, provided that it is used

according to an agreed protocol drawn up by the specialist and only used following training35.

Although adverse effects may occur, including respiratory depression, its safety is adequate for use

in the community setting.

The impact of not having buccal midazolam for the treatment of prolonged and/or acute repetitive

convulsive seizures, including convulsive status epilepticus where an intravenous access is

unavailable, would be lack of early seizure control and more prolonged seizures, resulting in more

cases of established and refractory status epilepticus and, consequently, increased mortality and

sequelae from brain damage and systemic complications. Increased numbers of patients will

require admission to medical facilities, including intensive care units in centres lacking such

facilities, and medical centres will be unable to cope with the higher load of patients due to lack of

safe transport systems and bed space.

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8d. Target population

Intravenous lorazepam is indicated as first line treatment for prolonged convulsive seizures and

status epilepticus in both children and adults.

Buccal midazolam is indicated for the treatment of acute repetitive convulsive seizures and

prolonged convulsive seizures, including status epilepticus where an intravenous access is

unavailable, in both children and adults.

9. Treatment details

9a. Lorazepam

Lorazepam is given intravenously at a dose of 0.1 mg/kg given over 30-60 sec in children35,39 and

as a 4 mg bolus given over 2 min in adults1,34,35. This may be repeated once if seizures persist for

more than 10 min after the injection34,39. In the U.S., a larger initial dose (0.1 mg/kg) is often used

in adults48. Immediately prior to intravenous use, the lorazepam formulation should be diluted

with an equal volume of compatible solution (e.g., sterile water for injection, sodium chloride

injection USP, 5% dextrose injection, USP) and mixed gently by inverting repeatedly the

container to ensure that a homogeneous solution is obtained1.

The usual precautions in treating status epilepticus should be employed, including assessing and

correcting potential causes of seizure activity, monitoring vital signs, securing a venous line,

maintaining unobstructed airway and having artificial ventilation equipment available.

9b. Midazolam

For buccal administration of midazolam, the parenteral injection formulation licensed for

intravenous and intramuscular use may be employed4. The recommended doses is usually about

0.3-0.5 mg/kg in children2,46,47,49,50,51 and 10 mg in adults2,49.

If the midazolam injection formulation is used, to administer the prescribed amount the

appropriate volume is drawn up from the ampoule through a filter straw attached to a syringe, and

the syringe is then placed into the side of the patient’s mouth, between the gums and the teeth.

Preferably, the dose is given half into one cheek and half into the other cheek4. Written

instructions on how and when to administer should be given to patient and caregivers.

A midazolam preparation specifically indicated for buccal administration as treatment for status

epilepticus, prolonged seizures and febrile seizures is marketed in the United Kingdom as an

Unlicensed Prescription Only Medicine (POM) under the trade name Epistatus2 by Special

Products Ltd, Unit 16, Trade City, Avro Way, Brooklands Business Park, Weybridge, Surrey

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KT13 0YF. It is available as a sugar-free buccal liquid (10 mg/mL, 4 x 10 mg doses in each

bottle).

10. Summary of comparative effectiveness in a variety of clinical settings:

10a. Identification of clinical evidence

A Medline search was undertaken, using the terms ‘status epilepticus and incidence’ and ‘status

epilepticus and treatment and lorazepam’, ‘status epilepticus and treatment and midazolam’, ‘acute

repetitive seizures and midazolam’ and ‘buccal midazolam’. Additionally reference lists of

publications thus located were searched.

10b. Intravenous lorazepam: Summary of available data

Five randomized comparative trials of intravenous lorazepam in the management of acute seizures

and status epilepticus were identified52,53,54,55,56, in addition to two Cochrane reviews, one from

2005 which dealt with anticonvulsant therapy for status epilepticus and included a metanalysis of

outcome data with lorazepam versus diazepam43, and the other from 2008 dealing with drug

management for acute tonic clonic convulsions including convulsive status epilepticus in

children10.

In a pivotal randomised, double-blind multicentre trial conducted in the United States, Treiman et

al.52 compared lorazepam (0.1 mg/kg), diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg),

phenobarbital (15 mg/kg), and phenytoin (18 mg/kg) as intravenous treatment in 384 adults with a

verified diagnosis of overt convulsive status epilepticus. Success rates in controlling seizures were

64.9% with lorazepam, 58.2% with phenobarbital, 55.8% with diazepam and 43.6% with

phenytoin. Lorazepam was significantly superior to phenytoin in a pairwise comparison (p=0.002).

In an additional group of 134 patients with subtle generalized convulsive status epilepticus, there

were no significant differences among the treatments, and no differences among the treatments

were found with respect to seizure recurrence over a 12-hour period or the incidence of adverse

reactions. The study concluded that, “for overt generalized convulsive status epilepticus,

lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than

phenobarbital or diazepam and phenytoin, it is easier to use”.

A second pivotal randomized, double-blind trial evaluated diazepam (5 mg), lorazepam (2 mg), or

placebo administered intravenously by paramedics for out-of-hospital treatment of status

epilepticus in the United States53. An identical second injection was given if needed. Participants

were 205 adults with prolonged (>5 minutes) or repetitive generalized convulsive seizures. On

arrival at the emergency department, status epilepticus had ceased in 59% of patients with

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lorazepam compared with 42.6% of patients with diazepam and 21.1% of patients with placebo

(P=0.001). After adjustment for covariates, the odds ratio (OR) for cessation of status epilepticus

in the lorazepam group was 4.8, 95% confidence intervals (CI) 1.9 to 13.0, compared with the

placebo group and 1.9 (CI 0.8 to 4.4) compared with the diazepam group. The study concluded

that “lorazepam is likely to be a better therapy than diazepam”.

In a smaller double-blind, randomized trial also conducted in the United States, lorazepam (4 mg)

was compared with diazepam (10 mg) in 78 adults with status epilepticus, comprising a total 81

episodes of status54. After administration of one or two doses, cessation of seizures occurred in

89% of the episodes treated with lorazepam and in 76% of those treated with diazepam. Adverse

effects occurred in 13% of cases with lorazepam and in 12% of cases with the diazepam.

A small randomized study only published in abstract form compared intravenous lorazepam (0.1

mg/kg) and midazolam (0.2 mg/kg) as initial treatment for status epilepticus in a total of 27

children55. Cessation of seizure occurred in 8 of 12 (67%) children treated with lorazepam and in

11 of 15 (73%) children treated with midazolam. In non-responders to the first dose, a second dose

of midazolam tended to be more effective than a second dose of lorazepam.

In another randomized study published in abstract form, three intravenous doses of lorazepam (1, 2

and 4 mg) were compared in 130 episodes of status epilepticus56. Cessation of seizures within 10

min after the first dose without recurrence in the subsequent 30 min occurred in 61% of cases with

1 mg, 57% of cases with 2 mg and 76% of cases with 4 mg (p=0.045 for the comparison of 4 mg

versus 1 mg and 2 mg combined).

A prospective, open, quasi-randomized 'odd and even dates' trial in the United Kingdom compared

lorazepam (0.05-0.1 mg/kg) with diazepam (0.3-0.4 mg/kg) in 102 children with acute convulsions

and status epilepticus57 . Treatments could be given intravenously or rectally. When only response

to intravenous treatment (one or two doses) was assessed, cessation of seizures occurred in 19/27

(70%) cases with lorazepam and in 22 or 34 (65%) cases with diazepam, which corresponds to a

relative risk (RR) of 1.09 (CI 0.77-1.54)39. Lorazepam, however, was superior in preventing

seizure relapses: only 6 of 27 lorazepam-treated children had a recurrence within 24 h, compared

with 12 of 34 diazepam-treated children having a relapse (RR 0.63, CI 0.27-1.46). Only one of 27

(4%) children given lorazepam needed additional anticonvulsant therapy, compared with 5 of 34

(15%) children given diazepam. Respiratory depression occurred in 4% of cases with lorazepam

and 21% of cases with diazepam (RR 0.18, CI 0.02-1.37).

A Cochrane review performed a metanalysis of the data from the above trial in which intravenous

lorazepam was compared with intravenous diazepam43. Compared with diazepam, lorazepam has a

statistically significant lower risk of non-cessation of seizures (32/130 versus 51/134 participants,

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RR 0.64, CI 0.45-0.90) and of continuation of status epilepticus requiring a different drug or

general anesthesia (32/130 versus 52/134 participants, RR 0.63, CI 0.45-0.88).

In addition to randomized studies, a number of comparative non-randomized studies also assessed

the effectiveness and safety of lorazepam in status epilepticus. In an early study, lorazepam, 4 to

10 mg and/or clonazepam, 1 mg, were administered intravenously in 61 hospitalized patients with

status epilepticus58. Improvement in EEG was greater with lorazepam, while clinical symptoms

responded more completely to clonazepam. A retrospecyive survey of 72 episodes of status

epilepticus in adults treated with either lorazepam or diazepam found the two drugs equally

effective at terminating seizures, but significantly fewer seizure recurrences followed lorazepam,

and fewer repeat doses were needed for lorazepam59. There were no differences in reported

adverse events or in drug costs. In a retrospective audit of outcomes of status epilepticus in

children admitted to an emergency unit, seizure cessation was reported in 11 of 17 (65%) episodes

treated with intravenous diazepam (0.32 mg/kg) and in 20 of 31 episodes (65%) patients treated

with lorazepam60.

10c. Buccal midazolam: Summary of available data

Three randomized trials46,47,49 and one quasi-randomized trial61 were identified that compared

buccal midazolam with other treatments in the management of acute seizures and status

epilepticus. In addition, a Cochrane review10 assessed studies on the drug management of acute

tonic-clonic convulsions, including convulsive status epilepticus in children.

A highly informative randomised multicentre controlled trial was conducted in the United

Kingdom by McIntyre et al.46, who compared buccal midazolam (0.5 mg/kg) with rectal

diazepam (0.5 mg/kg) as emergency-room treatment for children aged >6 months presenting to

hospital with active seizures and without intravenous access. A total of 177 children (219 seizure

episodes) were enrolled, and the actual dose ranged from 2.5 to 10 mg depending on age.

Therapeutic success (defined as cessation of seizures within 10 min and for at least 1 hour, without

respiratory depression requiring intervention) was reported in 56% (61 of 109) for buccal

midazolam compared with only 27% (30 of 110) for rectal diazepam (percentage difference 29%,

95% CI 16-41). Median time to seizure cessation was 8 min with buccal diazepam and 15 min

with rectal diazepam (p=0.01). Respiratory depression rates did not differ between groups. After

adjustment for covariates, buccal midazolam was found to be more effective than rectal diazepam.

A smaller randomized trial conducted at a British residential school with on-site medical facilities

enrolled students with epilepsy aged 5 to 19 years who experienced prolonged (>5 min) seizures49.

Participants were assigned to receive either buccal midazolam (40 seizures in 14 patients) or rectal

diazepam (39 seizures in 14 patients). Both drugs were given at a dose of 10 mg. Cessation of

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seizures within 10 min occurred in 30/40 cases (75%) with midazolam and in 23/39 cases (59%)

with diazepam (p=0.16). There were no clinically important adverse cardiorespiratory events in

either group.

A large single-blind randomized trial conducted recently in Uganda enrolled 330 consecutive

children aged 3 months to 12 years who presented to a pediatric emergency unit while convulsing

or with a seizure that lasted >5 min47. The children were randomly assigned to receive buccal

midazolam (about 0.5 mg/kg) plus rectal placebo or rectal diazepam (about 0.5 mg/kg) plus buccal

placebo and the primary outcome was cessation of visible seizure activity within 10 minutes

without recurrence in the subsequent hour. The underlying diagnosis was malaria in 67% of

treated children. A treatment failure occurred in 50 (30.3%) of 165 patients who received buccal

midazolam and in 71 of 165 (43.0%) of 165 patients who received rectal diazepam. In malaria-

related seizures, treatment failures were similar for midazolam (31.8% ) and for diazepam (35.8%)

, whereas in children without malaria, buccal midazolam was superior (success rate: 73.5%% vs

44.1%). Among children who had a seizure recurrence within 24 h, median time to recurrence was

longer in the midazolam group (5.11 h vs 1.81 h, p=0.001). Respiratory depression was

uncommon (1.2%) with both treatments. It was concluded that “buccal midazolam was as safe as

and more effective than rectal diazepam” although benefits were limited to children without

malaria.

A prospective, open, quasi-randomized 'odd and even dates' trial in Turkey compared buccal

midazolam with rectal diazepam in the treatment of acute convulsions in 43 children aged 2

months to 12 years at an emergency unit61. Cessation of seizures within 10 min occurred in 18/23

(78%) patients given midazolam and in 17/20 (85%) patients given diazepam. There were no

serious complications.

The effectiveness and safety of buccal midazolam is supported by additional findings from non-

randomized studies. In an open study from Turkey, 19 children aged 1 month to 15 years (13 with

prolonged seizures and 6 with status epilepticus) were treated with a 0.3 mg/kg dose of buccal

midazolam50. Cessation of seizures occurred within 10 min in 16 cases (84.2%), including all

cases who had presented with a duration of convulsions shorter than 30 min. A retrospective

survey of the use of buccal diazepam (5-10 mg) in the community to treat 78 episodes of

prolonged or serial seizures in children reported cessation of seizures within 2-20 min in 87% of

the cases62. In at telephone survey addressing the comparative effectiveness and convenience of

buccal or nasal midazolam in terminating prolonged seizures in the community in the United

Kingdom63, 33/40 (83%) families who had used the medication found midazolam effective and

easy to use and 20/24 (83%) preferred using midazolam to rectal diazepam. In a small study from

Kenya that included 33 children with convulsions associated with falciparum malaria, participants

13

received a single dose of midazolam (0.3 mg/kg) intravenously, intramuscularly or buccally51.

Although the primary goal of the study was to assess pharmacokinetics, outcome data were also

reported and cessation of seizures occurred in 13 of 13 children after the intravenous dose, in 9 of

12 after the intramuscular dose and in 5 of 8 after buccal administration.

Overall, the evidence on the effectiveness of buccal midazolam as summarized above has been

obtained both in high-income and in resource-poor countries. In particular, apart from studies

conducted in the United Kingdom, the largest randomized controlled trial was carried out in

Uganda, and there have been also studies in Kenya and Turkey. One critical aspect is that, if

exception is made for the study performed at a British residential school49, evidence on efficacy

and safety was generated at accident and emergency services and not at community level, despite

the fact that the value of buccal midazolam is expected to be greatest outside hospital settings.

This situation clearly relates to the difficulties in assessing medicines in the community,

particularly when the disorder being treated occurs acutely and unpredictably. Specifically, it

would be difficult to obtain reliable information on effectiveness (including, nature of the seizure

and duration of seizure activity before and after administering treatment) and to avoid reporting

bias in surveys done, for example, in rural areas in resource poor countries. A strong argument for

supporting the use of buccal midazolam in those settings, however, comes from the evidence from

well conducted hospital-based trials indicating that midazolam is more convenient, more socially

acceptable, probably more effective and at least as safe as rectal diazepam, the current standard to

treat prolonged convulsive seizures and acute repetitive seizures in community settings in all

countries of the world. This conclusion is in line with those reached by the Cochrane review10 on

the treament of seizure emergencies in children, according to which the data " ... provide evidence

to support the use of buccal midazolam as the first line treatment of an acute tonic-clonic

convulsion and convulsive status epilepticus in childhood where intravenous access in not

available".

10d. Summary of available estimates of comparative effectiveness

As discussed in section 10b, a Cochrane metanalysis analyzed data from randomized and quasi-

randomised trials that compared intravenous lorazepam with intravenous diazepam in patients with

status epilepticus38. Compared with diazepam, lorazepam was associated with a statistically

significant lower risk of non-cessation of seizures (32/130 versus 51/134 participants, RR 0.64, CI

0.45-0.90) and of continuation of status epilepticus requiring a different drug or general anesthesia

(32/130 versus 52/134 participants, RR 0.63, CI 0.45-0.88). No additional randomized

comparative trials of intravenous lorazepam and diazepam in status epilepticus have been reported

after publication of the Cochrane metanalysis.

14

There have been no metanalyses of data from studies that compared buccal midazolam with rectal

diazepam. Hence only the comparative data already provided in section 10c are available.

11. Summary of comparative evidence on safety:

11a. Estimate of total patient exposure to date

Lorazepam: Lorazepam has been commercially available since the early 70s, and it has been

widely used worldwide as a sedative, hypnotic and anxiolytic mostly by the oral route. Although

there is no data available on patient exposure to oral lorazepam, it is likely that well over 15

million person/years of exposure has been accumulated. The use of intravenous lorazepam to treat

status epilepticus has increased markedly following the publication of the large VA randomized

trial in 199852. Assuming an annual incidence of 30 cases of status epilepticus per 100,00014,45,

about 90,000 cases of status are expected to occur each year in the United States. If one third of

these cases are treated with lorazepam, which is a conservative estimate, 30,000 patients should

have received intravenous lorazepam each year in the United States alone.

Midazolam: Midazolam has been commercially available since the mid 80s and it is widely used

worldwide as oral medication as an hypnotic. Although there is no data available on patient

exposure to oral midazolam, it is likely that well over 5 million person/years of exposure has been

accumulated. Midazolam is also widely used parenterally in anesthesiology practice and also as an

anticonvulsant. Its exposure folowing intravenous and intramuscular dosing, therefore, is likely to

be much greater than that of parenteral lorazepam. There is no data available on patient exposure

to buccal midazolam but use by this route is increasing exponentially because buccal midazolam is

now regarded in many countries as the treatment of choice for acute repetitive seizures and

prolonged convulsive seizures, including status epilepticus where an intravenous access is

unavailable, particularly in children64,65.

11b. Description of adverse effects/reactions

Lorazepam: The most common serious adverse effect of intravenous lorazepam is respiratory

depression1,52,53,54,55,56,57, with respiratory failure being reported in 2.4% of the patients included in

two regulatory trials in status epilepticus1. Other adverse effects reported in these trials include

somnolence, hypotension, headache, stupor, and coma1. Other adverse reactions include

alterations in attention and coordination, paradoxical CNS reactions (e.g., agitation, irritability,

restlessness, aggression, psychosis), nausea, vomiting, skin rashes and reactions at the injection

site40. Intra-arterial injection may produce arteriospasm and, consequently, gangrene which may

require amputation. As with all benzodiazepine drugs, withdrawal symptoms, including insomnia,

15

anxiety, agitation, convulsions and psychotic reactions, may occur when lorazepam treatment is

stopped after prolonged administration.

Midazolam: The most common serious adverse effect of midazolam is respiratory depression,

although the risk is primarily associated with intravenous use, particularly in combination with

opiates during anesthesiology practice5,66. Less common serious adverse effects include

hypotension, cardiac arrhythmias, and hypersensitivity reactions such as angioedema and

bronchoconstriction5,66. Overall, the most common adverse effects of midazolam consist in

sedation and, less frequently, hiccups, cough, nausea and vomiting. Other adverse effects include

altered coordination, dyskinesias, and paradoxical reactions such as agitation, restlessness,

disorientation, hostility, aggression and rage 66. As with all benzodiazepine drugs, withdrawal

symptoms, including insomnia, anxiety, agitation, convulsions and psychotic reactions, may occur

when midazolam treatment is stopped after prolonged administration.

11c. Identification of variation in safety due to health systems and patient factors

Lorazepam: Some adverse effects of lorazepam, particularly respiratory and cardiovascular

depression, are serious and could require treatment which may not be available in resource-poor

countries. It is clear, however, from section 11d below that these complications occur no more

frequently (and some occur less frequently) with lorazepam than with the other anticonvulsants.

Midazolam: Some adverse effects of midazolam, particularly respiratory and cardiovascular

depression, are serious and could require treatment which may not be available in resource-poor

countries. It is clear, however, from section 11d below that the tolerability of buccal midazolam is

generally favorable and that complications occur no more frequently with buccal midazolam than

with other anticonvulsants used in the same setting.

11d. Summary of comparative safety against comparators

Lorazepam: The most meaningful comparator to assess the relative safety of intravenous

lorazepam is intravenous diazepam. In randomized comparative studies, lorazepam was

comparable or slightly superior to diazepam in safety and tolerability profile52,53,54,55. In the

randomized, double-blind trial that compared lorazepam (2 mg), diazepam (5 mg), and placebo as

out-of-hospital treatment of status epilepticus in the United States, the incidence of respiratory or

cardiocirculatory complications was 10.6% in the lorazepam group compared with 10.3% in the

diazepam group, and 22.5% in the placebo group53. The high rate of complications in the placebo

group highlights the difficulties in differentiating the adverse effects of treatment from those of

status epilepticus itself. In the prospective quasi-randomized trial in the United Kingdom that

16

compared lorazepam with diazepam in children with acute convulsions and status epilepticus57,

respiratory depression occurred in 4% of cases treated with lorazepam and 21% of those treated

with diazepam (RR 0.18, CI 0.02-1.37) 10,57. A Cochrane metanalysis of data from two studies that

compared intravenous lorazepam with intravenous diazepam in patients with status epilepticus

found no statisticallly significant difference in death rates between the two treatrments (5/103

versus 3/100 participants, risk difference 0.02, CI 0.04-0.08) 43. In the large double-blind VA

study, adverse effect rates for patients with overt status assigned to lorazepam, phenobarbital,

diazepam plus phenytoin and phenytoin were 26%, 34%, 32% and 27% respectively for

hypotension, 10%, 13%, 17% and 10% respectively for hypoventilation, and 7%, 3%, 2% and 7%

respectively for cardiac rhythm disturbances52. Adverse event rates were similar in patients with

subtle status, except that hypotension occurred with a higher frequency in these patients in all

treatment groups.

Midazolam: The most meaningful comparator to assess the relative safety of buccal midazolam is

rectal diazepam. In randomized comparative studies, lorazepam was comparable or slightly

superior to diazepam in safety and tolerability profile46,47,49,50. In a randomized trial conducted at a

British residential school in subjects with prolonged seizures, buccal midazolam was used to treat

40 seizures in 14 students, and rectal diazepam to treat 39 seizures in 14 students49. All patients

were closely monitored after every treatment. No clinically important adverse events were

identified in either group. Median decrease in systolic blood pressure was 11 mmHg for

midazolam and 6 mmHg for diazepam. Median decrease in diastolic blood pressure was 10 mmHg

for midazolam and 8.5 mmHg for diazepam. Median oxygen saturation was 97% in both groups.

The lowest oxygen saturation recorded was 93% after midazolam administration, which lasted

about 2 min before returning to 98%. In a larger randomised trial conducted in the United

Kingdom by McIntyre et al.46 in which buccal midazolam and rectal diazepam were compared in

219 seizure episodes in 177 children, respiratory depression was recorded in 5% of midazolam-

treated episodes and in 6% of diazepam treated episodes, a fequency possibly influenced by the

fact that about one third of children had already received rectal diazepam before presenting to

hospital. Five children required intubation, two after buccal midazolam and three after rectal

diazepam. In the trial in Uganda in which 330 patients with prolonged seizures were randomly

allocated to buccal midazolam or rectal diazepam, there were 4 children (1.2%) experienced

respiratory depression, 2 in the midazolam group and 2 in the diazepam group47. The only other

adverse event considered to be at least possibly related to the study drugs was intense pruritus in

one child in the midazolam group.

As discussed in section 10c, rectal diazepam is the current standard for the out-of hospital

treatment of prolonged convulsive seizures and acute repetitive seizures throughout the world. The

evidence reviewed above, indicating that buccal midazolam is as safe as rectal diazepam, is

17

reassuring for its proposed use at community level, in spite of the paucity of studies conducted in

such settings. To minimize risks associated with respiratory depression, however, it is prudent to

recommend that use of buccal midazolam in out-of-hospital settings, particularly in areas with

poor access to medical facilities, be restricted to dosages at the lower end of the effective range.

12. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group:

Lorazepam: The International Drug Price Indicator Guide67 currently does not provide a price for

parenteral lorazepam. However, it lists a price for lorazepam tablets - capsules (not injectable), which

is equal to U.S. $ 0.0054/ 2mg tablet-capsule, or $0.00675 per defined daily dose (2.5mg).

According to the British National Formulary, the price for injectable Lorazepam 4mg/ml is 37p per

1ml ampoule.

Midazolam: According to the International Drug Price Indicator Guide67, the median price of

midazolam 5 mg/mL is 0.30 U.S. $/mL

For either product, no formal comparative cost-effectiveness studies have been performed.

13. Summary of regulatory status of the medicines

Lorazepam: In the United States, lorazepam injection is licensed for the treatment of status epilepticus

and as a pre-anesthetic agent. Since the compound is off patent, there are several marketing

authorization holders, including the originator, Wyeth-Ayerst Laboratories.

Midazolam: In the Unites States, the parenteral formulation of midazolam is licensed for use

intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia, and intravenously for

sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, for

induction of general anesthesia before administration of other anesthetic agents, and for continuous

intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of

anesthesia or during treatment in a critical care setting. Since the compound is off patent, there are

several marketing authorization holders, including the originator Roche Laboratories. The use of

buccal midazolam in the treatmemt of acute repetitive seizures and status epilepticus is unlicensed.

As detailed in section 6, a midazolam maleate preparation specifically indicated for buccal

administration for the treatment of status epilepticus as an alternative to rectal diazepam is marketed in

the United Kingdom as an Unlicensed Prescription Only Medicine (POM) under the trade name

Epistatus2 by Special Products Ltd, Trade City, Avro Way, Brooklands Business Park, Weybridge,

Surrey KT13 0YF.

18

14. Availability of pharmacopoeial standards

Parenteral lorazepam is listed in various drug catalogues, including the British and the U.S.A.

formularies.

Parenteral midazolam is listed in various drug catalogues, including the British and the Australian

formularies.

15. Proposed text for the WHO Model Formulary

15a. Lorazepam

The following is adapted from Lorazepam Injection USP datasheet2:

LORAZEPAM

Therapeutic action

- Anticonvulsant, sedative, anxiolytic

Indications

- Status epilepticus. May also be used to treat prolonged convulsive seizures and acute repetitive

convulsive seizures

Presentation and route of administration

- 1 and 10 ml vials containing 2 mg/mL and 4 mg/mL for slow and diluted intravenous injection.

Dosage

- Child: 0.1 mg/kg intravenously over 30-60 sec

- Adult: 4 mg over 2 min

The dose may be repeated once if seizures persist for more than 10 min after the injection.

Immediately prior to intravenous use, the formulation should be diluted with an equal volume of

compatible solution (e.g., sterile water for injection, sodium chloride injection USP, 5% dextrose

injection, USP) and mixed gently by inverting repeatedly the container to ensure that a homogeneous

solution is obtained.

19

Contra-indications, adverse effects, precautions

- Do not administer to patients with severe respiratory insufficiency (unless mechanically

ventilated), acute narrow angle glaucoma, and known hypersensitivity to benzodiazepine drugs or to

its vehicle (polyethylene glycol, propylene glycol and benzyl alcohol).

- Assisted ventilation is essential in case of respiratory distress

- May cause: drowsiness, respiratory depression, hypotension, paradoxical reactions such as

agitation and aggressiveness, and reactions at the injection site.

- Pediatric patients, particularly neonates, may exhibit hypersensitivity to the vehicle used in

Lorazepam Injection.

- Patients over 65 years of age show a greater incidence of CNS depression, including increased

sedation and respiratory depression.

- Increased risk of sedation and other adverse effects when combined with alcohol and central

nervous system depressants such as other benzodiazepines, opiates and other narcotics, barbiturates,

MAO inhibitors, antipsychotics, antihistamines.

- Pregnancy and breast-feeding: risks linked to prolonged convulsive seizures, acute repetitive

convulsive seizures and status epilepticus appear greater than risks linked to lorazepam

Remarks

- Avoid perivascular extravasation. Intra-arterial route may cause gangrene

- Do not use if solution is discolored or contains a precipitate

- Do not mix with other drugs in the same syringe

- Warning: comes in ampoules of different strengths. Before injection, check concentration

- Lorazepam is subject to international controls: follow national regulations

- Injectable lorazepam is not included in the WHO list of essential drugs

- Storage: Store in a refrigerator

20

15b. Midazolam

The following is adapted from Midazolam (Epistatus) datasheet2, Midazolam hydrochloride

Injection, Injection USP datasheet1, Midazolam Injection BP, datasheet3:

MIDAZOLAM

Therapeutic action

- Anticonvulsant, sedative, anxiolytic, anesthetic

Indications

- Prolonged convulsive seizures and acute repetitive convulsive seizures. Status epilepticus when an

intravenous access is unavailable.

Presentation and route of administration

- 5 mg/mL (expressed as midazolam base) in 2 mL ampoule for buccal administration. Note: the

Epistatus formulation contains 10 mg/mL.

Dosage

- Child (6 months and older): 0.3 mg/kg (maximum single dose 10 mg) by the buccal route

- Adult: 10 mg by the buccal route

Repeat doses:

- If seizures persist after 10 min in small children at the lower end of the age range (<5 years), an

ambulance should be called and a further single dose may be given while en route to the emergency

department. A third dose must not be administered sooner than 6 h after the second dose.

- If seizures persist after 10 min in children at the upper end of the age range and the child is

breathing normally, give a second dose. If the child is breathing shallowly, call an ambulance and do

not give a second dose. If no effect is seen after the second dose, call an ambulance. A third dose

must not be administered sooner than 6 h in children under 40 kg and sooner than 12 h in adults.

Higher initial doses: An initial dose of 0.5 mg/kg (maximum single dose 10 mg) may be given if

the patient is at an emergency department with facilities for mechanical ventilation.

Contra-indications, adverse effects, precautions

- Do not administer to patients with severe respiratory insufficiency (unless mechanically

ventilated), acute narrow angle glaucoma, and known hypersensitivity to benzodiazepine drugs

21

- Assisted ventilation is essential in case of respiratory distress

- May cause: drowsiness, respiratory depression, hypotension, paradoxical reactions such as

agitation and aggressiveness.

- Patients over 65 years of age show a greater incidence of CNS depression, including increased

sedation and respiratory depression.

- Risk of increased sedation and other adverse effects when combined with alcohol and central

nervous system depressants such as other benzodiazepines, opiates and other narcotics, barbiturates,

antipsychotics, antihistamines.

- Pregnancy and breast-feeding: risks linked to prolonged convulsive seizures, acute repetitive

convulsive seizures and status epilepticus appear greater than risks linked to midazolam

Remarks

- In the treatment of status epilepticus, when an intravenous access is available, use intravenous

lorazepam or, if lorazepam is unavailable, intravenous diazepam.

- Do not mix with other drugs in the same syringe used for the buccal administration

- Warning: Ampoules of different strengths may be available. Before administration, check

concentration.

- Midazolam is subject to international controls: follow national regulations

- Midazolam is not included in the WHO list of essential drugs

- Storage: Store at 20-25°C, excursions permitted to 15-30°C

22

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