Kuwait Pharmacy Bulletin DRUG INFORMATION FOR THE HEALTH PROFESSIONAL

Vol 17. No 2 Summer 2013 ISSN 1028-0480

Sleep cycle Brain activity can be recorded by EEG during

wakefulness and sleep (Fig 1). Light sleep refer-

ring to stages 1 and 2 shows a relatively low volt-

age with mixed frequency activity, while deep

sleep referring to stages 3 and 4, which is also

called slow-wave sleep, is characterized by in-

creasing high voltage activity. In REM sleep brain

activity resembles that of wakefulness. Healthy

individuals may cycle between stages of NREM

and REM throughout the night (1, 2).

The average length of the first NREM-REM sleep

cycle is 70-100 min with 75-80% in NREM, and 20-

25% in REM sleep. Stage 1 lasts 1-7 min (2-5 % of

total sleep). Stage 2 lasts approximately 10-25 min

constituting 45-55% of the total sleep. In this stage,

an individual requires more intense stimuli than in

stage 1 to awaken. Stage 3 lasts only a few minutes

(3 to 8 % of sleep). Stage 4 of NREM lasts 20-40

min in the first cycle and constitutes 10-15% of

sleep. Stages 3 and 4 are classified as the deepest

stages of sleep (3,4).

REM sleep lasts only 1-5 min during the initial

cycle, but is progressively prolonged as sleep pro-

gresses. Here, the brain appears to be as active as

during wake periods (1); dreaming is associated

with this state of sleep. Also, in REM sleep there is

a loss of muscle tone and reflexes which is im-

portant to prevent the

individuals from act-

ing out their dreams

while sleeping. REM

sleep is important for

memory consolida-

tion (3).

New approaches towards New approaches towards New approaches towards

treatment of insomniatreatment of insomniatreatment of insomnia

In this issue Treatment of insomnia 1 Test your knowledge 9 Topical issues 9 News from the FDA 12 New Drug approvals 15

Sleep is a cyclical process consisting of two stages: Non-Rapid Eye Movement

(NREM) and Rapid Eye Movement (REM). NREM is divided into light (stage 1

and 2) and slow wave sleep (stage 3 and 4). Several neurotransmitters control the

sleep process including: serotonin, noradrenaline, dopamine, histamine, hypocretin, acetylcholine, GABA

and galanine. Absence of sleep stages and cycle is associated with insomnia. Elderly and women are more

prone to have insomnia. Other associated factors include medical conditions, taking certain medications,

physiological factors, chronobiological factors social factors such as divorce and being widowed and be-

havioural factors. Insomnia, if not treated, may result in depression, anxiety, obesity, diabetes and impaired

glucose tolerance, increased susceptibility to pathogens, compromised work productivity and increased risk

of accidents. Current pharmacological treatments include benzodiazepines and newer benzodiazepine-like

agents including zolpidem and zaleplon, ethanol, antihistamines, exogenous melatonin, chloral hydrate,

barbiturates and sedating anti-depressants. These drugs have several limitations that necessitate the devel-

opment of new drugs for the treatment of insomnia.

Fig 1. Brain activity recorded by EEG. Adapted from

http://sleepamongstspecies.wordpress.com

2 Kuwait Pharmacy Bulletin Summer 2013

Role of neurotransmitters

In the brainstem and posteriolateral hypothalamus,

wake promoting neurotransmitters include seroto-

nin (5-hydroxytryptamine, 5-HT), noradrenaline,

dopamine, histamine, hypocretin and acetylcholine

(Ach) (5). In the anterior hypothalamus, preoptic

area and the adjacent basal forebrain, there are

both wake promoting neurotransmitters, gamma-

aminobutyric acid (GABA) and Ach, and sleep

promoting neurotransmitters, GABA and galanine.

The synthesis and the release of sleep promoting

factors, such as interleukin 1 (IL-1), are induced by

serotonin (5). These relationships are illustrated in

Fig 2.

Factors associated with insomnia About 10-30% of the general population suffer from

insomnia. A persistent insomnia for more than 1

month, without the association of physical problem

and mental disorder, is considered primary insom-

nia. Association with specific events, including pe-

riods of stress or anxiety, and linkage to other psy-

Figure 2. Serotonin effect in wakefulness and NREM sleep. ACh, acetylcholine; DA, dopamine; GABA, γ-

aminobutyric acid; LC, locus coeruleus; LDT–PPT, laterodorsal and pedunculopontine tegmental nuclei; NA, nora-

drenaline; NREM, non-rapid eye movement; PeF, perifornical region; TMN, tuberomammillary nucleus; VTA, ven-

tral tegmental area. Adapted from (5).

Vol 17. No 2 Drug Information For The Health Professional 3

leading to impairment of glucose regulation because

of the lipolytic effects of adrenergic stimulation of

visceral adipose tissue. The impact of sleep loss on

glucose regulation suggests a mechanism whereby

short sleep time might increase mortality (10). Insomnia affects the immune system by impairing

host defense mechanisms and increasing the suscep-

tibility to viral and bacterial pathogens (11). Fur-

thermore, insomnia can lead to impairment of learn-

ing, thinking, memory, perceptual skills, deteriora-

tion of mood, attention and concentration which

may result in compromised work productivity.

Current treatments of insomnia and their limitations

Current pharmacological therapies include benzodi-

azepines, newer benzodiazepine-like agents includ-

ing zolpidem and zaleplon, ethanol, antihistamines,

exogenous melatonin, chloral hydrate, barbiturates,

and sedating anti-depressants.

Benzodiazepines

Benzodiazepines (used as anxiolytics, hypnotics or

anticonvulsants) modulate GABA receptor function

by enhancing GABA's inhibitory action in the brain

(1, 12). The most commonly prescribed benzodiaze-

pines are alprazolam (Xanax), clonazepam

(Klonopin), diazepam (Valium), and lorazepam

(Ativan); 1, 5-benzodiazepines have similar thera-

peutic properties as1,4-benzodiazepines but with

considerably less sedative and hypnogenic activity.

A modification of the benzodiazepine structure is by

the annelation of an additional ring system. For ex-

ample, triazolam and midazolam, which are highly

active substances result from the 1,2-annelation of

triazole or imidazole (Fig 3).

The prolonged use of benzodiazepines is associat-

ed with the development of amnesia, tolerance and

dependence (physical and psychological), and with-

drawal problems. Withdrawal syndrome, on the oth-

er hand, is described as having rebound insomnia

with the association of minor physical symptoms in

addition to the symptoms specific to benzodiazepine

withdrawal (13,14). Minor physical symptoms are

tachycardia, tremor, perspiration, dizziness, palpita-

tions, muscle tension or headache, and gastrointesti-

nal symptoms such as nausea and vomiting. Symp-

toms specific to benzodiazepine withdrawal include

changes of taste and smell, impaired vision and

hearing, impaired perception of motion, de-

personalization, de-realisation, paresthesia, loss of

appetite or loss of weight and muscle spasm. In pa-

tients with pulmonary disease, all benzodiazepines

chological or physical problems, is classified as

transient insomnia (6).

Age is an important risk factor, in addition to

some medical conditions like Alzheimer’s disease,

Parkinson’s disease, depression, anxiety, stress,

heartburn, respiratory disorders, dementia, urinary

incontinence, heart failure, cancer, and diabetes.

Furthermore, sleep patterns may be altered by

medications such as bronchodilators, β-blockers,

methyldopa, diuretics, theophylline, cimetidine,

phenytoin (6), amphetamines, antidepressants and

medications against anorexia and tuberculosis, in

addition to excessive consumption of caffeine and

chronic alcoholism (7). Women are more prone to have insomnia than

men. This is because during menstruation, preg-

nancy, and menopause, women experience hormo-

nal fluctuations that put women at higher risk of

insomnia. Additionally, anxiety and depressive

disorders are more likely to occur in women and

can cause insomnia. Other factors associated with

insomnia include social factors, physiologic fac-

tors, chronobiological factors, and behavioural fac-

tors.

As a social issue, it was found that divorced, sepa-

rated or widowed people have advanced rates of

insomnia. Physiologic factors include recurrent

limbs shaking syndrome, legs impatience syn-

drome, difficulty breathing during sleep, narcolep-

sy, some central nervous system injuries and night-

time awakening because of twinges and surgical

operation.

An example of chronobiological factor includes

people who work at night or have night shifts. Be-

havioral factors are characterized by having poor

night routines such as going to bed too early and

reading or watching television at bed time in addi-

tion to regular intellectual activities near bedtime,

having a late meal in the evening, exposure to un-

healthy or noisy environment, sleeping after each

lunch and physical hyperactivity (7).

Consequences of insomnia

Insomnia is associated with psychiatric disorders

(most commonly depression and anxiety) (8) more

frequently than any other medical condition. Addi-

tionally, sleep loss increases obesity by increasing

appetite. Sleep loss results in high levels of ghrelin

(a peptide that stimulates appetite) and low levels

of leptin (a hormone produced by adipose tissues

that reduces appetite) (9). Other consequences of

insomnia are diabetes and impaired glucose toler-

ance. Sleep loss can increase sympathetic activity

4 Kuwait Pharmacy Bulletin Summer 2013

can result in respiratory depression and the sleep-

inducing efficacy may be lost with prolonged use

(13, 14).

Newer benzodiazepine-like agents

Zolpidem and zaleplon (Fig 4) act as agonists at

GABA receptors similar to classic benzodiaze-

pines and can be used for chronic and transient

insomnia. These benzodiazepine-like agents are

able to cause shortened sleep latency and might

lead to antegrade amnesia or idiosyncratic daytime

sleepiness, and they don’t block withdrawal from

benzodiazepines (13).

Ethanol

The most widely self-used hypnotic drug is etha-

nol. GABA receptors are important in mediating

the CNS effects of ethanol in addition to voltage-

gated calcium channels and ligand-gated ion chan-

nels. Chronic use of ethanol can lead to tolerance

and dependence. It can reduce the efficiency and

quality of sleep and increases the risk of severe day-

time sleepiness and lowers daytime alertness.

Sedating anti-histamines

Sedating anti-histamines, more often diphenhydra-

mine, are one of over-the-counter sleeping pills.

They block H1 receptors and can result in anti-

cholinergic effects that may affect driving perfor-

mance daytime sleepiness, cognitive and psychomo-

tor impairment; tolerance might be a result of these

agents. Moreover, the evidence for their efficacy and

safety is very limited and they are not recommended

for use in the elderly (13, 15).

Exogenous melatonin

This is an over-the-counter medication that is howev-

er not recommended in the treatment of chronic in-

somnia because of the lack of efficacy and safety da-

ta. Melatonin (Fig 5) is an endogenous hormone se-

creted by the pineal gland and is linked to the sleep

cycle. It is not effective in the management of most

primary sleep disorders with short term use. Trials

evaluated the efficacy of melatonin as a chronobiotic

(phase-shifting agent) rather than as a hypnotic.

Headaches, dizziness, nausea, and drowsiness are the

most common adverse effects (16, 17).

Chloral hydrate and barbiturates

Although FDA approved for use in treating insomnia,

chloral hydrate and barbiturates are not generally rec-

ommended because of their likelihood of tolerance

and dependence, adverse effects, low therapeutic in-

dex and loss of effects with chronic use (13, 17).

Antidepressants

Tricyclic antidepressants are mainly used for patients

with chronic insomnia with associated symptoms of

depression. Their limitations are overdose hazard

and daytime hangover, and anti-cholinergic effects

such as dry mouth, constipation, blurred vision, uri-

nary retention, postural hypotension and erectile dys-

function. Sedating tricyclic antidepressants include

amitriptyline, imipramine and nortriptyline.

Herbal remedies

A study published in Psychopharmacology in 2005

found that sleep-disturbed rats treated with 300 mg

kava kava extract experienced a significant shorten-

ing in the sleep latency cycle. Although further hu-

man trials are required, researchers noted that kava

Fig 3. Representative examples of benzodiazepines.

Fig 4. Structures of benzodiazepine-like agents

Vol 17, No 2 Drug Information For The Health Professional 5

kava possesses sleep-quality enhancement effects.

The University of Maryland Medical Center rec-

ommends taking 100-250 mg of standardized kava

extract up to three times per day as needed. An-

other herbal remedy is chamomile. Valerian is an-

other herb widely used as a sleep aid. The Univer-

sity of Maryland Medical Center recommends tak-

ing 200-400 mg of valerian standardized extract

before bed to promote sleep.

New approaches in treating insomnia

Due to limitations of current treatments of insom-

nia, novel hypnotic drugs with different mecha-

nisms of action and different targets for promoting

sleep have been developed; some of these are cur-

rently in phase II/III clinical trials. Of the thera-

peutic agents listed in Table 1, gaboxadol, indip-

lon, almorexant, agomelatine and esmirtazapine

are discussed in the following section.

Gaboxadol

Gaboxadol (Fig 5A) is a selective extra-synaptic

GABA-A receptor agonist (18). Its functional activi-

ty is highest for δ-containing GABA-A receptors

which exist mainly extra-synaptically and are local-

ized in the thalamus, cerebellum, dentate gyrus and

cortex. They are insensitive to traditional benzodiaz-

epine (e.g triazolam) and non-benzodiazepine (e.g

zolpidem) hypnot-ics. Gaboxadol improves sleep

quality and positively affects daytime performance in

primary insomniacs (1). When 15 mg of gaboxadol

was used in adult patients, it decreased the amount of

time spent in stage 1 sleep, had no significant effect

on stage 2 sleep, and increased the amount of time

spent in stages 3 and 4 sleep (19) and is generally

well tolerated. The most common drug-related ad-

verse experiences are dizziness, nausea, fatigue and

vomiting. The pharmacokinetic parameters for

gaboxadol showed that the mean t1/2 was 1.7 h, tmax

Drug name Pharmacological target Indication Development phase

Silenor H1/H2 antagonist, muscarinic antag-

onist

Sleep disorders Phase III

Indiplon GABA-A BZ-site modulator Sleep disorders Awaiting approval

Eplivanserin. SR 46349 5-HT-2A receptor antagonist Sleep disorders Phase III

Volinanserin. M-100907 5-HT-2A receptor antagonist Sleep disorders Phase III

VEC-162 Melatonin receptor agonist Sleep disorders, de-

pression

Phase III

Esmirtazapine. ORG

50081

Noradrenergic. Specific serotonener-

gic antidepressant

Sleep disorders, hot

flushes

Phase III

agomelatine 5-HT-2B/5-HT-2C antagonist, mela-

tonin agonist

Depression, Sleep

disorders

Phase III

Almorexant. ACT-

078573

OX1 and OX2 receptor antagonist Sleep disorders Phase III

Gaboxadol GABA-A receptors agonist Sleep disorders Phase III

PD-6735 Melatonin receptor agonist Sleep disorders Phase II

Pruvanserin. EMD

281014

5-HT-2A receptor antagonist Sleep disorders Phase II

APD-125 5-HT-2A inverse agonist Sleep disorders Phase II

ACP-103 5-HT-2A receptor inverse agonist,

dopamine D2/D3 receptor partial

agonist, acetylcholine M1 receptor

agonist.

Sleep disorder, anti-

psychotic-induced

side effects. Parkin-

son's disease.

Phase II

HY10275 5-HT-2A and H1 receptor inverse

antagonist

Sleep disorders Phase II

GW649868 Orexin receptor antagonist Sleep disorders Phase II

Adipiplon. NG-2-73 GABA-A BZ-site modulator Sleep disorders Phase II

EVT-201 GABA-A BZ-site modulator Sleep disorders Phase II

Table 1. Novel therapeutic agents for insomnia (Adapted from ref 1).

6 Kuwait Pharmacy Bulletin Summer 2013

was 2 h, AUC0–∞ was 430 ng·hml-1 and Cmax was

139 ng ml-1. The most notable difference in phar-

macokinetics was the slightly shorter apparent ter-

minal t1/2 for elderly women compared to men.

Regarding the renal excretion of gaboxadol, stud-

ies showed that an average of 58% of gaboxadol

was recovered intact in the urine and the rest as

glucuronide conjugate. The major metabolite ex-

creted in human urine was gaboxadol-O-

glucuronide (20, 21).

Indiplon

Indiplon (Fig 5B) is a pyra-

zolopyrimidine compound

(22); it is an agonist for

benzodiazepine receptors

and has high selectivity and

affinity for the α1-subtype

of the GABA-A receptor

complex. It improves sleep

onset, sleep duration and

maintenance, and overall sleep quality in primary

insomnia. Studies have shown that this improve-

ment in sleep was sustained across all 3 months of

study treatment with no change in response with

time. Indiplon also improves daytime functioning

and quality of life in patients with primary insom-

nia symptoms (23, 24).

There are two formulations for indiplon; Indiplon

-IR (immediate release), which was developed for

difficulties in sleep onset, and indiplon-MR

(modified release), which was intended for sleep

maintenance insomnia. Adverse effects include

upper respiratory infection, amnesia, dizziness,

headache and somnolence.

When compared with benzodiazepines, discon-

tinuation of indiplon was not associated with any

increase in benzodiazepine-like withdrawal symp-

toms (23, 24). For indiplon, healthy young males

have shown Cmax at 0.73h with elimination t1/2 of

1.97h, while females have reached Cmax at 0.82h

with elimination t1/2 of 1.71. In the elderly popula-

tion, impaired renal and hepatic functions can re-

sult in a 3-fold increase in plasma concentrations

of indiplon and a doubling of t1/2 compared to the

values seen in younger adults.

Two major metabolites, N-desmethyl-indiplon

and N-deacetyl-indiplon are observed. N-desmethyl-

indiplon is formed by the cytochrome P450 CYP-

3A4 and CYP1A2 metabolic pathways, while N-

deacetyl-indiplon is formed by microsomal carboxy-

lesterases (25).

Almorexant

A tetrahydroisoquinoline derivative (Fig 5C), Al-

morexant is an orally potent dual (OX1R/OX2R)

orexin receptor antagonist for the treatment of pri-

mary insomnia (26,27). Orexin (or hypocretin) sys-

tem exhibits a key role in the

physiological and emotional

responses that are associated

with wakefulness such as

stress processing, appetite and

energy expenditure (28).

Orexins originate from a

group of neurons in the lateral

hypothalamus projecting to

many of the ascending excita-

tory pathways. Orexinergic

neurons are active during periods of wake and inac-

tive during sleep; antagonising orexin activity by

almorexant has a sleep-promoting effect.

Almorexant can promote REM and NREM sleep

and decreases alertness (1, 27). Somnolence, fa-

tigue, headache and nausea are reported as adverse

effects. Muscular weakness was reported only with

the highest almorexant dose (29). There were no

significant effects on memory, motor performance,

mood, calmness, subjective internal and external

perception, and feeling high (29,30).

Almorexant is rapidly absorbed and distributed

and has no tendency to accumulate with dose repeti-

tion. Almorexant has a median time to the Cmax of

1.5h and a quick disposition with a distribution t1/2

of 1.6h. In addition, it has a rapidly decreasing con-

centration to approximately 20% of the Cmax over 8h

and a terminal t1/2 of 32h. After rapid absorption,

almorexant is metabolised extensively, and the pre-

dominant route of elimination in humans is excre-

tion of metabolites in faeces (26).

Agomelatine

Also known as S20098 this is a napthalenic com-

pound with structural similarities to melatonin (2).

The bioavailability of agomelatine is higher in

women compared to men and it is increased with

oral contraceptive intake and decreased with smok-

ing (31,32). Agomelatine (Fig 5D) is a melatonergic

Vol 17, No 2 Drug Information For The Health Professional 7

agonist that acts on MT1/MT2 melatonergic recep-

tors suppressing cAMP formation. Also, it acts as a

complementary 5-HT2C antagonist and it enhances

slow wave sleep without affecting REM sleep and

can be used to treat depression (1).

The most common adverse effects are headaches,

mild sedation and fatigue, dizziness and reversible

elevations in serum alanine and/or aspartate trans-

aminases. As a result, liver function tests should be

performed at the onset of treatment, and then peri-

odically at 6, 12 and 26 weeks. Hepatic impair-

ment is a contraindication. Unlike older agents,

agomelatine does not cause any withdrawal symp-

toms when discontinued. Agomelatine's therapeu-

tic doses range between 25-50 mg/day (33, 34). It is

absorbed rapidly from the gastrointestinal tract and

transported immediately to the liver where it is me-

tabolized by CYPA1, CYPA2 and CYP2C9 isoen-

zymes.

Four metabolites of agomelatine have been iden-

tified. These metabolites are excreted through

urine and faeces, and only low levels of unchanged

agomelatine are excreted. It has a short t1/2 of about

2h. Its dissociation constant for MT1/MT2 melato-

nin receptors is 10 nM which is similar to that of

melatonin (33,34).

Esmirtazapine

An antagonist on the presynaptic α2 adrenergic re-

ceptors as well as postsynaptic 5HT2 and H1 recep-

tors, esmirtazapine (Fig 5E) has higher affinity to 5-

HT2 receptors and low affinity to 5-HT3 receptors

when compared with mirtazapine and R-

mirtazapine. Racemic mirtazapine is used for the

treatment of major depressive disorder. Esmirtazap-

ine is in phase III clinical development for the treat-

ment of primary insomnia and hot flushes. Doses

when used for insomnia are lower than those pre-

scribed for depression. The effective sleep promot-

ing doses of esmirtazapine range between 1.5-

4.5 mg (36).

Somnolence and fatigue are the most frequently

reported adverse events. Esmirtazapine has a long

t1/2 of 20h which raises the issue of residual daytime

drowsiness and driving impairment. Studies support

the notion that dose effects of esmirtazapine on

driving are related to the drug's concentration in

plasma. Esmirtazapine is metabolized through cyto-

chrome P450 CYP2D6 in the liver by demethylation

and hydroxylation and formation of S(+)-N-

desmethylmirtazapine and S(+) -8 hydroxymirtazap-

ine, followed by glucuronide conjugation. Its clear-

ance in poor metabolisers is twice lower when com-

pared to extensive metabolisers (36).

Conclusion

Using herbals and natural drugs to treat insomnia is

rarely effective. In addition, the side effects of the

current medications for insomnia necessitate the de-

A) aboxadol

B) indiplon

C) almorexant

D) agomelatine

E) esmirtazapine

Fig 5. Novel therapeutic agents for insomnia

8 Kuwait Pharmacy Bulletin Summer 2013

Ameena Al Marjan

Final Year student, 2013

Faculty of Pharmacy,

Kuwait University

velopment of new agents. Novel drugs including

gaboxadol, indiplon, almorexant, agomelatine, and

esmirtazapine have reached phase III clinical trials

and some are awaiting approval; these exhibit bet-

ter safety profiles and lesser side effects and with-

drawal symptoms. They have variable pharmacoki-

netic properties as some of them have short t1/2 and

some have long t1/2. They act on different receptors

and by different mechanisms and some of them can

be also used in other depressive disorders.

References

1. Wafford, K. A., & Ebert, B. (2008). Nature Rev Drug Disc

7(6), 530-540.

2. Brand, S., & Kirov, R. (2011). Int J Gen Med 4, 425–442.

Retrieved from http://www.ncbi.nlm.nih.gov/pmc/

articles/PMC3119585/

3. Colten, H. R., & Altevogt, B. M. (2006). Sleep Physiolo-

gy. Sleep disorders and sleep deprivation: an unmet pub-

lic health problem (pp. 33-53). Washington, DC: Institute

of Medicine.

4. Purves D, Augustine GJ, Fitzpatrick D, et al., editors.

Neuroscience. 2nd edition. Sunderland (MA): Sinauer

Associates; 2001. Stages of Sleep. Available from: http://

www.ncbi.nlm.nih.gov/books/NBK10996/

5. Imeri, L., & Opp, M. R. (2009). Nature Rev Neurosci, 10

(3), 199-210.

6. Golestan, B., Mousavi, F., Iran-Pour, et al. (2012). Iran J

Public Health, 41(1), 96–106. Retrieved from http://

www.ncbi.nlm.nih.gov/pmc/articles/PMC3481663/

7. Dollander, M. (2002). [etiology of adult insomnia]. 28(6

Pt1),493-502. Retrieved from http://www.ncbi.nlm.nih.

gov/pubmed/12506261

8. Roth, T. (2007). J Clin Sleep Med, 3(5), S7–S10. Spiegel,

K., Tasali, E., Penev, P., et al. (2004). Ann Intern Med,

141(11), 846-50.

9. Gottlieb, D. J., Punjabi, N. M., Newman, A. B., et al.

(2005). Arch Intern Med 165(8), 863-867.

10. Irwin, M. (2002). Brain, Behavior, and Immunity, 16(5),

503-512.

11. Möhler, H. (2002). Dialogues in Clinical Neuroscience, 4

(3), 261-269.

12. Pagel, J. F., & Parnes, B. L. (2001). Prim Care Compa-

nion J Clin Psychiatry, 03(03), 118-125. Blais, D., &

Petit, L. (1990). Can Fam Physician, 36, 1779–1782.

Retrieved from http://www.ncbi.nlm.nih.gov/pmc/

articles/PMC2280531/

13. Saddichha, S. (2010). Ann Indian Acad Neurol, 13(2), 94

14. Buscemi, N., Vandermeer, B., Hooton, N., et al. (2005). J

Gen Intern Med, 20(12), 1151-1158. Schutte-Rodin, S.,

Broch, L., & Buysse, D. (2008). J Clin Sleep Med, 4(5),

487–504.

15. Gaboxadol - PubChem. (n.d.). The PubChem Project.

2013, from http://pubchem.ncbi.nlm.nih.gov/summary/

summary.cgi?cid=3448&loc=ec_rcs

16. Lankford, D. A., Corser, B. C., & Zheng, Y. P., et al.

(2008). Sleep, 31(10), 1359–1370. Retrieved from http://

www.ncbi.nlm.nih.gov/pmc/articles/PMC2572741/

17. Boyle, J., Danjou, P., Alexander, R.,et al. (2009). Brit J

Clin Pharmacol, 67(2), 180-190.

Retrieved from PMC database.

21. Larsen, M., Holm, R., & Brodin, B. (2009). Br J Pharma-

col, 157(8), 1380–1389. Retrieved from http://

www.ncbi.nlm.nih.gov/pmc/articles/PMC2765307/

22. Indiplon Supplier | CAS 325715-02-4 | Tocris Bioscience |

NBI 34060. (n.d.). Tocris Bioscience | High Performance

Life Science Reagents. Retrieved May 9, 2013, from http://

www.tocris.com/dispprod.php?ItemId=230813

#.UaC3z6y61EN

23. Scharf, M. B., Black, J., & Hull, S. (2007). Sleep, 30(6),

743–752. Retrieved from http://www.ncbi.nlm.nih.gov/

pmc/articles/PMC1978349/

24. Lankford, A. (2007). Neuropsychiatr Dis Treat, 3(6), 765–

773. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/

articles/PMC2656319/

25. Gryskiewicz, K. A., & Semanco, M. (2006). Formulary,

41, 316-321. Retrieved from http://formularyjournal. mo-

dernmedicine.com/formulary-journal/news/clinical/clinical

-pharmacology/indiplon-short-acting-gaba-receptor-

agonist-se

26. Dingemanse, J., Hoever, P., & Hoch, M., et al. (2013).

Drug Metab Dispos, 41(5), 1046-59. Retrieved from http://

www.ncbi.nlm.nih.gov/pubmed/23431113

27. Neubauer, D. (2010). Curr Opin Investig Drugs, 11(1),

101-10. Retrieved from http://www.ncbi.nlm.nih.gov/

pubmed/20047164.

28. Steiner, M. A., Lecourt, H., & Strasser, D. S., et al. (2011).

Neuropsychopharmacology, 36(4), 848–856. Retrieved

from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055

7 32/

29. Hoever, P., Hay, J., Rad, M., et al. (2013). J Clin Psycho-

pharmacol, 33(3), 363-70.

30. Owen, R., Castañer, R., Bolos, J., & Estivill, C. (2009).

Almorexant. Drugs of the Future, 34(1), 5.

31. Venkat Rao, P., Prabhakar, T., & Ramakrishna, S. (2010).

Research Journal of Pharmaceutical, Biological and

Chemical Sciences, 1(2), 446- 450. Retrieved from http://

www.rjpbcs.com/pdf/Old files/63.pdf

32. Cayman Chemical. (2011, February 12). Agomelatine item

no. 13203. Retrieved from https://www.cayma nchem.c

om/pdfs/13203.pdf

33. de Bodinat, C., Guardiola-Lemaitre, B., & Mocaër, E., et

al. (2010). Nat Rev Drug Discov, 9(8), 628--642. Retrieved

from http://www.ncbi.nlm.nih.gov/pubmed/2057 7266

34. Srinivasan, V., Zakaria, R., & Othman, Z. (2012). J Neu-

ropsychiatry Clin Neurosci, 24(3), 290-308. Retrieved

from http://www.ncbi.nlm.nih.gov/pubmed/23037643

35. Vanover, K. E., & Davis, R. E. (2010). Nat Sci Sleep, 2,

139–150. Retrieved from http://www.ncbi.nlm.nih.gov/

pmc/articles/PMC3630942/

36. Ramaekers, J. G., Conen, S., & Braat, S., et al. (2011).

sychopharmacology, 215(2), 321–332. Retrieved from

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083504/

Vol 17, No 2 Drug Information For The Health Professional 9

Household cleaning products may contain toxic

substances linked to health problems such as asth-

ma, allergic reactions, and cancer, according to a

report by the US Environmental Working Group

(EWG).

They rated more than 2,000 household cleaners -

from laundry soaps and stain removers to bath-

room cleaners and floor care products. Products are

graded A to F based on the safety of the ingredi-

ents and how well the maker discloses those ingre-

dients.

One industry trade group disputes the findings

though, saying the report doesn't make the grade.

According to the EWG report, more than half the

products evaluated contain ingredients known to

harm the lungs. In other cases, it was difficult to

determine what was in the product because of in-

complete labeling.

Ninety-three percent [of the products] provided in-

gredient lists that were incomplete or not specific

enough. Few 'green' brands were still reticent about

their ingredients.

Cleaning products are largely unregulated. Some

cleaning products did get high marks. Among the

many products that received an A rating:

Whole Foods Market green MISSION Organic

Answers to MCQs on back page TEST YOUR KNOWLEDGETEST YOUR KNOWLEDGETEST YOUR KNOWLEDGE

1) Which of the following is a sleep promoting

neurotransmitter?

a) serotonin b) galanine c) noradrenaline d) dopamine e) histamine 2) Which of the following develops with prolonged use

of benzodiazepines?

a) amnesia b) tolerance c) physical dependence d) psychological dependence e) all of the above 3) Which of the following is a GABA-A BZ site modulator

awaiting approval for indication in sleep disorders?

a) agomelatine b) esmirtazapine c) gaboxadol d) indiplon e) almorexant

Is there a problem? A 56 year old patient was

prescribed the drug given in

the prescription for

hypertension. Is there any

error? major

KLM HOSPITAL

Patient Name: Mr. Ahmad Ali Age: 56 years

Address: Street No. 7

Rx

Nifedipine 5mg tablet

One tablet three times a day

Send one pack

Dr. MXD

Signature Date: 15/06/13

Answer (Prescription Exercise) Immediate release nifedipine is

not recommended for hyperten-

sion. Modified release nifedipine

is recommended for treatment of

hypertension.

Example: Adalat LA® (nifedipine) 20-30mg

once daily, maximum dose 90mg once daily.

(Source: British National Formulary)

TOPICAL ISSUES AND CONTROVERSIESTOPICAL ISSUES AND CONTROVERSIESTOPICAL ISSUES AND CONTROVERSIES

Toxins in cleaning products?Toxins in cleaning products?Toxins in cleaning products?

10 Kuwait Pharmacy Bulletin Summer 2013

All-Purpose Spray Cleaner & Degreaser, Lem-

on Zest for general cleaning

Arm & Hammer Baking Soda for general

cleaning

Seventh Generation National Tub &Tile

Cleaner,

Emerald Cypress & Fir

Green Shield Organic toilet bowl cleaner

The Honest Co. auto dishwasher gel, free &

clear

EWG Guide: Details EWG scientists compared the ingredients listed on

the labels of cleaning products and manufacturers'

web sites with information from toxicity databases

from government, industry, and academic sources.

They looked at medical literature on health and

environmental problems linked with cleaning

products.

Among the key findings, according to EWG:

About 53% of the products had ingredients

known to harm the lungs. Examples are ben-

zalkonium chloride, found in antibacterial

cleaners, and chlorine bleach.

About 22% had chemicals linked with asthma

in previously healthy people.

Some products use formaldehyde, a known hu-

man carcinogen, as a preservative, or it is re-

leased by other preservatives in the products.

The chemical 1,4-dioxane, suspected of being a

human carcinogen, is a common contaminant of

detergent chemicals.

Chloroform, also a suspected carcinogen, can

escape in fumes released by products contain-

ing chlorine bleach.

Sodium borate, sometimes called borax or boric

acid, is added

to many prod-

ucts. It can be

a hormone

disrupter

EWG scien-

tists suggest

entirely

avoiding

some prod-

ucts because

of ingredients. These include air fresheners, anti-

bacterial products, fabric softeners, and caustic

drain cleaners and oven cleaners.

EWG said even some ''green brands'' could do better

on disclosing ingredients. Among them: Earth

Friendly Products and BabyGanics. A spokeswom-

an for BabyGanics, said it was unfortunate that the

EWG deemed their descriptions inadequate. She

noted “one problem is a lack of uniform industry

standards. All BabyGanics products contain ingredi-

ent statements, including our household, hand hy-

giene, diapering, skin care, sun care, and oral care

solutions. The household product category remains

the only one that still does not have a uniform set of

industry standards."

It is a fact that anything can be safe or unsafe- it

all depends on the amount. Manufacturers work to

ensure that they use levels of ingredients that are

'just right' - in that they provide a benefit in the

products, but at the same time are safe. One option

is to make your own cleaning products from white

vinegar and water.

Adapted from www.medscape.com/viewarticle/770678?

src=nldne

Drug safety standards: need for transparency Drug safety standards: need for transparency Drug safety standards: need for transparency

Historically, the evaluation of harmful effects re-

sulting from prescription drug use has been con-

sidered less important than demonstrating drug

efficacy, yet the harms caused by specific adverse

drug reactions are a major, and avoidable, contrib-

utor to hospitalizations and deaths.

There are many reasons (both scientific and so-

cial) why reliable data on harmful effects may on-

ly emerge well after drug approval and marketing.

Drugs approved under a rapid regulatory review

process may be more likely to show problems with

safety post-marketing than drugs that go through a

slower evaluation process. And debates continue

about the best ways to meaningfully synthesize and

interpret data on the possible harmful effects of

drugs—for example, how passive surveillance sys-

tems (spontaneous reports of suspected adverse re-

actions) should be improved, whether new drugs

should go through a phased launch process with en-

hanced safety evaluations, and whether risk mitiga-

Vol 17, No 2 Drug Information For The Health Professional 11

tion strategies are appropriate for drugs with safe-

ty concerns.

One such debate- whether systematic reviews esti-

mating the risk of harmful effects should use evi-

dence from randomized trials or observational

studies- seems finally to have been laid to rest. In

a systematic overview, the authors demonstrate

that, for 19 specific drug–harm relationships, the

evidence on magnitude of risk for each particular

harm discovered through systematic reviews of

randomized trials was, on average, no different

from the evidence assembled via systematic re-

views of observational studies.(Golder et al (2011)

PLoS Med 8(5): e1001026) This is an important find-

ing. The implications of this study for future eval-

uations of drug safety are clear: systematic re-

viewers should consider all types of evidence in

trying to build a complete picture of harms associ-

ated with drug treatments.

Passive surveillance is still crucial for providing

early warning signals and generating new hypoth-

eses about possible harms associated with specific

approved drugs. However, new hypotheses emerg-

ing from such surveillance must subsequently be

explicitly tested, preferably using study designs

that can incorporate data on the size of the ex-

posed population (such as cohort or record linkage

studies). Such studies can therefore estimate the

relative increase in risk associated with exposure,

which is difficult or impossible to calculate from

passive surveillance data.

A new initiative established by the European

Medicines Agency (ENCEPP, the European Net-

work of Centres for Pharmacoepidemiology and

Pharmacovigilance) seeks to promote the conduct

of such studies and establish standards for post-

marketing safety evaluations.

Given the diversity of designs and multiple pos-

sible sources of bias in pharmacoepidemiology,

this will not be an easy job. But the initiative is

already showing signs of setting high standards in

some areas.

Studies conducted solely by industry will not be

eligible to qualify for ENCEPP approval; studies

must be publicly registered before collection of data,

and protocols and datasets must be released (with

some restrictions relating to data privacy) in a timely

way after completion. Critically, ENCEPP can still

potentially approve studies funded by the pharma-

ceutical industry, with involvement of industry part-

ners in design and analysis, providing the study's

lead investigator is based within an ENCEPP-

approved center. More worryingly, the code allows

for industry sponsors to retain control of datasets;

this, and other provisions, may enable conflicts of

interest to creep in during study design or data analy-

sis.

Clearly, for post-approval safety studies, one size

will not fit all. Conduct and reporting are unlikely to

be standardisable in the same way as has been possi-

ble for randomized trials, in which there is agreement

on what information needs to be registered about the

study and when, and specific standards for the re-

porting of studies are widely accepted. The ENCEPP

guidance avoids normative statements about study

design, instead preferring to highlight the methodo-

logical challenges and multiple sources of bias that

plague analysis and interpretation of data. However,

these challenges should not discourage investigators,

regulators, and patients from demanding a higher

safety standard for approved drugs.

Higher standards will require both greater transpar-

ency- in revealing what studies are being conducted

and what data that have been generated- and greater

willingness of funders to support new studies specifi-

cally addressing drug safety.

Source: The PLoS Medicine Editors (2011) Why Drug Safety

Should Not Take a Back Seat to Efficacy. PLoS Med 8(9):

e1001097.

Eyes grown from stem cellsEyes grown from stem cellsEyes grown from stem cells

With the proper culture conditions, mouse embry-

onic stem (ES) cells can spontaneously form the

rudiments of a retina. The results, published in

Nature, could help researchers answer some out-

standing questions about eye development and

dysfunction, and hold promise for the development

of retinal tissues for transplantation.

For the last decade, developmental biologist

Yoshiki Sasai at the RIKEN

Center for Developmental Biolo-

gy in Japan and his colleagues have worked to differ-

entiate ES cells into various cells of the nervous sys-

tem, including cerebral cortex neurons and retinal

cells. They were interested in more than just generat-

ing different nerve cells and wanted to learn how

those cells come together to form entire tissues and

12 Kuwait Pharmacy Bulletin Summer 2013

organs in developing embryos. Starting with the

culture conditions they had established for retinal

differentiation, the researchers added matrix pro-

teins that they hoped would encourage the for-

mation of the more rigid retinal epithelial struc-

tures. They then seeded the culture with mouse ES

cells.

Within a week, the cells formed small vesicles

and differentiated into two different tissue types:

Cells on one side of the vesicles formed the me-

chanically rigid pigment epithelium, while cells on

the other side differentiated into a more flexible

tissue that folded inward in the shape of an embry-

onic optic cup- the retina's precursor.

The biggest surprise was that we observed the

formation of the very real optic cup structure that

mimicked both the shape and tissue composition

and popped out from the [ES cell] aggregate.

The generation of retinal tissue from ES cells is

an exciting advance that may lead to regenerative

medicine applications. While doctors are not about

to start transplanting these synthetic retinas, ES cells

cultured under the proper conditions could yield cer-

tain cells that may prove therapeutically valuable.

The system might help answer how ES cells self-

organize into the complex retinal tissues. While the

retinal structures cultured in this study only devel-

oped into neonatal mouse retinas, which still lack

photoreceptor cells, it will likely just take a few

tweaks to the culture conditions to coax those struc-

tures into mature retinas, allowing researchers to ex

amine the entire process.

Furthermore, if researchers can replicate the results

using human induced pluripotent stem (iPS) cells, it

could shed light on retinal dysfunction. By creating

iPS cells from patients with [visual disorders] and

then making synthetic retinas from such iPS cells,

we could potentially study the disease process

caused by particular genetic defects.

Source: http://www.the-scientist.com/news/display/58105/

NEWS from the FDA NEWS from the FDA NEWS from the FDA

Using innovative technologies and other conditions of safe use to expand which drug products can be con-sidered nonprescription

FDA held a public hearing, in March 2012, to ob-

tain input on a potential new paradigm under

which FDA would approve certain drugs that

would otherwise require a pre-

scription for nonprescription use

under conditions of safe use spe-

cific to the drug product.

A. Prescription and nonpre-scription drugs

Prescription drugs are dispensed

upon receipt of a prescription

from a practitioner licensed by

law to administer the drug (which may include

health care professionals such as physicians, nurse

practitioners, physician's assistants, and others

whom we will refer to here as practitioners or pre-

scribers). In many instances, under the current reg-

ulatory system, a patient has to obtain at least the

initial prescription, and in some cases, prescription

refills, from a practitioner through an in person inter-

action. Obtaining a refill for other prescription drugs

involves at least a telephone call or other communi-

cation with the practitioner. In con-

trast, nonprescription drugs

(sometimes referred to as over-the-

counter or OTC products) can be

purchased by consumers in pharma-

cies, supermarkets, and other retail

establishments without the need for

a prescription.

Currently, consumers can pur-

chase nonprescription drugs from a

retailer for diseases or conditions that do not meet

the statutory criteria for prescription products and

that are safe and effective for use in self-medication

as directed in the labeling. Generally, OTC products:

(1), Are available to treat diseases or conditions that

can be self-diagnosed without a prior interaction

with a practitioner (2), are not associated with toxici-

Vol 17, No 2 Drug Information For The Health Professional 13

ties that require an evaluation of the benefits and

risks by a practitioner and (3), do not require a

practitioner's input for use.

B. Under-treatment of diseases and other effects on the health care system Under-treatment of many common diseases or

conditions in the US is a well-recognized public

health problem. Increasing the number of people

who are able to obtain for the first time and those

who continue on necessary drug therapy could

provide improved health outcomes.

The requirement to obtain a prescription for ap-

propriate medication (and to make one or more

visits to a practitioner) may contribute to under-

treatment of certain common medical conditions

including hyperlipidemia (high cholesterol), hy-

pertension (high blood pressure), migraine head-

aches, and asthma. For instance, some consumers

do not seek necessary medical care, which may

include prescription drug therapy, because of the

cost and time required to visit a health care practi-

tioner for an initial diagnosis and an initial pre-

scription. Some patients who obtain an initial pre-

scription do not continue on necessary medication

because they would need to make additional visits

to a health care practitioner for a prescription refill

after any refills authorized by the initial prescrip-

tion have been used or the time during which they

can be filled has expired. Some prescription medi-

cations require routine monitoring through the

prescribing practitioner such as blood tests to as-

sist in the diagnosis of a condition, or to determine

whether or how well

the medication is

working, or to adjust

the dose.

In addition to im-

proved health out-

comes for consumers

staying on their medi-

cations, the time and

attention that physi-

cians and other health

care providers ex-

pend on routine tasks related to prescription refills

reduces the time that they are available to attend

to more seriously ill patients. Eliminating or re-

ducing the number of routine visits could free up

prescribers to spend time with more seriously ill

patients, reduce the burdens on the already over-

burdened health care system, and reduce health care

costs.

FDA is aware that industry is developing new tech-

nologies that consumers could use to self-screen for

a particular disease or condition and determine

whether a particular medication is appropriate for

them. For example, kiosks or other technological

aids in pharmacies or on the Internet could lead con-

sumers through an algorithm for a particular drug

product.

Some drug products that would otherwise require a

prescription could be approved as nonprescription

drug products with some type of pharmacist inter-

vention as their condition of safe use. For example,

some diseases or conditions might require confirma-

tion of a diagnosis or routine monitoring using a di-

agnostic test (e.g., a blood test for cholesterol levels

or liver function) that could be available in a phar-

macy. A pharmacist, or consumer, could then use the

results to determine whether use of a certain drug

product is appropriate. Other potential roles for the

pharmacist include assessing whether the consumer

has any conditions or other risk factors that would

indicate that the drug should not be used, or assisting

the consumer in choosing between various drug

products. For drugs that require use of a diagnostic

test, creating a pathway for nonprescription use may

result in the development by industry of diagnostics

suitable for use by the patient or a pharmacy profes-

sional.

FDA is also considering whether the same drug

product could be simultaneously available as both a

prescription and nonprescription product with condi-

tions of safe use. Dual availability could

help ensure greater access to needed medi-

cations by making obtaining them more

flexible. Consumers could choose to con-

tinue seeing their health care practitioner

to diagnose diseases or conditions and ob-

tain prescriptions, and when their local

retail establishment is not equipped to of-

fer the nonprescription product with con-

ditions of safe use. Other consumers could

take advantage of the ability to obtain non-

prescription products with conditions of safe use

where they are available.

Source: https://www.federalregister.gov/articles/2012/02/28/

2012-4597/using-innovative-technologies-and-other-conditions

-of-safe-use-to-expand-which-drug-products-can-be

14 Kuwait Pharmacy Bulletin Summer 2013

In February 2012 the US FDA issued three draft

guidance documents on biosimilar product devel-

opment to assist industry in developing such prod-

ucts in the US.

These draft documents are designed to help in-

dustry develop biosimilar versions of currently ap-

proved biological products, which can enhance

competition and may lead to better patient access

and lower cost to consumers.

The Patient Protection and Affordable Care Act,

signed into law by President Obama on March 23,

2010, amended the Public Health Service Act to

create an abbreviated approval pathway for biolog-

ical products that are demonstrated to be highly

similar (biosimilar) to or interchangeable with an

FDA-licensed biological product.

Biological products are therapies used to treat

diseases and health conditions. They include a

wide variety of products including vaccines, blood

and blood components, gene therapies, tissues and

proteins. Unlike most prescription drugs made

through chemical processes, biological products

are made from human and/or animal materials.

A biosimilar is a biological product that is highly

similar to an already approved biological product,

notwithstanding minor differences in clinically in-

active components, and for which there are no clin-

ically meaningful differences between the biosimi-

lar and the approved biological product in terms of

the safety, purity, and potency.

Through this new approval pathway, biological

products are approved based on demonstrating they

are biosimilar to, or interchangeable with, a biolog-

ical product that is already approved by the FDA,

which is called a reference product.

The following three guidance documents provide

the FDA’s current thinking on key scientific and

regulatory factors involved in submitting applica-

tions for biosimilar products to the agency. FDA is

seeking public comment on these draft guidance

documents:

Scientific considerations in demonstrating bio-

similarity to a reference product The draft guidance is intended to assist companies

in demonstrating that a proposed therapeutic pro-

tein product is biosimilar to a reference product for

the purpose of submitting an application to the

FDA. This draft guidance describes a risk-based

“totality-of-the-evidence” approach that the FDA

intends to use to evaluate the data and information

submitted in support of a determination of biosimi-

larity of the proposed product to the reference prod-

uct. As outlined in the draft guidance, FDA recom-

mends a stepwise approach in the development of

biosimilar products.

Quality considerations in demonstrating biosimi-

larity to a reference protein product

The draft guidance provides an overview of analyti-

cal factors to consider when assessing biosimilarity

between a proposed therapeutic protein product and

a reference product for the purpose of submitting

the appropriate application. This includes the im-

portance of extensive analytical, physico-chemical

and biological characterization in demonstrating that

the proposed biosimilar product is highly similar to

the reference product notwithstanding minor differ-

ences in clinically inactive components.

Biosimilars: questions and answers regarding im-

plementation of the biologics price competition

and innovation act of 2009

The draft guidance provides answers to common

questions from people interested in developing bio-

similar products. The question and answer format

addresses questions that may arise in the early stag-

es of product development, such as how to request

meetings with the FDA, addressing differences in

formulation from the reference product, how to re-

quest exclusivity, and other topics.

Adapted from: http://www.fda.gov/NewsEvents/Newsroom/

PressAnnouncem ents/ucm291232.htm

FDA issues draft guidance on biosimilar product development

Vol 17, No 2 Drug Information For The Health Professional 15

STATE OF KUWAITSTATE OF KUWAITSTATE OF KUWAIT Pharmaceutical & Herbal Medicines Control and Registration AdministrationPharmaceutical & Herbal Medicines Control and Registration AdministrationPharmaceutical & Herbal Medicines Control and Registration Administration

Abilify Oral Solution. 1mg/ml; Aripiprazole-1mg; Bristol Myers Squibb Co. U.S.A.

Abraxane for Injectable Suspension 100mg (albumin-bound); Paclitaxel-100mg, Human Albumin-900mg;

Abraxis Bioscience LLC - U.S.A.

Asitalox Tablets 10, 20mg; Escitalopram-10, 20mg; Aurobindo Pharma Ltd - India

Aurotaz P 4.5g Injection; Piperacillin -4g, Tazobactam -0.5g; Aurobindo Pharma Ltd.- India

Avocom Aqueous Nasal Spray 0.05%; Mometasone Furoate-50µg; Middle East Pharma Ind. Co. Ltd. -

K.S.A.

Calciferol Biotika Forte Solution for Infusion 300,000 IU (7.5mg);Ergocalciferolum-300,000IU; Biotika

Bohemia, spol.s.r.a

Danzen Tablets 5mg; Serratiopeptidase 5mg; APM Co. Ltd.- Jordan

Elaprase Solution for IV Infusion 6mg/3ml; Idursulfase 6mg/3ml; Shire Human Genetic Therapies Inc-

U.S.A.

Eliquis Tablets 2.5mg; Apixaban-2.5mg; Bristol Myers Squibb/Pfizer EEIG- U.K.

Floratil Capsules 250mg; Saccharomyces boulardii-250mg; Merck KgaA- Germany

Floratil Powder for Oral suspension. Sachet 250mg; Saccharomyces boulardii 250mg; Merck KgaA-

Germany

Gaviscon Advance Peppermint Flavour Oral Suspension; Sodium Alginate-1000mg, Potassium hydrogen

carbonate 200mg; Reckitt Benckiser- U.K.

Gemcitabine Ebewe Concentrate for solution for Infusion 1000mg/25ml; Gemcitabine-1000mg; Ebewe

Pharma Ges m.b.H NFGKG- Austria

Gemcitabine Ebewe Concentrate for solution for Infusion 2000mg/50ml; Gemcitabine-2000mg; Ebewe

Pharma Ges m.b.H NFGKG- Austria

Gemcitabine Ebewe Concentrate for solution for infusion 200mg/5ml; Gemcitabine-200mg; Ebewe Phar

ma Ges m.b.H Nfg KG

GETZ Freeze Dried for Injection 200mg, 1g; Gemcitabine 200mg, 1g; Lab Richmond S.A.C.I.F-

Argentina

Glitra Tablets 1,2,4mg; Glimepiride 1,2,4mg; JPM- Jordan

Glypride Tablets 1,2,3,4mg; Glimepiride-1,2,3,4mgJulphar; Gulf Pharmaceutical Industries (Julphar)

U.A.E.

Hibiotic Tablets 1g; Amoxicillin Anhydrous-875mg, Clavulanic Acid-125mg; Amoun Pharmaceutical

company - Egypt

Kardam Tablets 5mg; Amlodipine-5mg; Aurobindo Pharma Ltd - India

Klar Tablets 250,500mg; Clarithromycin 250,500mg; Aurobindo Pharma Ltd.- India

Lanzopral Capsules 15mg; Lanzoprazole 15mg; Ram pharm Ind. Co. Ltd. - Jordan

Levox Infusion IV; Levofloxacin Hemihydrate 500mg; Claris Lifesciences Ltd.- India

Loratadina Korhispana 10mg Tablets; Loratadine-10mg; Lab. Korhispana- Spain

Lorinase Tablets; Loratadine 5mg Pseudoephedrine 120mg; Spimaco - K.S.A.

Lorvas SR Tablets 1.5mg; Indapamide-1.5mg; Torrent Pharma Ltd.- India

Meropenem powder for Solution for Injection/Infusion 500mg,1g; Meropenem 500mg,1g; Hospira U.K.

Ltd. – U.K.

MF-Day Tablets 500,850mg; Metformin-500,850mg; Aurobindo Pharma Ltd.- India

Modiodal Tablets 100,500mg; Modafinil-100,500mg; Cephalon France- France

Mofetab Tablets 500mg; Mycophenolate Mofetil 500mg; Tabuk Pharmaaceutical company- K.S.A.

Ozurdex Intravitreal Implant in applicator 700mcg; Dexamethasone 700mcg; Allergan Pharmaceuticals -

Ireland

New Pharmaceutical products approved from January to May 2013

16 Kuwait Pharmacy Bulletin Summer 2013

Answers to: Test your knowledgeAnswers to: Test your knowledgeAnswers to: Test your knowledge Correct answers:

1-b; 2-e; 3-d

The Kuwait Pharmacy Bulletin (ISSN 1028-0480) is published quarterly by the Faculty of Pharmacy, Kuwait University, and includes a list of recently approved drugs from the MOH. It aims to provide instructive reviews and topical news items on a range of drug related issues. It is widely distributed free within the university, to hospitals, polyclinics & private pharmacies as well as to other universities within the Gulf & Middle East region.

The information in this bulletin does not necessarily reflect the views of the editorship, nor should it be taken as an endorsement of any product that is mentioned herein. Articles are generally adapted from literature sources and rewritten or occasionally reproduced with permission from the appropriate sources. Readers wishing their own copy may ask to be added to the mailing list by contacting the Executive Editor. Executive Editor: Yunus Luqmani. Assistant Editors: Leyla Hasan Sharaf, Samuel Koshy

Editorial Office: Faculty of Pharmacy, Health Sciences Centre, Kuwait University, PO Box 24923 Safat, 13110 Kuwait, Fax:25342087; email: yunus@hsc.edu.kw

Panadol Extra with Optizorb; Paracetamol-500mg, Caffeine-65mg; GSK Consumer Healthcare Ltd.-

Ireland

Panadol Woman tablets; Paracetamol 500mg, Caffeine 65mg; GSK Euport Ltd.- U.K.

Paracetamol Kabi Solution for Infusion 1000mg/100ml; Paracetamol-1000mg; Fresenius Kabi- Germany

Paracetamol Kabi Solution for Infusion 500mg/50ml; Paracetamol-500mg; Fresenius Kabi- Germany

Pedovex Tablets 75mg; Clopidogrel 75mg; Tabuk- K.S.A.

Pentasa Tablets 1g; Mesalazine-1000mg; Ferring GmbH- Germany

Perjeta Concentrate for Solution for Infusion 420mg/14ml; Pertuzumab-420mg; Roche Pharmaceutic

(Schweiz) Ltd.- Switzerland

Prila Cream 5% w/v; Lidocaine-25mg, Prilocaine-25mg; Middle East Pharma Ind. Co. Ltd. - K.S.A.

Rebif Solution for Injection 66,132µg; Interferon Beta-1 66, 132µg ; Merck Serono Europe Ltd. - U.K.

Recozin Tablets 10mg; Cetirizine HCl-10mg; Plethico Pharma- India

Resicalm Tablets 2mg; Risperidone-2mg; Aurobindo Pharma Ltd. - India

Resolor Tablets 1,2mg; Prucalopride-1,2mg; Janssen-Cilag Int. N.V.- Belgium

Silosin Capsules 4,8mg; Silodosin-4,8mg; Algorithm S.A.L. - Lebanon

Sodium Chloride Injection USP 23.4%; Sodium Chloride-234g/L; Qatar Pharma-Qatar

Somazina 500,1000mg Oral Solution for Injection.; Citicoline-500,1000mg; Ferrer International S.A.-

Spain

Tacroz Ointment 0.03%; Tacrolimus-0.3mg; Glenmark Pharma Ltd.- India

Tetraspan Solution for Infusion 10%; Hydroxyethyl starch solution; B. Braun Melsungen AG- Germany

Ultrasolv Syrup; Oxomemazine-2mg, Carbocysteine-125mg, Guaifenesin-100mg; Amoun Pharma- Egypt

Vimovo MR Tabs 500/20mg; Naproxen-500mg, Esomeprazole-20mg; Astra Zeneca- Sweden

Water for Injection B.P; Sterilized distilled water -1ml; KSPICO- Kuwait

Wilate Powder & Solvent for Soln. for Inj. 500, 1000 IU Human Coagulation factor VIII; Human Von

willebrand factor– 500, 1000 IU; Octapharma Pharmazeutika Produktionsges GmbH- Austria

Xalexa Tablets 20mg; Paroxetine; Aurobindo Pharma Ltd - India

Zithrova Capsules 250mg; Azithromycin-250mg; Oman Pharma- Sultanate of Oman