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.
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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: [email protected]
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