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Kuwait Pharmacy Bulletin DRUG INFORMATION FOR THE HEALTH PROFESSIONAL

Vol 17. No 2 Summer 2013 ISSN 1028-0480

New approaches towards treatment of

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 (stage 3 and 4). Several control the sleep process including: , noradrenaline, , , hypocretin, , 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 , physiological factors, chronobiological factors social factors such as divorce and being widowed and be- havioural factors. Insomnia, if not treated, may result in depression, , obesity, diabetes and impaired glucose tolerance, increased susceptibility to pathogens, compromised work productivity and increased risk of accidents. Current pharmacological treatments include and newer -like agents including and , , , exogenous , hydrate, and sedating anti-. These drugs have several limitations that necessitate the devel- opment of new drugs for the treatment of insomnia.

Sleep cycle The average length of the first NREM-REM sleep Brain activity can be recorded by EEG during cycle is 70-100 min with 75-80% in NREM, and 20- wakefulness and sleep (Fig 1). Light sleep refer- 25% in REM sleep. Stage 1 lasts 1-7 min (2-5 % of ring to stages 1 and 2 shows a relatively low volt- total sleep). Stage 2 lasts approximately 10-25 min age with mixed frequency activity, while deep constituting 45-55% of the total sleep. In this stage, sleep referring to stages 3 and 4, which is also an individual requires more intense stimuli than in called slow-wave sleep, is characterized by in- stage 1 to awaken. Stage 3 lasts only a few minutes creasing high voltage activity. In REM sleep brain (3 to 8 % of sleep). Stage 4 of NREM lasts 20-40 activity resembles that of wakefulness. Healthy min in the first cycle and constitutes 10-15% of individuals may cycle between stages of NREM sleep. Stages 3 and 4 are classified as the deepest and REM throughout the night (1, 2). 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 In this issue while sleeping. REM sleep is important for Treatment of insomnia 1 consolida- Test your knowledge 9 tion (3). Topical issues 9 News from the FDA 12 Fig 1. Brain activity recorded by EEG. Adapted from New Drug approvals 15 http://sleepamongstspecies.wordpress.com

2 Kuwait Pharmacy Bulletin Summer 2013

Role of neurotransmitters factors, such as interleukin 1 (IL-1), are induced by serotonin (5). These relationships are illustrated in In the brainstem and posteriolateral hypothalamus, Fig 2. wake promoting neurotransmitters include seroto- nin (5-hydroxytryptamine, 5-HT), noradrenaline, Factors associated with insomnia dopamine, histamine, hypocretin and acetylcholine (Ach) (5). In the anterior hypothalamus, preoptic About 10-30% of the general population suffer from area and the adjacent basal forebrain, there are insomnia. A persistent insomnia for more than 1 both wake promoting neurotransmitters, gamma- month, without the association of physical problem aminobutyric acid (GABA) and Ach, and sleep and mental disorder, is considered primary insom- promoting neurotransmitters, GABA and galanine. nia. Association with specific events, including pe- The synthesis and the release of sleep promoting 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 chological or physical problems, is classified as leading to impairment of glucose regulation because transient insomnia (6). of the lipolytic effects of adrenergic stimulation of Age is an important risk factor, in addition to visceral adipose tissue. The impact of sleep loss on some medical conditions like Alzheimer’s disease, glucose regulation suggests a mechanism whereby Parkinson’s disease, depression, anxiety, stress, short sleep time might increase mortality (10). heartburn, respiratory disorders, , urinary Insomnia affects the immune system by impairing incontinence, heart failure, cancer, and diabetes. host defense mechanisms and increasing the suscep- Furthermore, sleep patterns may be altered by tibility to viral and bacterial pathogens (11). Fur- medications such as bronchodilators, β-blockers, thermore, insomnia can lead to impairment of learn- methyldopa, diuretics, theophylline, , ing, thinking, memory, perceptual skills, deteriora- (6), , and tion of mood, attention and concentration which medications against anorexia and tuberculosis, in may result in compromised work productivity. addition to excessive consumption of caffeine and chronic alcoholism (7). Current treatments of insomnia and their Women are more prone to have insomnia than limitations men. This is because during menstruation, preg- Current pharmacological therapies include benzodi- nancy, and menopause, women experience hormo- azepines, newer benzodiazepine-like agents includ- nal fluctuations that put women at higher risk of ing zolpidem and zaleplon, ethanol, antihistamines, insomnia. Additionally, anxiety and depressive exogenous melatonin, , barbiturates, disorders are more likely to occur in women and and sedating anti-depressants. can cause insomnia. Other factors associated with insomnia include social factors, physiologic fac- Benzodiazepines tors, chronobiological factors, and behavioural fac- Benzodiazepines (used as , or tors. ) modulate GABA function As a social issue, it was found that divorced, sepa- by enhancing GABA's inhibitory action in the brain rated or widowed people have advanced rates of (1, 12). The most commonly prescribed benzodiaze- insomnia. Physiologic factors include recurrent pines are (Xanax), limbs shaking syndrome, legs impatience syn- (Klonopin), (Valium), and drome, difficulty breathing during sleep, narcolep- (Ativan); 1, 5-benzodiazepines have similar thera- sy, some central nervous system injuries and night- peutic properties as1,4-benzodiazepines but with time awakening because of twinges and surgical considerably less and hypnogenic activity. operation. A modification of the benzodiazepine structure is by An example of chronobiological factor includes the annelation of an additional ring system. For ex- people who work at night or have night shifts. Be- ample, and , which are highly havioral factors are characterized by having poor active substances result from the 1,2-annelation of night routines such as going to bed too early and triazole or (Fig 3). reading or watching television at bed time in addi- The prolonged use of benzodiazepines is associat- tion to regular intellectual activities near bedtime, ed with the development of amnesia, tolerance and having a late meal in the evening, exposure to un- dependence (physical and psychological), and with- healthy or noisy environment, sleeping after each drawal problems. Withdrawal syndrome, on the oth- lunch and physical hyperactivity (7). er hand, is described as having rebound insomnia with the association of minor physical symptoms in Consequences of insomnia addition to the symptoms specific to benzodiazepine Insomnia is associated with psychiatric disorders withdrawal (13,14). Minor physical symptoms are (most commonly depression and anxiety) (8) more tachycardia, tremor, perspiration, dizziness, palpita- frequently than any other medical condition. Addi- tions, muscle tension or , and gastrointesti- tionally, sleep loss increases obesity by increasing nal symptoms such as nausea and vomiting. Symp- appetite. Sleep loss results in high levels of ghrelin toms specific to benzodiazepine withdrawal include (a peptide that stimulates appetite) and low levels changes of taste and smell, impaired vision and of leptin (a hormone produced by adipose tissues hearing, impaired perception of motion, de- that reduces appetite) (9). Other consequences of personalization, de-realisation, , loss of insomnia are diabetes and impaired glucose toler- appetite or loss of weight and muscle spasm. In pa- ance. Sleep loss can increase sympathetic activity tients with pulmonary disease, all benzodiazepines

4 Kuwait Pharmacy Bulletin Summer 2013 can result in respiratory depression and the sleep- nels. Chronic use of ethanol can lead to tolerance inducing may be lost with prolonged use and dependence. It can reduce the efficiency and (13, 14). quality of sleep and increases the risk of severe day- time sleepiness and lowers daytime alertness.

Sedating anti- 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 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 Fig 3. Representative examples of benzodiazepines. evaluated the efficacy of melatonin as a chronobiotic (phase-shifting agent) rather than as a . Newer benzodiazepine-like agents , dizziness, nausea, and drowsiness are the Zolpidem and zaleplon (Fig 4) act as at most common adverse effects (16, 17). GABA receptors similar to classic benzodiaze- pines and can be used for chronic and transient Chloral hydrate and barbiturates insomnia. These benzodiazepine-like agents are Although FDA approved for use in treating insomnia, able to cause shortened sleep latency and might chloral hydrate and barbiturates are not generally rec- lead to antegrade amnesia or idiosyncratic daytime ommended because of their likelihood of tolerance sleepiness, and they don’t block withdrawal from and dependence, adverse effects, low therapeutic in- benzodiazepines (13). dex and loss of effects with chronic use (13, 17).

Antidepressants 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 , and .

Fig 4. Structures of benzodiazepine-like agents Herbal remedies A study published in Psychopharmacology in 2005 Ethanol found that sleep-disturbed rats treated with 300 mg The most widely self-used hypnotic drug is etha- kava extract experienced a significant shorten- nol. GABA receptors are important in mediating ing in the sleep latency cycle. Although further hu- the CNS effects of ethanol in addition to voltage- man trials are required, researchers noted that kava gated calcium channels and -gated ion chan-

Vol 17, No 2 Drug Information For The Health Professional 5 kava possesses sleep-quality enhancement effects. The University of Maryland Medical Center rec- Gaboxadol (Fig 5A) is a selective extra-synaptic ommends taking 100-250 mg of standardized kava GABA-A receptor (18). Its functional activi- extract up to three times per day as needed. An- ty is highest for δ-containing GABA-A receptors other herbal remedy is . is an- which exist mainly extra-synaptically and are local- other herb widely used as a sleep aid. The Univer- ized in the thalamus, cerebellum, dentate gyrus and sity of Maryland Medical Center recommends tak- cortex. They are insensitive to traditional benzodiaz- ing 200-400 mg of valerian standardized extract epine (e.g triazolam) and non-benzodiazepine (e.g before bed to promote sleep. zolpidem) hypnot-ics. Gaboxadol improves sleep quality and positively affects daytime performance in New approaches in treating insomnia primary insomniacs (1). When 15 mg of gaboxadol

Due to limitations of current treatments of insom- was used in adult patients, it decreased the amount of nia, novel hypnotic drugs with different mecha- time spent in stage 1 sleep, had no significant effect nisms of action and different targets for promoting on stage 2 sleep, and increased the amount of time sleep have been developed; some of these are cur- spent in stages 3 and 4 sleep (19) and is generally rently in phase II/III clinical trials. Of the thera- well tolerated. The most common drug-related ad- peutic agents listed in Table 1, gaboxadol, indip- verse experiences are dizziness, nausea, fatigue and lon, , and vomiting. The pharmacokinetic parameters for are discussed in the following section. gaboxadol showed that the mean t1/2 was 1.7 h, tmax

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

Drug name Pharmacological target Indication Development phase

Silenor H1/, muscarinic antag- Sleep disorders Phase III onist GABA-A BZ-site modulator Sleep disorders Awaiting approval . SR 46349 5-HT-2A Sleep disorders Phase III . M-100907 5-HT-2A receptor antagonist Sleep disorders Phase III VEC-162 agonist Sleep disorders, de- Phase III pression Esmirtazapine. ORG Noradrenergic. Specific serotonener- Sleep disorders, hot Phase III 50081 gic flushes agomelatine 5-HT-2B/5-HT- antagonist, mela- Depression, Sleep Phase III tonin agonist disorders Almorexant. ACT- OX1 and OX2 receptor antagonist Sleep disorders Phase III 078573 Gaboxadol GABA-A receptors agonist Sleep disorders Phase III PD-6735 Melatonin receptor agonist Sleep disorders Phase II . EMD 5-HT-2A receptor antagonist Sleep disorders Phase II 281014 APD-125 5-HT-2A Sleep disorders Phase II ACP-103 5-HT-2A receptor inverse agonist, Sleep disorder, anti- Phase II dopamine D2/D3 receptor partial psychotic-induced agonist, acetylcholine M1 receptor side effects. Parkin- agonist. son's disease. HY10275 5-HT-2A and H1 receptor inverse Sleep disorders Phase II antagonist GW649868 antagonist Sleep disorders Phase II . NG-2-73 GABA-A BZ-site modulator Sleep disorders Phase II EVT-201 GABA-A BZ-site modulator Sleep disorders Phase II

6 Kuwait Pharmacy Bulletin Summer 2013

-1 was 2 h, AUC0–∞ was 430 ng·hml and Cmax was and N-deacetyl-indiplon are observed. N-desmethyl- -1 139 ng ml . The most notable difference in phar- indiplon is formed by the cytochrome P450 CYP- macokinetics was the slightly shorter apparent ter- 3A4 and CYP1A2 metabolic pathways, while N- minal t for elderly women compared to men. 1/2 deacetyl-indiplon is formed by microsomal carboxy- Regarding the renal of gaboxadol, stud- ies showed that an average of 58% of gaboxadol lesterases (25). was recovered intact in the urine and the rest as glucuronide conjugate. The major metabolite ex- Almorexant creted in human urine was gaboxadol-O- A tetrahydroisoquinoline derivative (Fig 5C), Al- glucuronide (20, 21). morexant is an orally potent dual (OX1R/OX2R) orexin receptor antagonist for the treatment of pri- mary insomnia (26,27). Orexin (or hypocretin) sys- Indiplon tem exhibits a key role in the Indiplon (Fig 5B) is a pyra- physiological and emotional zolopyrimidine compound responses that are associated (22); it is an agonist for with wakefulness such as benzodiazepine receptors stress processing, appetite and and has high selectivity and energy expenditure (28). Orexins originate from a affinity for the α1-subtype group of neurons in the lateral of the GABA-A receptor hypothalamus projecting to complex. It improves sleep many of the ascending excita- onset, sleep duration and tory pathways. Orexinergic maintenance, and overall sleep quality in primary neurons are active during periods of wake and inac- insomnia. Studies have shown that this improve- tive during sleep; antagonising orexin activity by ment in sleep was sustained across all 3 months of almorexant has a sleep-promoting effect. Almorexant can promote REM and NREM sleep study treatment with no change in response with and decreases alertness (1, 27). Somnolence, fa- time. Indiplon also improves daytime functioning tigue, headache and nausea are reported as adverse and quality of life in patients with primary insom- effects. Muscular weakness was reported only with nia symptoms (23, 24). the highest almorexant dose (29). There were no There are two formulations for indiplon; Indiplon significant effects on memory, motor performance, -IR (immediate release), which was developed for mood, calmness, subjective internal and external difficulties in sleep onset, and indiplon-MR perception, and feeling high (29,30). Almorexant is rapidly absorbed and distributed (modified release), which was intended for sleep and has no tendency to accumulate with dose repeti- maintenance insomnia. Adverse effects include tion. Almorexant has a median time to the Cmax of upper respiratory infection, amnesia, dizziness, 1.5h and a quick disposition with a distribution t1/2 headache and somnolence. of 1.6h. In addition, it has a rapidly decreasing con- When compared with benzodiazepines, discon- centration to approximately 20% of the Cmax over 8h tinuation of indiplon was not associated with any and a terminal t1/2 of 32h. After rapid absorption, almorexant is metabolised extensively, and the pre- increase in benzodiazepine-like withdrawal symp- dominant route of elimination in humans is excre- toms (23, 24). For indiplon, healthy young males tion of metabolites in faeces (26). have shown Cmax at 0.73h with elimination t1/2 of 1.97h, while females have reached Cmax at 0.82h Agomelatine with elimination t of 1.71. In the elderly popula- 1/2 Also known as S20098 this is a napthalenic com- tion, impaired renal and hepatic functions can re- pound with structural similarities to melatonin (2). sult in a 3-fold increase in plasma concentrations The of agomelatine is higher in of indiplon and a doubling of t1/2 compared to the women compared to men and it is increased with values seen in younger adults. oral contraceptive intake and decreased with smok- Two major metabolites, N-desmethyl-indiplon ing (31,32). Agomelatine (Fig 5D) is a

Vol 17, No 2 Drug Information For The Health Professional 7 agonist that acts on MT1/MT2 melatonergic recep- tors, esmirtazapine (Fig 5E) has higher affinity to 5- tors suppressing cAMP formation. Also, it acts as a HT2 receptors and low affinity to 5-HT3 receptors complementary 5-HT2C antagonist and it enhances when compared with and R- slow wave sleep without affecting REM sleep and mirtazapine. Racemic mirtazapine is used for the can be used to treat depression (1). treatment of major depressive disorder. Esmirtazap- The most common adverse effects are headaches, ine is in phase III clinical development for the treat- mild and fatigue, dizziness and reversible ment of primary insomnia and hot flushes. Doses elevations in serum alanine and/or aspartate trans- when used for insomnia are lower than those pre- aminases. As a result, function tests should be scribed for depression. The effective sleep promot- performed at the onset of treatment, and then peri- ing doses of esmirtazapine range between 1.5- odically at 6, 12 and 26 weeks. Hepatic impair- 4.5 mg (36).

A) aboxadol B) indiplon

C) almorexant

E) esmirtazapine

D) agomelatine

Fig 5. Novel therapeutic agents for insomnia ment is a contraindication. Unlike older agents, Somnolence and fatigue are the most frequently agomelatine does not cause any withdrawal symp- reported adverse events. Esmirtazapine has a long toms when discontinued. Agomelatine's therapeu- t1/2 of 20h which raises the issue of residual daytime tic doses range between 25-50 mg/day (33, 34). It is drowsiness and driving impairment. Studies support absorbed rapidly from the gastrointestinal tract and the notion that dose effects of esmirtazapine on transported immediately to the liver where it is me- driving are related to the drug's concentration in tabolized by CYPA1, CYPA2 and CYP2C9 isoen- plasma. Esmirtazapine is metabolized through cyto- zymes. chrome P450 CYP2D6 in the liver by demethylation Four metabolites of agomelatine have been iden- and hydroxylation and formation of S(+)-N- tified. These metabolites are excreted through desmethylmirtazapine and S(+) -8 hydroxymirtazap- urine and faeces, and only low levels of unchanged ine, followed by glucuronide conjugation. Its clear- agomelatine are excreted. It has a short t1/2 of about ance in poor metabolisers is twice lower when com- 2h. Its dissociation constant for MT1/MT2 melato- pared to extensive metabolisers (36). nin receptors is 10 nM which is similar to that of melatonin (33,34). Conclusion

Esmirtazapine Using herbals and natural drugs to treat insomnia is An antagonist on the presynaptic α2 adrenergic re- rarely effective. In addition, the side effects of the ceptors as well as postsynaptic 5HT2 and H1 recep- current medications for insomnia necessitate the de-

8 Kuwait Pharmacy Bulletin Summer 2013 velopment of new agents. Novel drugs including Retrieved from PMC database. gaboxadol, indiplon, almorexant, agomelatine, and 21. Larsen, M., Holm, R., & Brodin, B. (2009). Br J Pharma- col, 157(8), 1380–1389. Retrieved from http:// esmirtazapine have reached phase III clinical trials www.ncbi.nlm.nih.gov/pmc/articles/PMC2765307/ and some are awaiting approval; these exhibit bet- 22. Indiplon Supplier | CAS 325715-02-4 | Tocris Bioscience | ter safety profiles and lesser side effects and with- NBI 34060. (n.d.). Tocris Bioscience | High Performance drawal symptoms. They have variable pharmacoki- Life Science Reagents. Retrieved May 9, 2013, from http:// www.tocris.com/dispprod.php?ItemId=230813 netic properties as some of them have short t1/2 and #.UaC3z6y61EN some have long t1/2. They act on different receptors 23. Scharf, M. B., Black, J., & Hull, S. (2007). Sleep, 30(6), and by different mechanisms and some of them can 743–752. Retrieved from http://www.ncbi.nlm.nih.gov/ be also used in other depressive disorders. pmc/articles/PMC1978349/ 24. Lankford, A. (2007). Neuropsychiatr Dis Treat, 3(6), 765–

References 773. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC2656319/ 1. Wafford, K. A., & Ebert, B. (2008). Nature Rev Drug Disc 25. Gryskiewicz, K. A., & Semanco, M. (2006). Formulary, 7(6), 530-540. 41, 316-321. Retrieved from http://formularyjournal. mo- 2. Brand, S., & Kirov, R. (2011). Int J Gen Med 4, 425–442. dernmedicine.com/formulary-journal/news/clinical/clinical Retrieved from http://www.ncbi.nlm.nih.gov/pmc/ -pharmacology/indiplon-short-acting-gaba-receptor- articles/PMC3119585/ agonist-se 3. Colten, H. R., & Altevogt, B. M. (2006). Sleep Physiolo- 26. Dingemanse, J., Hoever, P., & Hoch, M., et al. (2013). gy. Sleep disorders and sleep deprivation: an unmet pub- Drug Metab Dispos, 41(5), 1046-59. Retrieved from http:// lic health problem (pp. 33-53). Washington, DC: Institute www.ncbi.nlm.nih.gov/pubmed/23431113 of Medicine. 27. Neubauer, D. (2010). Curr Opin Investig Drugs, 11(1), 4. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. 101-10. Retrieved from http://www.ncbi.nlm.nih.gov/ Neuroscience. 2nd edition. Sunderland (MA): Sinauer pubmed/20047164. Associates; 2001. Stages of Sleep. Available from: http:// 28. Steiner, M. A., Lecourt, H., & Strasser, D. S., et al. (2011). www.ncbi.nlm.nih.gov/books/NBK10996/ Neuropsychopharmacology, 36(4), 848–856. Retrieved 5. Imeri, L., & Opp, M. R. (2009). Nature Rev Neurosci, 10 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055 (3), 199-210. 7 32/ 6. Golestan, B., Mousavi, F., Iran-Pour, et al. (2012). Iran J 29. Hoever, P., Hay, J., Rad, M., et al. (2013). J Clin Psycho- Public Health, 41(1), 96–106. Retrieved from http:// pharmacol, 33(3), 363-70. www.ncbi.nlm.nih.gov/pmc/articles/PMC3481663/ 30. Owen, R., Castañer, R., Bolos, J., & Estivill, C. (2009). 7. Dollander, M. (2002). [etiology of adult insomnia]. 28(6 Almorexant. Drugs of the Future, 34(1), 5. Pt1),493-502. Retrieved from http://www.ncbi.nlm.nih. 31. Venkat Rao, P., Prabhakar, T., & Ramakrishna, S. (2010). gov/pubmed/12506261 Research Journal of Pharmaceutical, Biological and 8. Roth, T. (2007). J Clin Sleep Med, 3(5), S7–S10. Spiegel, Chemical Sciences, 1(2), 446- 450. Retrieved from http:// K., Tasali, E., Penev, P., et al. (2004). Ann Intern Med, www.rjpbcs.com/pdf/Old files/63.pdf 141(11), 846-50. 32. Cayman Chemical. (2011, February 12). Agomelatine item 9. Gottlieb, D. J., Punjabi, N. M., Newman, A. B., et al. no. 13203. Retrieved from https://www.cayma nchem.c (2005). Arch Intern Med 165(8), 863-867. om/pdfs/13203.pdf 10. Irwin, M. (2002). Brain, Behavior, and Immunity, 16(5), 33. de Bodinat, C., Guardiola-Lemaitre, B., & Mocaër, E., et 503-512. al. (2010). Nat Rev Drug Discov, 9(8), 628--642. Retrieved 11. Möhler, H. (2002). Dialogues in Clinical Neuroscience, 4 from http://www.ncbi.nlm.nih.gov/pubmed/2057 7266 (3), 261-269. 34. Srinivasan, V., Zakaria, R., & Othman, Z. (2012). J Neu- 12. Pagel, J. F., & Parnes, B. L. (2001). Prim Care Compa- ropsychiatry Clin Neurosci, 24(3), 290-308. Retrieved nion J Clin Psychiatry, 03(03), 118-125. Blais, D., & from http://www.ncbi.nlm.nih.gov/pubmed/23037643 Petit, L. (1990). Can Fam Physician, 36, 1779–1782. 35. Vanover, K. E., & Davis, R. E. (2010). Nat Sci Sleep, 2, Retrieved from http://www.ncbi.nlm.nih.gov/pmc/ 139–150. Retrieved from http://www.ncbi.nlm.nih.gov/ articles/PMC2280531/ pmc/articles/PMC3630942/ 13. Saddichha, S. (2010). Ann Indian Acad Neurol, 13(2), 94 36. Ramaekers, J. G., Conen, S., & Braat, S., et al. (2011). 14. Buscemi, N., Vandermeer, B., Hooton, N., et al. (2005). J sychopharmacology, 215(2), 321–332. Retrieved from Gen Intern Med, 20(12), 1151-1158. Schutte-Rodin, S., http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083504/ 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/ Ameena Al Marjan summary.cgi?cid=3448&loc=ec_rcs Final Year student, 2013 16. Lankford, D. A., Corser, B. C., & Zheng, Y. P., et al. (2008). Sleep, 31(10), 1359–1370. Retrieved from http:// Faculty of Pharmacy, www.ncbi.nlm.nih.gov/pmc/articles/PMC2572741/ Kuwait University 17. Boyle, J., Danjou, P., Alexander, R.,et al. (2009). Brit J Clin Pharmacol, 67(2), 180-190.

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

TEST YOUR KNOWLEDGE Answers to MCQs on back page

1) Which of the following is a sleep promoting ? Is there a problem? A 56 year old patient was a) serotonin prescribed the drug given in b) galanine the prescription for c) noradrenaline hypertension. Is there any d) dopamine major error? e) histamine KLM HOSPITAL 2) Which of the following develops with prolonged use of benzodiazepines? Patient Name: Mr. Ahmad Ali Age: 56 years Address: Street No. 7 Rx a) amnesia Nifedipine 5mg tablet b) tolerance One tablet three times a day c) physical dependence Send one pack d) psychological dependence Dr. MXD e) all of the above Signature Date: 15/06/13

3) Which of the following is a GABA-A BZ site modulator awaiting approval for indication in sleep disorders? Answer (Prescription Exercise) Immediate release nifedipine is a) agomelatine b) esmirtazapine not recommended for hyperten- c) gaboxadol sion. Modified release nifedipine d) indiplon is recommended for treatment of e) almorexant hypertension. Example: Adalat LA® (nifedipine) 20-30mg once daily, maximum dose 90mg once daily. (Source: British National Formulary)

TOPICAL ISSUES AND CONTROVERSIES Toxins in cleaning products?

Household cleaning products may contain toxic According to the EWG report, more than half the substances linked to health problems such as asth- products evaluated contain ingredients known to ma, allergic reactions, and cancer, according to a harm the lungs. In other cases, it was difficult to report by the US Environmental Working Group determine what was in the product because of in- (EWG). complete labeling. They rated more than 2,000 household cleaners - Ninety-three percent [of the products] provided in- from laundry soaps and stain removers to bath- gredient lists that were incomplete or not specific room cleaners and floor care products. Products are enough. Few 'green' brands were still reticent about graded A to F based on the safety of the ingredi- their ingredients. ents and how well the maker discloses those ingre- Cleaning products are largely unregulated. Some dients. cleaning products did get high marks. Among the One industry trade group disputes the findings many products that received an A rating: though, saying the report doesn't make the grade.  Whole Foods Market green MISSION Organic

10 Kuwait Pharmacy Bulletin Summer 2013

All-Purpose Spray Cleaner & Degreaser, Lem- acid, is added on Zest for general cleaning to many prod-  Arm & Hammer Baking Soda for general ucts. It can be cleaning a hormone  Seventh Generation National Tub &Tile disrupter Cleaner, EWG scien- Emerald Cypress & Fir tists suggest  Green Shield Organic toilet bowl cleaner entirely  The Honest Co. auto dishwasher gel, free & avoiding clear some prod- ucts because EWG Guide: Details of ingredients. These include air fresheners, anti- EWG scientists compared the ingredients listed on bacterial products, fabric softeners, and caustic the labels of cleaning products and manufacturers' drain cleaners and oven cleaners. web sites with information from toxicity databases from government, industry, and academic sources. EWG said even some ''green brands'' could do better They looked at medical literature on health and on disclosing ingredients. Among them: Earth environmental problems linked with cleaning Friendly Products and BabyGanics. A spokeswom- products. an for BabyGanics, said it was unfortunate that the EWG deemed their descriptions inadequate. She Among the key findings, according to EWG: noted “one problem is a lack of uniform industry  About 53% of the products had ingredients standards. All BabyGanics products contain ingredi- known to harm the lungs. Examples are ben- ent statements, including our household, hand hy- zalkonium chloride, found in antibacterial giene, diapering, skin care, sun care, and oral care cleaners, and chlorine bleach. solutions. The household product category remains  About 22% had chemicals linked with asthma the only one that still does not have a uniform set of in previously healthy people. industry standards."  Some products use formaldehyde, a known hu- It is a fact that anything can be safe or unsafe- it man carcinogen, as a preservative, or it is re- all depends on the amount. Manufacturers work to leased by other preservatives in the products. ensure that they use levels of ingredients that are  The chemical 1,4-dioxane, suspected of being a 'just right' - in that they provide a benefit in the human carcinogen, is a common contaminant of products, but at the same time are safe. One option detergent chemicals. is to make your own cleaning products from white  , also a suspected carcinogen, can vinegar and water. escape in fumes released by products contain- ing chlorine bleach. Adapted from www.medscape.com/viewarticle/770678? src=nldne  Sodium borate, sometimes called borax or boric Drug safety standards: need for transparency

Historically, the evaluation of harmful effects re- process may be more likely to show problems with sulting from use has been con- safety post-marketing than drugs that go through a sidered less important than demonstrating drug slower evaluation process. And debates continue efficacy, yet the harms caused by specific adverse about the best ways to meaningfully synthesize and drug reactions are a major, and avoidable, contrib- interpret data on the possible harmful effects of utor to hospitalizations and deaths. drugs—for example, how passive surveillance sys- There are many reasons (both scientific and so- tems (spontaneous reports of suspected adverse re- cial) why reliable data on harmful effects may on- actions) should be improved, whether new drugs ly emerge well after drug approval and marketing. should go through a phased launch process with en- Drugs approved under a rapid regulatory review 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- already showing signs of setting high standards in ty concerns. some areas. One such debate- whether systematic reviews esti- Studies conducted solely by industry will not be mating the risk of harmful effects should use evi- eligible to qualify for ENCEPP approval; studies dence from randomized trials or observational must be publicly registered before collection of data, studies- seems finally to have been laid to rest. In and protocols and datasets must be released (with a systematic overview, the authors demonstrate some restrictions relating to data privacy) in a timely that, for 19 specific drug–harm relationships, the way after completion. Critically, ENCEPP can still evidence on magnitude of risk for each particular potentially approve studies funded by the pharma- harm discovered through systematic reviews of ceutical industry, with involvement of industry part- randomized trials was, on average, no different ners in design and analysis, providing the study's from the evidence assembled via systematic re- lead investigator is based within an ENCEPP- views of observational studies.(Golder et al (2011) approved center. More worryingly, the code allows PLoS Med 8(5): e1001026) This is an important find- for industry sponsors to retain control of datasets; ing. The implications of this study for future eval- this, and other provisions, may enable conflicts of uations of drug safety are clear: systematic re- interest to creep in during study design or data analy- viewers should consider all types of evidence in sis. trying to build a complete picture of harms associ- Clearly, for post-approval safety studies, one size ated with drug treatments. will not fit all. Conduct and reporting are unlikely to Passive surveillance is still crucial for providing be standardisable in the same way as has been possi- early warning signals and generating new hypoth- ble for randomized trials, in which there is agreement eses about possible harms associated with specific on what information needs to be registered about the approved drugs. However, new hypotheses emerg- study and when, and specific standards for the re- ing from such surveillance must subsequently be porting of studies are widely accepted. The ENCEPP explicitly tested, preferably using study designs guidance avoids normative statements about study that can incorporate data on the size of the ex- design, instead preferring to highlight the methodo- posed population (such as cohort or record linkage logical challenges and multiple sources of bias that studies). Such studies can therefore estimate the plague analysis and interpretation of data. However, relative increase in risk associated with exposure, these challenges should not discourage investigators, which is difficult or impossible to calculate from regulators, and patients from demanding a higher passive surveillance data. safety standard for approved drugs. A new initiative established by the European Higher standards will require both greater transpar- Medicines Agency (ENCEPP, the European Net- ency- in revealing what studies are being conducted work of Centres for Pharmacoepidemiology and and what data that have been generated- and greater Pharmacovigilance) seeks to promote the conduct willingness of funders to support new studies specifi- of such studies and establish standards for post- cally addressing drug safety. marketing safety evaluations. Given the diversity of designs and multiple pos- Source: The PLoS Medicine Editors (2011) Why Drug Safety sible sources of bias in pharmacoepidemiology, Should Not Take a Back Seat to Efficacy. PLoS Med 8(9): this will not be an easy job. But the initiative is e1001097. Eyes grown from stem cells

With the proper culture conditions, mouse embry- Yoshiki Sasai at the RIKEN onic stem (ES) cells can spontaneously form the Center for Developmental Biolo- rudiments of a retina. The results, published in gy in Japan and his colleagues have worked to differ- Nature, could help researchers answer some out- entiate ES cells into various cells of the nervous sys- standing questions about eye development and tem, including cerebral cortex neurons and retinal dysfunction, and hold promise for the development cells. They were interested in more than just generat- of retinal tissues for transplantation. ing different nerve cells and wanted to learn how For the last decade, developmental biologist those cells come together to form entire tissues and

12 Kuwait Pharmacy Bulletin Summer 2013 organs in developing embryos. Starting with the to start transplanting these synthetic retinas, ES cells culture conditions they had established for retinal cultured under the proper conditions could yield cer- differentiation, the researchers added matrix pro- tain cells that may prove therapeutically valuable. teins that they hoped would encourage the for- The system might help answer how ES cells self- mation of the more rigid retinal epithelial struc- organize into the complex retinal tissues. While the tures. They then seeded the culture with mouse ES retinal structures cultured in this study only devel- cells. oped into neonatal mouse retinas, which still lack Within a week, the cells formed small vesicles photoreceptor cells, it will likely just take a few and differentiated into two different tissue types: tweaks to the culture conditions to coax those struc- Cells on one side of the vesicles formed the me- tures into mature retinas, allowing researchers to ex chanically rigid pigment epithelium, while cells on amine the entire process. the other side differentiated into a more flexible Furthermore, if researchers can replicate the results tissue that folded inward in the shape of an embry- using human induced pluripotent stem (iPS) cells, it onic optic cup- the retina's precursor. could shed light on retinal dysfunction. By creating The biggest surprise was that we observed the iPS cells from patients with [visual disorders] and formation of the very real optic cup structure that then making synthetic retinas from such iPS cells, mimicked both the shape and tissue composition we could potentially study the disease process and popped out from the [ES cell] aggregate. caused by particular genetic defects. The generation of retinal tissue from ES cells is an exciting advance that may lead to regenerative Source: http://www.the-scientist.com/news/display/58105/ medicine applications. While doctors are not about 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- refills, from a practitioner through an in person inter- tain input on a potential new paradigm under action. Obtaining a refill for other prescription drugs which FDA would approve certain drugs that involves at least a telephone call or other communi- would otherwise require a pre- cation with the practitioner. In con- scription for nonprescription use trast, nonprescription drugs under conditions of safe use spe- (sometimes referred to as over-the- cific to the drug product. counter or OTC products) can be purchased by consumers in pharma- A. Prescription and nonpre- cies, supermarkets, and other retail scription drugs establishments without the need for Prescription drugs are dispensed a prescription. upon receipt of a prescription Currently, consumers can pur- from a practitioner licensed by chase nonprescription drugs from a law to administer the drug (which may include retailer for diseases or conditions that do not meet health care professionals such as physicians, nurse the statutory criteria for prescription products and practitioners, physician's assistants, and others that are safe and effective for use in self-medication whom we will refer to here as practitioners or pre- as directed in the labeling. Generally, OTC products: scribers). In many instances, under the current reg- (1), Are available to treat diseases or conditions that ulatory system, a patient has to obtain at least the can be self-diagnosed without a prior interaction initial prescription, and in some cases, prescription 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 burdened health care system, and reduce health care risks by a practitioner and (3), do not require a costs. practitioner's input for use. FDA is aware that industry is developing new tech- nologies that consumers could use to self-screen for B. Under-treatment of diseases and other a particular disease or condition and determine effects on the health care system whether a particular medication is appropriate for Under-treatment of many common diseases or them. For example, kiosks or other technological conditions in the US is a well-recognized public aids in pharmacies or on the Internet could lead con- health problem. Increasing the number of people sumers through an algorithm for a particular drug who are able to obtain for the first time and those product. who continue on necessary drug therapy could Some drug products that would otherwise require a provide improved health outcomes. prescription could be approved as nonprescription The requirement to obtain a prescription for ap- drug products with some type of pharmacist inter- propriate medication (and to make one or more vention as their condition of safe use. For example, visits to a practitioner) may contribute to under- some diseases or conditions might require confirma- treatment of certain common medical conditions tion of a diagnosis or routine monitoring using a di- including hyperlipidemia (high ), hy- agnostic test (e.g., a blood test for cholesterol levels pertension (high blood pressure), migraine head- or liver function) that could be available in a phar- aches, and asthma. For instance, some consumers macy. A pharmacist, or consumer, could then use the do not seek necessary medical care, which may results to determine whether use of a certain drug include prescription drug therapy, because of the product is appropriate. Other potential roles for the cost and time required to visit a health care practi- pharmacist include assessing whether the consumer tioner for an initial diagnosis and an initial pre- has any conditions or other risk factors that would scription. Some patients who obtain an initial pre- indicate that the drug should not be used, or assisting scription do not continue on necessary medication the consumer in choosing between various drug because they would need to make additional visits products. For drugs that require use of a diagnostic to a health care practitioner for a prescription refill test, creating a pathway for nonprescription use may after any refills authorized by the initial prescrip- result in the development by industry of diagnostics tion have been used or the time during which they suitable for use by the patient or a pharmacy profes- can be filled has expired. Some prescription medi- sional. cations require routine monitoring through the FDA is also considering whether the same drug prescribing practitioner such as blood tests to as- product could be simultaneously available as both a sist in the diagnosis of a condition, or to determine prescription and nonprescription product with condi- whether or how well tions of safe use. Dual availability could the medication is help ensure greater access to needed medi- working, or to adjust cations by making obtaining them more the dose. flexible. Consumers could choose to con- In addition to im- tinue seeing their health care practitioner proved health out- to diagnose diseases or conditions and ob- comes for consumers tain prescriptions, and when their local staying on their medi- retail establishment is not equipped to of- cations, the time and fer the nonprescription product with con- attention that physi- ditions of safe use. Other consumers could cians and other health take advantage of the ability to obtain non- care providers ex- prescription products with conditions of safe use pend on routine tasks related to prescription refills where they are available. reduces the time that they are available to attend to more seriously ill patients. Eliminating or re- Source: https://www.federalregister.gov/articles/2012/02/28/ ducing the number of routine visits could free up 2012-4597/using-innovative-technologies-and-other-conditions prescribers to spend time with more seriously ill -of-safe-use-to-expand-which-drug-products-can-be patients, reduce the burdens on the already over-

14 Kuwait Pharmacy Bulletin Summer 2013

FDA issues draft guidance on biosimilar product development

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, FDA. This draft guidance describes a risk-based 2010, amended the Public Health Service Act to “totality-of-the-evidence” approach that the FDA create an abbreviated approval pathway for biolog- intends to use to evaluate the data and information ical products that are demonstrated to be highly submitted in support of a determination of biosimi- similar (biosimilar) to or interchangeable with an larity of the proposed product to the reference prod- FDA-licensed biological product. uct. As outlined in the draft guidance, FDA recom- Biological products are therapies used to treat mends a stepwise approach in the development of diseases and health conditions. They include a biosimilar products. wide variety of products including vaccines, blood and blood components, gene therapies, tissues and Quality considerations in demonstrating biosimi- proteins. Unlike most prescription drugs made larity to a reference protein product through chemical processes, biological products The draft guidance provides an overview of analyti- are made from human and/or animal materials. cal factors to consider when assessing biosimilarity A biosimilar is a biological product that is highly between a proposed therapeutic protein product and similar to an already approved biological product, a reference product for the purpose of submitting notwithstanding minor differences in clinically in- the appropriate application. This includes the im- active components, and for which there are no clin- portance of extensive analytical, physico-chemical ically meaningful differences between the biosimi- and biological characterization in demonstrating that lar and the approved biological product in terms of the proposed biosimilar product is highly similar to the safety, purity, and potency. the reference product notwithstanding minor differ- Through this new approval pathway, biological ences in clinically inactive components. products are approved based on demonstrating they are biosimilar to, or interchangeable with, a biolog- Biosimilars: questions and answers regarding im- ical product that is already approved by the FDA, plementation of the biologics price competition which is called a reference product. and innovation act of 2009 The following three guidance documents provide The draft guidance provides answers to common the FDA’s current thinking on key scientific and questions from people interested in developing bio- regulatory factors involved in submitting applica- similar products. The question and answer format tions for biosimilar products to the agency. FDA is addresses questions that may arise in the early stag- seeking public comment on these draft guidance es of product development, such as how to request documents: meetings with the FDA, addressing differences in formulation from the reference product, how to re- Scientific considerations in demonstrating bio- quest exclusivity, and other topics. similarity to a reference product Adapted from: http://www.fda.gov/NewsEvents/Newsroom/ The draft guidance is intended to assist companies PressAnnouncem ents/ucm291232.htm in demonstrating that a proposed therapeutic pro- tein product is biosimilar to a reference product for the purpose of submitting an application to the

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

STATE OF KUWAIT Pharmaceutical & Herbal Medicines Control and Registration Administration

New Pharmaceutical products approved from January to May 2013

Abilify Oral Solution. 1mg/ml; -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; -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/ 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; -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

16 Kuwait Pharmacy Bulletin Summer 2013

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; HCl-10mg; Plethico Pharma- India Resicalm Tablets 2mg; -2mg; Aurobindo Pharma Ltd. - India Resolor Tablets 1,2mg; -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.; -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, -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; ; Aurobindo Pharma Ltd - India Zithrova Capsules 250mg; Azithromycin-250mg; Oman Pharma- Sultanate of Oman

Correct answers: Answers to: Test your knowledge 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]