Clinical developments in 2009
Therapies that emerged in 2009 ranged from the first melatonergic agonist antidepressant to a cancer drug described as epigenetic. Harriet Adcock, The Pharmaceutical Journal’s news editor, highlights some important developments for pharmacy in the past 12 months
A vision of pharmacists as the clinician on the high street was set out by Scotland’s chief pharmaceutical officer in 2009 (PJ, 12 September 2009, p261). The community pharmacy contract north of the border is helping to achieve this — and the framework for Scotland’s chronic medication service came together towards the end of the year. The service will see pharmacists preparing pharmaceutical care plans for registered patients and is expected to be rolled out in spring (PJ, 19/26 December 2009, p669).
In England and Wales, more fragmented progress around provision of clinical services was seen, with various local initiatives taking shape. Vascular screening, swine influenza vaccination and sexual health services were among the developments.
Reflect on knowledge gaps
1. What are the advantages of the new incretin mimetic liraglutide?
2. For how long after sexual intercourse is ulipristal effective?
3. Why were some oral pain relief gels withdrawn from sale for use in people aged under 16 years?
Before reading on, think about how this article may help you to do your job better.
Act: practice points
Reading is only one way to undertake CPD and the Society will expect to see various approaches in a pharmacist’s CPD portfolio.
1. The Royal Pharmaceutical Society is producing practice guidance for over-the-counter tamsulosin. Cascade the contents of the guidance, expected in the next few weeks, to your staff.
2. Look out for guidance on the use of liraglutide from the National Institute for Health and Clinical Excellence in June 2010. How will this affect your patients with diabetes?
3. Discuss with a colleague how you would advise a prescriber as to where rupatadine fits for treating allergy.
For your work to be presented as CPD, you need to evaluate your reading and any other activities.
What have you learnt?
How has it added value to your practice? (Have you applied this learning or had any feedback?)
What will you do now and how will this be achieved?
Consider making this activity one of your nine CPD entries this year.
Medicines use review (MUR) services continued to grow, although the quality of some MURs was called into question by a senior Department of Health pharmacist (PJ, 27 June 2009, p759). An audit to provide feedback to pharmacists and primary care organisations on the quality and effectiveness of MURs was announced within weeks of her comments (PJ, 18 July 2009, p59).
Prescribing rights evolved, with steps taken to allow pharmacist independent prescribers to prescribe unlicensed medicines, a development that came to fruition by the end of the year (PJ, 2/9 January 2010, p6).
Lloydspharmacy led the way in providing web-based services, launching initiatives such as online screening for sexually transmitted infections and the provision of oral contraceptives, the latter in partnership with medical service provider Dr Thom (PJ, 26 September 2009, p321 and 24 January 2009, p64).
The value of pharmacy provision of such services was also recognised by primary care organisations, with the Isle of Wight rolling out a comprehensive sexual health screening service through its pharmacies (PJ, 28 November 2009, p584) and NHS Lambeth and Southwark piloting a patient group direction service for oral contraceptives (PJ, 19/26 December 2009, p670). There were also indications that primary care trusts were receptive to the NHS Health Check (or vascular screening) being provided through pharmacy (PJ, 31 October 2009, p472).
“Healthy living pharmacies”, a concept outlined in the 2008 White Paper for pharmacy in England, came a step closer to reality, with publication of the first healthy living pharmacy (HLP) prospectus by NHS Portsmouth (PJ, 12 December 2009, p641). The template for Portsmouth indicates that pharmacies awarded HLP status will be assigned an HLP level according to the services offered.
In the hospital sector, plans were announced for all accident and emergency departments in England to establish an acute oncology service, including pharmacy expertise. The proposals were described as “long overdue” by a leading oncology pharmacist (PJ, 5 September 2009, p232).
Across the UK, the responsible pharmacist Regulations, which came into force in October last year (PJ, 3 October 2009, p372), were, in part, designed to release pharmacists from the dispensing bench and to allow them more time to develop clinical services. Whether this will come to fruition remains to be seen.
Of the 20 or so new medicines launched in 2009 few can be described as truly innovative. Among the most noteworthy is the anti-interleukin-6 receptor antagonist tocilizumab, a biologic used to treat rheumatoid arthritis.
Several medicines just missed out on the coveted “first in class” title. The antidiabetic agent liraglutide, which follows exenatide, can at least stake its claim as the first once-daily human glucagon-like peptide-1 analogue for diabetes.
Also of note is the antiplatelet agent prasugrel and agomelatine, the first antidepressant to exhibit melatonergic agonist and 5-HT2C antagonist properties.
In addition to liraglutide (see below), a second antidiabetic agent was launched in 2009: saxagliptin (Onglyza) is used as add-on therapy in adults with type 2 diabetes to improve glucose control (PJ, 17 October 2009, p408). This new addition to the gliptin family improves control by reducing fasting and postprandial glucose concentrations.
Liraglutide (Victoza) was launched as a therapeutic option for diabetes half way through the year (PJ, 11 July 2009, p32). Delivered as a once-daily subcutaneous injection, this human glucagon-like peptide-1 analogue is licensed for the treatment of adults with uncontrolled type 2 diabetes. It can be used in combination with metformin or a sulphonylurea, with metformin and a sulphonylurea or with metformin and a thiazolidinedione.
Liraglutide stimulates insulin secretion and limits glucagon secretion to lower glucose levels only when they are high, a characteristic highlighted as an advantage over some other antidiabetic agents. Another positive effect of liraglutide, pointed out at Victoza’s launch, is its potential to cause weight loss.
Guidance on the use of liraglutide is expected from the National Institute for Health and Clinical Excellence in June 2010. Panel 1 lists other guidance released in 2009.
Panel 1: Guidance released in 2009
Increasing political interference rained down on the National Institute for Health and Clinical Excellence in 2009 with new appraisal rules introduced for end-of-life medicines (PJ, 3/10 January 2009, p7) and Government plans for some medicines to be granted an “innovation pass” before going through the NICE appraisal process (PJ, 5 December 2009, p609).
Despite this, the institute continued to produce evidence-based advice for clinicians and issued positive recommendations (although often with restrictions) on the use of:
Drugs that failed to clear the NICE hurdle included cetuximab for squamous cell cancer of the head and neck, bevacizumab, sorafenib and temsirolimus for first-line treatment, and sorafenib and sunitinib for second-line treatment, of renal cell carcinoma (PJ, 5 September 2009, p232).
In Scotland and Wales recommendations on the cost-effective use of medicines within the NHS were made by the Scottish Medicines Consortium and the All-Wales Medicines Strategy Group.
In the field of cardiovascular medicine, often a focus of pharmaceutical companies’ R&D departments, few new agents emerged. Of those that made it to market, prasugrel arguably stoked the most interest.
Prasugrel (Efient), a third-generation thienopyridine, was launched by Eli Lilly in March 2009 (PJ, 21 March 2009, p304). Co-administered with aspirin, it is used to prevent atherothrombotic events in patients with acute coronary syndrome undergoing primary or delayed percutaneous coronary intervention (PCI).
Prasugrel has a rapid onset of action and is more potent than the thienopyridine clopidogrel, according to Efient’s summary of product characteristics. Clinical trials also suggest that prasugrel is associated with fewer ischaemic events than clopidogrel in patients scheduled to undergo PCI. But this may be countered by more instances of bleeding, including life threatening and fatal episodes.
Other new cardiovascular medicines launched in 2009 include ranolazine (Ranexa), an add-on therapy for patients with stable angina pectoris (PJ, 17 January 2009, p36), and a combination product containing nicotinic acid and laropiprant (Tredaptive), used to treat dyslipidaemia (PJ, 22/29 August, p199).
The mechanism of action of ranolazine is largely unknown but the drug may exert some antianginal effects by inhibiting the late sodium current in cardiac cells. At the time of its launch, use of ranolazine was predicted to be limited by concerns over adverse effects, drug interactions and cost.
The nicotinic acid in Tredaptive decreases low-density lipoprotein cholesterol and triglyceride levels, while increasing high-density lipoprotein cholesterol levels.
Its combination with the DP1-receptor antagonist laropiprant is intended to reduce flushing, thought to result when prostaglandin D2, released from skin cells, interacts with its DP1 receptor. Tredaptive should be used with a statin unless statins are inappropriate or not tolerated.
Patients with rheumatoid arthritis who are not responding adequately to disease modifying antirheumatic drugs now have the option to be treated with tocilizumab, an interleukin-6 receptor antagonist.
Marketed by Roche as RoActemra, tocilizumab is licensed for the treatment of moderate to severe active rheumatoid arthritis. It is used to treat adult patients who have had an inadequate response to, or who are intolerant of, previous therapy with one or more disease-modifying antirheumatic drugs or tumour necrosis factor antagonists. It can be given as monotherapy when methotrexate is inappropriate. Therapy is contraindicated in patients with active, severe infections (PJ, 17 October 2009, p408).
Hot on the heels of tocilizumab, another agent launched for use in rheumatoid arthritis was certolizumab pegol (Cimzia), a pegylated antitumour necrosis factor drug (PJ, 17 October 2009, p408). Certolizumab can also be used to treat moderate to severe active rheumatoid arthritis.
It is given as a subcutaneous injection in combination with methotrexate, and, again, is indicated for adult patients inadequately responsive to disease-modifying antirheumatic drugs. It can also be given as monotherapy to patients unable to take methotrexate.
Central nervous system
Patients with depression and epilepsy saw their therapeutic options increase with the launch of agomelatine and eslicarbazepine, respectively. The exact mechanisms of action of eslicarbazepine (Zebinix; Eisai) are unknown, but in vitro studies suggest it acts by stabilising the inactivated state of voltage-gated sodium channels, preventing repetitive neuronal firing (PJ, 24 October 2009, p440). It is indicated as an adjunctive therapy for the treatment of epilepsy in adults with partial-onset seizures, with or without secondary generalisation.
Indicated for the treatment of major depressive episodes in adults, agomelatine (Valdoxan; Servier Laboratories) is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C receptor antagonist. The drug increases noradrenaline and dopamine release specifically in the frontal cortex of the brain, with no influence on extracellular levels of serotonin.
Agomelatine has been shown in clinical trials to improve the onset and quality of sleep without causing daytime clumsiness, or altering daytime vigilance or memory. At the time of its launch, agomelatine’s place in antidepressant therapy was unclear but it was suggested that the drug is likely to improve sleep without causing weight gain or sexual dysfunction (PJ, 6 June 2009, p666).
Several new agents for malignant disease were launched in 2009. Of these, the most noteworthy were arguably everolimus, introduced as a treatment for advanced kidney cancer, and azacitidine, used for adult patients with certain forms of blood cancer who are not eligible for stem cell transplantation, (see below).
Two new products were introduced for prostate cancer — degarelix (Firmagon; Ferring Pharmaceuticals), a gonadotrophin-releasing hormone antagonist for advanced hormone-dependent prostate cancer (PJ, 9 May 2009, p546), and an implant containing histrelin acetate (Vantas; Orion Pharma), a synthetic analogue of a naturally occurring gonadotrophin-releasing hormone (PJ, 27 June 2009, p764).
Everolimus (Afinitor), a protein kinase inhibitor, is used to treat advanced kidney cancer in patients whose disease has progressed despite first-line treatment with vascular endothelial growth factor targeted therapy. The drug is a selective mTOR (mammalian target of rapamycin) inhibitor. It reduces levels of vascular endothelial growth factor, which potentiates tumour angiogenic processes (PJ, 3 October 2009, p352).
Azacitidine (Vidaza; Celgene) is described by its manufacturer as an example of epigenetic therapy, treating disease by altering gene expression (PJ, 7 March 2009, p241). It is licensed for myelodysplastic syndromes, chronic myelomoncytic and acute myeloid leukaemia. Possible mechanisms of action include cytotoxic effects and the reversal of hypermethylation of DNA.
Two new contraceptive agents were launched onto the UK market in 2009. In May, Bayer introduced Qlaira, a new estradiol-based oral contraceptive. The dosing regimen of Qlaira consists of an oestrogen step-down and a progestogen step-up sequence, the main oestrogen being estradiol valerate — an ester of the natural human 17ß-oestradiol (PJ, 23 May 2009, p608). Later in the year, HRA Pharma launched ellaOne, an emergency hormonal contraceptive containing ulipristal.
Ulipristal is described by its manufacturer as “at least as effective as levonorgestrel” and as the first in a new class of drugs called synthetic selective progesterone receptor modulators. This emergency hormonal contraceptive is effective for up to five days after unprotected sexual intercourse. It acts by high-affinity binding to the progesterone receptor and is thought to inhibit or delay ovulation.
Alterations to the endometrium may also contribute to ulipristal’s efficacy (PJ, 10 October 2009, p375).
Other therapeutic areas
In other therapeutic areas, one medicine worth a mention is romiplostim, a drug indicated for the treatment of thrombocytopenic purpura. Marketed as Nplate by Amgen, it is a new platelet producer (PJ, 3 October 2009, p352) and is licensed for use by splenectomised patients who are refractory to other treatments. It can also be used as second-line treatment for non-splenectomised patients where surgery is contraindicated. Romiplostim is an Fc-peptide fusion protein that signals and activates intracellular pathways to increase platelet production.
Other new medicines launched in 2009 are listed in Panel 2. Of note is the observation that no innovative medicines to combat infectious diseases were launched in the past 12 months.
Panel 2: Other new medicines launched in 2009
Ustekinumab (Stelara; Janssen-Cilag), a new treatment for moderate to severe plaque psoriasis in adults (PJ, 14 February 2009, p153). This monoclonal antibody is believed to interrupt signalling and cytokine cascades that are connected to the pathology of psoriasis.
Rupatadine (Rupafin; GlaxoSmithKline), a second-generation, long-acting antihistamine with selective peripheral H1-receptor antagonist activity for the treatment of allergic rhinitis and chronic idiopathic urticaria (PJ, 13 June 2009, p698).
Nepafenac (Nevanac; Alcon), a new non-steroidal anti-inflammatory drug for the prevention and treatment of postoperative pain and inflammation associated with cataract surgery. The eye drop suspension penetrates the cornea and is converted to amfenac, another NSAID that inhibits the action of prostaglandin H synthase, which is required for prostaglandin production (PJ, 13 June 2009, p698).
Tolvaptan (Samsca; Otsuka Pharmaceutical), the first oral vasopressin receptor antagonist to be available in Europe to treat hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). The drug works by promoting the excretion of electrolyte-free water from the kidneys (PJ, 15 August 2009, p174).
Tafluprost (Saflutan; Merck Sharp & Dohme), in the form of a preservative-free eye drop for glaucoma. This new prostaglandin is indicated for the reduction of elevated intraocular pressure in open angle glaucoma and in ocular hypertension (PJ, 12 September 2009, p266).
Reclassifications and safety
April 2009 saw the launch of the first non-prescription weight loss drug — orlistat (Alli) — by GlaxoSmithKline (PJ, 25 April 2009, p473). Another POM-to-P switch that made progress during 2009 was for the benign prostatic hyperplasia drug tamsulosin. Its reclassification was completed towards the end of the year and the P medicine is expected to hit pharmacy shelves in early 2010 (PJ, 12 December 2009, p639).
Both reclassifications, however, were associated with safety concerns. Consumer champions were quick to scrutinise the handling of pharmacy sales of orlistat and the profession came in for criticism when some pharmacies were reported to be selling the drug inappropriately (PJ, 2 May 2009, p505 and 1 August 2009, p118). Guidance from the Royal Pharmaceutical Society emphasised the need for appropriate counselling and the need to be vigilant for vulnerable people who might try to obtain orlistat for the wrong purposes.
Concerns about tamsulosin’s switch were also expressed by the Society, which suggested that the pharmacy supply model put forward by Boehringer Ingelheim, the company behind the switch application, could allow patients to buy the product from more than one pharmacy, leading to overuse of the drug, or missed or delayed diagnosis (PJ, 24 January 2009, p64). Guidance on handling sales of tamsulosin is currently being prepared by the Society.
In contrast to these POM-to-P switches, some medicines had the restrictions associated with their use tightened in 2009.
A range of cough and cold medicines are no longer recommended for use in children under six years of age. And many general sale list cough and cold medicines approved for use in children aged six to 12 years have been reclassified as pharmacy medicines (PJ, 7 March 2009, p237).
Oral pain relief gels containing salicylate should no longer be used in children aged under 16 years (PJ, 25 April 2009, p471). The advice, issued by the Medicines and Healthcare products Regulatory Agency, is based on a theoretical risk that salicylate salts might have the same effect as aspirin and could increase the possibility of a child developing Reye’s syndrome.
Cardiac side effects and reports of progressive multifocal leukoencephalopathy prompted the respective withdrawals of orciprenaline sulphate syrup and efalizumab, a treatment for severe chronic plaque psoriasis, from the UK market (PJ, 7 November 2009, p499 and 13 June 2009, p696).
Concerns around the over use of antipsychotic drugs in dementia led to various Government strategies, with pharmacy input an integral part of the solutions put forward (PJ, 7 February 2009, p125 and 21 November 2009, p558).
For the pharmacy profession, 2009 was not a year of extremes as far as clinical developments were concerned. But a steady supply of new medicines and the continued roll out of innovative services kept things ticking along nicely. The Journal will continue to report similar developments in the year ahead (2010).
ACKNOWLEDGEMENT Katrina Simister, managing editor, new medicines scheme, National Prescribing Centre.
Citation: The Pharmaceutical Journal URI: 10992506
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