Company: Biogen Idec Ltd.

Legal category: Prescription. High tech. Sport permitted.

Active ingredient: Dimethyl fumarate 120mg, 240mg.

Description: Green/white or green gastro-resistant hard capsules marked with BG-12 and strength, respectively.

Presentation: 120mg-14, €283.00; 240mg-56, €1132.00.

Indication: Treatment of relapsing remitting multiple sclerosis.

Pharmacology: The mechanism by which dimethyl fumarate exerts therapeutic effects is not fully understood. Studies indicate that its pharmacodynamic responses are primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway. It up regulates Nrf2-dependent antioxidant genes in patients (e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]). Dimethyl fumarate has demonstrated anti-inflammatory and immunomodulatory properties and, along with its primary metabolite (monomethyl fumarate), significantly reduces immune cell activation and subsequent release of pro-inflammatory cytokines in response to inflammatory stimuli.

Dosage: Adult: Do not crush, divide, dissolve, suck or chew. Take with food. Initiate under supervision. Initially, 120mg twice daily. After 7 days, increase to 240mg twice daily. Reduce to 120mg twice daily if flushing and gastrointestinal adverse reactions occur (resume at 240mg twice daily within 1 month). Elderly: As per adults. Children: 10-18 years, not recommended. Under 10 years, no relevant use.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy (only if clearly needed), lactation. Consider non-hormonal contraception.

Special precautions: Resolve serious infections prior to initiation; consider suspending if develop during treatment (assess benefit/risk of re-initiation); patients should report symptoms of infections. Perform complete blood count, including lymphocytes, prior to initiation then every 3 months during treament. Consider suspending if lymphocyte counts <0.5×109/L persist for more than 6 months. Assess renal and hepatic function prior to initiation, 3 and 6 months after initiation, every 6-12 months thereafter and as indicated. Obtain baseline MRI (within 3 months) before initiation; perform immediately if Progressive Multifocal Leukoencephalopathy (PML) suspected. Caution: Severe renal/hepatic impairment, severe gastrointestinal disease, pre-existing low lymphocyte counts. Severe flushing reactions (may require hospitalisation). Severe prolonged lymphopenia (may be risk of opportunistic infection, including PML). Switching from other disease modifying therapies, safety and efficacy not established.

Drug interactions: Do not use live vaccines (assess risk/benefit). Avoid: Other fumaric acid derivatives. Not recommended: Acetylsalicylic acid (long term use for management of flushing). Caution: Anti-neoplastic or immunosuppressive therapies. Nephrotoxic drugs. Large quantities of undiluted strong alcohol (>30% alcohol by volume).

Adverse drug reactions: Gastroenteritis, lymphopenia, leucopenia, burning sensation, flushing, hot flush, gastrointestinal disorders, pruritus, rash, erythema, proteinuria, feeling hot, ketones measured in urine, albumin urine present, increased aspartate aminotransferase, increased alanine aminotransferase, decreased white blood cell count.

Full prescribing information and references available from Biogen Idec Ltd. Telephone: 1800 812 719. Fax: +44 1748 828 801. E-mail: biogen@professionalinformation.co.uk

Tara Sweeney

Company: Meda Health Sales Ireland Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Colecalciferol 4000IU.

Description: White to light yellow, oblong tablet with a score line to facilitate breaking for ease of swallowing.

Presentation: 70, €19.75.

Indication: Treatment of vitamin D deficiency.

Pharmacology: Vitamin D increases the intestinal absorption of calcium and phosphate. Vitamin D3 counteracts the increase of parathyroid hormone caused by calcium deficiency which causes increased bone resorption. In addition to bone and intestinal mucosa many other tissues have vitamin D receptors, to which the active hormonal form of vitamin D, calcitriol, binds.

Dosage: Adult: One tablet daily (maximum). Adjust dose based on serum levels of 25-hydroxycolecalciferol (25(OH)D), disease severity and response. Elderly: As per adults. Children: Under 12 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Diseases/conditions resulting in hypercalcaemia or hypercalciuria. Nephrolithiasis. Nephrocalcinosis. Hypervitaminosis D.

Special precautions: Severe renal impairment (do not use). Caution: Sarcoidosis (monitor calcium in serum and urine), renal impairment (monitor calcium and phosphate levels), long term treatment (monitor serum calcium and creatinine levels; esp. in elderly on concomitant cardiac glycosides or diuretics and in patients with a high tendency to calculus formation). Reduce dose or discontinue if hypercalciuria or renal impairment occurs. Hypercalcaemia may occur (excessive dosing): May increase risk of digitalis toxicity and serious arrhythmias; monitor ECG and serum calcium levels closely. Pregnancy (only in cases of vitamin D deficiency). Contains sucrose and isomalt.

Drug interactions: Other vitamin D products, thiazide diuretics, phenytoin, barbiturates, glucocorticoids (may need to increase Desunin dose), ion exchange resins (cholestyramine), laxatives (paraffin oil).

Adverse drug reactions: None common.

Full prescribing information and references available from Meda Health Sales Ireland Ltd. Telephone: (01) 802 6624. E-mail: info@meda.ie

Tara Sweeney

Company: Clonmel Healthcare Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Alendronic acid 70mg (as alendronate sodium trihydrate).

Description: White round effervescent tablets.

Presentation: 4, €19.64.

Indications: Treatment of postmenopausal osteoporosis. Reduces the risk of vertebral and hip fractures.

Pharmacology: Alendronate sodium trihydrate is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation. The buffered, drinkable solution of high pH with acid neutralising capacity minimises particulate alendronate from contacting the mucosa and prevents strong stomach acid from being present in the stomach, and diminishes damage potential in cases of oesophageal reflux.

Dosage: Adult: Do not chew or swallow whole. 70mg once weekly dissolved in half a glass of plain water followed by at least 30ml of plain water at least 30 minutes before the first food, beverage, or drug of the day. Re-evaluate need for continued treatment periodically, particularly after 5 or more years of use. Do not lie down for at least 30 minutes after first food of the day. Do not take at bedtime or before arising for the day. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Abnormalities of the oesophagus and other factors which delay oesophageal emptying, such as stricture or achalasia. Inability to stand or sit upright for at least 30 minutes. Hypocalcaemia. Pregnancy, lactation.

Special precautions: Not recommended: Renal impairment (GFR<35ml/min). Causes of osteoporosis other than oestrogen deficiency and ageing or glucocorticoid use should be considered. May cause local irritation of the upper gastrointestinal (GI) mucosa. Caution: Existing, or recent history of, upper GI problems (dysphagia, oesophageal disease, gastritis, duodenitis, ulcers, GI bleeding, surgery excluding pyloroplasty). Barrett’s oesophagus, assess risk/benefit. Warn patients of side effects (sometimes severe and requiring hospitalisation) in the oesophagus (oesophagitis, oesophageal ulcer, oesophageal erosion, rarely followed by oesophageal stricture). Patients should discontinue and seek medical advice if oesophageal irritation develops such as dysphagia, pain when swallowing, retrosternal pain, new or worsening heartburn. Greater risk in patients not taking dose correctly or continuing treatment despite symptoms (warn patients). Rare cases of gastric and duodenal ulcers (some severe and with complications). Treat hypocalcaemia and other disturbances of mineral metabolism (e.g. vitamin D deficiency and hypoparathyroidism) before initiating treatment; monitor serum calcium and symptoms of hypocalcaemia during treatment. Symptomatic hypocalcaemia reported rarely; severe cases in patients with predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency or calcium malabsorption). Ensure sufficient intake of calcium and vitamin D especially in patients receiving glucocorticoids. Osteonecrosis of the jaw reported. Dental examination with appropriate preventive dentistry should be considered prior to treatment in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene, history of dental disease, periodontal disease, smoking, poorly fitting denture). Avoid invasive dental procedures if possible. Good oral hygiene and routine dental check-ups recommended. Advise patients to report any thigh, hip or groin pain. Femoral stress fractures may occur (long-term treatment; discontinue pending evaluation). Reported: Severe skin reactions including Steven Johnson syndrome and toxic epidermal necrolysis (rare), bone, joint and/or muscle pain. Glucocorticoid-induced osteoporosis, no data. Contains sodium.

Drug interactions: Wait at least 30 minutes after taking alendronate before taking any other oral product (food, beverages including mineral water, calcium supplements, antacids, oral medicines). Caution: NSAIDs.

Adverse drug reactions: Headache, GI upset, oesophageal ulcer, dysphagia, abdominal distension/pain, acid regurgitation, musculoskeletal pain, dizziness, vertigo, alopecia, pruritus, joint swelling, asthenia, peripheral oedema.

Full prescribing information and references available from Clonmel Healthcare Ltd. Telephone: (052)-6177777. Fax: (052)-6177791. E-mail: medicalinformation@clonmel-health.ie

Tara Sweeney

In December 2015, the HPRA commenced publication of approved educational materials and tools for medicines on its website (www.hpra.ie).

Educational materials are additional risk minimisation measures that are intended to promote the safe and effective use of the medicinal product. While the approved product information (the Summary of Product Characteristics (SmPC), Package Leaflet (PL) and product labelling) provides all relevant information for medicinal products, educational materials focus on one or more specific safety concerns related to use of a particular medicinal product so as to provide clear information on these specific risks and describe concisely what actions are required to prevent and minimise such risks.

Educational materials may be intended for healthcare professionals (e.g. doctors, pharmacists and nursing staff) and/or patients and care-givers. For example, educational materials may outline what a doctor needs to consider before prescribing a medicine for their patient, or what specific monitoring (e.g. regular blood tests) is required while their patient is on that medicine. Likewise, educational materials may help in reminding patients about important safety information that they need to be aware of before and during treatment with a medicine so that they use the medicine safely and effectively. They may also provide advice to patients on when to seek medical advice. Examples of educational materials for healthcare professionals include healthcare professional guides, dosing and administration guides, prescriber checklists and monitoring charts. Examples of educational materials directed at patients include patient alert cards, patient guides and patient reminder cards.

Educational materials are produced and distributed by the Marketing Authorisation Holder (MAH, i.e. license holder) of the medicinal product and are specific to that medicinal product. They are not required for all medicines but rather are provided if it is considered that they will aid in optimising the safe and effective use of the product. The need for educational materials is agreed with the HPRA and may be decided at the time of approval of the medicinal product or at a later time in the lifecycle of the product.

Only educational materials which have been reviewed and approved by the HPRA are included on the list published on the HPRA website. These materials are published with the agreement of the MAH responsible for producing them and may be downloaded for use by healthcare professionals and patients. Please note the HPRA does not provide hard copies of these materials. If hard copies are required, the relevant MAH for the medicinal product should be contacted.

Currently available, approved educational materials are located on the HPRA website (under Medicines-Safety Information-Educational Materials for Medicines). Further information in relation to educational materials may be obtained by contacting the HPRA Vigilance Department at medvigilance@hpra.ie

Caroline McDermott

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recently advised that healthcare professionals and patients be informed of recent product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) changes in relation to the immunosuppressive effect of fingolimod and to reiterate some important recommendations for use.

Fingolimod is a sphingosine-1-phosphate receptor modulator, metabolised by sphingosine kinase to the active metabolite fingolimod-phosphate. It is indicated as single disease modifying therapy in adult patients with highly active relapsing remitting multiple sclerosis despite a full and adequate course of treatment with at least one disease-modifying therapy. It has been approved in the US since September 2010 and for use across the EU since March 2011.

Due to its potent immunosuppressive effects, patients are at risk of serious adverse reactions and healthcare professionals are advised as follows:

Advice to Healthcare Professionals

Basal Cell Carcinoma (BCC)

• Cases of BCC have been reported in patients receiving fingolimod from both the clinical trial setting and post-marketing surveillance.
• Healthcare professionals and patients should be aware that vigilance for skin lesions is warranted.
• Medical evaluation of the skin is recommended at initiation, after at least one year and then at least yearly taking into consideration clinical judgement.
• Patients should be referred to a dermatologist if suspicious lesions are detected.
• Patients with active malignancies (including BCC) should not be treated with fingolimod.

Opportunistic Infections

The immunosuppressive effects of fingolimod may increase the risk of CNS infections including opportunistic infections such as viral (e.g. herpes simplex virus, varicella zoster virus), fungal infections (e.g. cryptococcal meningitis) or bacterial infections (e.g. atypical mycobacterium). Prescribers are therefore reminded that:

• Initiation of treatment with fingolimod should be delayed in patients with severe active infection until the infection is completely resolved.
• The benefit-risk balance of using fingolimod should be considered for each individual patient prior to initiation of treatment and also prior to re-initiation of treatment.
• Suspension of treatment should be considered if a patient develops a serious infection.
• Following discontinuation of treatment, fingolimod may take up to two months to be eliminated from the body and healthcare professionals and patients should be alert for symptoms of infection during this period.

Lymphoma

• Cases of lymphoma have been reported in patients treated with fingolimod.

Progressive Multifocal Leukoencephalopathy (PML)

• PML is an opportunistic infection which may be fatal or result in severe disability and cases of PML have been reported in association with fingolimod.
• Before initiating treatment with fingolimod, a baseline MRI should be available (usually within 3 months as a reference).
• During routine MRI scans, healthcare professionals should pay attention to PML suggestive lesions.
• Patients and carers should be informed of the early symptoms suggestive of PML (e.g. change in behaviour/mood, memory lapses, speech difficulties) and recommended to seek immediate medical attention if any of these symptoms are experienced.
• If PML is suspected, treatment with fingolimod should be suspended until PML has been excluded.
• PML only occurs in the presence of a JCV infection. If JCV testing is undertaken however, it should be considered that the influence of lymphopenia on the accuracy of the anti-JCV antibody test has not been studied in fingolimod treated patients. Therefore a negative JCV antibody test does not preclude the possibility of subsequent JCV infection.

Complete Blood Count (CBC) Monitoring

• A recent (i.e. within the last six months or after discontinuation of prior therapy) complete blood count (CBC) should be available to healthcare professionals prior to initiating treatment with fingolimod to ensure that immune effects of previous therapy have resolved.
• Assessment of CBC is also recommended periodically during treatment i.e. three months after starting treatment and at least annually thereafter. CBC should also be measured in case of signs of infection.

Key Message

• In patients receiving fingolimod, medical evaluation of the skin before treatment initiation and during treatment is recommended due to a risk of BCC.
• Healthcare professionals/carers should be alert to the risk of PML and should inform patients/carers of early symptoms suggestive of PML recommending they seek medical advice if any experienced. During routine MRI scans, healthcare professionals should pay close attention to lesions suggestive of PML.
• Treatment with fingolimod should not be initiated in patients with severe active infection and suspension of treatment should be considered if a patient develops a serious infection.
• A complete blood count (CBC) should be available prior to initiating treatment and regular CBC is recommended (i.e. 3 months after commencing treatment and at least annually thereafter).
• A Direct Healthcare Professional Communication (DHPC) was circulated to relevant healthcare professionals in January and is available from the HPRA website.
• The product information for fingolimod (SmPC and PL) will be updated with this information.

*Further details on Gilenya are available on www.hpra.ie and www.ema.europa.eu

Caroline McDermott

Therapeutic Use Exemption (TUE) Committee Policy on Glucocorticoid Injections for Hay Fever

Depo-Medrone (Methylprednisolone) and Kenalog* (Triamcinolone) administered by intra-muscular injection as treatment for hay fever are prohibited in sport and therefore their use requires the athlete and their physician to strictly adhere to the TUE Policy. The TUE Policy is available at www.irishsportscouncil.ie/Anti-Doping/Athlete-Zone/Therapeutic-Use-Exemptions-/

• Athletes included in their International Federation Registered Testing Pool and/or athletes competing at International Competition will require a Therapeutic Use Exemption in advance of receiving an intra-muscular glucocorticoid. These athletes should contact their sport’s Anti-Doping Officer for assistance in identifying International Competitions and establishing the requirements for a TUE Application.

• Athletes included in the Sport Ireland Registered Testing Pool that are not competing at an International Competition should apply to Sport Ireland for a Pre-test Therapeutic Use Exemption, using the information in the Medical File section below to aid them, prior to receiving an intra-muscular glucocorticoid.

• Athletes eligible for a post-test TUE application (see www.irishsportscouncil.ie/Anti-Doping/Athlete-Zone/Therapeutic-Use-Exemptions-/) should ensure that they are capable of providing a medical file to the standard outlined below, prior to the administration of any intra-muscular glucocorticoid injection by a physician. Athletes may be required to submit this medical file to support a TUE application at a later date.

Medical File

Intra-muscular glucocorticoid TUE applications MUST be accompanied by a medical file reflecting current best medical practice to include:

1. A complete medical history i.e. when the hay fever began; the associated symptoms, their severity and effect on sporting performance; and symptoms suffered in previous hay fever episodes.
2. Clinical evidence of attempting to use alternative permitted oral, nasal and/or ophthalmic medications and justification as to why alternative permitted medications are not sufficient.
3. Copies of all relevant examinations, laboratory results/reports and clinical notes (for example, if a clinic visit is referenced in a letter or summary, a copy of the clinical notes taken during the visit must be submitted); provide details of any known allergens or allergic history including results of any previous immunological testing.
4. Exact name, speciality, address (including telephone, e-mail, fax) of examining physician.

Permitted Medications

Athletes and their physicians are reminded that there are a number of permitted medications, both over-the-counter and prescribed, that can be used for the treatment of hay fever (as checked on the Drugs in Sport Database on www.eirpharm.com, 23^rd March 2016) such as:

Over-the-counter medications (examples)

• Oral Antihistamines: e.g. Loratidine (brands – Clarityn, Lorat etc.), Cetirizine (brands – Cetriz, Cetrine Allergy), Chlorphenamine (brand – Piriton; note – can cause drowsiness)
• Decongestant Nasal Drops/Sprays: e.g. Otrivine Adult nasal drops, Otrivine Adult nasal spray
• Glucocorticoid Nasal Sprays: e.g. Beconase Hayfever, Flixonase Allergy
• Eye Drops: e.g. Otrivine-Antistin eye drops, Opticrom Allergy eye drops

Prescribed medications (examples)

• Oral Antihistamines: e.g. Neoclarityn, Telfast
• Oral Allergen Extracts: e.g. Grazax, Oralair
• Glucocorticoid Nasal Sprays: e.g. Avamys nasal spray, Rhinolast nasal spray, Nasonex nasal spray

*Note: While Kenalog Injection has been discontinued from the Irish market some unlicensed product may be available.

Updated 23^rd March 2016

Caroline McDermott

Details of a new national study ‘Understanding and Attitudes toward Cancer Clinical Research (CCR) among Patients with a Cancer Diagnosis’ were announced on Monday 18^th April 2016. The study aims to increase participation rates in Ireland to clinical trials by increasing patients’ understanding of cancer clinical trials.

The research is being conducted by All Ireland Cooperative Oncology Research Group (ICORG), and Dr Cathy Kelly and Dr Ciara Kelly from Mater Misericordiae University Hospital and Mater Private Hospital in Dublin are the principal investigators.

Currently only 3–5 % of all cancer patients participate in clinical trials annually. It is hoped that the research will ultimately result in increased participation rates in clinical trials.

The research will evaluate oncology patients’ understanding of the term ‘clinical trials’; assess attitudes towards personal participation in cancer clinical research including clinical trials; and compare study results between oncology patients and that of the general public. All 12 cancer centres in Ireland with clinical trial research units are participating in the study, and it is open to 1000-1200 patients.

Dr Kelly, Chair of ICORG Breast Group said, “Work conducted by the Irish Platform for Patient Organisations, Industry and Science (IPPOSI) showed that the general population were reluctant to participate in clinical trials and a pilot study conducted among individuals with a cancer diagnosis revealed that up to 44% of cancer patients were reluctant to participate in clinical trials due to perceived side effects of treatment, inability to see the benefit for them and preference for standard of care. Furthermore willingness to participate in a trial was significantly affected by level of education and whether that patient had advanced or early stage cancer”.

The study will be opening in all cancer centres around the country and patients will be asked to complete a questionnaire. The information obtained will be used improve understanding of the demographic characteristics of each cancer centre, identify the best forms of educational information about clinical trials and the best ways to deliver it in order to improve clinical trial participation.

For more information on the study, and to check if you are eligible for participation in same, please contact ICORG, 60 Fitzwilliam Square, Dublin 2, (01) 667 7211 (www.icorg.ie) for more information.

Caroline McDermott

Download PDF

Most cases of cervical cancer are preventable by routine screening with a Pap test (which may be combined with a test for human papillomavirus [HPV]) and by treatment of pre-cancerous lesions. Early detection greatly improves the chances of successful treatment and prevents any early cervical cell changes from becoming cancerous. Women with early cervical cancers and pre-cancers usually have no symptoms. Symptoms often do not begin until the cancer becomes invasive and grows into nearby tissue.

In Ireland, on average 180 women develop cervical cancer each year with 73 deaths from the disease. The average age at diagnosis is 46 years and of death is 56 years. Persistent HPV infection is recognised as the most important etiologic factor in cervical cancer, far outweighing other known risk factors. An estimated 80% of sexually active women become infected with at least one type of HPV by age 50 years.

Risk Factors

HPV is a double stranded DNA virus that infects squamous epithelia, including the skin and mucous membranes of the upper respiratory and anogenital tracts, where it causes warts and abnormal tissue growth.

Most genital HPV infections are asymptomatic and transient, with 70% of new genital HPV infections clear within one year and 91% within two years. However, high-risk types are more persistent than low-risk types. Persistent infection over a number of years may lead to grade 2 or 3 cervical intraepithelial neoplasia (CIN) and cervical cancer.

The strain of HPV infection is important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. HPV subtypes 16 and 18 cause approximately 70% of cervical cancers while HPV types 6 and 11 cause approximately 90% of genital warts.

Other risk factors for cervical cancer include:

• High parity
• Increased number of sexual partners
• Young age at time of first sexual intercourse
• Low socioeconomic status
• History of smoking
• Long-term use of oral contraceptives

Symptoms

Early cervical cancer is often asymptomatic, while locally advanced disease could cause symptoms including:

• Abnormal vaginal bleeding, such as bleeding after vaginal intercourse, bleeding after menopause, bleeding and spotting between periods, and having periods that are longer or heavier than usual. Bleeding after douching or after a pelvic exam may also occur.
• An unusual discharge from the vagina − the discharge may contain some blood and may occur between periods or after menopause.
• Pain during intercourse.

Diagnosis

The first step in finding cervical cancer is often an abnormal Pap test result. This will lead to further tests which can diagnose cervical cancer. Cervical cancer may also be suspected if symptoms are present. Tests for women with symptoms of cervical cancer or abnormal Pap results include:

• Medical history and physical exam
• HPV test
• Colposcopy
• Cervical biopsies
• Colposcopic biopsy
• Endocervical curettage
• Cone biopsy: Methods commonly used for cone biopsies are the loop electrosurgical excision procedure (LEEP), also called the large loop excision of the transformation zone (LLETZ), and the cold knife cone biopsy.

Pre-cancerous changes in a biopsy are called cervical intraepithelial neoplasia. CIN is graded on a scale of 1 to 3 based on how much of the cervical tissue looks abnormal when viewed under the microscope.

• CIN1; not much of the tissue looks abnormal (considered the least serious cervical pre-cancer)
• CIN2; more of the tissue looks abnormal
• CIN3; most of the tissue looks abnormal (most serious pre-cancer [includes carcinoma in situ])

The WHO recognises three categories of epithelial tumours of the cervix: squamous, adenocarcinoma, and other epithelial tumours including neuroendocrine tumours and undifferentiated carcinoma. Squamous cell carcinomas account for ∼70%–80% of cervical cancers and adenocarcinomas for 10%–15%.

Other diagnostic tests include: Cystoscopy, proctoscopy, and exam under anaesthesia; imaging studies; chest x-ray; computed tomography; magnetic resonance imaging; intravenous urography; positron emission tomography.

Staging and risk assessment

The cervical cancer Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) classification is based on clinical examination (tumour size, vaginal or parametrial involvement, bladder / rectum extension, and distant metastases).

It requires radiological imaging such as chest x-ray and intravenous pyelogram. Other imaging studies have been used to more accurately define the extent of disease. Computed tomography (CT) can detect pathologic lymph nodes, while magnetic resonance imaging (MRI) can determine tumour size, degree of stromal penetrations, vaginal extension, and corpus extension with high accuracy. Positron emission tomography (PET) has been seen to have the potential to accurately delineate the extent of disease, particularly in lymph nodes that are not macroscopically enlarged and in distant sites, with high sensitivity and specificity.

Tumour risk assessment includes tumour size, stage, depth of tumour invasion, lymph node status, lymphovascular space involvement (LVSI), and histological subtype. Lymph node status and number of lymph nodes involved are the most important prognostic factors. In stages IB-IIA, the 5-year survival rate without lymph node metastasis and with lymph node metastasis is 88%–95% and 51%–78%, respectively.

Prognostic Factors

The prognosis for patients with cervical cancer is affected by the extent of disease at the time of diagnosis. More than 90% of cervical cancer cases can be detected early through the use of the Pap test and HPV testing.

Clinical stage as a prognostic factor is acompanied by several gross and microscopic pathologic findings in surgically treated patients.

In a large, surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG), the factors that most prominently predicted for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumour, increasing tumour size, and increasing depth of stromal invasion (the latter being the most important and reproducible).

A multivariate analysis of prognostic variables in patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:

• Periaortic and pelvic lymph node status
• Tumour size
• Patient age
• Performance status
• Bilateral disease
• Clinical stage

Other prognostic factors that may affect outcome include:

• Human immunodeficiency virus (HIV) status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.
• C-myc overexpression: Patients with known invasive squamous carcinoma of the cervix with overexpression of the C-myc oncogene was associated with a poorer prognosis.
• Number of cells in S phase: May also have prognostic significance in early cervical carcinoma.
• HPV-18 DNA: Worse outcome observed when HPV-18 identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.
• Polymorphism in the Gamma-glutamyl hydrolase enzyme (related to folate metabolism): Shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.

Treatment options

The stage of a cervical cancer is the most important factor in choosing treatment. However, other factors that affect this decision include the exact location of the cancer within the cervix, the type of cancer (squamous cell or adenocarcinoma), age, overall physical condition, and whether the patient wants to preserve fertility.

Management of local / locoregional disease

Depending on stage, primary treatment consists of surgery, radiotherapy, or a combination of radiotherapy and chemotherapy. Definitive radiation therapy should consist of pelvic external beam radiation with high-energy photons and intracavitary brachytherapy, and must be administered at high doses and in a short time.

Management of advanced / metastatic disease

Patients with metastatic or recurrent cervical cancer are commonly symptomatic. The role of chemotherapy in such patients is palliative, with the primary objective to relieve symptoms and improve quality of life. The response rates after previous chemotherapy are worse compared with chemotherapy naïve patients.

Chemotherapy agents include: Cisplatin, carboplatin, paclitaxel, topotecan, gemcitabine, docetaxel, ifosfamide, irinotecan, and vinorelbine.

Single-agent cisplatin administered intravenously at 50mg/m² every 3 weeks has been the regimen most often used to treat recurrent cervical cancer since the drug was initially introduced in the 1970’s.

Cisplatin-based combination therapy, such as cisplatin-paclitaxel, cisplatin-topotecan, cisplatin-gemcitabine, cisplatin-ifosfamide, and cisplatin-vinorelbine are also used.

The targeted drug bevacizumab may be added to chemotherapy. It is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) and inhibits angiogenesis. Bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of patients with persistent, recurrent, or metastatic carcinoma of the cervix.

 Click on image to enlarge

References: 1. Health Service Executive. Immunisation Guidelines for Ireland 2013. Chapter 10 Human Papillomavirus. Available at http://www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/chapter10.pdf. Accessed 18^th April 2016. 2. Colombo N et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 23 (Supplement 7): vii27–vii32, 2012. 3. National Cancer Institute. Available at http://www.cancer.gov/types/cervical/hp/cervical-treatment-pdq. Accessed 18^th April 2016. 4. American Cancer Society. Available at http://www.cancer.org/cancer/cervicalcancer/index. Accessed 18^th April 2016.

MIMS Ireland Copyright®

Caroline McDermott

Company: Bristol-Myers Squibb Pharmaceuticals.

Legal category: Prescription. Hospital only. Sport permitted.

Active ingredient: Nivolumab 10mg/ml.

Description: Concentrate for solution for infusion in vial.

Presentation: 1 x 4ml, 1 x10ml; price available on request.

Indications: As monotherapy for treatment of advanced (unresectable or metastatic) melanoma. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. As monotherapy for treatment of advanced renal cell carcinoma (RCC) after prior therapy.

Pharmacology: Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that is involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands.

Dosage: Adult: Administer 3mg/kg as intravenous infusion over 60 minutes every 2 weeks. Treatment modifications: See SPC. Continue as long as benefit observed or until no longer tolerated. Elderly: As per adults. NSCLC: 75 years or older, limited data. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy, lactation. Use effective contraception during treatment and for at least 5 months following last dose.

Special precautions: Do not administer as intravenous push or bolus injection. Caution: Moderate or severe hepatic impairment. Severe renal impairment, limited data. Consider delayed onset of nivolumab effect before initiation in melanoma patients with rapidly progressing disease and non-squamous NSCLC. Monitor for immune-related adverse reactions (during treatment and for at least up to 5 months after last dose) such as pneumonitis, colitis, hepatitis, nephritis or renal impairment, endocrinopathies (see SPC), rash; evaluate if suspected and exclude other causes; based on severity, suspend nivolumab and administer corticosteroids; upon improvement, may resume nivolumab after corticosteroid taper; permanently discontinue for any severe reaction that recurs or is life-threatening. Caution: Melanoma and NSCLC patients, baseline performance score ≥2, active brain metastases or autoimmune disease, use of systemic immunosuppressants prior to initiation; melanoma patients only, ocular melanoma, Grade 4 adverse reaction to anti-CTLA-4 therapy; NSCLC patients only,  symptomatic interstitial lung disease; RCC patients only, brain metastases (or history), active autoimmune disease, conditions requiring systemic immunosuppression. Previously untreated BRAF mutation-positive melanoma, limited experience. Infusion reactions; severe or life-threatening (discontinue), mild or moderate (closely monitor and use premedication). Contains sodium.

Drug interactions: Avoid systemic corticosteroids and other immunosuppressants at baseline before initiation (can use after initiation).

Adverse drug reactions: Upper respiratory tract infection, infusion related reaction, hypersensitivity, hypothyroidism, hyperthyroidism, hyperglycaemia, decreased appetite, decreased weight, peripheral neuropathy, headache, dizziness, blurred vision, dry eye, hypertension, pneumonitis, dyspnoea, cough, gastrointestinal disorders, rash, pruritus, vitiligo, dry skin, erythema, alopecia, musculoskeletal pain, arthralgia, fatigue, pyrexia, oedema (including peripheral), hypocalcaemia, lymphopaenia, leucopoenia, thrombocytopaenia, anaemia, hypercalcaemia, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, neutropaenia, hypermagnesaemia, hypernatraemia. Increased: AST, ALT, alkaline phosphatase, lipase, amylase, creatinine, total bilirubin.

Full prescribing information and references available from Bristol-Myers Squibb Pharmaceuticals. Telephone:1 800 749 749. E-mail: medical.information@bms.com

Tara Sweeney

Company: Dr Falk Pharma UK Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Ursodeoxycholic acid 250mg/5ml.

Description: Oral suspension with lemon odour.

Presentation: 250ml, €29.95.

Indications: Treatment of primary biliary cirrhosis (PBC) without decompensated hepatic cirrhosis. Dissolution of cholesterol gallstones in functioning gall bladders. Children: Hepatobiliary disorders associated with cystic fibrosis (CF).

Pharmacology: Ursodeoxycholic acid is found in small amounts in human bile. It reduces cholesterol saturation of bile by inhibiting cholesterol absorption in the intestine and decreasing cholesterol secretion into bile. Presumably as a result of dispersion of the cholesterol and formation of liquid crystals, a gradual dissolution of cholesterol gallstones occurs. The effect of ursodeoxycholic acid in hepatic and cholestatic diseases is thought to be due to a relative exchange of lipophilic, detergent-like, toxic bile acids for the hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, to an improvement in the secretory capacity of the hepatocytes, and to immune-regulatory processes. Ursodeoxycholic acid can decrease bile duct proliferation, halt progression of histological damage and even reverse hepatobiliary changes in children with cystic fibrosis.

Dosage: Adult: PBC: 12-16mg per kg body weight (BW) daily. Take in divided doses for first 3 months. When liver function parameters improve, administer daily dose once a day in the evening. If symptoms worsen reduce dose to 250mg daily, then gradually increase. Gallstones: 10mg/kg/day at bedtime for 6-24 months. Children: CF: 1 month to 18 years, 20mg/kg/day in 2-3 divided doses, may increase to 30mg/kg/day if necessary. Under 10kg BW, use single-use syringe. PBC, gallstones: Administration based on body weight and condition. See SPC.

Contraindications: Hypersensitivity to bile acids or any excipient of the formulation. Acute inflammation of gall bladder or biliary tract. Occlusion of biliary tract (common bile duct or cystic duct). Frequent episodes of biliary colic. Radio-opaque calcified gallstones. Impaired contractility of gall bladder. Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia. Unreliable contraception. Pregnancy (unless clearly necessary).

Special precautions: Monitor liver function parameters every 4 weeks during first 3 months; thereafter every 3 months. Use effective non-hormonal contraceptives. Gallstones: Monitor by ultrasound or X-ray every 6-10 months; discontinue if gallstones have calcified or if no reduction in size after 12 months. Reduce dose if diarrhoea occurs; discontinue if persistent. PBC: Decomposition of hepatic cirrhosis observed very rarely. Contains sodium.

Drug interactions: Colestyramine, colestipol or antacids containing aluminium hydroxide and/or oxide which bind and prevent absorption. Ciclosporin, ciprofloxacin, nitrendipine, dapsone, oestrogenic hormones, blood cholesterol lowering agents (such as clofibrate).

Adverse drug reactions: Gastrointestinal upset.

Full prescribing information and references available from Dr Falk Pharma UK Ltd. Telephone: (0044) 1628 536 600.

Tara Sweeney

Company: Rowex Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Rasagiline 1mg (as tartrate).

Description: White, round tablets.

Presentation: 30, €37.25.

Indications: Idiopathic Parkinson’s disease as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.

Pharmacology: Rasagiline is a potent, irreversible MAO-B selective inhibitor, which may increase extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline’s beneficial effects seen in models of dopaminergic motor dysfunction.

Dosage: Adult: 1mg once daily. Elderly: As per adults. Children: Not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment.

Special precautions: Avoid: Moderate hepatic impairment. Caution: Mild hepatic impairment (discontinue if progresses to moderate impairment). Monitor for impulse control disorders regularly. Skin lesions should be evaluated by a specialist. May increase adverse effects of levodopa and exacerbate pre-existing dyskinesia. Hypotensive effects reported (with levodopa), especially in Parkinson’s patients. Pregnancy, lactation. Driving/using machines.

Drug interactions: Contraindicated: Other monoamine oxidase inhibitors or pethidine (or within 14 days of rasagiline discontinuation). Avoid: Fluoxetine, fluvoxamine (See SPC). Not recommended: Dextromethorphan, sympathomimetics. Caution: Selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, tricyclic/ tetracyclic antidepressants, potent CYP1A2 inhibitors. Smoking, entacapone.

Adverse drug reactions: Hallucinations, gastrointestinal disorders, neck pain. Monotherapy only: Influenza, skin carcinoma, leucopenia, allergy, depression, headache, conjunctivitis, vertigo, angina pectoris, rhinitis, dermatitis, musculoskeletal pain, arthritis, urinary urgency, fever, malaise. Adjunct therapy only: Decreased appetite, decreased weight, abnormal dreams, dyskinesia, dystonia, carpel tunnel syndrome, orthostatic hypotension, rash, arthralgia, falls, balance disorder.

Full prescribing information and references available from Rowex Ltd. Telephone: 1800 304 400. Fax: (027) 50417.
E-mail: rowex@rowa-pharma.ie

Tara Sweeney

Company: Rowex Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredients: Macrogol 3350/ sodium chloride/ sodium hydrogen carbonate/ potassium chloride 13.125/ 0.3507/ 0.1785/ 0.0466g.

Description: Powder for oral solution.

Presentation: 30, €6.94.

Indications: Treatment of chronic constipation. Faecal impaction.

Pharmacology: Macrogol 3350 induces a laxative effect through osmotic action in the gut. It increases stool volume, which triggers colon motility via neuromuscular pathways resulting in improved propulsive colonic transportation of softened stools and facilitation of defaecation.

Dosage: Adult: Dissolve each sachet in 125ml water. Constipation: 1-3 sachets daily in divided doses, according to individual response for 2 weeks (can repeat course if required). Faecal impaction: 8 sachets daily within a 6 hour period for up to 3 days. Impaired cardiovascular function: Max 2 sachets in any one hour.
Elderly: As per adults. Children: Over 12 years, as per adults. Under 12 years: Not recommended.

Contraindications: Hypersensitivity to the active substances or any of the excipients. Intestinal obstruction or perforation (caused by functional/ structural disorder of gut wall, ileus), severe inflammatory conditions of intestinal tract (e.g. ulcerative colitis, Crohn’s disease, toxic megacolon).

Special precautions: Not recommended: Prolonged use. Withdraw immediately and measure electrolytes if fluid/electrolyte shifts (e.g. oedema, shortness of breath, increasing fatigue, dehydration, cardiac failure) develop. Contains sorbitol. Pregnancy, lactation (only if essential).

Drug interactions: Alcohol-soluble and water-insoluble drugs. Anti-epileptics.

Adverse drug reactions: Abdominal distension and pain, anal discomfort, flatulence, dyspepsia, vomiting, borborygmi, nausea, mild diarrhoea, allergic reactions including anaphylactic reaction, dyspnoea, urticaria, rash, angioedema, pruritus, electrolyte disturbances, headache, peripheral oedema.

Full prescribing information and references available from Rowex Ltd. Telephone: 1800 304400. Fax: (027) 50417.
E-mail: rowex@rowa-pharma.ie

Tara Sweeney

Company: Chiesi Ltd.

Legal category: Prescription. High tech reimbursable. Sport permitted.

Active ingredient: Tacrolimus (as monohydrate) 0.75mg, 1mg, 4mg.

Description: Oval, white, uncoated prolonged-release tablets marked with strength on one side and TCS on reverse.

Presentation: 0.75mg-30, €47.14, 1mg-30, €62.86; 4mg-30, €251.42.

Indications: Prophylaxis of transplant rejection in kidney or liver allograft recipients. Treatment of allograft rejection resistant to other immunosuppressive drugs.

Pharmacology: Tacrolimus is a highly potent immunosuppressive agent. It inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. It suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and g-interferon) and the expression of the interleukin-2 receptor. Its effects are mediated by binding to a cytosolic protein (FKBP12) which is responsible for intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing
transcription of a discrete set of cytokine genes.

Dosage: Adult: See SPC. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to other macrolides. Lactation.

Special precautions: During initial post-transplant period, monitor blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (especially potassium), liver and renal function, haematology, coagulation values, plasma proteins. Adjust formulation/regimen under supervision of transplant specialist. Caution: Congenital Long QT Syndrome (or suspected). EBV-associated lymphoproliferative disorders, cases of pure red cell aplasia, ventricular hypertrophy or hypertrophy of the septum reported (monitor high risk patients). Monitor tacrolimus concentration if diarrhoea occurs. Limit exposure to sunlight and UV light. Posterior reversible encephalopathy syndrome (discontinue). Increased risk for opportunistic infections (including BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy). Severe hepatic impairment. Limited experience: Non-Caucasian patients, patients at elevated immunological risk (e.g. retransplantation, evidence of panel reactive antibodies). Driving/using machines. Pregnancy (if benefit outweighs risk). Contains lactose.

Drug interactions: Avoid: Grapefruit juice, St John’s wort and other herbals, live attenuated vaccines, potassium supplements, potassium sparing diuretics, ciclosporin (take care if previously received). Caution: CYP3A4 inhibitors/ inducers/ substrates, nephrotoxic/neurotoxic drugs, oral contraceptives. Plasma protein bound drugs, prokinetics, cimetidine, magnesium-aluminium-hydroxide, phenytoin, pentobarbital, antipyrine.

Adverse drug reactions: Tinnitus, primary graft dysfunction. Disorders: Metabolism and nutrition (e.g. diabetes, hyperglycaemic conditions, hyperkalaemia), psychiatric (e.g. insomnia), nervous system (e.g. headache, tremor), vascular (e.g. hypertension), gastrointestinal, hepatobiliary (e.g. abnormal liver function tests), renal and urinary (e.g. renal impairment), blood and lymphatic system, eye, cardiac, respiratory, thoracic and mediastinal, skin and subcutaneous tissue, musculoskeletal and connective tissue, general. See SPC.

Full prescribing information and references available from Chiesi Ltd. Telephone: +44 (0) 1614 885 555. E-mail: Medinfo.uk@chiesi.com

Tara Sweeney

Company: LEO Pharma.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredients: Calcipotriol (as monohydrate)/betamethasone (as dipropionate) 50mcg/0.5mg per gram.

Description: Cutaneous foam.

Presentation: 60g, price available on request.

Indication: Topical treatment of psoriasis vulgaris.

Pharmacology: Calcipotriol is a vitamin D analogue. It induces differentiation and suppresses proliferation of keratinocytes. It also has an immunomodulatory effect, suppressing activation and differentiation of Th17/Th1 cells while inducing a Th2/Treg response. Betamethasone dipropionate is a corticosteroid with anti-inflammatory and immunosuppresive properties.

Dosage: Adult: Apply once daily for 4 weeks. 15g maximum daily dose of calcipotriol (including other topical products containing calcipotriol). Do not exceed application to 30% total body surface area. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substances or to any of the excipients. Calcium metabolism disorders. Erythrodermic/pustular psoriasis. Viral skin lesions, fungal/ bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis, perioral dermatitis, atrophic skin, striae atrophicae, skin vein fragility, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers, wounds.

Special precautions: Avoid face, eyes, mucous membranes. Wash hands after application. Avoid use on large areas of damaged skin, under occlusive dressings, skin folds. Avoid excessive exposure to natural/ artificial sunlight. Risk of hypercalcaemia at doses >15g daily. Treat secondary infections (discontinue if worsen). Risk of rebound effects on discontinuation; continue medical supervision post-treatment. Long-term use, discontinue if adverse reactions occur. Guttate psoriasis, severe renal/hepatic impairment; no data. Pregnancy (assess risk/benefit), lactation (do not use on breast). Contains butylhydroxytoluene (E321).

Drug interactions: Avoid: Other steroids.

Adverse drug reactions: None common.

Full prescribing information and references available from LEO Pharma. Telephone: (01) 490 8924.

Tara Sweeney

The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has concluded its review of the known risk of pneumonia associated with inhaled corticosteroid (ICS) medicines when used to treat COPD.

The PRAC review confirmed that COPD patients treated with ICS medicines are at increased risk of pneumonia; however the Committee’s view was that the benefits of ICS continue to outweigh their risks. The PRAC also considered whether there were any differences in the risk of pneumonia between these products and did not find conclusive evidence of such a difference. Pneumonia remains a common side effect for all ICS medicines.

Advice for Healthcare Professionals

• Healthcare Professionals should remain vigilant for the possible development of pneumonia in patients treated with ICS for COPD as the clinical features of such infections may overlap with the symptoms of COPD exacerbations.
• Risk factors for pneumonia in patients with COPD include current smoking, age, low BMI and severe COPD.
• The product information (SmPC and PL) for ICS medicines will be updated shortly to reflect the outcome of this review.
• Any suspected adverse reactions should be reported to the HPRA using the usual methods (www.hpra.ie).

Key Message

• The EU review confirmed the known risk that COPD patients treated with inhaled corticosteroids (ICS) medicines are at increased risk of pneumonia
• This increased risk should be considered a class effect with ICS medicines
• Healthcare Professionals should be alert to the signs and symptoms of pneumonia, as clinical features may overlap with the symptoms of COPD exacerbations.

*Further details on ICS medicines are available on www.hpra.ie and www.ema.europa.eu

Caroline McDermott

Fusafungine-containing medicinal products (i.e. Locabiotal 1% solution) for oromucosal and nasal use will no longer be available in Ireland and across the EU as the marketing authorisations (i.e. licenses) for these products are being revoked. The European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) recently completed a review of the available data for these products and concluded that the benefits of fusafungine did not outweigh the risks, particularly the risk of serious allergic reactions. The HPRA and Marketing Authorisation Holder (Servier Laboratories) communicated the outcome of this review and the regulatory recommendations in relation to withdrawal of the product in Ireland to healthcare professionals via a Direct Healthcare Professional Communication (DHPC) in April 2016.

The majority of the serious allergic reactions involved bronchospasm and occurred soon after the use of fusafungine. Although the PRAC review found that serious allergic reactions were rare, they may be life-threatening, and no measures were identified that could sufficiently reduce this risk. With regard to the benefits, the PRAC considered that the evidence for the beneficial effects of fusafungine is weak. Therefore, taking into account the mild and self-limiting nature of upper respiratory tract infections such as rhinopharyngitis, the PRAC considered that the benefits of fusafungine did not outweigh the risks.

Advice for Healthcare Professionals

• Fusafungine-containing products will no longer be available on the Irish market.
• Pharmacies and wholesalers have been advised as regards action to take in relation to outstanding stock supplies.
• A Direct Healthcare Professional Communication was circulated to healthcare professionals in April 2016 and is available on the HPRA website (www.hpra.ie).

Key Message

Due to concerns regarding the risk of rare but serious cases of hypersensitivity, including allergic reactions and life threatening anaphylactic reactions, and limited evidence of benefit, the benefit-risk balance for fusafungine-containing medicines is no longer considered favourable and the marketing authorisation for Locabiotal is currently being withdrawn in Ireland.

Further information is available from www.hpra.ie and www.ema.europa.eu

Caroline McDermott

Click on image to enlarge

Figure 1. Diagnosis and Treatment Algorithm for Evaluating and Managing Patients with Allergic Rhinitis

Reference: 1. Seidman et al. Clinical Practice Guideline: Allergic Rhinitis. Otolaryngology – Head and Neck Surgery 2015, Vol. 152(1S) S1 – S43.

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Caroline McDermott

Click on image to enlarge

Figure 2. Overview of Common Clinical Scenarios in Allergic Rhinitis

Reference: 1. Seidman et al. Clinical Practice Guideline: Allergic Rhinitis. Otolaryngology – Head and Neck Surgery 2015, Vol. 152(1S) S1 – S43.

MIMS Ireland Copyright®

Caroline McDermott

Exacerbations are important events in the course of COPD because they impact negatively on a patient’s quality of life; have effects on symptoms and lung function that take several weeks to recover from; hasten the rate of deterioration of lung function; are associated with significant mortality (especially in patients requiring hospitalisation); and have high socioeconomic costs. ¹

A study examining if exacerbations in patients with mild COPD, or similar acute respiratory events in current and former smokers without airflow obstruction, affected lung decline, saw the greatest excess loss of FEV₁ in those with mild COPD. Acute respiratory events were not associated with additional FEV₁ decline in subjects who did not have airflow obstruction. This study concluded that exacerbations accelerate lung function loss in subjects with established COPD, particularly those with mild disease. ²

The assessment of an exacerbation is based on the patient’s medical history and clinical signs of severity and some laboratory tests, if available. ¹

Prevention of Acute COPD Exacerbations

COPD exacerbations can often be prevented. Smoking cessation, influenza and pneumococcal vaccines, knowledge of current therapy including inhaler technique, and treatment with long-acting inhaled bronchodilators, with or without inhaled corticosteroids, and possibly phosphodiesterase-4 inhibitors, are all therapies that reduce the number of exacerbations and hospitalisations. ¹

The American College of Chest Physicians and Canadian Thoracic Society released guidelines in 2015 on the prevention of acute exacerbations of COPD. Major recommendations included: ³

– Administration of the influenza vaccine annually.

– Smoking cessation counselling and treatment.

– Pulmonary rehabilitation for patients with moderate, severe, or very severe COPD who have suffered a recent exacerbation.

– Education with a written action plan and case management (including direct access to a healthcare specialist at least monthly for those patients with a history of COPD acute exacerbations).

– Moderate to severe COPD

• Long-acting beta₂ agonists (LABAs) are beneficial, but long-acting muscarinic antagonists (LAMAs) are superior (to prevent moderate to severe acute exacerbations).
• Short-acting muscarinic antagonist (SAMA) rather than a short-acting beta₂ agonist (SABA) as monotherapy (to prevent acute mild to moderate exacerbations).
• SAMA plus a SABA (to prevent acute moderate exacerbations).
• LABA monotherapy rather than SABA monotherapy.
• LAMA instead of a SABA (to prevent acute moderate to severe exacerbations).
• Combination of SAMA plus a LABA is better than LABA monotherapy (to prevent acute mild to moderate exacerbations).

– Stable, moderate severe, and very severe COPD

• Maintenance combination of inhaled corticosteroid (ICS) and LABA therapy is better than corticosteroid monotherapy or beta₂ agonist monotherapy.

– Stable COPD

• Maintenance combination of ICS and LABA therapy or inhaled LAMA monotherapy.
• Maintenance combination of inhaled LAMA, corticosteroid, and LABA therapy or inhaled LAMA monotherapy are both effective.

– Patients aged 40 years who are smokers or have a history of smoking

• To prevent acute exacerbations in patients with moderate to severe COPD with a history ≥1 moderate or severe exacerbations in the previous year despite optimal maintenance inhaler therapy, use a long-term macrolide.
• In patients with an acute exacerbation, systemic corticosteroids should be given orally or intravenously to prevent hospitalisation for subsequent acute exacerbations of COPD in the first 30 days (only) after initial exacerbation.
• Use roflumilast in patients with moderate-to-severe COPD and chronic bronchitis and a history of at least one exacerbation in the last year.
• In stable patients, use an oral slow-release theophylline twice daily.
• Moderate-to-severe COPD and ≥2 exacerbations in the last 2 years, use oral N-acetylcysteine.
• In stable patients who continue to have acute exacerbations in spite of maximal therapy to reduce them, oral carbocysteine should be used if available. ³

Treatment Setting

Treatment for COPD exacerbations are aimed at minimising the impact of the current exacerbation and preventing the development of successive exacerbations. An exacerbation can be managed in an outpatient or inpatient setting, depending on the severity of an exacerbation and/or the severity of the underlying disease. More than 80% of exacerbations can be managed on an outpatient basis with therapies including bronchodilators, corticosteroids, and antibiotics. The risk of dying from an exacerbation is closely related to the development of respiratory acidosis, the presence of serious comorbidities, and the need for ventilation support. Patients lacking these features are not at high risk of dying. ¹

Indications for Hospital Assessment and Potential Admission

Some of the indications for hospital assessment and potential admission include a marked increase in intensity of symptoms (e.g. sudden development of resting dyspnoea); severe underlying COPD; appearance of new physical signs (e.g. cyanosis, peripheral oedema); lack of response of the exacerbation to initial medical management; the presence of significant comorbidities (e.g. heart failure, newly occurring arrhythmias); and frequent exacerbations. ¹

References: 1. Global Initiative for Chronic Obstructive Lung Disease (updated 2016). Available at: www.goldcopd.org. 2. Kunisaki KM et al. Effect of Acute Respiratory Events on Lung Function Decline in Current and Former Smokers with and Without COPD. Abstract 3981. Presented at the American Thoracic Society 2016 International Conference, San Francisco. Available at http://www.newswise.com/articles/view/653123/. 3. Mosenifar Z et al. Chronic Obstructive Pulmonary Disease Treatment & Management. Medscape reference. Available at http://emedicine.medscape.com/article/297664. Accessed 16th May 2016.

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Caroline McDermott

The Global Initiative for Asthma defines asthma as a heterogeneous disease, usually characterised by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation.¹

Asthma in Ireland – Facts and Figures

• 470,000 people in Ireland have asthma
• Ireland has the fourth highest prevalence of asthma in the world
• 60% of people have uncontrolled asthma, meaning they are at risk of an asthma attack
• More than 1 person dies every week from asthma
• There are more than 5,000 asthma admissions to hospital each year
• There are 20,000 asthma related Emergency Department attendances annually
• 90% of asthma deaths are preventable
• 1 in every 10 adults has asthma
• 1 in every 5 children has asthma
• Adults miss an average of 12 days of work each year due to asthma
• Children miss an average of 10 days of school each year due to asthma
• The economic burden of asthma in Ireland is estimated at €500m per year ²

Asthma control in the Irish Population

Although 91% of people feel managing their condition is important to them, only 13% have a personalised Asthma Management Plan, according to new research revealed this year at the launch of the ‘Make Asthma Personal’ campaign. This national campaign focuses on the importance of people living with asthma working with their healthcare professional to develop an Asthma Management Plan in order to help take control of their condition.

Many people living with asthma in Ireland are unaware that their asthma may not be well controlled. According to research carried out amongst an online sample of 294 adults (self-declared and diagnosed with asthma), 62% believe their asthma to be under control. However, 35% use their reliever inhaler more than twice a week which is higher than the guidelines recommend, and means that their asthma may not be well controlled. Having uncontrolled asthma symptoms can put someone at risk of an asthma attack.

While the research shows that on average more than three quarters of people agree that they feel comfortable initiating a discussion about their asthma with their healthcare professional, many people living with asthma tend not to take a proactive approach to managing their condition; 6 in 10 have never heard of an Asthma Management Plan, nor discussed it with their GP; 40% admit to not recording their symptoms or how they feel, and more than one in 6 (17%) say they don’t know what triggers their asthma.

Eighty one per cent of people whose asthma symptoms may not be fully controlled agree that this impacts on their quality of life. According to the survey:

• 64% agree that their asthma leaves them feeling drained and tired
• 43% agree that they can no longer participate in sports or physical activities
• 35% agree that their asthma impacts their ability to complete daily activities, e.g. household chores
• 27% agree that they feel embarrassed by their asthma ³

Personalised Asthma Management Plans help patients with asthma make changes to their treatment in response to changes in their level of asthma control, as indicated by symptoms and/or peak expiratory flow in accordance with written pre-determined guidelines.

Asthma Management Plans are a vital part of patient self-management, as introduction of these plans have been shown to significantly reduce acute exacerbations. The utilisation of these plans is low in Ireland and the ICGP guidelines on ‘Asthma Control in General’ Practice recommend that more attention should be given to this aspect of education. Asthma Management Plans are available at www.asthma.ie ⁴

These management plans include the following information:

• A list of medication and when to take it
• How to tell if symptoms are getting worse
• What to do when symptoms get worse
• A list of triggers, vaccinations and the asthma education received
• A peak flow diary to help monitor how well the patient’s lungs are working
• What the patient should to do if they have an asthma attack
• Important contact information, such as GP and emergency contacts⁵

MANAGEMENT OF ASTHMA

Goals of long-term management:

• Achieve and maintain control of symptoms
• Maintain normal activity levels, including exercise
• Maintain lung function as close to normal as possible
• Prevent asthma exacerbations
• Minimise adverse effects from treatment
• Prevent asthma mortality

Asthma can be effectively controlled in most patients by intervening to suppress and reverse inflammation as well as treating bronchoconstriction and related symptoms. Patients are assigned to one of five treatment steps depending on their current level of control and treatment is adjusted in a continuous cycle driven by changes in their asthma control status. This cycle involves assessing asthma control, treating to achieve control and monitoring to maintain control. ⁴

Assess asthma control

Check the two domains of asthma control – symptom control and future risk of adverse outcomes.

Symptom control

Ask the patient about symptom control over the last 4 weeks

Daytime symptoms >twice per week?   Yes/No

Night time wakening due to asthma?   Yes/No

Use of reliever >twice per week?   Yes/No

Limitation of activity due to asthma?   Yes/No

Well controlled asthma symptoms – none of these features

Partly controlled asthma symptoms – 1 to 2 of these features

Uncontrolled asthma symptoms – 3 to 4 of these features

Future risk of adverse outcomes

Assess the patient’s future risk for exacerbations, fixed airflow limitation and medication side-effects, even when symptom control is good. Risk factors for exacerbations that are independent of symptom control include a history of ≥1 exacerbations in the previous year, poor adherence, incorrect inhaler technique, low lung function, smoking, and blood eosinophilia.

Lung function is most useful as an indicator of future risk. Record lung function at diagnosis, 3 to 6 months after starting treatment, and periodically thereafter.

Also check treatment issues such as inhaler technique and adherence, and side-effects. Comorbidities such as rhinitis, rhinosinusitis, gastroesophageal reflux, obesity, obstructive sleep apnoea, depression and anxiety can contribute to symptoms and poor quality of life, and sometimes to poor asthma control.

It is important to distinguish between severe asthma and asthma that is uncontrolled, e.g. due to incorrect inhaler technique and/or poor adherence. ¹

Treat to achieve control

Start treatment at the step most appropriate to initial severity of the disease and achieve early control. Improve control by stepping up treatment as necessary, and stepping down when control is good to find and maintain the lowest controlling step.

Before stepping up, adherence with existing therapies, inhaler technique, persistent allergen exposure and comorbidities should be checked. It is generally considered that combination inhalers aid adherence and also have the advantage of guaranteeing that the long-acting βbeta₂ agonist is not taken without the inhaled corticosteroid.

Regular review of patients as treatment is stepped down is important. When deciding which drug to step down first and at what rate, take all of the following into account: Severity of asthma, side effects of the treatment, time on current dose, beneficial effect achieved and patient’s preference.

Patients should be maintained at the lowest possible dose of inhaled corticosteroid. Reduction in inhaled corticosteroid dose should be slow as patients deteriorate at different rates. Reductions should be considered every three months, decreasing the dose by approximately 25-50% each time. ⁶

Monitor to maintain control

Patients should be reviewed 1 to 3 months after starting controller treatment, and every 3 to 12 months after that. Review pregnant women with asthma every 4 to 6 weeks. The Asthma Control Test is a useful tool for patients to check their level of control at home, and is available at www.asthma.ie. ⁴

References: 1. Global Initiative for Asthma (updated 2016). Available at: www.ginasthma.org. 2. Asthma Society of Ireland Pre-Budget Submission 2016. Available at www.asthma.ie. Accessed 16th May 2016. 3. Make Asthma Personal. Available at www.makeasthmapersonal.ie. Accessed 16th May 2016. 4. Asthma Control in General Practice. GINA/ICGP guidelines. 2nd edition. Published June 2013. 5. Asthma – Health Service Executive. Available at https://www.hse.ie/eng/health/az/A/Asthma/ 6. BTS/SIGN British Guideline on the Management of Asthma. Published October 2014. Available at www.sign.ac.uk

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Caroline McDermott