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“The identification and appropriate management of this often unidentified, high risk patient group, represents a significant opportunity in general practice to improve survival and reduce the risk of heart attack and stroke.”¹

Summary

Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis, most commonly presents in the lower limbs, but also serves as an indicator for atherosclerotic disease at other vascular sites. Patients with PAD have an increased risk of coronary and cerebrovascular events including myocardial infarction, stroke and death. Up to 30% die within 5 years of presenting to their doctor with symptoms, mostly from cardiovascular disease.¹ The defining symptom of PAD, intermittent claudication, is evident in only a minority of patients, while the majority will remain asymptomatic throughout their life, leading to this condition frequently going undetected. Early diagnosis and secondary prevention in primary care are paramount to effective treatment of PAD. Evidence suggests, however, that there is currently a lack of awareness regarding PAD in clinical practice and in the general public, leading to underdiagnosis and undertreatment.^1-3

Atherosclerosis

Atherosclerosis in the peripheral arteries is a chronic, slowly developing condition causing narrowing of the femoral and popliteal, subclavian, carotid, iliac and renal arteries. Depending on the degree of narrowing at each vascular site, a range of severity of symptoms may develop, while the majority of patients remain asymptomatic throughout their lifetime. Occasionally acute events occur, often associated with thrombosis and/or embolism and/or occlusion of a major artery.⁴

The most important implication of PAD in terms of morbidity and mortality is that PAD serves as an indicator for artherosclerotic disease at other vascular sites, and is associated with an increased risk of coronary and cerebrovascular events including myocardial infarction, stroke and death.¹

Prevalence

The occurrence of PAD is strongly age related; uncommon before 50 years, rising steeply at older ages.⁴ The risk of PAD increases two- to three-fold for every 10 year increase in age after 40 years.⁵ PAD is frequently reported in the literature to affect approximately 20% of adults older than 55 years, although estimates of the prevalence of PAD vary widely.⁶

Worldwide, the estimated prevalence in high-income countries ranged from 5.3% for individuals 45 to 49 years of age, to 18.6% for individuals 85 to 89 years old for data collected in 2000 to 2010. The incidence of PAD reportedly increased significantly over the preceding decade (13.1%) which may be attributable to factors such as population ageing and diabetes.⁷

Prevalence rates between men and women are inconsistent; some studies report a two-fold male predominance, while others fail to demonstrate any significant difference in PAD between the two sexes.^5-8 Intermittent claudication may be more common in men, whereas asymptomatic PAD and severe ischaemia may occur more frequently in women.⁶

Awareness

Despite its prevalence, PAD remains relatively poorly publicised compared to other life-threatening conditions such as myocardial infarction, stroke and cancer. A number of population based studies have shown a low level of awareness and knowledge of PAD amongst both doctors and the general public.^1,3,9

A recent survey conducted to assess the awareness of PAD among patients attending a tertiary vascular clinic for management of PAD in Ireland indicates that the level of knowledge of this disease and strategies for secondary prevention is low. However, it does show increased health awareness between those at their first visit to the vascular clinic and those who were return patients, indicating that education by a medical professional can affect patients understanding of the disease.³

Compared to other patient groups, this patient cohort generally has poor interaction with modern educational tools such as the internet, and in general make little effort to seek further information. Since a high number of patients report getting their information from their GP, it suggests that primary care represents an important gateway for educating this patient group on PAD and secondary prevention.³

Clinical presentation

PAD has several different presentations, categorised according to the Fontaine or Rutherford classifications (see table 1). Even with a similar extent and level of disease progression, symptoms and their severity may vary from one patient to another.⁴

Intermittent claudication is the most typical symptom of PAD. However, only 10% to 30% of patients present with intermittent claudication, and the majority are asymptomatic or have atypical symptoms, even with advanced disease.^4,6

Claudication is characterised by cramping, or tightness in the calf, thigh or buttock, brought on by exercise and relieved by rest. Calf claudication is by far the most common symptom but some patients may describe buttock claudication and impotence due to severe aortoiliac disease.¹

Many patients dismiss their symptoms as the normal effects of ageing, and do not seek medical attention until they become severely disabled. Doctors who rely on classic intermittent claudication alone to detect PAD will miss approximately 85% to 90% of patients who are asymptomatic.¹

Other symptoms of PAD may include:¹⁰

• Leg numbness or weakness
• Hair loss or slower hair growth on legs and feet
• Brittle, slow-growing toenails
• Ulcers on legs and feet which do not heal
• Changing skin colour on legs, turning pale or bluish
• Coldness in lower leg or foot
• Shiny skin
• Muscles in legs may shrink
• No pulse or a weak pulse in legs and feet
• Erectile dysfunction in men

Critical limb ischaemia is the most severe clinical manifestation of PAD and is defined in patients who present with lower extremity ischaemic rest pain, skin ulceration, or gangrene. In these individuals, the untreated natural history of severe PAD would lead to major limb amputation within 6 months.¹¹

Patients with critical limb ischaemia usually present with limb pain at rest, with or without trophic skin changes or tissue loss. The discomfort is often worse when the patient is supine and may lessen when the limb is maintained in the dependent position. Arterial ulcers are usually extremely painful; they are frequently secondary to local trauma. When pain is absent, peripheral neuropathy should be considered. Ulcers are often complicated by local infection and inflammation.^4,11

The risk of a person with claudication progressing to critical limb ischaemia and needing amputation is low (<1% per year). However the risk of death mainly from coronary and cerebrovascular events, is high at 5% to 10% per year.¹

Further examination of the cardiovascular system may disclose signs of subclavian or cervical (both carotid and vertebral) bruits, abdominal aneurysm, cardiac murmurs, arrhythmia, or other conditions that might affect patient health.¹

The presence of PAD whether symptomatic or asymptomatic, is associated with grave prognostic implications. Up to 30% of patients die within 5 years of presenting to their doctor with intermittent claudication, with cardiovascular disease accounting for up to 75% of deaths.¹

Table 1. Clinical staging of lower extremity PAD⁴

Prognosis

Five-year natural history of patients presenting to their doctor with intermittent claudication:¹²

• 50% will improve, 25% will stabilise and 25% will worsen. Of those who worsen, 20% (5% of total) will need intervention and 8% (2% of total) will need a major limb amputation.
• 5-10% will have a non-fatal cardiovascular event.
• 30% will die: cardiac 16%, cerebral 4%, other vascular 3%, non-vascular 7%.
• 55-60% will survive with no cardiovascular event.

The prognosis following amputation is poor. Two years following a below-knee amputation, 30% are dead, 15% have an above-knee amputation, 15% have a contralateral amputation, and only 40% have full mobility.⁴

Risk factors

Risk factors for PAD include:¹

• Smoking*
• Diabetes*
• Hypertension
• Hyperlipidaemia
• Hyperhomocysteinaemia
• Elevated plasma fibrinogen
• Age

*Account for over half the attributable risk of PAD

Diagnosis

Techniques used to diagnose PAD should include:

• Medical history
• Physical examination
• Diagnostic tests (including the ankle-brachial index)

Ankle-brachial index

The recommended assessment strategy for PAD is the ankle-brachial index (ABI). Measurement of the ABI enables lower limb systolic blood pressures to be compared with normal brachial blood pressure. It is a simple, reliable, non-invasive and inexpensive test to diagnose PAD in primary care (a maternity Doppler device is not suitable for measurement).¹

Additionally, the ABI is useful in assessing the severity and progression of PAD (see table 2). The ABI is helpful in stratifying the risk of mortality in PAD patients. The lower the ABI, the greater the risk of serious cardiovascular events.¹

Table 2. Interpretation of ABI measurement^4,12

*cut-off points vary slightly in the literature – some papers suggest

>1.4 for incompressible/calcified arteries or <0.5 for severe PAD.

The ABI may not be accurate in individuals in whom systolic blood pressure cannot be abolished by inflation of an air-filled blood pressure cuff. Incompressaible/calcified arteries are often observed in patients with diabetes, end-stage renal disease and the very elderly. Importantly, a substantial proportion of patients with an elevated ABI actually do have occlusive artery disease. Patients with either severely stenotic or totally occluded iliofemoral arteries may also have a normal ABI value at rest if sufficient collaterals are present. Thus, for patients in whom symptoms strongly suggest lower extremity PAD, the presence of a normal or high ABI should not be presumed to rule out this diagnosis, and an alternative diagnostic test (e.g., toe-brachial pressure, Doppler waveform analysis, pulse volume recording, exercise ABI test, or duplex ultrasound) should be performed.^4,12

Targeted ABI screening

Targeted screening of PAD is recommended by all professional vascular societies in order to increase the frequency of diagnosis, improve the use of appropriate medical therapies, and consequently reduce cardiovascular morbidity and mortality rates.¹³

In the context of identifying a high risk population, the ACC/AHA practice guidelines recommend that persons who should be considered for ABI screening include:¹²

• Age less than 50 years with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
• Age 50 to 69 years and history of smoking or diabetes
• All patients aged 70 years and older
• Leg symptoms with exertion (suggestive of claudication) or ischaemic rest pain
• Abnormal lower extremity pulse examination
• Known atherosclerotic coronary, carotid, or renal artery disease

The Irish Heart Foundation Council on PAD also recommends that the following routine investigations should be performed – full blood count, urea and creatinine, fasting blood glucose, and fasting lipid profile.¹

Additional optional parameters include – HbA1c, serum fibrinogen, serum homocysteine, high sensitivity C reactive protein and an ESR.¹

Secondary prevention for PAD

Lifestyle modification, including exercise and smoking cessation, combined with pharmacologic therapy to manage risk factors have been shown effective in reducing cardiovascular risks in patients with PAD.²

Exercise

Exercise significantly improves maximum walking time and overall walking ability in stable intermittent claudication patients. Exercise has been reported as more effective than angioplasty or antiplatelet therapy for improving walking time and quality of life, but remains similar to surgical treatment. Exercise also improves gait patterns in non-surgical patients.⁶ Patients should be clearly advised of the benefits of exercise for overall cardiovascular health.¹

Smoking cessation

Cigarette smoking is associated with a marked increased risk for peripheral atherosclerosis. The number of pack years is associated with disease severity, an increased risk of amputation, peripheral graft occlusion, and mortality. Pharmacologic therapy, including nicotine replacement and anti-depressants, can assist in smoking cessation.⁵

Treatment of diabetes

Diabetes is strongly linked to early onset vascular disease, leading to premature cardiovascular events and mortality. There is a more rapid progression in diabetic patients with an 11 times higher rate of major lower limb amputation compared to non-diabetics and a doubling of the 5-year mortality. Diabetic ulcers also heal more slowly and are the main cause of non-traumatic lower limb amputation.⁶

Anti-platelet therapy

Anti-platelets delay the rate of PAD progression, reduce the need for intervention and the rate of graft failure following revascularisation procedures. The CAPRIE trial reported a 8.7% relative risk reduction for myocardial infarction, stroke or cardiovascular death when clopidogrel was compared to aspirin in high-risk patients. Apirin is indicated in all patients with PAD while clopidogrel should be considered for higher risk patients particularly those with severe cardiac disease and diabetes.⁶

Statin therapy

The Heart Protection Study demonstrated that in patients with PAD, aggressive LDL cholesterol-lowering therapy with a statin was associated with a reduction in cardiovascular events of about 25%.⁵ Statins have been reported to reduce the incidence of new onset intermittent claudication whilst improving pain-free walking distances as well as reducing intimal-media thickness in carotid artery stenosis.⁶

Antihypertensives

Hypertension is an independent risk factor for PAD that is associated with a 2- to 3-fold increase. The angiotensin-converting-enzyme (ACE) system plays an important role in the pathogenesis and progression of atherosclerosis, and ACE-inhibitors are useful for reducing the risk of cardiovascular events in clinical and subclinical PAD.^5,14

It is recommended that all patients with PAD should be on anti-platelets, lipid-lowering therapy and anti-hypertensives as appropriate.^1,14

Indications for referral to a vascular surgeon

Patients with absent pulses and/or other indications of peripheral ischaemia require referral to a vascular surgeon. Urgent referral by telephone should be undertaken for patients with critical limb ischaemia (rest pain, ulceration, or gangrene).

Surgery is indicated in all patients with critical limb ischaemia and in patients with severe lifestyle limiting claudication. Critical limb ischaemia is a a serious threat to the limb and usually warrants revascularisation or amputation.^1,15

Referral may also be considered if:

• Not confident about the diagnosis
• Concern that the symptoms may have an unusual cause
• Patients present with claudication significantly affecting their quality of life
• Patient preference

Surgical and endovascular interventions

Surgery is only considered in patients in whom smoking cessation has been successful and in whom the full range of secondary prevention is employed.¹

Currently the procedures available include angioplasty (with or without stenting), bypass surgery, endarterectomy, or a combination of all of these procedures and is dependent on patient and lesion characteristics.¹

References:

1. Peripheral Arterial Disease. A Management Guide for General Practice 2004. Available at https://www.irishheart.ie/media/pub/padcd/pad_guidelines.pdf

2. Mukherjee D. and Eagle K. Curr. Vasc. Pharmacol. 8(3):293-300.

3. Owens M. et al. Ir Med J. 2013;106(4):116-8.

4. Tendera M. et al. Eur Heart J 2011;32:2851–2906.

5. Hiatt WR. J Vasc Surg 2002;36(6):1283-91.

6. O’Donnell ME. et al. Ulster Med J 2011;80(1):33-41.

7. Fowkes F. et al. Lancet 2013;382(9901):1329–1340.

8. Sigvant B. et al. J Vasc Surg 2007;45(6):1185-91.

9. Vaidya A. et al. BMC Public Health 2014;14(89).

10. Health Service Executive. Available at http://www.hse.ie/eng/health/az/P/Peripheral-arterial-disease/Treating-peripheral-arterial-disease.html. Last accessed 9th February 2015.

11. Hirsch AT. et al. Circulation 2006;113:e463 – e654.

12. Burns P. et al. BMJ 2003;326:584-8.

13. Norgren L. et al. J Vasc Surgery 2006; 45(1) Supplement S.

14. Coppola G. et al. Vasc Health Risk Manag 2008:4(6);1179-87.

15. Changing Cardiovascular Health. National Cardiovascular Health Policy 2010 – 2019. Published May 2010. Department of Health and Children.

Caroline McDermott

Company: Teva Pharmaceuticals Ireland.

Legal category: Prescription. High Tech. Sport permitted.

Active ingredient: Glatiramer acetate 40mg/ml (equivalent to 36mg glatiramer base).

Description: Solution for injection.

Presentation: 12 pre-filled syringes, €848.45.

Indication: Treatment of relapsing forms of multiple sclerosis (MS).

Pharmacology: The mechanism by which glatiramer acetate exerts its effects is not fully elucidated. It is thought to act by modifying immune processes that are currently believed to be responsible for the pathogenesis of MS. Studies suggested that upon its administration, glatiramer acetate-specific suppressor T cells are induced and activated in the periphery.

Dosage: Adult: 40mg by subcutaneous injection 3 times a week (at least 48 hours apart). Use different site for each injection. Self-injection sites include abdomen, arms, hips, thighs. Elderly: Not studied. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Pregnancy.

Special precautions: Not for primary or secondary progressive MS. Do not administer by intravenous or intramuscular injection. Caution: Pre-existing cardiac disorders. Renal impairment, monitor renal function (glomerular deposition of immune complexes cannot be excluded). May occur (rarely): Convulsions and/or anaphylactoid or allergic reactions. If a hypersensitivity/severe adverse event occurs, discontinue and seek immediate medical advice. Lactation (caution).

Drug interactions: Protein-bound drugs. Corticosteroids.

Adverse drug reactions: Infection, influenza, bronchitis, gastroenteritis, herpes simplex, otitis media, rhinitis, tooth abscess, vaginal candidiasis, benign skin neoplasm, neoplasm, lymphadenopathy, hypersensitivity, anorexia, increased weight, anxiety, depression, nervousness, headache, dysgeusia, hypertonia, migraine, speech disorder, syncope, tremor, diplopia, eye disorder, ear disorder, palpitations, tachycardia, vasodilatation, dyspnoea, cough, seasonal rhinitis, gastrointestinal disorders, abnormal liver function test, rash, ecchymosis, hyperhidrosis, pruritus, skin disorder, urticaria, arthralgia, pain (including chest, back, neck), micturition urgency, pollakiuria, urinary retention, asthenia, injection site reactions, injection site atrophy, chills, local reaction, oedema (including peripheral, face), pyrexia.

Full prescribing information and references available from Teva Pharmaceuticals Ireland. Telephone: 1800 201700.

Tara Sweeney

Company: Actavis Ireland Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredient: Colistimethate sodium 2 mega units.

Description: Powder for solution for injection, infusion or inhalation in vial with lilac cap.

Presentation: 10, €42.56.

Indications: Treatment by inhalation, for Pseudomonas aeruginosa lung infection in patients with cystic fibrosis (CF). Treatment by intravenous (IV) administration, for serious infections caused by Gram negative bacteria (including urinary tract infections and lower respiratory tract infections).

Pharmacology: Colistimethate sodium is a cyclic polypeptide antibiotic derived from Bacillus polymyxa var. colistinus.  Polymyxin antibiotics, which are selective for Gram-negative bacteria, are cationic agents that damage the cell membrane, with lethal affects to the bacterium.

Dosage: Adult-Child: IV: Dose determined by severity and type of infection (may increase if necessary). May be given as 50ml IV infusion over 30 mins (or as 10ml bolus injection for up to 2 mega units over minimum 5 mins if totally implantable venous access device in place). Over 60kg: 1-2 mega units 3 times daily (maximum 6 mega units/ 24 hrs). Renal impairment: Mild, 1-2 mega units every 8 hrs; moderate, 1 mega unit every 12-18hr; severe, 1 mega unit every 18-24hr. Up to 60kg: 50,000 units/kg/day (maximum 75,000 units/kg/day). Divide total daily dose into 3 doses at 8 hr intervals. Duration: Minimum 5 days; may be continued for up to 12 days in CF patients with respiratory exacerbations. Inhalation: Over 2 years, 1-2 mega units twice daily. Under 2 years, 500,000 units-1 mega unit twice daily. Adjust dose according to response.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Myasthenia gravis.

Special precautions: Caution: Porphyria, renal impairment. Nephrotoxicity or neurotoxicity may occur if recommended parenteral dose exceeded. Bronchospasm or coughing may occur on inhalation (withdraw if troublesome). Estimate serum levels (especially in renal impairment, neonates and CF patients). Monitor renal function (assess baseline), serum colistimethate sodium levels. Reported: Hypersensitivity reactions including skin rash (withdraw), sore throat or mouth. Local injection site irritation may occur. Pregnancy (only if benefit outweighs risk), lactation (only when clearly needed).

Drug interactions: Avoid: Neurotoxic and/or nephrotoxic medicines (gentamicin, amikacin, netilmicin, tobramycin). Caution: Cephalosporins, neuromuscular blocking drugs, ether.

Adverse drug reactions: Systemic treatment: Neurological events (CF patients), nephrotoxicity signs (seriously ill hospitalised non-CF patients).

Full prescribing information and references available from Actavis Ireland Ltd. Telephone: 1890 333231.

Fax: (021) 4619049. E-mail: contact@actavis.ie

Tara Sweeney

Company: Janssen-Cilag Ltd.

Legal category: Prescription. Hospital. Sport permitted.

Active ingredients: Darunavir (as ethanolate)/cobicistat 800/150mg.

Description: Pink, oval, film-coated tablet marked 800 on one side and TG on reverse.

Presentation: 30, €509.53.

Indication: Treatment of human immunodeficiency virus-1 (HIV-1) infection in combination with other antiretrovirals. In antiretroviral therapy (ART)-experienced adults without darunavir resistance associated mutations (DRV-RAMs), with plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥100 cells x 10⁶/l. In ART-naïve adults.

Pharmacology: Darunavir is an inhibitor of the dimerisation and catalytic activity of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles. Cobicistat is a mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of darunavir.

Dosage: Adult: One tablet once daily. Swallow whole within 30mins after food. Only alter dosage or discontinue therapy under doctor’s instruction. See SPCs of drugs used in combination with Rezolsta. Elderly: Over 65 years, caution (limited data). Children: 3-17 years, not recommended. Under 3 years, do not use.

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients. Severe hepatic impairment. Lactation. Special precautions: Do not initiate if creatinine clearance (cc) <70mL/min if any co-administered agent requires dose adjustment based on cc. ART-experienced patients; combinations with optimised background regimens other than ≥ 2 NRTIs (not studied); HIV-1 clades other than B (limited data). Caution: Sulphonamide allergy, mild/moderate hepatic impairment, pre-existing liver dysfunction (including chronic hepatitis B or C), first two weeks of treatment (if switching from ritonavir). Reported: Drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (rarely), toxic epidermal necrolysis, acute generalised exanthematous pustulosis. Discontinue immediately if severe skin reactions develop (may be accompanied by fever and/or transaminases elevations). Consider increased AST/ALT monitoring in patients with underlying chronic hepatitis, cirrhosis, or pre-treatment elevations of transaminases, especially during first several months of treatment. If new or worsening liver dysfunction develops promptly consider interrupting or discontinuing treatment. Immune reconstitution inflammatory syndrome may occur (evaluate any inflammatory symptoms), reactivation of herpes simplex/zoster observed with darunavir administered with low dose ritonavir. Immune reactivation (autoimmune disorders such as Graves’ disease reported, can occur many months after initiation). Lack or loss of virological response (perform resistance testing). May occur: Hyperglycaemia, new onset or exacerbation of diabetes, lipodystrophy, osteonecrosis, drug-induced hepatitis. Haemophiliacs (increased bleeding risk). Pregnancy (use only if benefit outweighs risk). Driving/using machines (dizziness).

Drug interactions: Do not use voriconazole (unless benefit outweighs risk), ritonavir, other drugs containing darunavir or cobicistat, other antiretrovirals requiring pharmacoenhancement or CYP3A substrates with a narrow therapeutic index. Contraindicated: CYP3A inducers (including efavirenz, rifapentine, rifabutin, phenobarbital, see appendix I), amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine, alfuzosin, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, quetiapine, sertindole, triazolam, orally administered midazolam (caution parenteral administration), simvastatin, lovastatin, colchicine (renal/hepatic impairment), ticagrelor, sildenafil for pulmonary arterial hypertension (PAH), avanafil for erectile dysfunction (ED). Not recommended: Budesonide or fluticasone (unless benefit outweighs risk), etravirine, nevirapine, apixaban, dabigatran etexilate, rivaroxaban, salmeterol, everolimus, boceprevir, telaprevir, simeprevir, bosentan, tadalafil (for PAH). Caution: Disopyramide, flecainide, mexiletine, propafenone, clarithromycin, artemether/ lumefantrine, dasatinib, nilotinib, vinblastine, vincristine, some antifungals, some antiangina/ antiarrhythmics, some PDE-5 inhibitors (for ED). May require dose adjustments (see SPC): Digoxin, maraviroc, paroxetine, sertraline, metformin, alfentanil. Substrates of CYP3A, CYP2D6, p-glycoprotein, BCRP, MATE1, OATP1B1, OATP1B3. Other CYP3A inhibitors, didanosine (within 1hr before or 2hrs after), tenofovir disoproxil fumarate (with underlying systemic or renal disease or nephrotoxic agents), warfarin, drugs highly bound to α1-acid glycoprotein, perphenazine, risperidone, thioridazine, beta-blockers, corticosteroids, ciclosporin, sirolimus, tacrolimus, some calcium channel blockers, some narcotic analgesics/ opioid dependence treatments, some sedatives/ hypnotics. Oestrogen-based contraceptives. See SPC.

Adverse drug reactions: Hypersensitivity, anorexia, diabetes, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia, abnormal dreams, headache, gastrointestinal disorders, increased hepatic enzyme, increased blood creatinine, rash (see SPC), angioedema, pruritus, urticaria, myalgia, fatigue.

Full prescribing information and references available from Janssen-Cilag Ltd. Telephone: +44 1 494 567 444.

Tara Sweeney

Company: Rowex Ltd.

Legal category: Prescription. GMS. Sport restricted beta agonists.

Active ingredients: Salmeterol (as xinafoate)/fluticasone propionate 50/250mcg, 50/500mcg.

Description: Pre-dispensed inhalation powder.

Presentation: 50/250mcg-60 dose unit, €29.32; 50/500mcg-60 dose unit, €38.34.

Indications: Asthma (both strengths): Regular treatment of asthma where use of a combination product (long-acting beta-2-agonist and inhaled corticosteroid) is appropriate. COPD (50/500mcg only): Symptomatic treatment of chronic obstructive pulmonary disease (COPD) in patients with a FEV1 <60% predicted normal (pre-bronchodilator).

Pharmacology: Salmeterol is a selective long-acting beta-2-adrenoceptor agonist. Inhaled fluticasone propionate has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.

Dosage: Adult: Titrate to lowest effective dose. May titrate to once daily. Asthma: One inhalation of 50/250mcg or 50/500mcg twice daily. Once controlled, consider stepping down to inhaled corticosteroid alone (review regularly). COPD: One inhalation of 50/500mcg twice daily. Elderly: As per adults. Children: Asthma: 12 years and older, as per adults. Under 12 years, do not use. COPD: Do not use.

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients.

Special precautions: Caution: Pulmonary tuberculosis, severe cardiovascular disorders, heart rhythm abnormalities, diabetes, thyrotoxicosis, uncorrected hypokalaemia, predisposition to low levels of serum potassium. Consider increasing corticosteroid therapy. Consider additional systemic corticosteroids during elective surgery or periods of stress. Down-titrate under supervision. Discontinue immediately if paradoxical bronchospasm occurs. History of diabetes (very rare reports of blood glucose level increases). Prolonged use with high doses, adrenal suppression and acute adrenal crisis may occur (very rarely with fluticasone propionate doses between 500mcg to <1000mcg). Systemic effects may occur (especially at high doses with prolonged use and especially in children and adolescents <16 years; regularly monitor height) including Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (especially in children). Patients transferring from oral steroids or previously required high dose emergency corticosteroid therapy (risk of impaired adrenal reserve). Asthma: Not for acute symptoms or for initial management of mild asthma. Do not initiate during an exacerbation, or with significantly worsening or acutely deteriorating asthma. Manage with a stepwise program (monitor lung function); continue treatment but seek medical advice if symptoms remain uncontrolled or worsen (especially if of black African or Afro-Caribbean ancestry); seek urgent medical assessment if sudden and progressive deterioration in control (potentially life threatening); review if increasing use of short-acting bronchodilators or dosage inadequate. Serious adverse events and exacerbations may occur. COPD: Monitor for development of pneumonia and other lower respiratory tract infections (clinical features and exacerbation frequently overlap); re-evaluate if patient with severe COPD experienced pneumonia. Discontinuation, asthma (withdraw gradually); COPD (supervise). Contains lactose. Pregnancy, lactation (only use if benefit outweighs risk).

Drug interactions: Avoid: Ritonavir, ketoconazole, other potent CYP3A4 inhibitors, non-selective or selective beta-blockers. Other beta-adrenergic containing drugs.

Adverse drug reactions: Candidiasis of mouth and throat, pneumonia, bronchitis, hypokalaemia, headache, nasopharyngitis, throat irritation, hoarseness/dysphonia, sinusitis, contusions, muscle cramps, traumatic fractures, arthralgia, myalgia.

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

Tara Sweeney

Interferon beta-1a and interferon beta-1b are indicated for the treatment of relapsing multiple sclerosis* and in patients with a single demyelinating event with an active inflammatory process. Interferon beta-1b products may also be used in patients with secondary progressive multiple sclerosis with active disease evidenced by relapses.

In July 2014, a European review of interferon beta products* and associated reports of thrombotic microangiopathy (TMA) and nephrotic syndrome was concluded. Cases of TMA, including fatal cases, had been reported during treatment of multiple sclerosis with interferon beta. Most TMA cases presented as thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome. Cases of nephrotic syndrome with different underlying nephropathies have also been reported in association with these products. The review could not rule out a causal association between interferon beta products and TMA or nephrotic syndrome.

Advice to Healthcare Professionals

Thrombotic microangiopathy

• TMA may develop several weeks to several years after starting treatment with interferon beta.
• Be vigilant for signs and symptoms of TMA and manage it promptly in line with the advice below.
• Clinical features of TMA include thrombocytopenia, new onset hypertension, fever, impaired renal function and central nervous system symptoms (e.g. confusion and paresis).
• If clinical features of TMA are observed, platelet levels, serum lactate dehydrogenase levels, renal function and red blood cell fragments on a blood film should be performed.
• If TMA is diagnosed, prompt treatment (e.g. plasma exchange should be considered) is required and immediate discontinuation of interferon beta is recommended.

Nephrotic syndrome

• Nephrotic syndrome may develop several weeks to several years after starting treatment with interferon beta.
• Be vigilant for the development of this condition and manage it promptly in line with the advice below.
• Renal function should be monitored periodically and early signs or symptoms of nephrotic syndrome (e.g. oedema, proteinuria and impaired renal function, especially in high risk groups) should be noted.
• If nephrotic syndrome occurs, it should be treated promptly and consideration should be given to stopping treatment with interferon beta.

The product information (Summary of Product Characteristics (SmPC) and package leaflet (PL)) for all interferon beta products has been updated and will be fully harmonised with information on TMA and nephrotic syndrome.

Key messages

• Cases of TMA including fatal cases have been reported during treatment of multiple sclerosis with interferon beta products.
• Most TMA cases presented as thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome.
• Cases of nephrotic syndrome with different underlying nephropathies have also been reported.
• Both TMA and nephrotic syndrome may develop several weeks to several years after starting treatment with interferon beta.
• Be vigilant for the development of these conditions and manage them promptly if they occur.

*The following interferon beta products are authorised for the treatment of multiple sclerosis: Avonex (interferon beta-1a), Rebif (interferon beta-1a), Betaferon (interferon beta-1b), Extavia (interferon beta-1b), Plegridy (peginterferon beta-1a).

Further details available at www.hpra.ie.

Caroline McDermott

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COPD:

• Mid-life onset
• Slowly progressing symptoms
• History of tobacco smoking/exposure to smoke from home cooking, heating fuels or to occupational dusts or chemicals

Asthma:

• Early onset in life (often childhood)
• Varying symptoms from day to day
• Symptoms worse at night/early morning
• Presence of allergy, rhinitis, and/or eczema
• Family history of asthma
• Airflow limitation that is largely reversible

Congestive heart failure:

• Fine basilar crackles on auscultation
• Dilated heart on chest radiography
• Pulmonary oedema
• Pulmonary function tests indicate volume restriction, not airflow limitation

Bronchiectasis:

• Large volume of purulent sputum
• Commonly associated with bacterial infection
• Chest X-ray/CT shows bronchial dilation, bronchial wall thickening

Tuberculosis:

• Onset at all ages
• Chest X-ray shows lung infiltrate
• Microbiological confirmation
• High local prevalence of tuberculosis

Obliterative bronchiolitis:

• Onset in younger age, non-smokers
• May have history of rheumatoid arthritis or acute fume exposure
• Seen after lung or bone marrow transplantation
• Hypodense areas on expiration on CT

Diffuse panbronchiolitis:

• Most patients are male, non-smokers
• Almost all have chronic sinusitis
• Patients are predominantly of Asian descent
• Diffuse small centrilobular nodular opacities and hyperinflation on chest x-ray and HRCT

*These features tend to be characteristic of the respective diseases, but do not occur in every case.
CT: Computed tomography; HRCT: High resolution computed tomography

References: 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Updated 2015. Available at: http://www.goldcopd.com 2. American Thoracic Society. Available at http://www.thoracic.org/professionals/clinical-resources/copd-guidelines/for-health-professionals/clinical-assessment-testing-and-differential-diagnosis/differential-diagnosis.php. Accessed 12th March 2015.

Caroline McDermott

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Reference: [adapted from] Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Updated 2015. Available at: http://www.goldcopd.com

Caroline McDermott

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Symptoms and airflow limitation should both be taken into account to guide the management of chronic obstructive pulmonary disease (COPD). Airflow limitation, which is linked to the frequency of exacerbations and measure future risks, has poor correlation with the daily impact of the disease upon the individual patient, and therefore serves as little practical use on its own.

The major goal of COPD management is thus two fold:

• Reduce symptoms (measured by the modified Medical Research Council (mMRC) dyspnoea scale and/or COPD Assessment Tool (CAT))
• Reduce future risk (measured by the severity of airflow limitation and/or exacerbation history in the previous 12 months)

The current GOLD guidelines also emphasise the importance of comorbidities, which have to be assessed and treated as part of these goals.

Once the diagnosis of COPD is done, patients are divided into four groups (A, B, C and D) according to their symptom/risk profile (see Table 1).

Table 1: Combined severity assessment of COPD based on risk/symptom profile

The patient group determines the pharmacotherapy strategy recommended for stable COPD (see algorithm).

Non-pharmaceutical management
Three pivotal features of non-pharmacological management include:

• Reduction of exposure to risk factors (principally tobacco smoke)
• Promotion of exercise
• Immunisation against influenza and pneumococcal disease

Pharmaceutical management
Long-acting bronchodilators, which include long-acting muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA), are the gold-standard maintenance therapy for the maintenance of COPD, and their mechanism of action is well-known (see box below). Long-acting bronchodilators are preferred over short acting formulations.

Also note that based on efficacy and tolerability inhaled bronchodilators are preferred to oral bronchodilators, and theophylline is not recommended unless bronchodilators are unavailable/unaffordable for long-term treatment. The phosphodiesterase-4 inhibitor roflumilast may be considered as add on to bronchodilator treatment in patients with chronic bronchitis, severe airflow limitation and frequent exacerbations not controlled by long-acting bronchodilators.

See algorithm for a proposed model for the pharmaceutical management of COPD.

References:
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Updated 2015. Available at: http://www.goldcopd.org
2. Gruffydd-Jones K. GOLD guidelines 2011: what are the implications for primary care? Prim Care Respir J 2012; 21(4): 437-441.

Caroline McDermott

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed a review of the safety of ambroxol and bromhexine-containing medicines*.  Ambroxol and bromhexine are indicated for mucolytic therapy in patients with short or long-term respiratory conditions. Ambroxol lozenges are available for pain relief of sore throats. The majority of these medicines are available over-the-counter (OTC) in Ireland and are marketed as single products.

Ambroxol-containing medicines authorised and marketed in Ireland include:

- Ambrobene 3mg/ml and 6mg/ml Oral Solution
- Lysopadol 20mg Lozenges

Bromhexine-containing medicines authorised and marketed in Ireland include:
- Bisolvon 4mg/5ml Oral Solution

The review of these products was initiated following post-marketing reports of hypersensitivity reactions (including anaphylactic reactions) and accumulating evidence from case reports and literature demonstrating that ambroxol is potentially responsible for severe cutaneous adverse reactions (SCARs).

The review has concluded as follows:
- Severe hypersensitivity reactions have been reported in patients receiving ambroxol. These include:

• Severe allergic reactions including anaphylactic reactions;
• SCARs including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis and acute generalised exanthematous pustulosis.

Advice to Healthcare Professionals

• Ambroxol and bromhexine are associated with a small increased risk of immediate and delayed hypersensitivity reactions, anaphylactic reactions including anaphylactic shock, angioedema, pruritus, rash and urticaria.
• There is a possibility of a risk of SCARs (including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis and acute generalised exanthematous pustulosis) associated with ambroxol and bromhexine.
• If symptoms of allergy or SCARs occur, treatment with ambroxol or bromhexine should be immediately discontinued.

Key messages

• The PRAC considered that ambroxol and bromhexine are associated with a small increased risk of hypersensitivity reactions.
• The PRAC considered that there is a reasonable possibility of a risk of SCARs associated with ambroxol and bromhexine.
• The PRAC was of the view that the risk of SCARs should be addressed by its inclusion in the product information accompanied by a warning for patients and caregivers to recognise the prodromes of SCARs and to discontinue treatment immediately in the event of such signs.

*Further details on ambroxol and bromhexine-containing products are available at www.hpra.ie

Caroline McDermott

Company: Biogen Idec (Ireland) Ltd.

Legal category: Prescription. High tech. Sport permitted.

Active ingredient: Peginterferon beta-1a 63mcg/0.5ml, 94mcg/0.5ml, 125mcg/0.5ml.

Description: Solution for injection in pre-filled pens labelled orange, blue or grey, respectively.

Presentation: Initiation pack: 1 x 63mcg and 1 x 94mcg pre-filled pen, €884.00. Maintenance pack: 125mcg-2 pre-filled pens, €884.00.

Indication: Treatment of relapsing remitting multiple sclerosis.

Pharmacology: A definitive mechanism of action of peginterferon beta-1a is not known. It binds to the type I interferon receptor on the surface of cells and elicits a cascade of intracellular events leading to the regulation of interferon-responsive gene expression. It may mediate biological effects including up-regulation of anti-inflammatory cytokines, down-regulation of pro-inflammatory cytokines and inhibiting the migration of activated T cells across the blood brain barrier; however additional mechanisms may be involved.

Dosage: Adult: Initiate under supervision. Administer by subcutaneous injection into abdomen, upper arm, thigh (rotate sites). Dose 1: Day 1, 63mcg. Dose 2: Week 2, 94mcg. Dose 3: Week 4 (and every 2 weeks thereafter), 125mcg. Elderly: Over 65 years, safety and efficacy not established. Children: Under 18 years, no data.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Severe depression, suicidal ideation. Pregnancy, lactation.

Special precautions: Caution: Severe hepatic/ renal impairment, previous depressive disorders, history of seizures. Test complete blood and differential blood cell counts, platelet counts (myelosuppression may require more intensive monitoring), and blood chemistries, including liver function tests prior to initiation, at regular intervals following initiation, then periodically thereafter. Monitor for hepatic injury, decreased peripheral blood counts. Depression (monitor closely); consider discontinuation. Patients should immediately report any symptoms of depression and/or suicidal ideation. Significant cardiac disease such as congestive heart failure, coronary artery disease or arrhythmia (monitor for worsening cardiac disease, especially during initiation). Flu-like symptoms may occur, consider dose titration (at initiation). Reported with interferon-beta products: Injection site reactions (including necrosis), seek medical advice if skin breakage occurs; periodically monitor for early signs of nephrotic syndrome with different underlying nephropathies (especially if at high risk of renal disease, may occur after several years of treatment), consider prompt treatment and discontinuation; if thrombotic microangiopathy diagnosed (may be fatal, may occur several weeks to years after initiation) treat promptly with plasma exchange and immediately discontinue; hypothyroidism and hyperthyroidism observed (test thyroid function regularly in patients with history of thyroid dysfunction). Serious hypersensitivity reactions (discontinue). Switching between pegylated and non-pegylated interferons (no data). Neutralising antibodies may develop. Driving/using machines.

Drug interactions: Caution: Drugs with a narrow therapeutic index and largely dependent on CYP450 (e.g. some antidepressant classes, antiepileptics).

Adverse drug reactions: Headache, gastrointestinal upset, pruritus, myalgia, arthralgia, influenza like illness, pyrexia, chills, asthenia, hyperthermia, pain, increased body temperature, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyl-transferase, decreased haemoglobin, decreased white blood cell counts, depression, injection site reactions.

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

Tara Sweeney

Company: MSD Ireland (Human Health) Ltd.

Legal category: Prescription. Hospital. Sport permitted.

Active ingredient: Posaconazole 300mg.

Description: Concentrate for solution for infusion.

Presentation: 1 vial, €452.37.

Indications: Treatment of invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, coccidioidomycosis, in adults with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicines (see SPC). Prophylaxis of invasive fungal infections (IFI) in: 1) Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing IFI; 2) Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing IFI.

Pharmacology: Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.

Dosage: Adult: 300mg loading dose twice on the 1st day, then 300mg once daily thereafter. Treatment: Duration, based on the severity of the underlying disease, recovery from immunosuppression, and clinical response. Prophylaxis: Duration, based on recovery from neutropenia or immunosuppression. AML or MDS, start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises >500 cells per mm³. Administer via central venous line (including a central venous catheter or peripherally inserted central catheter) by slow intravenous (IV) infusion over approximately 90 mins or peripheral venous catheter over approximately 30 mins. Switch to oral suspension as soon as condition allows. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Pregnancy (unless benefit outweighs risk), lactation. Women must use contraception during therapy.

Special precautions: Do not give by bolus administration. Caution: Hypersensitivity to other azoles; hepatic impairment (evaluate liver function at the start of and during therapy, monitor patients who develop abnormal tests; consider discontinuation if liver disease suspected); pro-arrhythmic conditions (such as congenital or acquired QTc prolongation, cardiomyopathy (especially in the presence of cardiac failure), sinus bradycardia, existing symptomatic arrhythmias), peripheral administration, any sign or symptom of thromboembolic events. Monitor and correct electrolyte disturbances (especially potassium, magnesium, calcium) before and during therapy. Moderate or severe renal impairment (use oral formulations unless benefit outweighs risk); closely monitor serum creatinine levels. Monitor for breakthrough fungal infections (severe renal impairment). Posaconazole plasma concentrations higher with Noxafil IV than oral suspension (limited safety data). Driving/using machines. Contains sodium.

Drug interactions: Contraindicated: Ergot alkaloids, certain CYP3A4 substrates and HMG-CoA reductase inhibitors. Avoid: Sirolimus, rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), efavirenz, vinca alkaloids. Caution: Other drugs prolonging QTc interval, ciclosporin, tacrolimus, other CYP3A4 substrates (including HIV protease inhibitors, midazolam, triazolam, alprazolam, calcium channel blockers). UDP glucuronidation or P-gp efflux inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin) or inducers (rifampicin, rifabutin). Sulfonylureas (e.g. glipizide), fosamprenavir, digoxin.

Adverse drug reactions: Neutropenia, electrolyte imbalance, anorexia, hypokalaemia, paresthesia, dizziness, somnolence, headache, gastrointestinal disorders, elevated liver function tests, rash, pruritis, pyrexia, fatigue, decreased appetite, hypomagnesaemia, dysgeusia, hypertension.

Full prescribing information and references available from MSD Ireland (Human Health) Ltd. Telephone: 01 2998700.

Tara Sweeney

Company: Galen Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredients: Codeine phosphate/paracetamol 15/500mg.

Description: White, oblong, tablet marked K1 on both sides of scoreline.

Presentation: 100, €7.80.

Indication: Relief of moderate pain.

Pharmacology: Paracetamol has analgesic and antipyretic effects. The mechanism of action is unclear, although it is believed to exert its action by inhibition of prostaglandin synthesis. Codeine is a centrally acting weak analgesic. Codeine exerts its effects through μ opioid receptors, and its analgesic effect is due to its conversion to morphine.

Dosage: Adult: 2 tablets four hourly as required; maximum 8 in 24hrs. Elderly: As per adults. Children: 16 years and over, 2 tablets six hourly as required (maximum 8 in 24hrs); 12-15 years, 1 tablet six hourly as required (maximum 4 in 24hrs); under 12 years, contraindicated.

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients. Respiratory depression, raised intracranial pressure, head injury, acute asthma, acute alcoholism, extensive or ultra-rapid CYP2D6 metabolisers. Children ≤18 years who undergo tonsillectomy/ adenoidectomy for obstructive sleep apnoea. Pregnancy, lactation.Special precautions: Not recommended: Children with compromised respiratory function (including neuromuscular disorders, severe cardiac/ respiratory conditions, upper respiratory/ lung infections, multiple trauma, extensive surgery). Caution: Elderly, debilitated, prostatic hypertrophy, inflammatory/ obstructive bowel disorders, Addison’s disease. CYP2D6-deficient patients. Severe renal/hepatic impairment. Prolonged use. Driving/using machines.

Drug interactions: Do not take other paracetamol- or codeine-containing drugs. Contraindicated: Monoamine oxidase inhibitors within 2 weeks. Avoid alcohol, other central nervous system depressants. Warfarin and other coumarins (prolonged regular use). Metoclopramide, domperidone, colestyramine.

Adverse drug reactions: Dizziness, drowsiness, gastrointestinal upset, urinary retention, confusion, euphoria, dysphoria, miosis, bradycardia, allergic reactions, pruritus.

Full prescribing information and references available from Galen Ltd. Telephone: +44 (0)28 3833 4974. Fax: +44 (0)28 3835 0206. E-mail: customer.services@galen-pharma.com

Tara Sweeney

Company: Janssen-Cilag Ltd.

Legal category: Prescription. Sport permitted.

Active ingredient: Ibrutinib 140mg.

Description: White opaque, hard capsule marked ibr 140mg.

Presentation: Price pending reimbursement.

Indications: Treatment of relapsed or refractory mantle cell lymphoma (MCL). Treatment of patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in patients with 17p deletion or TP53 mutation unsuitable for chemo-immunotherapy.

Pharmacology: Ibrutinib is a potent inhibitor of Bruton’s tyrosine kinase (BTK). BTK is an important signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and CLL.

Dosage: Adult: Swallow whole with water at same time each day. MCL: 4 capsules once daily. CLL: 3 capsules once daily. Continue until disease progression or no longer tolerated. Hepatic impairment: Mild (2 capsules daily); moderate (1 capsule daily). Doses may be interrupted or reduced if significant adverse reactions occur; see SPC. Elderly: As per adults. Children: ≤18 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy, lactation. Women should use contraception during treatment and for up to 3 months after (add a barrier method).

Special precautions: Pre-existing atrial fibrillation requiring anticoagulant therapy, consider alternative treatment. Not recommended: Severe hepatic impairment. Renal impairment, mild to moderate (monitor serum creatinine levels); severe (only if benefit outweighs risk; monitor closely for toxicity). Dialysis (no data).  Major and minor haemorrhagic events reported. Suspend at least 3 to 7 days pre- and post-surgery. Congenital bleeding diathesis (not studied). Leukostasis reported. High number of circulating lymphocytes (>400,000/mcL); closely monitor and consider suspending treatment. Infections observed (some associated with hospitalisation, death); monitor for fever, neutropenia. Grade 3 or 4 cytopenias reported; monitor complete blood counts monthly. Atrial fibrillation and atrial flutter reported (monitor). Arrhythmic symptoms or new onset of dyspnoea (evaluate). Assess risk for thromboembolic disease if atrial fibrillation develops; consider tightly controlled anticoagulant treatment if alternatives unsuitable and at high risk. Monitor closely if at risk of tumour lysis syndrome. Congenital short QT syndrome or family history. Driving/using machines.

Drug interactions: Do not use warfarin or other vitamin K antagonists. Contraindicated: St. John’s Wort. Avoid: Supplements (e.g. fish oil, vitamin E), strong/ moderate CYP3A4 inhibitors/ inducers (assess risk/benefit). Narrow therapeutic range P-gp substrates (within 6hrs), other anticoagulants, drugs inhibiting platelet function, CYP3A4 inhibitors/ inducers/ substrates, proton pump inhibitors.

Adverse drug reactions: Musculoskeletal pain, upper respiratory tract infection, bruising, rash, pyrexia, neutropenia (including febrile), anaemia, pneumonia, thrombocytopenia, sinusitis, sepsis, urinary tract infection, skin infection, leucocytosis, lymphocytosis, dehydration, hyperuricaemia, dizziness, headache, blurred vision, atrial fibrillation, haemorrhage, petechiae, subdural haematoma, epistaxis, gastrointestinal disorders, arthralgia, peripheral oedema.

Full prescribing information and references available from Janssen-Cilag Ltd. Telephone: +44 1 494 567 444.

Tara Sweeney

Company: Janssen-Cilag Ltd.

Legal category: Prescription. Hospital only. Sport permitted.

Active ingredient: Decitabine 50mg.

Description: Powder for concentrate for solution for infusion.

Presentation: 1 vial, €1110.00.

Indications: Treatment of patients with newly diagnosed de novo or secondary acute myeloid leukaemia, who are not candidates for standard induction chemotherapy.

Pharmacology: Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases, resulting in gene promoter hypomethylation that can result in reactivation of tumour suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.

Dosage: Elderly: 65 years and older, 20mg/m2 body surface area by intravenous infusion over 1 hour daily for 5 consecutive days. Maximum total daily dose 20mg/m2; maximum total dose per treatment cycle 100mg/m2. Repeat cycle every 4 weeks and treat for minimum 4 cycles (depending on response and toxicity), may require more cycles to achieve complete/partial remission. Consider alternative treatment if haematological values have not returned to pre-treatment levels/ disease progression occurs after 4 cycles (see SPC). Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to active ingredient or to any of the excipients. Pregnancy, lactation. Men and women must use effective contraception during treatment and men should not father a child until 3 months after.

Special precautions: Caution: Hepatic impairment, severe renal impairment. May exacerbate myelosuppression and associated complications (potentially fatal); regularly perform complete blood and platelet counts, as indicated and prior to each treatment cycle; monitor for infection; consider suspending treatment if complications (see SPC) occur. History of severe congestive heart failure or unstable cardiac disease. May affect fertility. Driving/using machines. Contains potassium, sodium.

Drug interactions: Caution: Drugs activated by sequential phosphorylation/metabolised by enzymes implicated in the inactivation of decitabine (e.g. cytidine deaminase).

Adverse drug reactions: Pyrexia, anaemia, thrombocytopaenia, pneumonia, neutropaenia (including febrile), urinary tract infection, infections (viral, bacterial, fungal), septic shock, sepsis, sinusitis, leukopaenia, hypersensitivity (including anaphylactic reaction), headache,  epistaxis, gastrointestinal disorders.

Full prescribing information and references available from Janssen-Cilag Ltd. Telephone: +44 1 494 567 444.

Tara Sweeney

Company: Ferring Ireland Ltd.

Legal category: GMS. Prescription.  Sport prohibited in competition.

Active ingredient: Budesonide 9mg.

Description: White, round, biconvex, film-coated, gastro-resistant, prolonged release tablet marked MX9.

Presentation: 30, €85.00.

Indication: Induction of remission in patients with mild to moderate active ulcerative colitis where 5-ASA treatment is not sufficient.

Pharmacology: Budesonide inhibits many inflammatory processes including cytokine production, inflammatory cell activation and expression of adhesion molecules on endothelial and epithelial cells. The exact mechanism of action is not fully understood.

Dosage: Adult: Swallow whole with glass of water. One tablet in the morning, for up to 8 weeks. Elderly: Limited experience. Children: 18 years and under, not recommended.

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

Special precautions: Caution: Hepatic/renal impairment, infections, hypertension, diabetes or glaucoma (or family history), osteoporosis, peptic ulcer, cataracts, current or history of severe affective disorders (including first degree relatives). Withdraw gradually. Transferring from other steroid therapy. Increases risk of infections. Surgery/other stresses (use additional systemic corticosteroids). Avoid exposure to Chicken pox and measles if not previously exposed; consider reduction or discontinuation if infected. Systemic effects may occur (see SPC), especially at high doses for prolonged periods. Driving/using machines. Contains lecithin (soya oil), lactose. Pregnancy (assess risk/benefit).

Drug interactions: Avoid: Potent CYP3A4 inhibitors, grapefruit juice. CYP3A4 inducers, heart glycosides, diuretics, cholestyramine or antacids (within 2hrs), vaccines.

Adverse drug reactions: Gastrointestinal upset, headache, insomnia, altered mood, decreased blood cortisol, influenza, upper respiratory tract viral infection.

Full prescribing information and references available from Ferring Ireland Ltd. Telephone: (01) 4637355.

E-mail: enquiries.ireland@ferring.com.

Tara Sweeney

The Health (Pricing and Supply of Medical Goods) Act 2013 has introduced a system of generic substitution and reference pricing. Under this legislation, interchangeable medicines are defined as those medicines that contain the same active ingredient in the same strength, are in the same pharmaceutical form, and have the same route of administration. Reference pricing involves setting a common reimbursement price for selected groups of medicines that have been listed by the HPRA as interchangeable, and is introduced one medicine at a time. For each active substance the HPRA has or will publish and maintain a list of interchangeable medicines on their website (see http://www.hpra.ie/homepage/medicines/medicines-information/generics-lists) and the HSE has or will subsequently set a reference price (see http://www.hse.ie/eng/health/hl/Generics/ref/).

The Interchangeable Medicines and Reference Pricing section in the MIMS Ireland directory contains a table of all active ingredients on the interchangeable medicines list, their strength, pharmaceutical form, and route of administration. It also includes reference prices for selected groups of medicines, where they have been introduced. Medicines which can be substituted by another medicine on this list are denoted by the interchangeable medicines symbol in their product monographs throughout the MIMS Ireland publication. Information is reviewed monthly and correct at the time of publication.

Last updated April 2015 – download section here.

Click on images to enlarge

Caroline McDermott

Therapeutic Use Exemption (TUE) Committee Policy on Glucocorticosteroid 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/tue.

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 using an intra-muscular glucocorticosteroid. 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 Irish Sports Council Registered Testing Pool that are not competing at an International Competition should apply to the Irish Sports Council for a Pre-test Therapeutic Use Exemption, using the information in the Medical File section below to aid them, prior to using an intra-muscular glucocorticosteroid.

Athletes eligible for a post-test TUE application (see www.irishsportscouncil.ie/tue) should ensure that they are capable of providing a medical file to the standard outlined below, prior to the administration of any intra-muscular glucocorticosteroid 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 glucocorticosteroid 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, 14th April 2015) such as:

Over-the-counter medications (examples)

• Oral Antihistamines: e.g. Loratidine (brands – Clarityn, Lorat etc.), Cetirizine (brands- Cetirelief Allergy, Cetrine Allergy), Chlorphenamine (brand – Piriton; note – can cause drowsiness)
• Decongestant Nasal Drops/Sprays: e.g. Otrivine nasal drops, Otrivine nasal spray
• Glucocorticosteroid Nasal Sprays: e.g. Beconase Hayfever, Flixonase Allergy Relief
• 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
• Glucocorticosteroid 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 14th April 2015.

Caroline McDermott

The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has completed a periodic review of one of the bisphosphonate medicines, Aclasta (zoledronic acid). Bisphosphonates are used in the treatment of osteoporosis and are associated with a known, small risk of osteonecrosis of the jaw (ONJ). The HPRA has previously communicated on the risk of ONJ with these medicines and the steps to be taken by healthcare professionals and patients to reduce this risk (HPRA Drug Safety Newsletters 23rd edition, 27th edition, 35th edition and 63rd edition).

Following the routine periodic review for Aclasta, the PRAC has recommended a number of new measures, including an update to the product information and in particular the introduction of a patient reminder card, to reinforce the key risk minimisation messages for patients.

The card recommended by the PRAC will remind patients about:
– the benefit of treatment of osteoporosis;
– the risk of ONJ associated with treatment with Aclasta;
– the need to highlight any dental problems to their doctors/nurses before starting treatment;
– the need to ensure good dental hygiene during treatment;
– the need to inform their dentist of treatment with Aclasta and to contact the doctor and dentist if problems with the mouth or teeth occur during treatment. Patients may wish to show the reminder card to their dentist when discussing their dental treatment.

The product information (i.e. Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) will also include further information on how to minimise this risk.

The PRAC will consider similar revisions to the product information and the introduction of patient reminder cards for other intravenous bisphosphonates, used for osteoporosis or for preventing bone complications of cancers, as well as for denosumab which is also associated with a risk of ONJ. These will be considered during the upcoming and on-going periodic reviews, which are planned to take place over the course of 2015/2016.

The PRAC recommendations for Aclasta have been sent to EMA’s Committee for Medicinal Products for Human Use (CHMP) for final opinion.

Advice to Healthcare Professionals

Before initiation of treatment / new treatment course

• The following factors should be considered when evaluating a patient’s risk of developing ONJ
  – Route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy,
  – Potency of the medicinal product for inhibiting bone resorption (highly potent compounds are a higher risk),
  – Known risk factors for ONJ include previous treatment with bisphosphonates, older age, poor oral hygiene, history of dental disease, poorly fitting dentures, periodontal disease, invasive dental procedures (tooth extractions, dental implants etc.), co-morbid disorders (e.g. pre-existing dental disease, anaemia, infection, coagulopathies etc.), smoking and concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors and radiotherapy to head and neck).
• Ensure patients have a dental examination and an individual benefit-risk assessment before commencing treatment especially those with concomitant risk factors.
• Delay the start of treatment or a new course of treatment in patients with unhealed open soft tissue lesions in the mouth that may require oral or dental procedures.

During treatment

• Patients should maintain good oral hygiene practices throughout their treatment and maintain routine dental examinations.
• Patients should be advised to immediately report any oral symptoms (such as dental mobility, pain or swelling, non-healing of sores or discharge) during their treatment.
• Invasive dental procedures should be performed only after careful consideration and should be avoided in close proximity to administration of bisphosphonates or denosumab.
• If a patient experiences ONJ while on bisphosphonates or denosumab therapy, a management plan for the individual patient should be developed in close collaboration with a dentist and/or oral surgeon with expertise in the area.
• Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated, where possible.
• Please report any suspected cases of ONJ with bisphosphonates or denosumab to the HPRA via the online, downloadable or post-paid reporting options available at www.hpra.ie.

Key messages

• Patients should be evaluated for ONJ risk factors prior to commencing treatment with bisphosphonates or denosumab.
• Prior to commencing treatment, patients should visit their dentist for a dental examination and necessary dental surgical procedures should be completed prior starting treatment.
• During treatment, patients should maintain excellent dental hygiene and attend routine dental examinations.
• Patients should immediately report any oral symptoms experienced and healthcare professionals are requested to report any cases of suspected ONJ to the HPRA.
• The Product information (SmPC and PL) for Aclasta will be updated to reflect the additional risk minimisation measures.
• A patient reminder card will be available for Aclasta shortly to reinforce the key risk minimisation messages for patients in relation to ONJ.

*Bisphosphonates currently authorised in Ireland include Fosamax, Fosavance, Osteomel, Bonviva, Bonefos, Actonel, Zometa & Aclasta. Further details of their product information are available at  www.hpra.ie and www.ema.europa.eu

*Denusomab products currently authorised in Ireland include Prolia and Xgeva. Further details of their product information are available at www.hpra.ie and www.ema.europa.eu

Caroline McDermott

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INCIDENCE IN IRELAND

• Colorectal cancer (CRC) is the second most common invasive cancer diagnosed in women (after breast cancer) and in men (after prostate cancer). Approximately 1,031 women and 1,405 men were diagnosed with CRC annually during 2009-2011.
• 11.5% (in women) and 13.7% (in men) of all invasive cancers (excluding non-melanoma skin cancer) were CRC in 2009-2011. Between 2005 and 2011, 93.1% of patients diagnosed with CRC were aged 50 years or older.
• CRC was the third leading cause of cancer death in women, after lung cancer and breast cancer, and the second leading cause of cancer death in men after lung cancer in 2009-2011. It accounted for 10.3% and 13% of cancer deaths in females and males respectively in 2011.¹

DIAGNOSIS AND STAGING

Clinical or biochemical suspicion of metastatic CRC (mCRC) should always be confirmed by radiological imaging.

Laboratory tests should include:

• Complete blood count
• Blood chemistries and liver/renal function tests
• Serum carcinoembryonic antigen

Imaging studies may include:

• Chest radiography
• Chest/abdominal/pelvic computed tomography (CT)
• Abdominal barium study
• Contrast ultrasonography of the abdomen and liver
• Abdominal/pelvic magnetic resonance imaging
• Positron emission tomography (PET), including fusion PET-CT scan

Other procedures may be warranted:

• Colonoscopy
• Sigmoidoscopy
• Biopsy of suspicious lesions
• Double-contrast barium enema.²

THERAPEUTIC STRATEGIES

Factors influencing choice of first-line treatment

Selecting the best treatment strategy for patients with mCRC should be undertaken by a multidisciplinary expert team. Relevant factors which should be considered are:

Tumour biology-related factors

• Localization
  – Liver- or lung-only metastases vs multiple sites
  – Potentially R0-resectable lesions after induction chemotherapy and sufficient downsizing vs massive disease extension
• Growth dynamics
  – Aggressive vs indolent growth
• Asymptomatic vs symptomatic disease
• Imminent relevant tumour symptoms if low active or inactive treatment
• Second-line treatment after ineffective first-line single-agent treatment may not be possible anymore
• Chemosensitivity
• Prognostic molecular or biochemical markers (e.g. BRAF mutation)

Patient-related factors

• Age
• Co-morbidities
• Physical capacity to tolerate more intensive treatment
• Eligibility for potential secondary resection of liver/lung
• Psychological capacity/willingness to undergo more intensive treatment

Efficacy/safety profile of therapy

• Potential to induce maximal regression of metastases size/number
• Potential to prolong progression-free survival (PFS) or overall survival (OS)
• Safety profile
• Drug sensitivity/predictive biomarkers.³

Currently available treatments

Cytotoxic agents used to treat mCRC include:

• Fluoropyrimidines
  – 5-fluorouracil (5-FU), given intravenously with a second drug called leucovorin (5-FU/LV), or alternatively,
  – capecitabine, given orally (e.g. Capecitabine Sandoz, Xeloda)
• Oxaliplatin (e.g. Hospira Oxaliplatin)
• Irinotecan (e.g. Actavis Irinotecan, Campto)

Several combination regimens may be considered:

• 5-FU/LV/oxaliplatin (FOLFOX)
• 5-FU/LV/irinotecan (FOLFIRI)
• Capecitabine/oxaliplatin (CAPOX)
• 5-FU/LV/oxaliplatin/irinotecan (FOLFOXIRI)

Targeted biological agents include:

Anti-vascular endothelial growth factor (VEGF) agents

• Bevacizumab (Avastin)
• Aflibercept (Zaltrap)

Anti-epidermal growth factor receptor (EGFR) antibodies

• Cetuximab (Erbitux)
• Panitumumab (Vectibix)

Multikinase inhibitor

• Regorafenib (Stivarga)⁴

Stratification of patients for first-line treatment

Patients can be subdivided into four clinical groups:

Group 0: Clearly R0-resectable liver and/or lung metastases
Patients in whom metastases are limited to liver and/or lung metastases, which are clearly R0 resectable.

Group 1: Potentially resectable liver and/or lung metastases
Achievement of a disease-free status after downsizing by induction chemotherapy, enabling secondary surgery, is the only means of giving the potential of long-term survival or cure in an otherwise incurable/palliative situation. The most active induction chemotherapy should be selected upfront.

Group 2: Unlikely resectable disseminated disease
The treatment aim here is palliative rather than curative (with individual exception, e.g. in case of high chemosensitivity and extensive response). In patients with symptoms, more aggressive biology or extensive disease, very active first-line treatment with a high likelihood to induce metastases regression in short time, is appropriate.

Group 3: Never-resectable metastatic disease
Maximal shrinkage of metastases is not the primary treatment aim; without present or imminent symptoms and limited risk for rapid deterioration, the aim is rather prevention of tumour progression and prolongation of life with minimal treatment burden. Non-intensive/sequential treatment may be appropriate for these patients.^3,4

Selection of treatment strategy

The definition of a treatment aim is important for the choice of a first-line treatment.

Surgical resection provides the only potentially curative option for patients with limited metastatic disease in the liver and/or lung. Perioperative chemotherapy or postoperative adjuvant chemotherapy with FOLFOX may be considered.

Five-year survival rates of 20%–45% have been reported with surgical resection of R0-resectable liver metastases. Resection of resectable lung metastases also offers 25%–35% five-year survival rates in carefully selected patients.

Most patients have metastatic disease that initially is not suitable for potentially curative resection. However, some of these patients can have metastases that become suitable for resection after a major response has been achieved with combination chemotherapy.

It is recommended that patients are re-evaluated during treatment by a multidisciplinary team including interventional radiologists and radiation oncologists, since ablative techniques (e.g. radiofrequency ablations, stereotactic body radiation therapy and infusional ablative methods) may be helpful in controlling disease.⁴

Treatment of patients with clearly unresectable mCRC should be seen as a continuum of care in which the determination of the goals of the treatment is important; prolongation of survival, cure, improving tumour-related symptoms, stopping tumour progression and/or maintaining quality of life.

Survival is longer when a patient is exposed to all of the available cytotoxics at some point during the course of treatment, and this could also be applied to the targeted biological agents. The ESMO have therefore proposed different strategic scenarios (see algorithm below). The choice of scenario depends on molecular characterisation of the tumour, the goal of treatment, the toxicity of agents and activity of anti-EGFR antibodies in later lines.

Combination chemotherapy FOLFOX or FOLFIRI provides higher response rates (RRs), longer PFS and better survival than 5-FU/LV alone. FOLFOX and FOLFIRI result in similar outcomes when used as first-line therapy; the choice between them is often based upon expected side effects. They also have potentially different interactions with biologicals.

CAPOX is an alternative to FOLFOX based on similar activity and safety profiles; however, some side-effects (including diarrhea and hand-foot syndrome) may be more pronounced with CAPOX.⁴

Bevacizumab is a monoclonal antibody that binds VEGF, the key driver of vasculogenesis and angiogenesis. It is indicated for the treatment of mCRC in combination with fluoropyrimidine-based chemotherapy. It enhances the anti-tumour effect of other chemotherapy regimens, but is not effective when given by itself.

Bevacizumab has been shown to increase the survival, PFS and RR in first-line treatment in combination with FOLFIRI and in combination with 5-FU/LV or capecitabine alone. It has also been shown to improve the PFS in combination with a fluoropyrimidine plus oxaliplatin in first-line treatment of mCRC. The combination of FOLFOXIRI plus bevacizumab has shown better PFS and RR than FOLFIRI plus bevacizumab in a trial with also one of the longest survivals reported to date.

However, the benefits of adding bevacizumab to these chemotherapy regimens must be balanced against the potentially serious side-effects that can occur with this drug (e.g. bleeding, blood clots). Bevacizumab is usually continued in combination with a cytotoxic agent/combination until progression or toxicity.⁴

Aflibercept is a recombinant fusion protein that binds to VEGF  and prevents it from activating its receptors on tumour cells. It is indicated in combination with FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.

Cetuximab is a monoclonal antibody directed against EGFR, which is found in about 80 percent of colorectal cancers. It is indicated for the treatment of EGFR-expressing, wild-type RAS mCRC in combination with irinotecan-based chemotherapy, in first-line in combination with FOLFOX, or as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.

Panitumumab is a monoclonal antibody which also targets EGFR. It is indicated for wild-type RAS mCRC in first-line in combination with FOLFOX or FOLFIRI, in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan), or as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The benefit of anti-EGFR antibodies in all treatment lines and either as a single agent or in combination with any chemotherapy regimen is limited to patients with wild-type RAS mCRC. The availability of an expanded RAS status is a prerequisite for any use of anti-EGFR antibodies and must not be used otherwise. Anti-EGFR antibodies are not recommended in combination with capecitabine-based regimens, and should not be combined with bevacizumab or aflibercept.⁴

Regorafenib is a protein kinase inhibitor which blocks multiple kinases including those involved in tumour angiogenesis and the tumour microenvironment. It is indicated for the treatment of mCRC in patients who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.

Regorafenib has shown significant improvement of survival and PFS in patients refractory to all available cytotoxics and to bevacizumab and to the anti-EGFR antibodies; it can be proposed as a standard treatment in last line in fit and motivated patients with mCRC.

In patients who started with bevacizumab (in combination with a cytotoxic doublet) in first-line, the targeted biological options for second-line treatment are bevacizumab, aflibercept and, in wild-type RAS patients, anti-EGFR antibodies such as cetuximab or panitumumab. Considerations include the choice of treatment in first-line, the biology of the disease, the molecular characterisation of the tumour, the time on first-line treatment (very short treatment on bevacizumab does not favour the continuation of bevacizumab), the toxicity of the agents, and the activity of the anti-EGFR antibodies in later lines. Continuation of bevacizumab with changed cytotoxic backbone in second-line increases the outcome after progression in first-line. Therefore, 5-FU/LV and bevacizumab could be continued throughout first- and second-line treatment, and solely irinotecan and oxaliplatin will be exchanged by each other.⁴

Click on image to enlarge

References:
1. Cancer in Ireland 1994-2011: Annual report of the National Cancer Registry Ireland. Published May 2014.

2. http://emedicine.medscape.com/article/277496-overview. Accessed 20th April 2015.

3. Schmoll H. J. et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012, 23: 2479–2516.

4. Van Cutsem E. et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014, 25 (Suppl. 3): iii1–iii9.

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Caroline McDermott