Download PDF

Alcohol plays a significant role in Irish society. It is associated with many aspects of Irish social and cultural life and is generally consumed for enjoyment, relaxation and sociability. However, it has major public health implications and it is responsible for a considerable burden of health and social harm at individual, family and community levels. According to a survey on alcohol consumption conducted in 2013 by the Health Research Board, alcohol misuse is widespread in Ireland and the majority of Irish people drink in a harmful manner:

• More than half (54.3%) of Irish drinkers aged 18 – 75 years were classified as harmful drinkers using the World Health Organization’s AUDIT-C screening tool. When the proportion of survey respondents classified as harmful drinkers is applied to the population, it indicates that there were between 1.3 and 1.4 million harmful drinkers in Ireland in 2013.
• In the same age group, 6.9% scored positive for dependence using the DSM-IV criteria, which is a set of criteria for measuring dependence and is the gold standard for identifying dependence in a clinical setting. This indicates that there were somewhere between 149,300 and 203,897 dependent drinkers aged 18 – 75 years in Ireland in 2013.
• Almost two-fifths (37.3%) of all respondents consumed six or more standard drinks on a single occasion one or more times a month in the last year; this practice is known as risky single-occasion drinking (RSOD) or binge drinking. One-in-five (21.1%) drinkers engaged in binge drinking at least once a week. Monthly binge drinking was most common among males aged 18 – 24 years (67.8%).
• In addition, a considerable proportion of self-defined light or moderate drinkers drink 60g or more of alcohol on a typical drinking occasion (equivalent to binge drinking) and do not realise that they consume alcohol in an unhealthy manner.

The findings of the report lead to the conclusion that harmful drinking is the norm in Ireland, in particular for men and women under 35 years. It also reveals that we underestimate what we drink by about 60%. If this is the case, the situation is much worse than what has been presented in the report.

The National Substance Misuse Strategy Steering Group report published in 2012 also found that Irish children are drinking from a younger age and drinking more than ever before. Over half of Irish 16 year old children have been drunk and one in five is a weekly drinker^1,2.

Types of Alcohol Misuse

There are three main types of alcohol misuse:

• Hazardous drinking
• Harmful drinking
• Dependent drinking

Hazardous drinking is a pattern of alcohol consumption that increases the risk of harmful consequences for the user or others. Hazardous drinking patterns are of public health significance despite the absence of any current disorder in the individual user.

Harmful drinking refers to alcohol consumption that results in consequences to physical and mental health. Some would also consider social consequences among the harms caused by alcohol.

Alcohol dependence is a cluster of behavioural, cognitive, and physiological phenomena that may develop after repeated alcohol use. Typically, these phenomena include a strong desire to consume alcohol, impaired control over its use, persistent drinking despite harmful consequences, a higher priority given to drinking than to other activities and obligations, increased alcohol tolerance, and a physical withdrawal reaction when alcohol use is discontinued³.

Alcohol-Related Harm

High levels of alcohol consumption and a high prevalence of binge drinking, especially among young people, have serious health implications. Alcohol increases the risk of more than 60 medical conditions and alcohol misuse is a major risk factor for a range of life-threatening diseases such as heart disease, stroke, liver cirrhosis and certain cancers (e.g., mouth, pharynx, larynx, oesophagus, liver, pancreas, bowel and breast). Alcohol misuse is also associated with family and social harms, and costs the state vast amounts of money and resources. The more alcohol an individual consumes, the greater the risk of injuries, automobile crashes, workplace problems, domestic violence, drowning, suicide, and a variety of other social and legal problems. As with second-hand smoke, excessive drinking has secondary effects on the health and wellbeing of persons in the drinker’s immediate social environment.

• Alcohol is the third leading risk factor for death and disability in the EU after tobacco and high blood pressure. 88 deaths every month in Ireland are directly attributable to alcohol. There are almost twice as many deaths due to alcohol in Ireland as due to all other drugs combined.
• The projected number of new cases of alcohol-related cancers in the Republic of Ireland is expected to double by the year 2020 for women and to increase by 81% for men during the same period. 900 people are diagnosed with alcohol-related cancers and around 500 people die from these diseases every year, according to the National Cancer Control Programme (NCCP). Alcohol is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC) and it is one of the most important causes of cancer in Ireland, being a risk factor in eight types of cancer.
• Links between alcohol and crime are well established. Intoxication of both perpetrator and victims has been noted in a high percentage of instances of homicide and sexual assault. Alcohol has been identified as a contributory factor in 97% of public order offenses as recorded under the Garda PULSE system. One in eleven, or approximately 318,000 of the full adult population, said that they or a family member were assaulted by someone under the influence of alcohol in the past year.
• 16% of child abuse and neglect cases are associated with adult alcohol problems and 1 in 11 Irish children are negatively impacted by a parent’s drinking. Alcohol abuse is a factor in martial disharmony and break-up and in cases of domestic violence.
• Excessive alcohol use frequently leads to unsafe sex resulting in unplanned pregnancies and sexually transmitted diseases.
• One in four deaths of young men aged 15-39 in Ireland is due to alcohol.
• A recent study of suicide in Ireland found that half of those who took their own lives had abused alcohol in the previous 12 months. Suicide is the leading cause of death among young Irish men aged 15-24.
• Alcohol-related disorders were the third most common reason for admission to Irish psychiatric hospitals between 1996 and 2005.
• More than one in four of those attending accident and emergency departments have alcohol related injuries, almost half of which occurred to people aged under 30 years. One in three road crash deaths is alcohol-related.
• Alcohol-related problems cost Ireland an estimated 3.7 billion in 2007 – that’s a cost of 3,318 on each person paying income tax in Ireland.
• Treating alcohol-related injuries and diseases cost the healthcare system an estimated 1.2 billion – around 8.5% of the total annual healthcare budget.
• Every night, 2,000 hospital beds are occupied for alcohol-related reasons.
• 10% of all general in-patient hospital costs, 7% of GP costs and up to 30% of emergency department costs are alcohol-related.
• Excessive alcohol consumption impacts work performance and is frequently the cause of absenteeism and physical injuries in the workplace^3,4,5,6.

Early Identification of Individuals at Risk of Alcohol-Related Harm

Alcohol misuse includes much more than alcohol dependence. Alcohol dependence affects a small but significant proportion of the adult population in Ireland (6.9%), but hazardous and harmful drinking affects a much larger portion of the population (54.3%). Primary care health workers are in a unique position to identify and intervene with patients whose drinking is hazardous or harmful to their health. They may also play a critical role in leading patients with alcohol dependence to enter treatment.

Hazardous and harmful drinkers respond well to primary care intervention. Unlike persons with alcohol dependence, who should be referred to specialist care, hazardous and harmful drinkers should be given simple advice and brief counselling, respectively. These brief interventions have been shown in numerous clinical trials to reduce the overall level of alcohol consumption, change harmful drinking patterns, prevent future drinking problems, improve health, and reduce health care costs.

Various screening methodologies have proven to be useful including the WHO Alcohol Use Disorders Identification Test (AUDIT). This test is administered by means of a questionnaire containing 10 questions on frequency and intensity of drinking. A brief self-report screening test can be distributed with other forms patients are asked to complete in the waiting room, or the questions can be integrated into a routine medical history interview. Other tests include the Paddington Alcohol Test, and the Fast Alcohol Screening Tests (FAST).

Experience gained from numerous research studies and clinical programs indicates that almost all patients are cooperative when asked about their drinking, and most are appreciative when health workers show an interest in the relationship between alcohol and health. According to the HRB report on alcohol attitudes in the general public, there is near complete support (≥95%) for healthcare professionals asking about alcohol consumption where it is linked to the patient’s condition or treatment. In general, patients perceive alcohol screening and brief counselling as part of the health worker’s role^3,6.

Medication

There are currently three licensed medications that can be used in the treatment of alcohol misuse:

• Acamprosate (Campral) is indicated as therapy to maintain abstinence in alcohol dependent patients. It should be combined with counselling. Acamprosate works by affecting levels of a chemical in the brain known as gamma-amino-butyric acid (GABA). GABA is thought to be partially responsible for inducing a craving for alcohol⁷.
• Disulfiram (Antabuse) is indicated as an adjuvant in the treatment of carefully selected and co-operative patients with drinking problems. It should be used in conjunction with appropriate psychiatric treatment. The effect of disulfiram is primarily due to irreversible inactivation of liver aldehyde dehydrogenase. In the absence of this enzyme, the metabolism of ethanol is blocked and the intracellular acetaldehyde concentration rises – this leads to a series of extremely unpleasant physical reactions if alcohol is consumed⁸.
• Nalmefene (Selincro) is indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL), without physical withdrawal symptoms and who do not require immediate detoxification. Nalmefene should be initiated only in patients who continue to have a high DRL two weeks after initial assessment, and should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption. Nalmefene is an opioid system modulator with a distinct µ, δ, and κ receptor profile. It reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions. No abuse or dependence potential is expected⁹.

References:

1. Long J. and Mongan D. Alcohol Consumption in Ireland: Analysis of a National Alcohol Diary Survey (2013). Health Research Board. 2. Steering Group Report on the National Substance Misuse Strategy (2012). Department of Health. 3. Babor T. F. et al. (2001). The Alcohol Use Disorders Identification Test: Guidelines for Use in Primary Care (2nd edition). World Health Organisation. 4. Health Service Executive. Available http://www.hse.ie/eng/health/az/A/Alcohol-misuse/. Last accessed 15th December 2014. 5. Alcohol Action Ireland. Available at http://alcoholireland.ie/facts/alcohol-related-harm-facts-and-statistics/. Last accessed 15th December 2014. 6. RCPI Policy Group on Alcohol: Reducing Alcohol Health Harm Policy (2013). Royal College of Physicians of Ireland. 7. Campral SPC, October 2012. 8. Antabuse SPC, July 2010. 9. Selincro SPC, February 2013.

Caroline McDermott

Download PDF

Lundbeck is pleased to announce the launch of Selincro (nalmefene), the first medicine approved for the reduction of alcohol consumption in alcohol-dependent patients with a high drinking risk level.¹

The endogenous opioids play a key role in the rewarding (addictive) properties of ethanol by activation of the mesolimbic dopamine system. Nalmefene is an opioid system modulator with antagonist activity at the µ and d receptors and partial agonist activity at the k receptor.

The approval follows the results of a post hoc analysis of two randomised controlled 6-month studies (ESENSE 1 and ESENSE 2) designed to evaluate the efficacy and safety of as-needed nalmefene in reducing alcohol consumption in alcohol-dependent patients with a high drinking risk level.

Rationale

ESENSE 1 and ESENSE 2 have shown that nalmefene as-needed reduces the total amount of alcohol consumption and number of heavy drinking days in patients with alcohol dependence. However, in both studies a significant proportion of patients (18%, and 33%, respectively) considerably reduced their alcohol consumption in the first two weeks between the initial visit (screening) and randomisation. At randomisation, these patients consumed such a small amount of alcohol that there was little room for further improvement (floor effect), resulting in a substantial underestimation of the treatment effect.

This population of patients may represent excessive drinkers who after making the decision to seek help can reduce their drinking with minimal intervention. Taking this phenomenon into account, a post hoc analysis was designed which included the subgroup of patients who continued their high level of alcohol consumption after initial assessment until the start of treatment, as these were expected to derive the highest clinical benefit from nalmefene.

Study design

The post hoc analysis included a pooled population of 667 patients (from ESENSE 1 and ESENSE 2) who did not reduce their alcohol consumption after an initial assessment, i.e. with at least a high drinking risk level (men: >60g/day; women: >40g/day) at both screening and randomisation. Nalmefene 18mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Data on clinical improvement, liver function and safety were also collected throughout the study.

Daily alcohol consumption reduced from more than 100g/day to 40g/day with Selincro*

Nalmefene as-needed was found to be superior to control in reducing daily alcohol consumption. Mean baseline values were approximately 100g/day for alcohol consumption in ESENSE 1 and 110g/day in ESENSE 2. For the pooled target population (Figure A), the estimated mean reduction from baseline in total alcohol consumption at Month 6 was -51.4g/day for the control group and -65.7 g/day for the nalmefene group, corresponding to a treatment effect of -14.3 g/day (p < 0.0001) in favour of nalmefene.

Number of heavy drinking days reduced from  23 days to 10 days per month with Selincro

Benefits similar to those obtained for total alcohol consumption were observed for the number of heavy drinking days. At baseline, the mean number of heavy drinking days was approximately 23 days/month in ESENSE 1, and 22 days/month in ESENSE 2. For the pooled target population (Figure B), the estimated mean reduction in heavy drinking days at Month 6 was -9.4 days/month for the control group and -12.6 days/month for the nalmefene group, corresponding to a treatment effect of -3.2 heavy drinking days/month (p < 0.0001) in favour of nalmefene.

For both co-primary outcomes, the magnitude of the treatment effect was greater in the target population of high risk drinkers than in the total treatment population (in both trials separately as well as in the pooled data of both trials).

Improvements in clinical status and liver parameters were also found to be greater in the nalmefene group compared with the control group. Adverse events and adverse events leading to dropout were more common with nalmefene than control. The incidence of serious adverse events was similar in control patients (3.7%) and nalmefene patients (4.5%).

Click on image to enlarge

Conclusion

As-needed Selincro was efficacious in reducing alcohol consumption in patients with a high drinking risk level at both screening and randomisation, and the effect in this subgroup was larger than in the total population of alcohol-dependent patients. Based on this finding, the authors concluded that Selincro should be offered to those alcohol-dependent patients in primary care and outpatient addiction treatment services who are not able to reduce their alcohol consumption following an initial assessment or brief intervention.

Selincro should be initiated only in patients who continue to have a high drinking risk level two weeks after initial assessment, and should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption.

Selincro is to be taken as-needed: On each day the patient perceives a risk of drinking alcohol, one tablet should be taken, preferably 1-2 hours prior to anticipated time of drinking.  If the patient has started drinking alcohol without taking Selincro, the patient should take one tablet as soon as possible.

*1 standard drink = 10g of alcohol, equivalent in Irish standard to half a pint of beer, a small glass of wine, or one pub measure of spirits.

Reference:

1- van den Brink W et al. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies.  Alcohol Alcoholism 2013 Sep-Oct;48(5):570-8.

Caroline McDermott

Download PDF

Janssen-Cilag Ltd. is pleased to announce that Invokana (canagliflozin) has received European approval for the treatment of adults with type 2 diabetes mellitus to improve glycaemic control.

Invokana is a member of a new class of drugs known as sodium glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors contribute to controlling blood glucose levels via the kidney. As glucose is filtered from the blood into the kidneys, it is reabsorbed back into the bloodstream. Canagliflozin selectively inhibits SGLT2, an important transport carrier in the renal proximal tubule responsible for this reabsorption, and as a result, promotes the loss of glucose via the urine, lowering blood glucose levels in adults with type 2 diabetes. This mechanism of action is independent of b-cell function and insulin.¹

Canagliflozin is indicated as a once-daily oral medication to improve glycaemic control in adults with type 2 diabetes mellitus. It is for use as a monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance; or as an add-on therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.¹

The marketing authorisation is based on the results of an extensive, phase 3 clinical trial programme which enrolled 10,285 patients with type 2 diabetes in nine double-blind, controlled clinical efficacy and safety studies.^1-3 Several of these phase 3 studies have directly compared Invokana to current standard treatments. One such head-to-head comparative study evaluated the efficacy and safety of Invokana as an add-on therapy versus sitagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.²

Study design

After a 2 week single-blind, placebo run-in period, type 2 diabetes patients who had inadequate glycaemic control on metformin therapy (n=1,284) were randomised to receive canagliflozin 100mg or 300mg, sitagliptin 100mg, or placebo for a 26 week, placebo- and active-controlled, double-blind period followed by a 26 week, active-controlled, double-blind period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Secondary endpoints included changes in HbA1c at week 52, body weight, fasting plasma glucose (FPG) and systolic blood pressure (BP) at weeks 26 and 52. Baseline demographic and disease characteristics were similar across treatments groups.²

Invokana 300mg demonstrated statistical superiority to sitagliptin in reduction of HbA1c

At week 26, canagliflozin 100mg and 300mg significantly reduced HbA1c from baseline compared with placebo (difference in least squares [LS] mean changes of −0.62% and−0.77%, respectively; p <0.001 for both); the change in HbA1c with sitagliptin was −0.66% relative to placebo (Figure 1A). A greater proportion of patients treated with canagliflozin 100mg and 300mg achieved HbA1c <7.0% than with placebo (45.5%, 57.8% and 29.8%, respectively; p =0.000 for both); 54.5% of sitagliptin-treated patients achieved HbA1c <7.0%. Both canagliflozin doses significantly reduced FPG at week 26 vs placebo (p <0.001 for all). FPG was also reduced from baseline with sitagliptin.

Canagliflozin 100mg and 300mg demonstrated non-inferiority, and canagliflozin 300mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (−0.73%, –0.88%,–0.73%, respectively) at week 52; differences (95% CI) vs sitagliptin were 0% (−0.12, 0.12) and −0.15% (−0.27, –0.03) for the 100mg and 300mg doses respectively (Figure 1B). A higher proportion of patients treated with canagliflozin 300mg achieved HbA1c <7.0% compared with those treated with canagliflozin 100mg or sitagliptin (54.7%, 41.4% and 50.6%, respectively). The proportion of patients  reaching HbA1c <6.5% was 26.9%, 21.9% and 24.9% for those treated with canagliflozin 300mg, canagliflozin 100mg and sitagliptin, respectively. Over 52 weeks, canagliflozin 100mg and 300mg provided greater reductions in FPG than sitagliptin (difference in LS mean changes of −0.5 and −1.0 mmol/l, respectively; p <0.001 for both).²

Patients experienced secondary benefits of reductions in body weight and blood pressure with Invokana

At week 26, canagliflozin 100mg and 300mg significantly reduced body weight compared with placebo (p <0.001); body weight change was −1.2% with both sitagliptin and placebo. Both canagliflozin doses were associated with significant decreases vs placebo in systolic BP (p <0.001 for both). Reductions from baseline in diastolic BP were also observed with both canagliflozin doses. Sitagliptin was associated with decreases from baseline in systolic and diastolic BP.

At 52 weeks, canagliflozin 100mg and 300mg significantly reduced body weight compared with sitagliptin, with differences in LS mean per cent changes vs sitagliptin of −2.4% (-2.1kg) and −2.9% (-2.5kg), respectively (p <0.001 for both) (Figure 1C). Both canagliflozin doses significantly decreased systolic BP relative to sitagliptin at 52 weeks (difference in LS mean changes of −2.9 and −4.0 mmHg, respectively; p <0.001 for both).²

Click on image to enlarge

Safety and tolerability

Canagliflozin treatment was generally well tolerated, but was associated with a higher proportion of patients reporting genital mycotic infections and osmotic diuresis-related adverse events than with sitagliptin or placebo/sitagliptin. These were generally mild or moderate in severity, occurred at a low incidence and infrequently led to discontinuation. The incidence of documented hypoglycaemia was low but was slightly higher with both canagliflozin doses (6.8%) than with sitagliptin (4.1%) or placebo/sitagliptin (2.7%). The incidence of urinary tract infections was similar with canagliflozin 100mg and 300mg and the control groups (i.e. sitagliptin and placebo/sitagliptin).² Results from this trial was included in a pooled analysis of placebo-controlled, phase 3 studies to assess the safety and tolerability profile of canagliflozin in a broad range of type 2 diabetes patients on various background anti-hyperglycaemic treatments; the type and incidence of adverse events associated with canagliflozin was similar across all studies. Dose-related increases in the incidence of hypoglycaemia episodes were seen with canagliflozin vs placebo in patients on background sulfonylurea. Hypoglycaemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin vs placebo.⁴

Invokana 300mg demonstrated statistical superiority to sitagliptin in HbA1c reduction in triple therapy

The results of the current study complement and support findings from a similar head-to-head, 52 week, phase 3 trial comparing canagliflozin 300mg with sitagliptin 100mg in patients with type 2 diabetes inadequately controlled with metformin plus sulfonylurea.³ In that study, canagliflozin 300mg demonstrated non-inferiority and statistical superiority to sitagliptin in HbA1c-lowering effect at 52 weeks (difference in LS mean changes of −0.37%). Greater reductions in body weight (difference of −2.8%), FPG and systolic BP were observed with canagliflozin relative to sitagliptin. Overall adverse events incidence was similar with canagliflozin and sitagliptin but the incidence of genital mycotic infection and osmotic diuresis-related adverse events was higher with canagliflozin. The incidence of hypoglycaemia was similar with canagliflozin and sitagliptin but was higher than that observed in the current study, which is likely related to the additional sulfonylurea treatment.^2,3

Conclusion

Canagliflozin is the third SGLT-2 inhibitor for type 2 diabetes available in Ireland. Canagliflozin vs sitagliptin as add-on to metformin improved glycaemic control from baseline and showed statistical superiority to sitagliptin at 52 weeks. It also demonstrated a low but slightly higher risk of hypoglycaemia than with sitagliptin. Treatment with canagliflozin resulted in significant reductions in bodyweight and blood pressure vs sitagliptin, and was well tolerated.² The efficacy and safety results from this study are consistent with the findings from other trials for canagliflozin.^2-4

References:

1. Invokana Summary of Product Characteristics, April 2014. Available from www.medicines.ie

2. Lavalle-González FJ et al. Diabetologia 2013;56:2582–2592.

3. Schernthaner G et al. Diabetes Care 2013;36:2508-2515.

4. Usiskin K et al. Postgraduate Medicine 2014;126(3):16-34.

Caroline McDermott

Agomelatine* is a melatonergic agonist (MT₁ and MT₂ receptors) and 5-HT_2C antagonist, indicated in the treatment of major depressive episodes in adults. It was first authorised for use across the EU since 2009 on the basis of studies showing that the medicine has comparable effects to other antidepressants.  Since agomelatine has a different mode of action and a different safety profile to existing antidepressants, it was concluded that, as long as their liver function is tested regularly, agomelatine could be a valuable treatment for some patients. In the post marketing setting, hepatic adverse reactions have continued to be reported and an EU level review has recently been finalised which concluded that the benefit risk balance for agomelatine remains positive. However there is a need to reiterate the importance of liver monitoring, which is the cornerstone for the safe use of this product.

A risk of hepatic adverse effects has been known to be associated with agomelatine since it was first authorised and the product information has included warnings about these risks and the requirement for regular monitoring of liver function tests during treatment with agomelatine. In December 2012 and December 2013, the HPRA highlighted the risk of hepatotoxicity in its Drug Safety Newsletter (51^st and 57^th edition) and emphasised the importance of liver function monitoring.

The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recently concluded its regular benefit-risk assessment (known as a periodic safety update report or PSUR) of agomelatine. As part of this assessment, the PRAC considered cumulative data on severe hepatic adverse effects associated with agomelatine and recommended further reinforcement of measures to minimise the risk of hepatotoxicity.

Reports of hepatic failure included a small number of cases which resulted in a fatal outcome or liver transplantation in patients with hepatic risk factors. Elevations of liver enzymes exceeding 10 times the upper limit of normal, hepatitis and jaundice have also been reported in patients treated with agomelatine in the post-marketing setting. The majority of these abnormalities occurred during the first months of treatment. The pattern of liver damage appears mainly hepatocellular.

Extra vigilance is advised for patients with risk factors for hepatic injury. The balance of benefits and risks should be carefully considered before initiating treatment in a patient with risk factors for hepatic injury e.g. obesity/overweight/non-alcoholic fatty liver disease, diabetes, substantial alcohol intake and in patients receiving concomitant medicinal products associated with hepatic injury. Caution should be exercised when Valdoxan is administered to patients with pretreatment elevated transaminases.

Efficacy has not been demonstrated in patients ≥75 years and use of agomelatine is not recommended for patients in this age group. Prescribers are reminded that agomelatine is contraindicated in patients with hepatic impairment i.e. cirrhosis or active liver disease and in patients with transaminases exceeding 3 times the upper limit of normal. Elevations of transaminases (>3 times the upper limit of the normal range) occur more frequently in patients treated with 50mg compared to 25mg.  For some patients treated in clinical practice, hepatic reactions occurred following an increase in dose.

Advice for Healthcare Professionals

• Baseline liver function tests should be performed in every patient and treatment should not be started in patients with transaminases exceeding 3 times the upper limit of normal.

• Liver function must be monitored regularly during treatment, at 3, 6, 12 and 24 weeks and regularly thereafter when clinically indicated.

• Treatment must be discontinued immediately if the increase in serum transaminases exceeds 3 times the upper limit of normal, or if patients present with symptoms or signs of potential liver injury.

• Patients should be informed of the symptoms of potential liver injury and the importance of liver function monitoring, and should be advised to stop taking Valdoxan immediately and to seek urgent medical advice if these symptoms appear.

Key Message

• Cases of liver injury, including hepatic failure, where a small number of cases have resulted in a fatal outcome or liver transplantation, in patients with hepatic risk factors have been reported in association with post-marketing use of agomelatine.

• Liver function tests (LFTs) should be monitored in all patients before and during treatment, in line with the recommendations described in the approved product information.

 
*Product information for agomelatine is available at  www.hpra.ie

Caroline McDermott

Download PDF

There is growing evidence that long-acting injectable antipsychotics (LAIs) may be more effective for maintaining treatment adherence, reducing the rate of relapse and rehospitalisation, and preserving brain function, compared with oral antipsychotics, in first-episode or recent-onset schizophrenia. Given that the rates of nonadherence to antipsychotics are particularly high during the critical period of the first 2 to 5 years, when long-term trajectories of clinical and social outcome are established, many experts recommend that LAIs should be more actively considered with first-episode schizophrenia^1,2,3,4.

Recent updates to clincial guidelines

The majority of current clinical guidelines on the treatment of schizophrenia restrict the use of LAIs to multiple-episode and to noncompliant patients¹. However, there have been subtle changes in more recent guidelines, e.g., the recent Canadian guidelines recommend the use of LAIs in all phases of psychotic illness, including the first 2 to 5 years³. Furthermore, the recently published consensus-based guidelines for the use of LAIs in clinical practice by the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) recommends systematic offering of second-generation long-acting injectable antipsychotics (SG-LAIs) as first-line treatment to schizophrenic patients who need maintenance therapy⁵. Also, an international group of expert psychiatrists have set up an educational initiative called The Centres of Excellence for Relapse Prevention (CERP) in Schizophrenia Program⁶ to address the worldwide issue of relapse among patients with schizophrenia. It is a new forum for education and information sharing around the topic of relapse and relapse prevention strategies, and recommends that clinicians should offer LAIs during the early stages of illness^6,7.

Nonadherence and relapse rates high during critical period

The primary clinical and psychosocial deterioration associated with schizophrenia occurs within the first 5 years following the onset of the illness, called the critical period. Therefore, it is important to provide intensive interventions during this period in an effort to improve the long-term prognosis. The primary goal of treatment during the critical period is to prevent a subsequent relapse and to restore social and occupational functioning to the premorbid level. The relapse rate in patients with FEP is relatively low during the first year of the illness but substantially rises to rates of 53.7% and 81.9% after 2 and 5 years, respectively. The most common cause of relapse in patients with schizophrenia is a lack of adherence to oral medication. The discontinuation of antipsychotics in patients with FEP increases the risk of relapse by approximately five times. One study reported a 59% rate of poor adherence (39% nonadherent and 20% inadequately adherent) within one year after the first-episode².

Many complex factors influence adherence with antipsychotic treatment in patients with schizophrenia. These include poor insight into the illness itself, adverse effects from antipsychotic treatment, comorbid substance abuse and environmental factors. Other factors may also play a role, including organisation of psychiatric services and the extent of education provided to patients and caregivers regarding the important role of medications in their illness and quality of life⁸.

Benefits of LAIs in first-episode schizophrenia

Recent studies investigating the use of LAIs in first-episode schizophrenia confirm their potential benefits in this population. A cohort study in Finland examined the use of oral and depot antipsychotics after first hospitalisation for schizophrenia in 2,588 FEP patients and found that fewer than 50% of patients continue treatment for the first 2 months after an initial hospitalisation. In this study, LAIs had a 64% lower relapse rate than equivalent oral medication⁹. Another study compared relapse rates in patients diagnosed with FEP and treated with either long-acting injectable risperidone (RLAI) or oral risperidone. At 1 and 2 years of follow-up, patients on RLAI had significantly lower relapse rates associated with longer periods of adherence, and higher rates of adherence than patients on oral risperidone (68% vs. 32%). Additional benefits in the RLAI treated patients included greater reduction in the total Positive and Negative Syndrome Scale and in the Clinical Global Impression-Severity scale, and greater functional improvement as measured by the General Assessment of Functioning scale, with patients on RLAI showing an increase of 26% while patients on oral risperidone experienced a 0.5% improvement (p = 0.001). No significant differences in extrapyramidal symptoms or frequency of prolactin-related adverse effects were noted in either group¹⁰.

There may be evidence that improved medication adherence with LAI in early treatment of schizophrenia influences some of the putative underlying causes of the illness. Two studies compared the effects of RLAI with oral risperidone on frontal lobe intracortical myelin and white matter volume in FEP patients^11,12. Frontal white matter volume remained stable over the 6-month study period in patients on RLAI but declined significantly in the oral risperidone group. Stability in frontal lobe white matter volume was associated with a faster reaction time in executive tasks of working memory and mental flexibility. Further analysis focused on intracortical myelination (ICM) volume, which is known to decline with illness chronicity in schizophrenia. Compared to baseline, patients treated with RLAI had increased ICM volume compared with controls, while ICM volume in the group treated with oral risperidone was comparable with controls. This preliminary evidence indicates that improved adherence associated with LAIs might mitigate disruption in myelination that has been hypothesised to contribute to the aetiology of schizophrenia^7,11,12.

Advantages of LAIs over oral antipsychotics

LAIs have a number of advantages over oral antipsychotics:

• administered by a mental health professional which has the potential of increasing therapeutic contacts
• allow for the easy and quick detection of nonadherence which facilitates immediate intervention
• decrease the risk of accidental or deliberate overdose
• the parenteral route avoids first-pass metabolism, which reduces the risk of drug-drug interactions
• since injections offer stable plasma concentrations that avoid high fluctuations, they should induce less side effects and minimise antipsychotic withdrawal symptoms resulting from partial compliance^7,13.

Image of LAIs among clinicians

LAIs are generally not considered by clinicians in FEP, despite evidence that early and effective treatment with depot antipsychotics favourably alters outcomes. Some clinicians may associate LAIs with increased risk of certain side effects, although such evidence is not forthcoming in the literature⁸. Clinical studies investigating LAIs with their oral equivalents have found comparable safety and tolerability profiles^8,14,15.

Clinicians frequently assume patients will not accept LAIs and are reluctant to offer or discuss this option. Such an assumption can be driven by concerns that patients will perceive the proposal of LAIs as an intrusive treatment that is reserved for more serious forms of the illness⁸. More than 50% of patients are not offered the option of LAIs, and less than 30% of patients are prescribed LAIs in preference to oral antipsychotics. A recent study conducted in Germany found that clinicians were reluctant to prescribe LAIs, even when they suspected or anticipated nonadherence. Another survey conducted in the UK reported that although half of the psychiatrists considered LAIs as an option in FEP patients, less than 15% went on to prescribe LAIs. Results from attitudinal surveys conducted in 2007 and 2011 show that psychiatrists believe that FEP patients will probably reject LAIs. However, 73% of patients with first-episode schizophrenia participating in a prospective trial accepted the recommendation to receive RLAI. Additionally, it cannot be ignored that patients who have tried LAIs prefer this treatment over oral antipsychotics⁸.

Psychiatrists also assume that the availability of second-generation antipsychotics in LAI formulations is limited. However, several second-generation antipsychotics are now available as LAIs and data are accumulating on their efficacy and tolerability in FEP patients⁷.

SG-LAIs currently available in Ireland include apripiprazole (Abilify Maintena), olanzapine (Zypadhera), palperidone (Xeplion), and risperidone (Risperdal Consta).

Conclusion

Considering that poor adherence to oral antipsychotic treatments and the very high relapse rates early in the illness due to nonadherence are the rule rather than an exception, psychiatrists should think in terms of relapse prevention from the outset of the illness, identify and overcome local barriers to use LAIs, and consider the option of SG-LAIs in all patients with first-episode or recent-onset schizophrenia in a shared decision-making approach.⁸

However, LAIs are not a panacea; they do not guarantee adherence themselves but their use does allow for a more accurate means of assessing nonadherence⁸. Antipsychotic treatment should be enhanced by psychosocial interventions within an appropriate relapse prevention program^1,6.

There is still need for more open-label or double-blind randomised controlled trials in early phases of schizophrenia, regarding the long-term efficacy, safety, and global functional outcome of SG-LAIs compared to oral antipsychotics in order to obtain a more robust clinical database for evidence-based medicine. Such studies should also determine whether or not LAIs introduced early in the development of schizophrenia can change the course of the disease¹.

Key messages

• Many psychiatric experts now recommend that SG-LAIs should be offered to patients with first-episode schizophrenia
• Nonadherence continues to represent a significant issue compromising long-term prognosis, especially during the first 2 to 5 years
• LAIs should improve adherence to antipsychotics, decrease rates of relapse and rehospitalisation, and improve clinical functioning
• There are misconceptions among clinicians about LAIs, associating them with increased risk of side effects, and assuming that they will be rejected by patients with first-episode schizophrenia
• LAIs have similar safety and tolerability profiles to their oral equivalents, and have a high acceptance rate among FEP patients
• Clinicians should discuss LAIs as a treatment option with FEP patients in a shared decision making approach within an appropriate relapse prevention program
• There is still need for more studies examining the long-term efficacy, safety and tolerability, and global outcomes of SG-LAIs compared to oral antipsychotics in first episode or recent-onset schizophrenia

References:

1. Parellada P et al. Schizophr Res Treatment 2012. Available at http://dx.doi.org/10.1155/2012/318535.

2. Kim B et al. Schizophr Res Treatment 2012. Available at http://dx.doi.org/10.1155/2012/560836.

3. Malla A et al. Can J Psychiatry 2013;58:30S–5S.

4. Prikryl R et al. Schizophr Res Treatment 2012. Available at http://dx.doi.org/10.1155/2012/764769.

5. Llorca PM et al. BMC Psychiatry 2013;13:340

6. Lambert TJ et al. Schizophr Res 2010; 117(2-3):295–296.

7. Heres S et al. Eur Psychiat 2014;29 (S2):1409–1413.

8. Agid O et al. Expert Opin. Pharmacother 2010;11(14):2301-2317.

9. Tiihonen J et al. Am J Psychiatry 2011;168:6.

10. Kim B et al. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1231–5.

11. Bartzokis G et al. Schizophr Res 2011;132:35–41.

12. Bartzokis G et al. Schizophr Res 2012;140:122–8.

13. Zhornitsky S and Stip E. Schizophr Res Treatment 2012. Available at http://dx.doi.org/10.1155/2012/407171.

14. Fleischhacker W et al. Brit J Psychiat 2014;205: 135–144.

15. Kane JM et al. J Clin Psychiatry 2012 May;73(5):617-24.

Caroline McDermott

GlaxoSmithKline is updating the appearance of Relvar ▼Ellipta (fluticasone furoate/vilanterol). Relvar Ellipta is an approved inhaled corticosteroid (ICS) and long acting β2-agonist (LABA) combination, for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The changes are effective from the end of January and are limited to the packaging and labelling only. The colour of the Ellipta inhaler mouthpiece cover and packaging will change from pale blue to yellow. New strength colour indicators will be included on the packaging to make the two different doses of Relvar Ellipta easier to identify. The lower strength (92/22mcg) will be marked with a green band and the higher strength (184/22mcg) will be marked with a red band. The instructions on the packaging relating to how to use this medicine will be easier to read and understand. Further information is available at GSK Medical Information on 1800 244 255.

Tara Sweeney

Company: Dr Falk Pharma UK Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredient: Mesalazine 1.5g.

Description: Gastro-resistant prolonged-release granules in sachets.

Presentation: 60, €56.05.

Indications: Treatment of acute episodes and maintenance of remission of ulcerative colitis.

Pharmacology: The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role. Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-aminosalicylic acid / 5-ASA) may also function as a radical scavenger of reactive oxygen compounds.

Dosage: Adult: Acute treatment: 3 sachets of Salofalk 500mg/1g, 1 or 2 sachets of Salofalk 1.5g or 1 sachet of Salofalk 3g once daily preferably in the morning; alternatively 1 sachet of Salofalk 500mg or 1g 3 times daily (equiv. 1.5-3g daily) as required. Maintenance: 1 sachet of Salofalk 500mg 3 times daily or 3g once daily in patients at increased risk for relapse. Swallow without chewing, with plenty of liquid. Elderly: As per adults. Children: Under 6 years, not recommended. 6 years and older, acute treatment: 30-50mg/kg/day once daily preferably in the morning or in divided doses, maximum 75mg/kg/day; maintenance: Initially, 15-30 mg/kg/day in divided doses. Usually: Up to 40kg, half adult dose; over 40kg, normal adult dose.

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

Special precautions: Caution: Hepatic impairment. Renal impairment (do not use); consider renal toxicity if renal function deteriorates during treatment. Determine differential blood count, liver function, serum creatinine and urinary status prior to and during treatment (14 days after initiation, then two to three tests at 4 week intervals); if findings are normal follow up every 3 months; test immediately if additional symptoms occur. Acute intolerability reactions (discontinue immediately). Pulmonary disease (especially asthma), history of adverse drug reactions to sulphasalazine; carefully monitor. Contains aspartame, sucrose. Pregnancy, lactation (discontinue if infant develops diarrhoea); only if benefit outweighs risk.

Drug interactions: Caution: Azathioprine, 6-mercaptopurine, thioguanine. Warfarin, lactulose or similar preparations which lower stool pH.

Adverse drug reactions: None common.

Full prescribing information and references available from Dr Falk Pharma UK Ltd. Telephone: (0044) 1628 536600. E-mail: office@drfalkpharma.co.uk

Tara Sweeney

Company: Nutricia Advanced Medical Nutrition.

Legal category: Nutrition. GMS.

Contents: Xanthan gum based powdered thickener; gluten and lactose free.

Description: White, odourless, tasteless powder designed to maintain the original appearance of fluids.

Presentation: 1 x 175g, €8.19.

Indications: Thickening of food and fluid in dysphagia.

Contraindications: Children under 3 years.

Full prescribing information and references available from Nutricia Advanced Medical Nutrition. Telephone: (01) 2890283.

Tara Sweeney

Company: AstraZeneca Pharmaceuticals (Ireland) Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredient: Exenatide 2mg.

Description: Powder and solvent for prolonged-release suspension for injection.

Presentation: 4 pre-filled pens, €89.48.

Indications: Treatment of type 2 diabetes mellitus in combination with metformin, sulphonylurea (SU), thiazolidinedione, metformin + SU or metformin + thiazolidinedione in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.

Pharmacology: Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits several antihyperglycaemic actions of GLP-1. The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activate the known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signalling pathways.

Dosage: Adult: 2mg by subcutaneous injection once weekly, on same day each week. In combination with SU, consider reducing SU dose to reduce hypoglycaemia risk. Elderly: >75 years, limited experience. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Pregnancy, lactation. Women should use contraception during treatment and not plan a pregnancy for ≥3 months after.

Special precautions: Not for use in type 1 diabetes, diabetic ketoacidosis. Do not administer by intravenous or intramuscular injection. Not recommended: Moderate/severe renal impairment, end-stage renal disease, severe gastrointestinal disease. Caution: History of pancreatitis. Risk of acute pancreatitis (advise patients to report symptoms of persistent or severe abdominal pain); discontinue if suspected; do not resume if diagnosis confirmed. May occur: Weight loss >1.5kg/week (may be harmful); altered renal function (rare). Avoid hypoglycaemia while driving/using machines.

Drug interactions: Not recommended: Insulin, D-phenylalanine derivatives (meglitinides), α-glucosidase inhibitors; no data. Caution: Warfarin/coumarol derivatives, HMG CoA reductase inhibitors.

Adverse drug reactions: Hypoglycaemia (with a SU), decreased appetite, dizziness, headache, gastrointestinal disorders, injection site reactions, fatigue, somnolence.

Full prescribing information and references available from AstraZeneca Pharmaceuticals (Ireland) Ltd. Telephone: (01) 6097100. Fax: (01) 6796650. Email: medical.informationuk@astrazeneca.com

Tara Sweeney

Company: Vifor Pharma UK Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredient: Iron (as sucroferric oxyhydroxide) 500mg.

Description: Brown, circular tablets marked PA500.

Presentation: 90, €179.78.

Indications: Control of serum phosphorus levels in chronic kidney disease patients on haemodialysis or peritoneal dialysis. Should be used as part of a multiple therapeutic approach (could include calcium supplement, 1,25-dihydroxy vitamin D3 or one of its analogues, or calcimimetics).

Pharmacology: Sucroferric oxyhydroxide is also known as a mixture of polynuclear iron(III)-oxyhydroxide (pn‑FeOOH), sucrose and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of the gastrointestinal tract. Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption.

Dosage: Adult: Chew or crush tablets. Initially 3 tablets daily with meals. Up or down titrate in increments of 1 tablet per day every 2-4 weeks until acceptable serum phosphorus level reached (regularly monitor thereafter). Maximum 6 tablets per day. Elderly: As per adults. Children: Under 18 years, safety and efficacy not established.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Haemochromatosis and any other iron accumulation disorders.

Special precautions: Recent peritonitis (within 3 months), significant gastric/ hepatic disorders or major gastrointestinal surgery; assess risk/benefit. May cause discoloured (black) stool (may mask gastrointestinal bleeding). Contains sucrose, starches. Pregnancy (only if clearly needed), lactation; assess risk/benefit.

Drug interactions: Drugs with a narrow therapeutic window. Drugs interacting with iron (e.g. alendronate, doxycycline). Cephalexin, levothyroxine, doxercalciferol, paricalcitol (during 1 hour before or 2 hours after).

Adverse drug reactions: Gastrointestinal disorders, abnormal product taste.

Full prescribing information and references available from Vifor Pharma UK Ltd. Telephone: (0044) 1276 853600.

Tara Sweeney

Company: GlaxoSmithKline (Ireland) Ltd.

Legal category: Prescription. Hospital only. Sport permitted.

Active ingredients: Dolutegravir (as sodium)/abacavir (as sulfate)/lamivudine 50/600/300mg.

Description: Purple, biconvex, oval, film-coated tablets marked 572 Trı.

Presentation: 30, €1294.00.

Indication: Treatment of Human Immunodeficiency Virus (HIV).

Pharmacology: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Abacavir and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Lamivudine-TP (an analogue for cytidine) and carbovir-TP (the active triphosphate form of abacavir, an analogue for guanosine) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination.

Dosage: Adult: One tablet once daily. Elderly: 65 years and over (caution), limited data. Children: Over 12 years (at least 40kg bodyweight), as per adults. Under 12 years, safety and efficacy not established.

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

Special precautions: Not for use in patients carrying the HLA-B*5701 allele. Screen for HLA-B*5701 allele before initiation in any patient, irrespective of racial origin. Do not use in patients under 40kg or those requiring dose adjustments. Not recommended: Moderate to severe hepatic impairment, creatinine clearance (cc) <50 ml/min, integrase inhibitor resistance. Caution: Hepatomegaly (especially obese women), hepatitis or other risk factors for liver disease and hepatic steatosis (including certain drugs and alcohol). Monitor liver aminotransferases and bilirubin. Lactic acidosis (sometimes fatal; usually associated with hepatomegaly and hepatic steatosis) reported with nucleoside analogues. Discontinue if hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly or rapidly elevating aminotransferase levels occur. Hypersensitivity reactions may occur; permanently discontinue if suspected (if suspended for other reasons (see SPC) restart where medical assistance is available). Evaluate for lipodystrophy; consider measuring fasting serum lipids and blood glucose. Pre-existing liver dysfunction (including chronic active hepatitis); consider interruption or discontinuation if liver disease worsens. Hepatitis B or C co-infection (monitor liver chemistries). Chronic hepatitis B or C (increased risk of severe and potentially fatal hepatic adverse reactions). Hepatitis B co-infected patients; withdrawal may acutely exacerbate hepatitis B (periodically monitor liver function tests and markers of HBV replication if discontinue); may require an additional antiviral. Evaluate any inflammatory symptoms; autoimmune disorders (such as Graves’ disease) reported in the setting of immune reactivation (can occur months after initiation). Minimize modifiable risk factors for myocardial infarction (e.g. smoking, hypertension, hyperlipidaemia). Osteonecrosis reported (especially with advanced HIV-disease or long-term exposure); advise patients to seek medical advice if joint aches and pain, joint stiffness or difficulty in movement occur. Opportunistic infections and other complications of HIV may occur. Transmission. Pregnancy (only if benefit justifies risk). Driving/using machines (dizziness).

Drug interactions: Contraindicated: Dofetilide. Do not use polyvalent cation-containing antacids (during 6 hours before or 2 hours after) or other drugs containing dolutegravir, abacavir, lamivudine or emtricitabine. Avoid: St. John’s wort, phenobarbital, phenytoin, oxcarbazepine, carbamazepine. Not recommended: Etravirine (unless also receiving atazanavir/ritonavir, lopinavir/ritonavir or darunavir/ritonavir); efavirenz, nevirapine, rifampicin, tipranavir/ritonavir, cladribine. Caution: Alpha interferon and ribavirin (hepatitis C co-infection), ribavirin. Magnesium/ aluminium-containing antacids or calcium/iron (during 6 hours before or at least 2 hours after), metformin, inhibitors or inducers of CYP3A4 or P-gp, certain anti-acid agents, inducers or inhibitors of UGT enzymes, compounds eliminated through alcohol dehydrogenase, drugs where excretion is OCT2 or MATE-1- dependent, trimethoprim/sulfamethoxazole (renal impairment), methadone (some patients). P-pg and BCRP, drugs where excretion is OCT1/OCT2 or OAT3-dependent.

Adverse drug reactions: Gastrointestinal disorders, insomnia, dizziness, headache, hypersensitivity, anorexia, abnormal dreams, depression, nightmare, sleep disorder, somnolence, lethargy, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, muscle disorders, fatigue, fever, malaise, creatine phosphokinase elevations, ALT/AST elevations.

Full prescribing information and references available from GlaxoSmithKline (Ireland) Ltd. (01) 4955000. Fax: (01) 4955105.

Tara Sweeney

Company: GlaxoSmithKline (Ireland) Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredient: Umeclidinium 55mcg per delivered dose.

Description: Inhalation powder.

Presentation: 30 dose unit, €34.00.

Indications: Maintenance bronchodilator treatment to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD).

Pharmacology: Umeclidinium bromide is a long acting muscarinic receptor antagonist. It exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine to muscarinic cholinergic receptors on airway smooth muscle.

Dosage: Adult: One inhalation of 55mcg once daily (maximum) at same time each day. Elderly: As per adults. Children: Under 18 years, no relevant use.

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

Special precautions: Not for use in asthma or acute episodes of bronchospasm. Discontinue immediately if paradoxical bronchospasm occurs. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control. Re-evaluate treatment regimen if COPD deteriorates. Caution: Severe hepatic impairment, severe cardiovascular disorders (especially cardiac arrhythmias), urinary retention, narrow-angle glaucoma. Contains lactose. Pregnancy, lactation (assess risk/benefit).

Drug interactions: Not recommended: Other long-acting muscarinic antagonists.

Adverse drug reactions: Nasopharyngitis, upper respiratory tract infection, urinary tract infection, sinusitis, headache, tachycardia, cough.

Full prescribing information and references available from GlaxoSmithKline (Ireland) Ltd. (01) 4955000. Fax: (01) 4955105.

Tara Sweeney

Company: Gilead Sciences Ltd.

Legal category: Prescription. Hospital only. Sport permitted.

Active ingredient: Ledipasvir/sofosbuvir 90/400mg.

Description: Orange, diamond-shaped, film-coated tablet marked GSI on one side and 7985 on reverse.

Presentation: 28, price available on request.

Indications: Treatment of chronic hepatitis C in patients with genotypes 1, 3 or 4.

Pharmacology: Ledipasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. Sofosbuvir, a nucleotide prodrug, is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. It undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.

Dosage: Adult: Swallow whole. One tablet once daily. If vomiting occurs within 5 hours take another. For specialist use only. Genotype 1/4 (including HIV co-infection): Patients without cirrhosis, Harvoni only for 12 weeks (may consider 8 weeks in treatment-naïve patients with genotype 1; consider 24 weeks for previously treated patients with uncertain subsequent retreatment options); patients with compensated cirrhosis, Harvoni only for 24 weeks (may consider 12 weeks for patients at low risk of disease progression with subsequent retreatment options); patients with decompensated cirrhosis/who are pre-/post-liver transplant (assess risk/benefit), Harvoni + ribavirin for 24 weeks. Genotype 3 (including HIV co-infection): With cirrhosis/prior treatment failure, Harvoni + ribavirin for 24 weeks. See Ribavirin SPC. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substances or to any of the excipients. Pregnancy, lactation. Women or their male partners must use contraception during treatment (see ribavirin SPC if used).

Special precautions: Do not use in patients with HCV genotypes 2, 5 and 6. If a potentially ribavirin-related serious adverse reaction occurs, modify dose (see SPC) or discontinue ribavirin. Retreatment of patients who failed with either a subsequent NS5A inhibitor-containing regimen or prior therapy that included an NS3/4A protease inhibitor (no data). Severe renal impairment or end stage renal disease requiring haemodialysis (safety not established). HCV genotype 3/4 (limited data). HCV/HBV co-infection (no data). Creatinine clearance <50mL/min using ribavirin. See SPC of ribavirin if used in combination with Harvoni. Contains lactose, sunset yellow FCF aluminium lake.

Drug interactions: Contraindicated: Rosuvastatin, St. John’s wort. Do not use proton pump inhibitors (before Harvoni), other medicines containing sofosbuvir, potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin), phenobarbital, oxcarbazepine. Not recommended: Rifabutin, rifapentine, simeprevir, tipranavir (ritonavir boosted). Caution: CYP3A4/ CYP2C/ UGT1A1 substrates with a narrow therapeutic range, digoxin, pharmacokinetic enhancers (e.g. ritonavir, cobicistat). P-gp or breast cancer resistance protein substrates. Antacids (within 4 hours), tenofovir disoproxil fumarate, HMG-CoA reductase inhibitors, pravastatin, dabigatran etexilate. H2-receptor antagonists (do not exceed doses comparable to famotidine 40mg twice daily).

Adverse drug reactions: Headache, fatigue.

Full prescribing information and references available from Gilead Sciences Ltd. Telephone: (01) 2078156. Fax: +441223 897281. E-mail: ukmedinfo@gilead.com

Tara Sweeney

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recently concluded its review of ivabradine (Procoralan) and has made recommendations aimed at reducing the risk of adverse cardiac effects, including myocardial infarction and bradycardia in patients being treated for symptomatic chronic stable angina in coronary artery disease. This review was initiated in May 2014 following preliminary results of the SIGNIFY¹ study and these preliminary results were communicated at that time via a Direct Healthcare Professional Communication (DHPC) and in the 62^nd edition of the HPRA Drug Safety Newsletter.

The preliminary results showed a small but statistically significant increase in the combined risk of cardiovascular death and non-fatal myocardial infarction with ivabradine compared with placebo in a pre-specified subgroup of patients with symptomatic angina of CCS class II or more. Initial data indicated that the adverse cardiovascular outcomes may be mostly associated with a target heart rate below 60 beats per minute (bpm) however, further evaluation of the data from the SIGNIFY study was needed to fully understand its implications for the clinical use of ivabradine.

The final data from the SIGNIFY study² showed that in a subgroup of patients who had symptomatic angina, there was a small but significant increase in the combined risk of cardiovascular death or non-fatal myocardial infarction with ivabradine compared with placebo (3.4% vs. 2.9% yearly incidence rates). The data also indicated a higher risk of bradycardia with ivabradine compared with placebo (17.9% vs. 2.1%). Additional data assessed by the PRAC also showed that the risk of atrial fibrillation (AF) is increased in patients treated with ivabradine compared with controls (4.86% vs. 4.08%).

The benefit risk balance of ivabradine remains positive following review of the final data from the SIGNIFY study for its authorised indications* however a small but significant increase of the combined risk of cardiovascular death, myocardial infarction and cardiac failure was seen in patients with symptomatic angina.

Advice to Healthcare Professionals:

• The benefit-risk balance of Corlentor/Procoralan remains positive for its authorised indications.
• In the symptomatic treatment of patients with chronic stable angina, ivabradine is indicated in adults unable to tolerate, or with a contra-indication to the use of beta-blockers, or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose.
• Ivabradine is indicated for symptomatic treatment only, of chronic stable angina pectoris because ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death) in patients with symptomatic angina.
• Ivabradine is also indicated for treatment of chronic heart failure on the basis of results from the previous SHIFT study. The results of the SIGNIFY study do not impact on the heart failure indication.
• Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or diltiazem is now contraindicated.
• Treatment with ivabradine should only be initiated in patients whose resting heart rate is at least 70 bpm.
• Prior to starting treatment with ivabradine or prior to dose titration, patients should be carefully monitored (serial heart rate measurements, E.C.G. or ambulatory 24-hour monitoring) for the occurrence of too low resting heart rates or symptoms of bradycardia.
• The risk of developing AF is increased in patients treated with ivabradine. Regular clinical monitoring for the signs and symptoms of AF is recommended and if AF develops, the balance of benefits and risks of continued treatment should be carefully considered.
• Treatment with ivabradine should be discontinued if the symptoms of angina do not improve within 3 months, or the improvement is limited and there is no clinically relevant reduction in resting heart rate within 3 months.
• The usual recommended starting dose of ivabradine is 5 mg twice daily. The maintenance dose should not exceed 7.5 mg twice daily.
• If the resting heart rate decreases persistently below 50 beats per minute or the patient experiences symptoms related to bradycardia, the ivabradine dose must be down-titrated, including the possible dose of 2.5 mg twice daily. The dose should only be increased to 7.5 mg twice daily after three to four weeks of treatment if the therapeutic response with 5 mg twice daily is insufficient and if the 5 mg dose is well tolerated. The effect of a dose increase on the heart rate should be carefully monitored.
• A Direct Healthcare Professional Communication (DHPC) outlining these recommendations has been circulated by the Marketing Authorisation Holder and is available from the HPRA website. The approved product information* (Summary of Product Characteristics (SmPC)) and package leaflet (PL)) will be updated accordingly.

Key messages

• Ivabradine is indicated for symptomatic treatment only, of chronic stable angina pectoris because ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death) in patients with symptomatic angina.
• Serial heart rate measurements are required prior to initiation of therapy or prior to dose titration.
• Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or diltiazem is now contraindicated.
• Treatment with ivabradine should only be initiated in patients whose resting heart rate is at least 70 bpm.
• Healthcare professionals should take note of the recommendations and relevant precautions in the product information for ivabradine, particularly in relation to dosing recommendations (not exceed the recommended daily dose of 7.5mg bd), maintenance of therapy, risk of developing AF, monitoring of and the potential impact of concomitant heart rate reducing effects of other medicines.

*Products currently authorised in Ireland include Procoralan. Further details of indications are available at www.hpra.ie and www.ema.europa.eu

References:

1. Study assessInG the morbi-mortality beNefits of the If inhibitor ivabradine in patients with coronary arterY disease.

2. Fox K. Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014; 371: 1091-9. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1406430

Caroline McDermott

Company: Ferring Ireland Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredient: Mesalazine 4g.

Description: White-grey to pale white-brown prolonged-release granules in sachet.

Presentation: 30, €90.28.

Indication: Mild to moderate ulcerative colitis.

Pharmacology: Mesalazine is the active component of sulfasalazine. It inhibits leukocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. The mechanism of action of mesalazine is, however, still not understood.

Dosage: Adult: Determine doses individually. Active: Up to 4g once daily or divided into 2-4 doses, placed on the tongue and washed down with water or orange juice (do not chew). Maintenance: 2g once daily. Elderly: As per adults. Children: Determine doses individually. 6-18 years, limited data. Active: Initially 30-50mg/kg/day in divided doses. Maximum 75mg/kg/day in divided doses; maximum total dose 4g/day. Maintenance: Initially, 15-30mg/kg/day in divided doses; maximum 2g/day. General recommendation: Up to 40kg body weight, half the adult dose; >40kg, as per adults. <6 years, safety and efficacy not established.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Severe liver/renal impairment.

Special precautions: Not recommended: Haemorrhagic diathesis, renal impairment. Caution: Active peptic ulcer, allergy to sulphasalazine, hepatic impairment. Acute intolerance symptoms (discontinue immediately). Regularly monitor serum creatinine (especially at start of treatment); determine urinary status prior to and during treatment; if renal dysfunction develops suspect nephrotoxicity. Pulmonary disease (especially asthma); carefully monitor. Prior to and during treatment, monitor hepatic/renal function, differential blood counts. Follow-up tests recommended, 14 days after initiation, 2-3 tests at 4 week intervals, every 3 months thereafter; additional symptoms (test immediately). Cardiac hypersensitivity reactions, blood dyscrasias, reported rarely/very rarely, respectively; discontinue. Lactation (diarrhoea, discontinue), pregnancy; only if benefit outweighs risk.

Drug interactions: Caution: Azathioprine, 6-mercaptopurine, thioguanine. Warfarin, other nephrotoxic agents (e.g. non-steroidal anti-inflammatory drugs).
Adverse drug reactions: Headache, gastrointestinal disorders, rash.

Full prescribing information and references available from Ferring Ireland Ltd. Telephone: (01) 4637355. Email: enquiries.ireland@ferring.com

Tara Sweeney

Company: Consilient Health Ltd.

Legal category: OTC. Sport permitted. GMS reimbursement from 1st April 2015.

Active ingredient: Levonorgestrel 1500mcg.

Description: White, flat, rimmed tablet marked G00.

Presentation: €6.31.

Indication: Emergency contraception within 72 hours of unprotected sexual intercourse or failure of a contraceptive method.

Pharmacology: Levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the preovulatory phase, when the likelihood of fertilisation is the highest.

Dosage: Adult: One tablet as soon as possible, preferably within 12 hours but no later than 72 hours after unprotected intercourse. If vomiting occurs within three hours, take another tablet immediately. Can be used at any time during the menstrual cycle unless menstrual bleeding is overdue. Children: Not recommended. Under 16 years (limited data).

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy. Breast feeding (within 8 hours).

Special precautions: Not recommended: Patients at risk of ectopic pregnancy, severe hepatic impairment. It is an occasional use medicine and should not replace a regular contraception method. If no withdrawal bleed occurs in next pill-free period after regular hormonal contraception, exclude pregnancy. If pregnancy occurs, consider ectopic pregnancy. Severe malabsorption syndromes (such as Crohn’s disease). Repeated administration within a menstrual cycle. Increasing body weight or body mass index. May modify fertility date. Contains lactose.

Drug interactions: Barbiturates (including primidone), phenytoin, carbamazepine, St. John’s Wort, rifampicin, ritonavir, rifabutin, griseofulvin. Cyclosporin.

Adverse drug reactions: Headache, dizziness, gastrointestinal upset, bleeding not related to menses, delay of menses more than 7 days, irregular menstruation, breast tenderness, fatigue.

Full prescribing information and references available from Consilient Health Ltd. Telephone: (01) 2057760.

Tara Sweeney

Company: Actelion Pharmaceuticals UK Ltd.

Legal category: Prescription. High Tech. Sport permitted.

Active ingredient: Macitentan 10mg.

Description: Round, biconvex, white, film-coated tablets marked 10.

Presentation: 28, price available on request.

Indication: Long-term treatment of pulmonary arterial hypertension (WHO Functional Class II to III). As monotherapy or in combination.

Pharmacology: Macitentan is a potent endothelin receptor antagonist. It prevents endothelin-mediated activation of second messenger systems that result in vasoconstriction and smooth muscle cell proliferation.

Dosage: Adult: Swallow whole. 10mg once daily at about same time. For specialist use only. Elderly: Over 75 years, limited experience (caution). Children: Safety and efficacy not established.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Severe hepatic impairment, elevated hepatic aminotransferases (>3 × ULN). Pregnancy, lactation. Women must use contraception during treatment and for 1 month after.

Special precautions: WHO functional class I (benefit/risk ratio not established). Not recommended: Patients undergoing dialysis, moderate hepatic impairment, initiation in severe anaemia. Caution: Severe renal impairment. Renal impairment, consider monitoring blood pressure and haemoglobin. Prior to initiation measure haemoglobin concentrations (and as clinically indicated thereafter) and liver enzymes (monitor ALT and AST monthly). Monitor for hepatic injury. Discontinue if sustained, unexplained, aminotransferase elevations occur (or if accompanied by increased bilirubin (>2 × ULN) or liver injury symptoms); may consider reinitiation if levels return to normal (unless experienced liver injury). If signs of pulmonary oedema occur consider pulmonary veno-occlusive disease. Cases of anaemia requiring blood cell transfusion reported. Contains lactose, lecithin (soya). Driving/using machines. May affect male fertility.

Drug interactions: Avoid: Strong CYP3A4 inducers. Caution: Strong CYP3A4 inhibitors (including telithromycin). Drugs transported by breast cancer resistance protein. See appendix I.

Adverse drug reactions: Nasopharyngitis, bronchitis, pharyngitis, influenza, urinary tract infection, anaemia, headache, hypotension.

Full prescribing information and references available from Actelion Pharmaceuticals UK Ltd.

Telephone: 0044 (0)208 987 3333. E-mail: medinfo_uk@actelion.com

Tara Sweeney

Company: Novartis Consumer Health.

Legal category: Pharmacy only. Sport permitted.

Active ingredients: Acetylsalicylic acid (aspirin)/paracetamol/caffeine 250/250/65mg.

Description: White, oblong-shaped, film-coated tablet marked E.

Presentation: 10, €2.66; 20, €4.66.

Indications: Acute treatment of headache and migraine attacks with or without aura.

Pharmacology: Acetylsalicylic acid (ASA) has analgesic, antipyretic and antiinflammatory properties, primarily due to the inhibition of the biosynthesis of prostaglandins and thromboxanes from arachidonic acid by irreversible acetylation of cyclooxygenase enzymes. Paracetamol has analgesic and antipyretic properties. Caffeine augments the antinociceptive effects of ASA and paracetamol.

Dosage: Adult: Take with a full glass of water. Do not exceed 6 tablets in 24 hours. Headache: 1 tablet (can take a second tablet 4-6 hours later if necessary). For intense pain dose can be doubled. Duration, up to 4 days. Migraine: 2 tablets. If needed an additional 2 tablets can be taken, with 4 to 6 hours between doses. Duration, up to 3 days. Elderly: Over 65 years, caution (especially with low body weight). Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients. Patients in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by ASA or other non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or ibuprofen. Active gastric or intestinal ulcer, gastrointestinal (GI) bleeding or perforation, history of peptic ulceration. Haemophilia or other haemorrhagic disorders. Severe hepatic/renal/ cardiac failure.  Pregnancy, lactation.

Special precautions: Do not use if patients vomit with >20% or require bedrest with >50% of migraine attacks. Caution: Mild to moderate hepatic/ renal impairment, dehydration, gout, uncontrolled hypertension, diabetes, severe glucose-6-phosphate dehydrogenase deficiency, metrorrhagia or menorrhagia, (history of) alcohol abuse. Exclude other potentially serious neurological conditions in migraine-naïve patients and in migraineurs with atypical symptoms. Seek medical advice if no migraine relief from the first dose. Carefully monitor patients with haemostasis defects. GI bleeding, ulceration or perforation (can be fatal) reported with all NSAIDs; withdraw immediately if GI bleeding or ulceration occurs (especially elderly). Surgery and post-surgery (including tooth extraction); may increase bleeding tendency. May mask infections. May precipitate bronchospasm, induce asthma exacerbations or other hypersensitivity reactions. Prolonged use, hyperthyroidism, arrhythmia.

Drug interactions: Contraindicated: Methotrexate (>15mg per week). Do not use other products containing ASA or paracetamol. Avoid: Alcohol, selective serotonin reuptake inhibitors, disulfiram, quinolones, terbinafine, cimetidine, fluvoxamine, oral contraceptives. Not recommended: Other NSAIDs, corticosteroids, oral anticoagulants, thrombolytics, heparin and platelet aggregation inhibitors, liver enzyme inducers or potentially hepatotoxic substances, zidovudine (unless monitored by doctor), probenecid, lithium, ephedrines, sympathomimetics, levothyroxine, clozapine, other potentially hepatotoxic drugs or drugs inducing liver microsomal enzymes (e.g. rifampicin, isoniazide, chloramphenicol, hypnotics, antiepileptics including phenobarbital, phenytoin, carbamazepine). Methotrexate (≤15mg/week), valproate, aldosterone antagonists, loop diuretics, antihypertensives, uricosurics, sulphonylureas, insulin, propantheline/ metoclopramide or other agents slowing/ accelerating gastric emptying, cholestyramin (within 1 hour), theophylline, nicotine, phenytoin, phenylpropanolamine. Caffeine-containing products. Interferes with several lab tests (see SPC).

Adverse drug reactions: Nervousness, dizziness, GI upset.

Full prescribing information and references available from Novartis Consumer Health. Telephone: (0044) 1276 687 202. E-mail: medicalaffairs.uk@norvartis.com

Tara Sweeney

Company: Teva Pharmaceuticals Ireland.

Legal category: Prescription. GMS. Sport restricted beta2 agonists.

Active ingredients: Budesonide/formoterol (fumarate dihydrate) 160/4.5mcg, 320/9mcg per delivered dose.

Description: Inhalation powder.

Presentation: 160/4.5mcg-120 dose unit, €34.80; 320/9mcg-60 dose unit, €34.12.

Indications: Regular treatment of asthma in adults where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate. Symptomatic treatment of severe COPD in adults.

Pharmacology: Budesonide and formoterol have different modes of action and show additive effects in reduction of asthma exacerbations. Their specific properties allow the combination to be used either as maintenance and reliever therapy, or as maintenance treatment of asthma. Budesonide is a glucocorticosteroid which has an anti-inflammatory action in the airways. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown. Formoterol is a selective β2 adrenoceptor agonist that results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction.

Dosage: Adult: Asthma: Maintenance therapy, 1-2 inhalations of 160/4.5mcg twice daily (maximum 4 inhalations twice daily) or 1 inhalation of 320/9mcg twice daily (maximum 2 inhalations twice daily). When control achieved with twice daily dosing using lower strength, consider once daily dosing. Use lowest effective dose (assess regularly).  Maintenance and reliever therapy: Use 160/4.5mcg strength only. Two inhalations daily plus 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Maximum 6 inhalations on any single occasion. Maximum, 8 inhalations daily; 12 inhalations may be used for a limited period with medical advice. COPD: 2 inhalations of 160/4.5mcg twice daily, or 1 inhalation of 320/9mcg twice daily. Elderly: As per adults. Children: Under 18 years, not recommended.

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

Special precautions: Not intended for initial management of asthma or regular prophylactic use (e.g. before exercise). Do not initiate during an exacerbation or if significantly worsening or acutely deteriorating asthma occurs. Withdraw gradually. Caution: Transferring from oral steroids (monitor HPA axis function), thyrotoxicosis, phaeochromocytoma, diabetes, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders (such as ischaemic heart disease, tachyarrhythmias, severe heart failure), QTc prolongation. Hypokalaemia may occur (high doses, unstable asthma with variable use of bronchodilators, severe acute asthma; caution, monitor serum potassium levels). Once control of asthma achieved, consider stepping down to an inhaled corticosteroid alone; review regularly. Seek medical advice if sudden and progressive deterioration occurs, if more than 8 inhalations of 160/4.5mcg strength for reliever therapy required daily or if treatment is ineffective or condition worsens. Closely monitor if frequently take high numbers of as-needed inhalations. Review therapy if increasing use of rapid-acting bronchodilators required. Discontinue immediately if paradoxical bronchospasm occurs. Patients with impaired adrenal function during periods of stress (e.g. severe infections, surgery). Systemic effects 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 may occur with prolonged use at high doses. Oropharyngeal thrush may occur. Active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways (re-evaluate therapy). Severe liver cirrhosis. Pregnancy, lactation (only if benefit outweighs risk). Contains lactose.

Drug interactions: Do not use beta-adrenergic blockers (including eye drops). Avoid: Potent CYP3A4 inhibitors (including posaconazole, telithromycin, HIV protease inhibitors), see appendix I. Drugs inducing hypokalaemia (e.g. xanthine-derivatives, steroids, diuretics), drugs prolonging QTc-interval (quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors, tricyclic antidepressants), L-Dopa, L-thyroxine, oxytocin, alcohol, furazolidone, procarbazine, anaesthesics (halogenated hydrocarbons), other beta-adrenergics or anticholinergics, digitalis glycosides.

Adverse drug reactions: Oropharyngeal candidiasis, headache, tremor, palpitations, mild throat irritation, coughing, hoarseness.

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

Tara Sweeney

Following identification of a signal of administration errors with Eligard and concerns that such errors may impact on clinical efficacy, this issue was reviewed at EU level by the Pharmacovigilance Risk Assessment Committee (PRAC). A cumulative review of reported global cases identified errors related to storage, preparation and reconstitution of Eligard. Appropriate reconstitution is a critical step in the administration of the product to ensure the effective and safe treatment of patients with prostate cancer.  Lack of efficacy may occur due to incorrect reconstitution of Eligard.

Eligard is indicated for the treatment of hormone dependent advanced prostate cancer and for the treatment of high risk localised and locally advanced hormone dependent prostate cancer in combination with radiotherapy. It is available in six-monthly (45mg), three-monthly (22.5mg) and one-monthly (7.5mg) formulations. In the majority of patients, androgen deprivation therapy (ADT) with Eligard results in testosterone levels below the standard castration threshold (<50ng/dL; <1.7 nmol/L); and in most cases, patients reach testosterone levels below <20ng/dL.

Advice to Healthcare Professionals

• Appropriate reconstitution of Eligard is a critical step in the administration of the product.
• It is important that all staff involved in the reconstitution and administration of Eligard are familiar with and adhere to the instructions for appropriate methods of reconstitution and administration before using the product.
• Testosterone levels should be measured in suspected cases of maladministration of Eligard.
• The storage conditions for the product have been updated and the product information reflecting this update is available on the HPRA website (www.hpra.ie). The syringe will be modified to simplify reconstitution and administration. The modified syringe (the blue plunger rod design is changing) will be made available as soon as possible.
• A Direct Healthcare Professional Communication (DHPC) was circulated to relevant healthcare professionals in December 2014 and is available on the HPRA website.
• All cases of incorrect storage, reconstitution and administration of Eligard should be reported to the HPRA.

Key messages

• There have been global reports of medication errors related to storage, preparation and reconstitution of Eligard.
• Lack of clinical efficacy may occur due to incorrect reconstitution of Eligard.
• Reconstitution instructions in section 6.6 of the SmPC for Eligard must be followed exactly.

*Further details on Eligard are available at www.hpra.ie

Caroline McDermott