Company: Rowex Ltd.

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

Active ingredient: Methylphenidate hydrochloride 18mg, 27mg, 36mg.

Description: Round, yellow, grey or white, film-coated prolonged-release tablets with a delivery orifice, respectively.

Presentation: 18mg-30, €14.97; 27mg-30, €16.49; 36mg-30, €20.37.

Indication: As part of a comprehensive treatment programme for Attention Deficit Hyperactivity Disorder when remedial measures alone insufficient. See SPC.

Pharmacology: Methylphenidate HCl is a mild central nervous system stimulant thought to block the reuptake of noradrenaline and dopamine into the presynaptic neurone and increase their release into the extraneuronal space.

Dosage: Children: Initiate under specialist supervision. Swallow whole once daily in morning. 6 years and older: Start at lowest dose, adjust in 18mg weekly increments. Maximum 54mg daily. Methylphenidate-naïve patients: 18 mg once daily (limited experience). Methylphenidate-experienced patients: If previous dose 5mg, 10mg or 15mg three times daily, take 18mg, 36mg or 54mg Metidate XL once daily, respectively. Under 6 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Glaucoma, phaeochromocytoma, hyperthyroidism, thyrotoxicosis, severe depression (or history), anorexia nervosa/anorexic disorders, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic/borderline personality disorder, severe and episodic (Type I) Bipolar (affective) Disorder (not well-controlled, or history), cardiovascular disorders (see SPC), cerebrovascular disorders cerebral aneurysm, vascular abnormalities (including vasculitis, stroke). Pregnancy, lactation.

Special precautions: Not for normal fatigue (or prevention). Not recommended: Structural cardiac abnormalities. Caution: Emotionally unstable patients, epileptics. Regularly monitor growth, drug misuse, weight, appetite, psychiatric and cardiovascular status. Monitor long-term use. Seizures (discontinue). Reduce or discontinue if paradoxical symptom aggravation or other serious adverse events occur. Consider discontinuation if leukopenia, thrombocytopenia, anaemia, serious renal or hepatic disorders, psychotic/ manic symptoms (including exacerbation), suicidal ideation or behaviour occurs. May exacerbate tics and Tourette’s syndrome. Cerebrovascular disorders. Supervise drug withdrawal.  Over 18 years; safety and efficacy not established. Sudden death reported with CNS stimulants. Gastrointestinal obstruction potential. Driving/using machines. Contains lactose.

Drug interactions: Contraindicated: Non-selective, irreversible monoamine oxidase inhibitors (within 14 days). Caution: Halogenated anaesthetics, other drugs (especially with narrow therapeutic window), other drugs elevating blood pressure, dopaminergic drugs (including antipsychotics). Coumarin anticoagulants, anticonvulsants, some antidepressants, anti-hypertensives. Avoid alcohol. Positive test for amphetamines (especially with immunoassay).

Adverse drug reactions: Insomnia, nervousness, headache, nasopharyngitis, anorexia, decreased appetite, decreased weight, moderately reduced weight and height gain/ growth retardation (prolonged use), lability affect, aggression, agitation, anxiety, depression, irritability, abnormal behaviour, mood swings, tics, dizziness, dyskinesia, psychomotor hyperactivity, somnolence, arrhythmia, tachycardia, palpitations, hypertension, cough, oropharyngeal pain, gastrointestinal disorders, alopecia, pruritis, rash, urticaria, arthralgia, pyrexia, fatigue, blood pressure and heart rate changes.

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

Tara Sweeney

Company: AbbVie Ltd.

Legal category: Prescription. Hospital only. Sport permitted.

Active ingredient: Dasabuvir (as sodium monohydrate) 250mg.

Description: Beige, ovaloid, film-coated tablets marked AV2.

Presentation: 2, 56; price available on request.

Indication: Treatment of chronic hepatitis C in patients with genotype 1 in combination with other drugs.

Pharmacology: Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. Co-administration of dasabuvir with ombitasvir/paritaprevir/ritonavir combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Dosage: Adult: Swallow whole with food. One tablet twice daily. For specialist use only. Genotype 1b (including HIV-1 co-infection): Patients without cirrhosis, Exviera + ombitasvir/ paritaprevir/ ritonavir, 12 weeks; patients with compensated cirrhosis, Exviera + ombitasvir/ paritaprevir/ ritonavir + ribavirin, 12 weeks. Genotype 1a (including HIV-1 co-infection and unknown genotype 1 subtype/ mixed genotype 1): Exviera + ombitasvir/ paritaprevir/ ritonavir + ribavirin (patients without cirrhosis, 12 weeks; patients with compensated cirrhosis, 24 weeks). Liver transplant recipients: Exviera and ombitasvir/ paritaprevir/ ritonavir + ribavirin (consider lower initial ribavirin dose), 24 weeks. Elderly: As per adults. Children: Under 18 years, safety and efficacy not established.

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients. Severe hepatic impairment. Pregnancy, lactation. See ribavirin SPC if used.

Special precautions: Do not use monotherapy; see SPCs of drugs used in combination with Exviera. Do not use for patients with genotypes other than 1, HIV co-infected patients without suppressive antiretroviral therapy. Seek immediate medical advice if signs of liver inflammation occur. Re-treatment (including previous exposure to drugs anticipated to be cross-resistant); no data. HCV/HBV co-infection, safety and efficacy not established. Contains lactose. Driving/using machines.

Drug interactions: Contraindicated: Ethinylestradiol; strong/ moderate enzyme inducers (eg. carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, etravirine, enzalutamide, mitotane, rifampicin, St. John’s Wort), ketoconazole, strong CYP2C8 inhibitors (e.g. gemfibrozil), lopinavir/ritonavir, NNRTIs other than rilpivirine. Not recommended: Pitavastatin, fluvastatin. Caution: Dabigatran, deferasirox, teriflunomide, sulfasalazine, rilpivirine. Atazanavir, darunavir. Ciclosporin, tacrolimus, omeprazole, esomeprazole/lansoprazole, alprazolam, levothyroxine, imatinib, amlodipine, rosuvastatin. BCRP/ UGT1A1/ UGT1A4/ 1A6/ intestinal UGT2B7/ CYP2C19 substrates, digoxin, warfarin, s-mephenytoin, furosemide.

Adverse drug reactions: Pruritus, anaemia, insomnia, nausea, fatigue.

Full prescribing information and references available from AbbVie Ltd. Telephone: (01) 4287900.

Tara Sweeney

Company: A. Menarini Pharmaceuticals Ireland Ltd/ AstraZeneca.

Legal category: Prescription. GMS. Sport restricted beta-2 agonists.

Active ingredients: Aclidinium (as bromide)/formoterol (as fumarate dihydrate) 340/12mcg per delivered dose.

Description: Inhalation powder.

Presentation: 60 dose unit, €42.00.

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

Pharmacology: The combination of two bronchodilators with different mechanisms of action results in additive efficacy compared to that achieved with either component alone. Aclidinium is a competitive, long-acting, selective muscarinic receptor antagonist. Inhaled aclidinium bromide acts locally in the lungs to antagonise M3 receptors of airway smooth muscle and induce bronchodilation. It is quickly broken down in plasma, the level of systemic anticholinergic undesirable effects is therefore low. Formoterol is a potent, long-acting, selective β2-adrenoceptor agonist. Bronchodilation is induced by causing direct relaxation of airway smooth muscle as a consequence of the increase in cyclic AMP through activation of adenylate cyclase.

Dosage: Adult: One inhalation of 340/12mcg twice daily. Elderly: As per adults. Children: Under 18 years, no relevant use.

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

Special precautions: Not for use in asthma. Discontinue if paradoxical bronchospasm occurs. Do not use for relief of acute episodes of bronchospasm. Caution: Myocardial infarction during previous 6 months, unstable angina, newly diagnosed arrhythmia within previous 3 months, hospitalisation within previous 12 months for heart failure (NYHA classes III and IV), prolongation of the QTc interval (or history of), severe cardiovascular disorders, convulsive disorders, thyrotoxicosis, phaeochromocytoma, symptomatic prostatic hyperplasia, narrow-angle glaucoma, urinary retention. Increases in pulse rate, blood pressure or changes in ECG (may need to discontinue). Dental caries may occur with long term therapy. Hypokalaemia may occur (high doses). Severe COPD (hypoxia and concomitant treatment may potentiate hypokalaemia). Contains lactose. Pregnancy, lactation (no data, only use if benefit outweighs risk). Driving using/machines (blurred vision, dizziness).

Drug interactions: Not recommended: Other anticholinergic/long-acting β2-adrenergic agonist containing drugs. Caution: Methylxanthine derivatives, steroids, non-potassium-sparing diuretics, β-adrenergic blockers, drugs prolonging the QTc interval.

Adverse drug reactions: Nasopharyngitis, urinary tract infection, sinusitis, tooth abscess, insomnia, anxiety, headache, dizziness, tremor, cough, gastrointestinal upset, myalgia, muscle spasms, peripheral oedema, increased blood creatine phosphokinase.

Full prescribing information and references available from A. Menarini Pharmaceuticals Ireland Ltd. Telephone: (01) 2846744.  E-mail: ireland@menarini.ie

Tara Sweeney

Company: MSD Ireland (Human Health) Ltd.

Legal category: Prescription. GMS. Sport permitted.

Active ingredients: Ezetimibe 10mg and atorvastatin (as calcium trihydrate) 10mg, 20mg, 40mg, 80mg.

Description: Capsule-shaped, biconvex, white, film-coated tablets marked 257, 333, 337 or 357, respectively.

Presentation: 30, €38.14.

Indications: Adjunctive therapy to diet for primary (heterozygous familial and non-familial) hypercholesterolaemia (HC) or mixed hyperlipidaemia in patients not appropriately controlled with a statin alone or already treated with a statin and ezetimibe. Adjunctive therapy to diet for Homozygous Familial Hypercholesterolaemia (HoFH).

Pharmacology: Ezetimibe/atorvastatin are lipid-lowering compounds with complementary mechanisms of action that selectively inhibit the intestinal absorption of cholesterol and related plant sterols and inhibit the endogenous synthesis of cholesterol. Ezetimibe targets the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols. Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Dosage: Adult: HC: 10/10mg once daily. Adjust dose (see SPC) at intervals of ≥4 weeks. Dose range 10/10 – 10/80mg daily. Consider LDL cholesterol level, coronary heart disease risk status, response to current cholesterol-lowering therapy when initiating/ adjusting dose. HoFH: 10/10 to 10/80mg daily. Elderly: As per adults. Children: Not recommended.

Contraindications: Hypersensitivity to the active substances or to any of the excipients. Liver disease, unexplained persistent elevations in serum transaminases >3 times ULN. Pregnancy, lactation.

Special precautions: CPK levels >5xULN (do not initiate). Measure CPK level before initiation in patients with renal impairment, hypothyroidism, personal or familial history of hereditary muscular disorders, history of muscular toxicity with a statin or fibrate, history of liver disease/ alcohol abuse, elderly (>70 years), SLCO1B1 polymorphism. Perform liver function tests before initiation, periodically thereafter or as indicated. Increased transaminase levels (monitor until resolved). Transaminase ≥3 times ULN observed (reduce dose or withdraw if persist). Not recommended: Moderate or severe hepatic impairment. Caution: Hepatic impairment, pre-disposition to rhabdomyolysis, alcohol abuse/ history of liver disease. Prior hemorrhagic stroke or lacunar infarct (assess risk/benefit). Monitor if at risk for diabetes. Promptly report muscle pain, cramps, or weakness (especially with malaise/ fever); measure CPK levels (suspend if >5 times ULN until normal, re-start at lowest dose and monitor). Consider suspending treatment if severe muscular symptoms cause daily discomfort. Discontinue if CPK levels >10 times ULN, or if rhabdomyolysis suspected. Immune-mediated necrotising myopathy reported very rarely during or after treatment. Discontinue if interstitial lung disease suspected. Myopathy and rhabdomyolysis reported rarely. Contains lactose.

Drug interactions: Not recommended: Fusidic acid, fibrates, large quantities of grapefruit juice. Avoid: Potent CYP3A4 inhibitors, transport protein inhibitors, CYP450 3A4 inducers. Caution: Colchicine. Bile acid sequestrants (during ≥4 hours before or ≥2 hours after), moderate CYP3A4 inhibitors, anticoagulants, digoxin, niacin, oral contraceptives.

Adverse drug reactions: Diarrhoea, myalgia.

Full prescribing information and references available from MSD Ireland (Human Health) Ltd. Telephone: +353 1 299 8700. Fax: +353 1 299 8701. E-mail: medinfo_ireland@merck.com

Tara Sweeney

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 AbbVie Ltd is pleased to announce that Viekirax (ombitasvir/paritaprevir/ritonavir) and Exviera (dasabuvir), an interferon-free regimen, have been granted European approval for the treatment of patients with chronic hepatitis C virus (HCV) infection. The treatment has been approved with or without ribavirin for patients with genotype 1 chronic HCV infection, including those with compensated liver cirrhosis, HIV-1 co-infection, liver transplant recipients and patients on opioid substitution therapy. Additionally, Viekirax has been approved for use with ribavirin in genotype 4 chronic HCV-infected patients.

Viekirax, when co-administered with Exviera, combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Viekirax consists of ombitasvir, an NS5A inhibitor, paritaprevir, an NS3/4A protease inhibitor, and ritonavir, while Exviera is composed of dasabuvir, a non-nucleoside NS5B polymerase inhibitor. Ritonavir is not active against HCV; however, as a pharmacokinetic enhancer of paritaprevir, it facilitates once-daily dosing, and results in higher drug exposures than with administration of paritaprevir alone.

The marketing authorisation for Viekirax and Exviera is supported by a clinical development programme consisting of six pivotal phase 3 trials which studied the efficacy and safety of the treatment regimen in more than 2,300 patients.^1,2 In two such trials, the regimen was administered to patients with HCV genotype 1 infection and no cirrhosis who were previously untreated (Sapphire I), or who had previously been treated with peginterferon-ribavirin (Sapphire II). A third trial evaluated the regimen in previously untreated and previously treated adults with chronic HCV genotype 1 infection and compensated cirrhosis (Turquoise II).^3-5

Study design

Sapphire I and Sapphire II were double-blind, placebo-controlled trials in which patients were randomly assigned to receive active treatment (n=473 and n=297, respectively) or matching placebos in a 3:1 ratio over a 12 week double-blind period. The active treatment regimen consisted of ombitasvir 25mg, paritaprevir 150mg and ritonavir 100mg, dosed once daily, with dasabuvir 250mg, dosed twice daily, plus ribavirin administered according to body weight.^3,4

In Turquoise II, an open-label trial, 380 patients were randomly assigned in a ratio of approximately 1:1 to receive either 12 or 24 weeks of active treatment (n=208 and n=172, respectively). This study was not placebo-controlled, because of the risk of hepatic decompensation among untreated patients. Also, there was no active-comparator group owing to the increased toxic effects of standard interferon-containing regimens in patients who also have cirrhosis.⁵

In all three trials, the primary efficacy end point was sustained virologic response (HCV RNA level <25 IU/ml) at 12 weeks after the end of treatment.^3-5

Sustained virologic response superior to historical control groups

Sapphire I and Sapphire II

Among those who received active treatment over the double-blind period in the placebo-controlled trials, the overall rates of sustained virologic response at post-treatment week 12 were 96.2% and 96.3%, respectively, which were non-inferior and superior to the rates in corresponding historical control groups (i.e. those who received telaprevir plus peginterferon-ribavirin, or, who had received retreatment with telaprevir plus peginterferon-ribavirin, respectively).

The efficacy of different treatment regimens with antiviral agents may vary according to HCV subgenotype (1a or 1b). In both of these trials, the rates of sustained virologic response at post-treatment week 12 were similar among patients with HCV genotype 1a infection (95.3% and 96%, respectively) and those with HCV genotype 1b infection (98.0% and 96.7%, respectively), which were superior to the historical control rates.

For those who had previously been treated with peginterferon-ribavirin (Sapphire II), rates were 95.3% among patients with a prior relapse, 100% among patients with a prior partial response, and 95.2% among patients with a prior null response.

Rates of sustained virologic response were high across subgroups defined by gender, race, age, body mass index, fibrosis score, IL28B genotype, and baseline viral load.^3,4

Turquoise II

The rates of sustained virologic response at post-treatment week 12 was 91.8% of patients who received 12 weeks of treatment and 95.9% of patients who received 24 weeks of treatment. In both treatment groups, the primary efficacy end points met the pre-specified criteria for non-inferiority and superiority to the historical rate with telaprevir plus peginterferon-ribavirinamong patients with HCV genotype 1 infection and cirrhosis. The difference in rates was not significant (P=0.09). Rates of sustained virologic response in subgroups defined by HCV subgenotype, status with respect to prior treatment, and type of treatment failure among previously treated patients were superior to the historical rate, and were similar in the two treatment groups across the randomisation strata (see Figure 1).

Among patients with HCV genotype 1a infection and a prior null response, 92.9% of patients in the 24 week group had a sustained virologic response at post-treatment week 12, as compared with 80% of patients in the 12 week group. The numerically higher rate of sustained virologic response with the 24 week regimen suggests that the longer treatment duration is more effective in this subgroup of patients.

Rates did not differ substantially according to baseline characteristics such as race, body mass index, IL28B genotype, or baseline viral load.⁵

Figure 1. Sustained Virologic Response at Post-Treatment Week 12 in Patients with Chronic Hepatitis C Virus (HCV) Genotype 1 Infection and Cirrhosis (Turquoise II trial)

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Safety

The three most common adverse events across all three clinical trials in the active regimen groups were fatigue (34.7%, 33.3%, 32.7% [12 week group] and 46.5% [24 week group], respectively), headache (33%, 36.4%, 27.9% and 30.8%, respectively), and nausea (23.7%, 20.2%, 17.8% and 20.3%, respectively). Overall, the rates of serious adverse events and drug discontinuations due to adverse events were low.^3-5

Conclusion

These clinical trials demonstrated that Viekirax, when co-administered with Exviera, an interferon-free regimen, results in high rates of sustained virologic response in HCV-infected patients regardless of baseline characteristics, such as prior treatment status, type of treatment failure among previously treated patients, HCV subgenotype or the presence of cirrhosis, and is associated with a low rate of treatment discontinuation. ^3-5

Viekirax (ombitasvir 25mg/paritaprevir 150mg/ritonavir 100mg) should be taken once daily, and Exviera 250mg should be taken twice daily, with or without ribavirin taken twice daily, in the treatment of genotype 1 chronic HCV infection. Viekirax and Exviera are taken for 12 weeks with or without ribavirin, except in genotype 1a patients with cirrhosis, who should take it for 24 weeks.^1,2

For the treatment of genotype 4 chronic hepatitis C patients, the regimen consists of Viekirax dosed once daily, taken with ribavirin dosed twice daily, for 12 weeks (no cirrhosis) or for 24 weeks (with cirrhosis).¹

References:

1. Viekirax Summary of Product Characteristics.
2. Exviera Summary of Product Characteristics.
3. Feld J.J. et al. N Engl J Med 2014;370:1594-603.
4. Zeuzem S. et al. N Engl J Med 2014;370:1604-14.
5. Poordad F. et al. N Engl J Med 2014;370:1973-82.

Full prescribing information and references available from AbbVie Ltd. Telephone (01) 4287900.

MIMS Ireland Copyright®

Caroline McDermott

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Reference: [adapted from] British Thoracic Society/Scottish Intercollegiate Guidelines Network British Guideline on the Management of Asthma. Published October 2014. Available at www.brit-thoracic.org.uk/ and www.sign.ac.uk

Caroline McDermott

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Reference: [adapted from] British Thoracic Society/Scottish Intercollegiate Guidelines Network British Guideline on the Management of Asthma. Published October 2014. Available at www.brit-thoracic.org.uk/ and www.sign.ac.uk

Caroline McDermott

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Reference: [adapted from] British Thoracic Society/Scottish Intercollegiate Guidelines Network British Guideline on the Management of Asthma. Published October 2014. Available at www.brit-thoracic.org.uk/ and www.sign.ac.uk

Caroline McDermott

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Asthma in Ireland

•  470,000 people in Ireland have asthma, the fourth highest prevalence of asthma in the world
• Asthma is the most common chronic disease in Ireland
• More than 1 in every 10 people have asthma in Ireland
• 60% of people with asthma do not have their asthma under control
• Around 20,000 people visit hospital due to asthma every year
• At least 1 person a week dies from asthma
• 90% of these deaths are preventable
• Asthma causes adults to miss an average of 12 days of work each year
• Asthma causes children to miss an average of 10 days of school each year¹

Aims of Pharmaceutical Management

The goal of asthma management is control of the disease. Complete control is defined as:

• No daytime symptoms
• No night-time awakening due to asthma
• No need for rescue medication
• No asthma attacks
• No limitations on activity including exercise
• Normal lung function (FEV₁ and/or PEF >80% predicted or best)
• Minimal side effects from treatment

The Stepwise Approach to Management

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

Stepping Up

Before stepping up, adherence with existing therapies, inhaler technique, persistent allergen exposure and comorbidities should be checked.

It is generally considered that combination inhalers aid adherence and also have the advantage of guaranteeing that the long-acting βbeta₂ agonist is not taken without the inhaled corticosteroid.

Stepping Down

Regular review of patients as treatment is stepped down is important. When deciding which drug to step down first and at what rate, the following should all be taken into account:

• Severity of asthma
• Side effects of the treatment
• Time on current dose
• Beneficial effect achieved
• Patient’s preference

Patients should be maintained at the lowest possible dose of inhaled corticosteroid. Reduction in inhaled corticosteroid dose should be slow as patients deteriorate at different rates. Reductions should be considered every three months, decreasing the dose by approximately 25-50% each time.²

Managing Comorbidities

Several comorbidities are commonly present in patients with asthma, particularly those with difficult-to-treat or severe asthma. Active managment of comorbidities is recommended because they may contribute to symptom burden, impair quality of life, and lead to medication interactions. Some comorbidities also contribute to poor asthma control. Examples include:

• Obesity
• Gastroesophageal reflux disease
• Anxiety and depression
• Food allergy and anaphylaxis
• Rhinitis, sinusitis and nasal polyps³

Algorithms

Overview of the Stepwise Management of Asthma in Adults

Overview of the Stepwise Management of Asthma in Children aged 5 to 12 years

Overview of the Stepwise Management of Asthma in Children under 5 years

References:

1. Asthma Society of Ireland. Available at www.asthma.ie. Accessed 22nd May 2015.
2. British Thoracic Society/Scottish Intercollegiate Guidelines Network British Guideline on the Management of Asthma. Published October 2014. Available at www.brit-thoracic.org.uk/ and www.sign.ac.uk
3. Global Strategy for Asthma Management and Prevention. Revised 2014. Available at: www.ginasthma.org

Caroline McDermott

To view KAPAKE API please click link below

PMR-JAN-2015-0007 Kapake 15-30 500mg ROI Combined API Draft 3

Brendan McDermott

The HPRA would like to remind healthcare professionals of the importance of regular review and monitoring of product information for medicines, to support awareness of relevant updates/changes which may affect prescribing, dispensing, administration or monitoring practices. It is also important that patients and care-givers, as appropriate, are made aware of the information contained in the Package Leaflet (PL) and should be encouraged to read it prior to and during their treatment.

 The product information is comprised of the Summary of Product Characteristics (SmPC) and the PL. These documents are issued when a medicine is first licensed for use and are reviewed and updated as necessary throughout the lifetime of a medicine, to reflect the current state of knowledge of the medicine and the risks associated with its use. The SmPC is mainly intended for use by healthcare professionals and SmPCs for all medicines currently authorised in Ireland are accessible on the HPRA website (www.hpra.ie) via the ‘Find a Medicine’ search function. The PL reflects the more comprehensive information described in the SmPC, but is required to be presented in an abbreviated and easy-to-read format for patients. The majority of PLs are also accessible from the HPRA website, with work on-going to complete this option to facilitate access to all PLs as soon as possible. Marketing Authorisation Holders (MAHs) are also required to ensure that current copies of the product information are included when medicines are supplied to pharmacies.

The SmPC provides the basis of information for healthcare professionals to use a medicine safely, effectively and in the most appropriate manner. It is also a legal document, agreed between the HPRA/EMA (European Medicines Agency) and the relevant pharmaceutical company. The format and content of the SmPC is laid down in EU/national legislation and regulatory guidance documents. Use of a medicine outside the conditions/recommendations described in the SmPC falls under the responsibility of the healthcare professional.

 It is important to note that the SmPC is not intended to provide general advice on the treatment of particular medical conditions. On the other hand, specific aspects of the treatment related to use of the medicine, or its effects may be mentioned. Similarly, general advice on administration procedures is not included, but any advice specific to the medicine concerned will be included, if appropriate.

 The PL is drawn up in accordance with the SmPC and is subject to user-testing to ensure its ease of readability by patients/consumers. It plays an essential part in supporting the safe and effective use of a medicine by a patient. Consequently, it is important that a PL is provided each time a product is dispensed. Patients and care-givers should be encouraged to read the current version of the PL that accompanies their medicine(s) and to discuss any relevant concerns with a healthcare professional involved in their care.

Key message

• Product information (SmPC and PL) is available for medicines currently authorised in Ireland from the HPRA/EMA websites (accessible from www.hpra.ie) as well as from the relevant MAHs.

• The current versions of the product information should be consulted regularly to ensure medicines are are used in the safest and most effective manner.

• Patients should be encouraged to read the PLs provided with their medicines and to discuss any concerns with a relevant healthcare professional.

Caroline McDermott

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Caroline McDermott

Company: Consilient Health Ltd.

Legal category: Prescription. Sport permitted.

Active ingredient: Desogestrel 75mcg.

Description: White, round, biconvex film-coated tablets marked D on one side and 75 on reverse.

Presentation: 3×28, €8.00.

Indication: Oral contraception.

Pharmacology: Desogestrel inhibits ovulation and increases viscosity of cervical mucus.

Dosage: Adult: 1 tablet taken daily at the same time every day so that the interval between two tablets always is 24 hours. 1st tablet taken on 1st day of menstrual bleeding. Start new blister directly the day after previous one. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active venous thromboembolic disorder, severe hepatic disease (or history) as long as liver function values not normal, sex-steroid sensitive malignancies, undiagnosed vaginal bleeding.

Special precautions: Withdraw immediately if pregnancy occurs during use. Assess risk/benefit if presence/ appearance/ aggravation of: Breast cancer, liver cancer, liver function disturbances. Caution: History of thrombo-embolic disorders, diabetes. Discontinue if: Thrombosis, long-term immobilisation due to surgery or illness, sustained hypertension. Avoid sun/UV if tendency to chloasma. Bleeding disturbances may occur; consider another contraceptive method if very frequent and irregular. Ectopic pregnancies reported rarely. Contains lactose.

Drug interactions: Microsomal enzyme-inducing drugs, use a barrier method during and for 28 days after admin. Medicinal charcoal.

Adverse drug reactions: Altered mood, decreased libido, depressed mood, headache, nausea, acne, breast pain, irregular menstruation, amenorrhoea, increased weight.

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

Tara Sweeney

The HPRA greatly appreciates the contribution of busy healthcare professionals in reporting suspected adverse reactions which aids in facilitating the continued surveillance of the safety of medicines. While the time-consuming nature of form-filling and the provision of follow-up is recognised and acknowledged; the collection and evaluation of comprehensive reports is essential to ensure that appropriately detailed case information is available for the continuous surveillance of the safety of medicines. Such reports are essential for the HPRA to ensure that regulatory action/proposals take account of all available data. There are several options in place for reporting suspected adverse reactions to the HPRA. These are as follows:

• By following the links (‘Report an Issue’ tab) to the online reporting options accessible from the HPRA website homepage (www.hpra.ie);
• Using the downloadable report form also accessible for the HPRA website, which may be completed manually and submitted to the HPRA via ‘freepost’;
• Using the traditional ‘yellow card’ report, which also utilises a freepost system. ‘Yellow cards’ are available from the HPRA Pharmacovigilance department on request.
• By telephone to the HPRA Pharmacovigilance section (01-6764971).

Since July 2012, when new legislation came into force, patients and consumers across the EU were enabled to directly report any suspected adverse reactions they may have experienced to their national reporting system. Information on this option is available from the HPRA website and the package leaflet that accompanies medicines and has also been highlighted via patient organisations. It is HPRA practice to routinely check all reports received for possible duplicates of cases received from other sources and to collate all relevant information related to case reports, as far as possible.

The revised legislation also introduced the concept of additional monitoring, previously highlighted in the DSN (editions 50 and 53), to support prompt identification of any new safety hazards. Healthcare professionals and patients are particularly encouraged and reminded to report all adverse reactions associated with the use of these medicines, identifiable by an inverted black triangle on the product information. An explanatory statement is included both in the Summary of Product Characteristics (SmPC) and Package Leaflet (PL):

▼ This medicinal product is subject to additional monitoring

The European Medicines Agency (EMA) first published the list of medicines subject to additional monitoring in April 2013 (which is accessible from the HPRA and EMA websites), with an increased focus on reporting of suspected adverse reactions associated with the products concerned. This list is reviewed and updated as necessary, following consideration by the Pharmacovigilance Risk Assessment Committee (PRAC) at its monthly meetings. Medicines remain on the additional monitoring list for a five year period, or until PRAC decide to remove it from the list.

Key message

• All products subject to additional monitoring are identifiable by a black inverted triangle accompanied by an explanatory statement in the product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)).

• Reports of suspected adverse reactions to these medicines are particularly valuable for regulatory monitoring purposes.

Caroline McDermott

Non-steroidal anti-inflammatory drugs (NSAIDs) are valuable therapeutic agents in the treatment of pain and inflammation and the risk-benefit profile of these medicines has been closely monitored nationally and at EU level. Previous EU reviews have confirmed that NSAIDs, as a class, are associated with a small increased risk of arterial thromboembolic events (such as myocardial infarction and stroke) particularly if used at high dose and for long-term treatment. The product information for all NSAIDs warns of the risks and class labelling recommends that NSAIDs be used at the lowest effective dose for the shortest period of time necessary to control symptoms.

Ibuprofen is an NSAID commonly used for the reduction of pain, inflammation and fever. The most recent EU review completed by the Pharmacovigilance Risk Assessment Committee (PRAC) has confirmed a small increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke) in patients taking high doses of ibuprofen (≥ 2,400mg/day). The review clarified that the risk with high dose ibuprofen (≥ 2,400mg/day) is similar to the risk seen with COX-2 inhibitors and diclofenac. There are no or limited data on the arterial thrombotic risk of ibuprofen at doses between 1,200mg and 2,400mg/day which makes it difficult to determine exactly how the risk changes over this dosage range. However the PRAC considered that it is likely that there is a dose-dependent increase in risk with increasing doses between 1,200mg and 2,400mg/day. The review did not suggest an increase in cardiovascular risk with ibuprofen at doses up to 1,200mg/day i.e. at the maximum daily doses typically used in the case of products available as over the counter medicines.

The PRAC also reviewed data on the interaction between ibuprofen and low-dose aspirin when the latter is taken to reduce the risk of myocardial infarction and stroke. The PRAC noted that ibuprofen has been shown in non-clinical studies to reduce the anti-platelet effects of aspirin. However, the epidemiological data available to date does not support a clinically significant interaction but the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose aspirin cannot be excluded. The review concluded that occasional use of ibuprofen should not affect the benefits of low-dose aspirin.

Advice for Healthcare Professionals

• Ibuprofen (and all NSAIDs) should be prescribed at the lowest dose for the shortest duration possible to minimise the risk of undesirable effects.
• Cardiovascular risk may be higher in patients with cardiovascular disease (e.g. severe heart failure NYHA Class IV), and high doses of ibuprofen should be avoided in this population.
• Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (≥ 2,400mg/day) should be avoided.
• Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking), particularly if high doses of ibuprofen (≥ 2,400mg/day) are required.
• The product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) for all systemic ibuprofen-containing products will be updated as soon as possible to reflect this updated advice.
• Further information about this review is available on the HPRA and EMA websites.

*Further details on ibuprofen-containing products are available at www.hpra.ie

Key message

• The PRAC considered that there is a small increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke) in patients taking high doses of ibuprofen (≥ 2,400mg/day).
• There is no evidence to suggest an increase in cardiovascular risk with ibuprofen at doses up to 1,200mg/day (which is the maximum daily OTC dose).
• Ibuprofen should be avoided in patients with existing cardiovascular disease and used in caution in patients with certain cardiac conditions (e.g. uncontrolled hypertension, congestive heart failure, established ischaemic heart disease etc.).
• There is no evidence to suggest that occasional use of ibuprofen affects the benefits of low-dose aspirin.
• Ibuprofen should be prescribed at the lowest dose for the shortest duration possible.

Caroline McDermott

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Figures B and C: Antihyperglycaemic Therapy in Type 2 Diabetes – Adapted Recommendations to Avoid Hypoglycaemia or Weight Gain

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Reference:

1. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149 [adapted]

Caroline McDermott

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Figure A: Antihyperglycaemic Therapy in Type 2 Diabetes – General Recommendations

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Reference:

1. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149 [adapted]

Caroline McDermott

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Table 2: Antihyperglycaemic Therapy in Type 2 Diabetes – Pros and Cons

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Reference:

1. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149 [adapted]

Caroline McDermott

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Table 1: Antihyperglycaemic Therapy in Type 2 Diabetes – List of agents available in Ireland

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Caroline McDermott

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The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) released a position statement in 2012 on the management of type 2 diabetes mellitus. This was deemed necessary because of the increasing number and variety of pharmacotherapies available to reduce hyperglycaemia, and uncertainty regarding their proper selection and sequence. There were also new uncertainties regarding the benefits of intensive glycaemic control on macrovascular complications. These treatment guidelines advocated a more individualised approach, and not as much a strict glycated haemoglobin (HbA1c) target, with an emphasis on patient-centred care and shared decision making.

Glycaemic targets

• Lowering HbA1c to <7.0% is recommended in most patients to reduce the onset and progression of microvascular complications.
• The impact of glucose control on cardiovascular complications remains uncertain; a more modest benefit is likely to be present, but probably emerges only after many years of improved control.
• Intensive glycaemic control to achieve near normal HbA1c targets, while essential in some patients, may not be applicable to every patient and may indeed present some risk.
• Therefore, instead of a one-size-fits-all approach, personalisation is necessary, balancing the benefits of glycaemic control with its potential risks, taking into account the adverse effects of glucose-lowering medications (particularly hypoglycaemia), and other factors including the patient’s age, life expectancy and comorbidities.
• More stringent HbA1c targets (e.g., 6.0– 6.5%) might be considered in selected patients (with short disease duration, long life expectancy, no significant CVD) if this can be achieved without significant hypoglycaemia or other adverse effects of treatment.
• Less stringent HbA1c goals (e.g., 7.5–8.0% or even slightly higher) may be appropriate for patients with a history of severe hypoglycaemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-management education, repeated counselling, and effective doses of multiple glucose-lowering agents, including insulin.

Patient-centred care and shared decision making

• The guidelines advise adapting treatment to each patient’s situation, including history, wishes, and willingness to make lifestyle changes, since the achievement of any degree of glucose control requires active participation and commitment. Engaging patients in health care decisions may enhance adherence to therapy.
• Actual treatment targets which are now emphasised are patient-oriented outcomes, in general related to micro- and macrovascular events (e.g. stroke, cardiac infarction, blindness, nephropathy, neuropathy, amputation) rather than the surrogate HbA1c. Any target should reflect an agreement between patient and clinician.

Multiple agents needed for most people with diabetes

Initial therapy

• The first and most widely used medical treatment is metformin, a biguanide whose mechanism of action predominately involves reducing hepatic glucose production. Metformin helps nearly every facet of the type 2 diabetes syndrome. It lowers blood sugar levels and may help reduce cardiovascular risk without increased risk of hypoglycaemia and weight gain. However, metformin is associated with initial GI side effects, and caution is also advised to avoid its use in patients at risk for lactic acidosis (e.g. in advanced renal insufficiency, alcoholism). A slow increase of dose (oral solution may be used) may improve gastrointestinal tolerability.

Advancing to dual combination therapy

• If the HbA1c target is not achieved after ~3 months, there are six drug choices including a second oral agent (sulfonylurea, TZD, DPP-4 inhibitor, or SGLT2 inhibitor), a GLP-1 receptor agonist, or basal insulin (see FigA general algorithm). Notably, the higher the HbA1c, the more likely insulin will be required.
• Because there has been no good quality study comparing all available treatment strategies, there is no clear-cut decision tree as there was in the previous hyperglycaemia guidelines, and shared decision making with the patient is important to help in the selection of therapeutic option. The choice is based on patient and drug characteristics – including willingness to self-inject or need for weight loss – with the over-riding goal of improving glycaemic control while minimising side effects. An important consideration in most cases is to add an agent that does not cause weight gain and does not cause hypoglycaemia. Algorithms FigB and C are suggested treatment algorithms in case the treatment goal is avoiding hypoglycaemia or avoiding weight gain, respectively.
• On average, any second agent is typically associated with a further reduction in HbA1c of approximately 1%. If no clinically meaningful glycaemic reduction (i.e. “non-responder”) is observed, then, after adherence has been investigated, discontinue that agent, and replace it with another with a different mechanism of action.

Advancing to triple combination therapy

• Evidence suggests that there is some advantage in adding a third noninsulin agent to a two-drug combination not achieving the glycaemic target. Reconsider the approach promptly if it proves to be unsuccessful, as months of uncontrolled hyperglycaemia should specifically be avoided.
• Not surprisingly, however, the most robust response will usually be with insulin. Since diabetes is associated with progressive beta-cell loss, many patients, especially those with long-standing disease, will ultimately need to be transitioned to insulin. Insulin should be preferred in circumstances where the degree of hyperglycaemia (e.g. ≥8.5%) makes it unlikely that another drug will be sufficiently effective. Most patients are reluctant to start injectable therapy, but encouragement and education can usually overcome such reticence.
• In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action.

Recommendations to Guide Treatment Selection in Combination Therapy

DPP-4 inhibitors

While still somewhat expensive, and modestly effective in HbA1c reduction, these once daily agents are convenient, weight neutral, with a very favourable adverse-effect profile, and they do not cause hypoglycaemia. Should be used with caution in patients with a prior history of pancreatitis or with pre-existing heart failure (HF).

GLP-1 receptor agonists

Despite issues with adverse effects and cost, GLP-1 RA demonstrate efficacy in lowering HbA1c and achieving weight loss. It is not clear whether the limited occurrence of pancreatitis observed with these agents is causative or associative. While GLP-1 RA are associated with GI adverse effects, these seem to decline dramatically with time.

SGLT2 inhibitors

This novel class of antidiabetics has shown efficacy in reduction of HbA1c comparable to other standard oral agents, with a low risk of hypoglycaemia. Their mechanism of action is independent of insulin, and therefore may be used at any stage of type 2 diabetes, even after insulin secretion has waned significantly. Other advantages of SGLT2 inhibitors include weight loss and blood pressure reduction. Associated with genital mycotic infections and UTIs. They also possess a diuretic effect. Depending on the agent, use is restricted or not recommended when the estimated GFR is <45 – 60ml/min.

Basal insulin

Insulin (especially, basal or basal +1 analogue therapy) continues to be a favoured candidate for early use, as an add-on shortly after metformin and/or an additional oral agent to establish control while minimising risk of hypoglycaemia or weight gain.

Sulfonylureas

Often favoured for their affordability, but pose a high risk for hypoglycaemia, contribute to weight gain, and lack durability related to glycaemic control (“beta-cell burnout”). Evidence also suggested poor cardiovascular outcomes in some trials. The low cost of medication must be weighed against the potential higher costs of morbid outcomes.

Thiazolidinediones (actually, only pioglitazone)

Do not cause hypoglycaemia, but were cited for concern about adverse effects, including the risk of weight gain, fluid retention, heart failure, and bone fractures in women. Pioglitazone appeared to have a modest impact on reducing cardiovascular events in one study. Earlier concerns about an association with bladder cancer have largely been allayed by subsequent evidence.

Pre-mixed and non-analogue insulins*

Concerns about weight gain or hypoglycaemia—both highly undesirable adverse effects as demonstrated by results from landmark diabetes treatment trials.

ADA-EASD Treatment Guidelines – main 2015 updates

The 2015 updates incorporate new data from recent clinical trials.

• The major change in treatment options since the publication of the 2012 position statement has been the availability of a new class of glucose-lowering drugs, the SGLT2 inhibitors.
• Updates to safety concerns relating to TZDs (bladder cancer), DPP-4 inhibitors (HF, pancreatitis) and GLP-1 RA (pancreatitis).
• In patients on basal insulin with one or more oral agents whose diabetes remains uncontrolled, the addition of a GLP-1 RA or mealtime insulin is now recommended (or in refractory patients, an SGLT2 inhibitor or TZD may be considered – see FigA).
• Includes proposed dosing instructions for the various insulin strategies, including the addition of rapid-acting insulin analogues before meals or the use of premixed insulin formulations.

DPP-4: Dipeptidyl peptidase-4; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium glucose co-transporter 2; TZD: Thiazolidinedione; UTIs: Urinary tract infections *Regular human insulin and Neutral Protamine Hagedorn (NPH)

Key Recommendations

• Individualise glycaemic targets and glucose-lowering therapies.
• Diet, exercise, and education remain the foundation of all type 2 diabetes treatment programmes.
• Metformin is the optimal first-line drug in the absence of contraindications.
• After metformin, though data are more limited, it is reasonable to consider combination therapy with an additional 1-2 oral or injectable agents with the objective of minimising side effects where possible.
• For many patients insulin therapy alone or in combination with other agents will ultimately be required to maintain glucose control.
• All treatment decisions, where possible, should take into account the patient’s preferences, needs and values.
• A major focus of therapy must be comprehensive cardiovascular risk reduction.

References:

1. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149 [adapted].

2. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2012;35:1364-1379 [adapted]        

MIMS Ireland Copyright®

Tables

Table 1: Antihyperglycaemic Therapy in Type 2 Diabetes – List of agents available in Ireland

Table 2: Antihyperglycaemic Therapy in Type 2 Diabetes – Pros and Cons

Algorithms

Figure A: Antihyperglycaemic Therapy in Type 2 Diabetes – General Recommendations

Figures B and C: Antihyperglycaemic Therapy in Type 2 Diabetes – Adapted Recommendations to Avoid Hypoglycaemia or Weight Gain

Caroline McDermott