Significant Benefits of Bedtime Therapy

Variation in blood pressure levels display circadian rhythms, with a morning surge in blood pressure (BP) known to increase the risk of myocardial events in the first several hours post awakening. Time of ingestion of hypertension medications can affect this circadian pattern of BP, and there is emerging evidence that this translates into an effect on clinical outcomes.

Clinical studies have documented differences in BP-lowering efficacy, duration of action, safety profile of several different classes of hypertension medications, depending on administration-time (morning or evening). Regardless of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning.

MAPEC study¹

In the prospective MAPEC study, a total of 2156 hypertensive subjects were randomised to ingest all their prescribed hypertension medications upon awakening or at least one of them at bedtime.

The results showed that bedtime chronotherapy with at least one BP-lowering medication, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality.

Subjects ingesting medication at bedtime showed:¹

• Significantly lower mean sleep-time BP, higher sleep-time relative BP decline,
• Reduced prevalence of non-dipping (34% versus 62%; p<0.001),
• Higher prevalence of controlled ambulatory BP (62% versus 53%; p<0.001).
• Significantly lower relative risk of total CVD events (number of events: 187 versus 68; p<0.001) after a median follow-up of 5.6 yrs.
• Significantly lower relative risk of major CVD events (including CVD death, myocardial infarction, ischemic stroke, and haemorrhagic stroke) (number of events: 55 versus 18; p<0.001).
• The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival.

Hypertension and Diabetes²

A similar study was conducted in 448 hypertensive patients with type 2 diabetes, with similar results. Among patients with diabetes, treatment with at least one hypertension medications at bedtime, compared with all medications upon waking, resulted in improved ambulatory blood pressure control and significantly reduced cardiovascular morbidity and mortality.

After a median follow-up of 5.4 years, patients with diabetes ingesting at least one hypertension medications at bedtime showed:²

• Significantly lower sleep time BP and higher prevalence of controlled ambulatory BP (62.5 vs. 50.9%; p=0.013).
• A cardiovascular risk (adjusted by age and sex) of one third that of subjects ingesting all medications upon awakening (p<0.001).
• An adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) of one fourth that of subjects ingesting all medications upon awakening (p=0.003).
• There was a significant 12% cardiovascular risk reduction per each 5mmHg decrease in asleep systolic BP during follow-up (p<0.001).

Hypertension and CKD³

Nocturnal hypertension is more common among patients with chronic kidney disease (CKD) who may thus experience greater effects of time medications for hypertension. A new study conducted with a similar design in 661 patients again showed that, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.

After a median follow-up of 5.4 years, patients with CKD who took at least one BP-lowering medication at bedtime had:³

• Significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, p=0.003).
• An adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularisation, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (p<0.001).
• A similar significant reduction (more than one third) in risk for a composite outcome of major cardiovascular events (including cardiovascular death, myocardial infarction, and stroke) (p<0.001).
• Each 5mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (p<0.001).

Cochrane review⁴

A Cochrane review of the administration-time-related-effects of evening versus morning dosing antihypertensive regimen was also conducted. It included 21 randomised controlled trials (RCTs) in 1,993 patients with primary hypertension. The results confirm that better blood pressure control is achieved with bedtime dosing than morning administration of antihypertensive medication.

Conclusion

“Advantages of bedtime compared to morning treatment on nighttime blood pressure regulation have been clearly and consistently documented”, said lead author Dr Ramon Hermida. “While many studies have already reported that nighttime BP is a better prognostic marker than daytime BP, ours was the first trial to further document, in patients evaluated repeatedly with ambulatory blood pressure monitoring during the years of follow-up, that decreasing nighttime BP was significantly associated with increased survival“.

“There is no clinical or scientific reason to recommend morning ingestion of hypertension medications, as no one ever before tested time of treatment as an influential factor of cardiovascular risk”, she continued. “Cardiovascular events are indeed more frequent at the end of the resting span and initial hours after awakening; ingesting the medications with breakfast (as most patients currently do), that is, AFTER the peak in the prevalence of events and risk, is probably not the wiser thing to do”.

Dr Hermida explained that most medications do not have homogeneous effect of reducing BP for over 24 hours, and no medication ingested in the morning is able to reduce nighttime BP to the same amount as daytime BP. “Altogether, these issues help to understand the documented advantages of bedtime treatment to increase ambulatory BP control and, eventually, to reduce cardiovascular risk”.

The reduction of about 60% in the rate of events with bedtime treatment was even larger than what the researchers anticipated. To prospectively corroborate their results, the researchers are currently coordinating a prospective multicentre trial with similar hypotheses to MAPEC, carried out in 36 clinical sites and with over 8000 patients already recruited.

References

1- Hermida RC et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010 Sep;27(8):1629-51.

2- Hermida RC et al. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2011 Jun;34(6):1270-6.

3- Hermida RC et al. Bedtime Dosing of Antihypertensive Medications Reduces Cardiovascular Risk in CKD. J Am Soc Nephrol. 2011 Dec;22(12):2313-21.

4- Zhao P et al. Evening versus morning dosing regimen drug therapy for hypertension. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004184.

2011 NICE Hypertension Guidelines

Updated NICE guidelines on hypertension¹, published in October last year in conjunction with the British Hypertension Society (BHS), recommend that a diagnosis of hypertension should be made using 24-hour ambulatory blood pressure monitoring (ABPM).

The process involves wearing a type of mobile blood pressure monitor that straps around the waist and records numerous blood pressure measurements throughout the day and night. The guidelines recommend that ABPM replaces the traditional method of monitoring BP – i.e. repeated measurement of blood pressure in the doctor’s clinic.

These recommendations are based on substantial new evidence, including a paper published in the Lancet, which suggest that ABPM is a more accurate and cost effective way of diagnosing hypertension than both clinic and home monitoring.²

Study Design and Results

The study was conducted in a hypothetical primary-care population aged 40 years or older with a screening blood-pressure measurement greater than 140/90mmHg. The researchers compared three diagnostic strategies – further blood pressure measurement in the clinic, at home, and with an ambulatory monitor – in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness.

• Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages, with the greatest savings observed in women aged 40 years.
• Ambulatory monitoring resulted in more quality-adjusted life years for men and women older than 50 years.

More Accurate High BP Diagnosis

The authors concluded that ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs. While the challenge for GPs is around purchasing the ABPM equipment, additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment.

Professor Bryan Williams,  Chairman of the NICE hypertension guideline, commented that as many as 25% of people diagnosed as having high blood pressure using the traditional method of diagnosis, may not be hypertensive and may not need treatment.

“This new guideline is going to change the way blood pressure is diagnosed and treated for millions of people around the world. We are using new technologies to improve the way we diagnose high blood pressure. It means that we will be more accurate in treating those who need treatment and in avoiding treating those who don’t”.

Professor Williams stressed that ABPM should be used for making new diagnoses of hypertension and that patients already diagnosed with hypertension do not need to come forward for re-testing as they will be assessed during their annual review.

Key Recommendations for BP diagnosis and monitoring

• Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs. It should be offered to patients if the clinic blood pressure is 140/90mmHg or higher.
• If a person is unable to tolerate ambulatory BP monitoring, home BP monitoring (HBPM) is a suitable alternative to confirm the diagnosis of hypertension.
• Severe hypertension: Consider starting antihypertensive drug treatment immediately, without waiting for the results of ABPM or HBPM, for people with severe hypertension (clinic SBP ≥180mmHg, or clinic DBP ≥110mmHg).
• Monitoring: Use clinic blood pressure measurement to monitor the response to treatment. For people identified as having a ‘white-coat effect’*, consider ambulatory or home BP monitoring as an adjunct to clinic BP measurements to monitor the response to treatment.

* It is thought that up to a quarter of patients experience white coat effect – where a patient experiences a temporary increase in blood pressure while having their blood pressure measured by their doctor.

Specific advice

The updated guideline also simplifies the treatment strategy for high blood pressure, focussing on the most effective treatments. They also contain specific advice on the treatment of blood pressure in young adults and the very elderly.

• The updated guidelines recommend for the first time that patients over the age of 80 are treated for hypertension (with treatment similar to people aged 55–80 years, taking into account any comorbidities).
• For people aged under 40 years with stage 1 hypertension and no evidence of target organ damage, cardiovascular disease, renal disease or diabetes, consider seeking specialist evaluation of secondary causes of hypertension and a more detailed assessment of potential target organ damage (as 10-year CV risk assessments can underestimate the lifetime risk of CV events in this population).
• The use of calcium-channel blockers rather than diuretics is now recommended for patients over 55 or patients of African or Caribbean family origin, following the emergence of new evidence.

References:

1- National Institute for Health and Clinical Excellence (NICE). Hypertension Guidelines: Clinical management of primary hypertension in adults, available at www.nice.org.uk/guidance/CG127

2- Lovibond K. Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: A modelling study. Lancet. 2011 Oct 1;378(9798):1219-30.

Lucentis (ranibizumab) is now approved to treat visual impairment due to macular oedema secondary to retinal vein occlusion (including branch RVO or central RVO).

Retinal vein occlusion (RVO) is the second most common retinal vascular disorder after diabetic retinopathy. Occlusion of the outflow channel of the retinal circulation markedly increases intraluminal venous pressure, resulting in haemorrhage, oedema and loss of vision. There are two basic types of vein occlusion:  Branch RVO, in which one of the branches of the main retinal vein is blocked, and central RVO, in which the main vein is blocked.

Ranibizumab is a monoclonal antibody fragment which prevents binding of vascular endothelial growth factor (VEGF) to its receptors, with effect on vessel permeability. The new approval follows the BRAVO¹ and CRUISE² studies which tested ranibizumab in patients with visual impairment due to macular oedema secondary to branch RVO (n=397) and central RVO (n=392), respectively.

Study design

BRAVO and CRUISE were randomised, double-masked, controlled studies that recruited 397 subjects with branch RVO and 392 subjects with central RVO, respectively. In both studies, participants received either ranibizumab 0.3mg or 0.5mg for 12 months or sham injections for 6 months followed by ranibizumab 0.5mg for the next 6 months.

18 letter gains achieved by branch RVO Lucentis-treated patients at 1 year

Mean increase in visual acuity at 6 months was significantly greater in the ranibizumab-only group than the sham/ranibizumab group in both studies (Figures 1 and 2; p<0.0001).

Gains of 18 letters and 14 letters were achieved by Lucentis-treated patients in the BRAVO and CRUISE studies, respectively.  Overall, 60.3% of ranibizumab patients with branch RVO (BRAVO) and 50.8% of those with central RVO (CRUISE) experienced a gain of 15 or more letters by 12 months, compared with 43.9% and 33.1%, of sham/ranibizumab patients respectively.

Lucentis-treated patients experienced a rapid response, with a 7.5 and 9.3 letter gain by day 7, in the BRAVO and CRUISE studies respectively.

Figure 1: Mean change of best-corrected visual acuity over time in branch RVO patients (BRAVO)

18 letter gain sustained at 12 months

Figure 2: Mean change of best-corrected visual acuity over time in central RVO patients (CRUISE)

14 letter gain sustained at 12 months

Marked reduction in central foveal thickness

In both studies, the improvement of vision was accompanied by a continuous and significant reduction in the macular oedema as measured by central retinal thickness. In sham/ranibizumab patients, the reduction in central foveal thickness was marked after the first as-needed ranibizumab injection and sustained through month 12.

The improvement in visual acuity observed with ranibizumab treatment at 6 and 12 months was accompanied by patient-reported benefits as measured by the National Eye Institute Visual Function Questionnaire (VFQ-25) sub-scales related to near and distance activity.

No new ocular or nonocular safety events were identified. In both studies, there was a low incidence of serious arterial thromboembolic events (0.7-2.3%) after 12-month ranibizumab treatment and 1 case of death in each of the treatment groups.

Conclusion

Altogether, these results show that intraocular injections of VEGF-targeting antibody Lucentis provide an effective treatment for macular oedema after retinal vein occlusion, including both branch and central RVO.

Lucentis is also licensed for neovascular (wet) age-related macular degeneration and visual impairment due to diabetic macular oedema. Dosing for the new indication is the same as for the other indications: 0.5mg given monthly as a single intravitreal injection until maximum visual acuity is achieved (i.e. visual acuity stable for three consecutive months).

References

1- Brown DM et al. Ophthalmology. 2011 Aug;118(8):1594-602.

2- Campochiaro PA et al. Ophthalmology. 2011 Oct;118(10):2041-9

Full prescribing information and references available on request from Novartis Ireland Ltd.

Telephone: (01) 2601255.

MIMS Ireland Copyright^®

Products include: Cipramil/Bellcital/Ciprager/Ciprapine/Ciprotan/Citalopram Actavis/Citalopram Teva/ Citrol and Lexapro/Escipriex/Escitalpro/Escitomar

Citalopram and escitalopram are selective serotonin reuptake inhibitors (SSRIs) indicated in the treatment of depressive illness (see the Summaries of Product Characteristics (SPCs) for full details of licensed indications).

Following a review of the available information on the risk of QT prolongation with these medicines, the Pharmacovigilance Working Party (PhVWP) has recommended that the product information for citalopram and escitalopram be updated with new contraindications and warnings and a reduction in the maximum dose for use in the elderly for both active substances. For citalopram, there has additionally been a general reduction in the maximum dose and in the maximum dose for patients with impaired liver function.  This information was recently communicated to Healthcare Professionals by the marketing authorisation holder, in agreement with the IMB and is available on www.imb.ie.

Advice to Healthcare Professionals

• Citalopram and escitalopram have been found to cause a dose-dependent prolongation of the QT interval.

• Cases of ventricular arrhythmia including Torsade de Pointes (TdP) have been reported, predominantly in females, with hypokalaemia and with pre-existing QT interval prolongation or other cardiac diseases.

• Citalopram and escitalopram are now contraindicated in patients with known QT interval prolongation or congenital long QT syndrome.

• Co-administration with other medicinal products known to prolong the QT-interval is also contraindicated (e.g. Class IA and III antiarrythmics, antipsychotics, tricyclic antidepressants and some antimicrobial agents such as moxifloxacin).

• Caution is advised in patients at higher risk of developing TdP, e.g. those with congestive heart failure, myocardial infarction, bradyarrhythmias or a predisposition to hypokalaemia or hypomagnesaemia because of concomitant illness/medicines.

• Healthcare professionals are advised to review elderly patients taking citalopram or escitalopram at doses above the new recommended maximum dose, and gradually reduce the dose accordingly (the product information advises on how to minimise the risk of withdrawal symptoms).

Information on the data assessed

The new recommendations for citalopram-containing products follow an assessment of a QT-study which revealed a dose dependant increase of the QT-interval observed with ECG. In addition, review of data from spontaneous reports has identified cases of QT prolongation and ventricular arrhythmia including TdP.  Furthermore, studies have not shown an added benefit in the treatment of depression at doses higher than 40mg daily. The product information for citalopram-containing products will be revised to reflect the study findings and the following new dosage and usage recommendations:

• The recommended maximum dose of citalopram in adults has been lowered from 60mg to 40mg daily due to risk of QT interval prolongation with higher doses.

• The recommended maximum dose of citalopram in the elderly is accordingly lowered from 40mg to 20mg daily.

• The recommended maximum dose is lowered from 30mg to 20mg citalopram daily in patients with reduced hepatic function.

In addition to the data evaluated for citalopram, the PhVWP assessed the results of a QT-study undertaken in healthy volunteers given doses of 10mg and 30mg escitalopram and concluded that a dose dependent increase in QT interval was shown in this study, particularly with 30mg/day. The PhVWP also noted that cases of QT interval prolongation and ventricular arrhythmia including TdP were spontaneously reported, predominantly in female patients with hypokalaemia, pre-existing QT interval prolongation or other cardiac diseases. Most of the reported cases of TdP had a temporal relationship with starting treatment with escitalopram, or with the increase in dosing, and/or at the time of other risk situations, e.g. hypokalaemia. Recovery from the event was reported when escitalopram was discontinued in most of the reported cases. The data from spontaneous reporting indicates a signal for QT prolongation and the potential for under-reporting is recognised.

The PhVWP considered that it is not possible to conclude that there is a substantially lower risk for QT-prolongation with escitalopram than with citalopram, and therefore, the same risk minimisation measures should apply. In considering the appropriate risk minimisation strategy, the PhVWP also noted that elderly patients achieve higher systemic exposure than younger patients and made the following recommendations:

• In the elderly (> 65 years of age), the recommended maximum dose of escitalopram is now reduced to 10mg daily.

• The maximum dose of escitalopram for adults ≤ 65 years remains 20mg daily.

Patients treated with citalopram or escitalopram should be advised to contact a healthcare professional immediately if they experience symptoms of an abnormal heart rate or rhythm.  Patients should not stop taking these medicines or change or reduce the dose without first consulting their healthcare professional, as withdrawal symptoms may occur.  Cases of QT interval prolongation have been reported also in association with other SSRIs, for further information please refer to the respective SPCs.  Suspected adverse reactions associated with the use of citalopram or escitalopram, particularly cardiac disorders, should be reported to the IMB via the usual routes.

Key Message: Citalopram and escitalopram are associated with dose-dependent QT interval prolongation. Risk minimisation measures will be implemented including new contraindications and warnings and dosing recommendations.

Company: Dr Falk Pharma UK Ltd.
Legal category: Prescription. GMS. Sport prohibited in competition.
Active ingredient: Budesonide 9mg.
Description: Gastro-resistant granules.
Presentation: 60 sachets, €177.20.
Indication: Induction of remission in patients with active collagenous colitis.
Pharmacology: The exact mechanism of budesonide in the treatment of inflammatory bowel diseases is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action is predominantly based on a local anti-inflammatory action in the gut.
Dosage: Adult: One sachet once daily in the morning 30 minutes before breakfast. Maximum duration, 8 weeks. Elderly: As per adults. Children: Under 18 years, not recommended.
Contraindications: Hypersensitivity to budesonide or any of the ingredients. Hepatic cirrhosis. Pregnancy, lactation.
Special precautions: Increased susceptibility to infections. Caution: Tuberculosis, hypertension, osteoporosis, peptic ulcer, cataracts, family history of diabetes or glaucoma, septicaemia, exposure to chickenpox or measles, live vaccines, hepatic impairment. Systemic effects may occur including Cushing’s syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and, very rarely, psychiatric/behavioural effects. May suppress the HPA axis and reduce the stress response. Contains sucrose, lactose and sorbitol.
Drug interactions: Avoid: Potent CYP3A4 inhibitors (including ketoconazole, ritonavir, itraconazole, clarithromycin, grapefruit juice). CYP3A4 inducers (carbamazepine, rifampicin), CYP3A4 substrates, cardiac glycosides, saluretics. Steroid-binding compounds such as colestyramine and antacids (take 2 hours apart).
Adverse drug reactions: None common.
Full prescribing information and references available from Dr Falk Pharma UK Ltd. Telephone: +44 (1628) 536600. Email: office@drfalkpharma.co.uk

Company: Pfizer Healthcare Ireland.
Legal category: Prescription. GMS. Sport prohibited.
Active ingredient: Bazedoxifene 20mg.
Description: White, capsule shaped, film coated tablet marked WY20 on one side.
Presentation: 28, €20.86.
Indications: Treatment of postmenopausal osteoporosis in women at increased risk of fracture.
Pharmacology: Bazedoxifene belongs to a class of compounds known as selective estrogen receptor modulators (SERMs) and acts as both an oestrogen receptor agonist and/or antagonist, depending upon the cell and tissue type and target genes. It decreases bone resorption and reduces biochemical markers of bone turnover to the premenopausal range. These effects on bone remodeling lead to an increase in bone mineral density, which in turn contributes to a reduction in the risk of fractures.
Dosage: Adult: One tablet once daily. Elderly: As per adults. Children: Not applicable.
Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Unexplained uterine bleeding. Patients with signs or symptoms of endometrial cancer. Women of child bearing potential. Pregnancy, lactation.
Special precautions: Not recommended: Women at an increased risk for venous thromboembolic events (eg. advanced age, obesity, immobilisation, surgery, major trauma, malignancy), premenopausal women, hepatic impairment. Caution: Hypertriglyceridaemia, severe renal impairment. Driving/using machines. Contains lactose.
Drug interactions: None known.
Adverse drug reactions: Hot flushes, muscle spasms (including leg cramps), hypersensitivity, somnolence, dry mouth, urticaria, peripheral oedema, increased blood triglycerides, increased alanine aminotransferase, increased aspartate aminotransferase.
Full prescribing information and references available from Pfizer Healthcare Ireland. Telephone: (01) 4676500.

Company: Athlone Laboratories Ltd.
Legal category: Prescription. GMS. Sport permitted.
Active ingredient: Capsules: Flucloxacillin Na+ 250mg, 500mg. Oral solution: Flucloxacillin Na+ 125mg/5ml, 250mg/5ml.
Description: Capsules: Opaque caramel body and opaque grey cap marked FXN250 and FXN500. Oral solution: Pink powder for oral solution.
Presentation: Capsules: 250mg-100, €15.38; 500, €76.99; 500mg-100, €30.78; 500, €153.99. Oral solution: 125mg/5ml-100ml, €2.48; 250mg/5ml-100ml, €5.95.
Indications: Infections due to sensitive Gram-positive organisms, including β-lactamase-producing staphylococci and streptococci. As prophylactic agent during major surgery.
Pharmacology: Flucloxacillin is an isoxazolyl penicillin of the β-lactam group of antibiotics exerting a bactericidal effect upon many Gram-positive organisms including β-lactamase-producing staphylococci and streptococci, except those of group D (Enterococcus faecalis) staphylococci. It is not active against methicillin-resistant staphylococci.
Dosage: Adult: Administer oral doses ½-1 hour before meals. 250mg-500mg four times daily. Osteomyelitis, endocarditis: Up to 8g daily, in divided doses every 6-8 hours. Surgical prophylaxis: 1 to 2g intravenously at induction of anaesthesia followed by 500mg every 6 hours intravenously, intramuscularly or orally up to 72 hours. Severe renal impairment (cc<10ml/min): Reduce dose or extend dose interval. Elderly: As per adults. Children: Over 10 years, as per adults. 2-10 years, half adult dose. Under 2 years, quarter adult dose.
Contraindications: Hypersensitivity to β-lactam antibiotics or excipients. History of flucloxacillin-associated jaundice/hepatic impairment.
Special precautions: Caution: Hepatic impairment, patients ≥ 50 years, serious underlying disease, renal impairment, risk of hyperbilirubinemia in newborn. Prolonged use may lead to superinfection; monitor hepatic and renal functions regularly. Contains sodium. Pregnancy, lactation (only if benefits outweigh risks). Oral solution: Contains sucrose.
Drug interactions: Probenecid, sulfinpyrazone, combined oral contraceptives, piperacillin, oral typhoid vaccine, methotrexate, sugammadex, bacteriostatic drugs.
Adverse drug reactions: Minor GI upset.
Full prescribing information and references available from Athlone Laboratories Ltd.

Company: A. Menarini Pharmaceuticals Ireland Ltd / Daiichi Sankyo Ltd.
Legal category: Prescription. GMS. Sport prohibited.
Active ingredients: Olmesartan medoxomil/amlodipine besilate/hydrochlorothiazide, 20/5/12.5mg, 40/5/25mg, 40/10/25mg.
Description: Light orange, light yellow or greyish red film-coated tablets marked C51, C54 or C57 on one side respectively. 20/5/12.5mg: Round. 40/5/25mg, 40/10/25mg: Oval.
Presentation: 20/5/12.5mg-28, €22.70; 40/5/25mg-28, €29.11; 40/10/25mg-28, €29.96.
Indication: Substitution therapy in essential hypertension where blood pressure (BP) is adequately controlled on olmesartan medoxomil, amlodipine and HCTZ taken as single-component and dual-component formulations.
Pharmacology: The combination of olmesartan medoxomil, an angiotensin II receptor antagonist, amlodipine besilate, a calcium channel blocker, and HCTZ, a thiazide diuretic, has an additive antihypertensive effect, reducing BP to a greater degree than each component alone.
Dosage: Adult: 1 tablet daily. Titration of individual components is recommended before changing to the fixed combination. Maximum 40/10/25mg daily. Mild-moderate renal impairment: Maximum 20/5/12.5mg daily; monitor serum K+ and creatinine levels periodically. Moderate hepatic impairment: Maximum 20/5/12.5mg daily; monitor BP and renal function. Elderly: Monitor BP closely if maximum daily dose required. Children: Under 18 years, not recommended.
Contraindications: Hypersensitivity to the active substances, to dihydropyridine derivates, to sulfonamide-derived substances or to any of the excipients. Severe renal impairment. Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia. Severe hepatic impairment, cholestasis and biliary obstruction. Shock (including cardiogenic shock), severe hypotension, outflow tract obstruction of the left ventricle (eg. high grade aortic stenosis), haemodynamically unstable heart failure after acute myocardial infarction. Pregnancy, lactation.
Special precautions: Correct volume and/or Na+ depletion before treatment. Not recommended: Primary aldosteronism. Caution: Severe congestive heart failure, underlying renal disease including renal artery stenosis, mild-moderate hepatic impairment, aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy, diabetes. Renal impairment; thiazide diuretic-associated azotaemia may occur; if worsens, consider discontinuation. Serum electrolyte imbalances may occur; monitor periodically. May occur: Pulmonary oedema (NYHA III and IV heart failure patients), elevated cholesterol and triglyceride levels, hyperuricaemia, myocardial infarction or stroke. No data: Recent kidney transplant, end-stage renal impairment. Discontinue if photosensitivity reactions occur. History of allergy or bronchial asthma. May exacerbate or activate systemic lupus erythematosus. Less effective in black patients. Driving/using machines.
Drug interactions: Not recommended: K+ supplements, K+ sparing diuretics or salts, lithium, heparin, ACE inhibitors, drugs inducing K+ loss. Caution: Baclofen, NSAIDs, CYP3A4 inhibitors, CYP3A4 inducers, Ca++ salts, cholestyramine and colestipol resins, digitalis glycosides, torsades de pointes-inducing drugs, non-depolarizing skeletal muscle relaxants, anticholinergic agents, antidiabetics, metformin, beta-blockers, diazoxide, pressor amines, antigout drugs, amantadine, cytotoxic agents, salicylates, methyldopa, ciclosporin, tetracyclines. Amifostine, other antihypertensives, alcohol, barbituates, narcotics, antidepressants, antacids.
Adverse drug reactions: Upper respiratory tract infections, urinary tract infection, dizziness, headache, hypotension, GI upset, muscle spasm, joint swelling, pollakiuria, peripheral oedema, fatigue, increased blood creatinine, increased blood urea, increased blood uric acid, arthritis, back pain, skeletal pain, haematuria, influenza-like symptoms, chest pain, pain, increased creatine kinase, liver enzyme elevations, somnolence, oedema, electrolyte imbalances, hyperglycaemia, glycosuria, confusional state, pitting oedema.
Full prescribing information and references available from A. Menarini Pharmaceuticals Ireland Ltd. Telephone: (01) 2846744.

Company: Rowex Ltd.
Legal category: Prescription. GMS. Sport permitted.
Active ingredient: Latanoprost 50mcg/ml.
Description: Eye drops solution.
Presentation: 2.5ml-1, €16.15.
Indications: Reduction of elevated intraocular pressure (IOP) in patients with open angle glaucoma and ocular hypertension. Reduction of elevated IOP in paediatric patients with elevated IOP and paediatric glaucoma.
Pharmacology: Latanoprost, a prostaglandin F2α analogue, is a selective prostanoid FP receptor agonist which reduces IOP by increasing the outflow of aqueous humour. Reduction of IOP starts about three to four hours after administration and maximum effect is reached after eight to twelve hours. Pressure reduction is maintained for at least 24 hours.
Dosage: Adult: One drop in the affected eye(s) once daily, preferably in the evening. Elderly: As per adults. Children: As per adults. Under 1 year, limited experience. Preterm infants (<36 weeks gestational age), no data.
Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy, lactation.
Special precautions: May permanently change colour in mixed coloured irides; inform patient. Caution: Chronic angle closure, inflammatory, neovascular, congenital or pigmentary glaucoma, open angle glaucoma of pseudophakic patients, inflammatory ocular conditions, acute attacks of closed angle glaucoma, cataract surgery, aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, risk factors for cystoid macular oedema or iritis/uveitis, asthma, dyspnoea. Periorbital skin discolouration, punctate or toxic ulcerative keratopathy may occur. Soft contact lenses (avoid); wait at least 15 minutes before reinsertion. Driving/using machines (transient blurred vision). Contains benzalkonium chloride.
Drug interactions: Not recommended: Other prostaglandins.
Adverse drug reactions: Increased iris pigmentation, conjunctival hyperaemia eye irritation, eyelash and vellus hair changes, transient punctate epithelial erosions, blepharitis, eye pain.
Full prescribing information and references available from Rowex Ltd. Telephone: 1800 304400. Fax: (027) 50417. E-mail: rowex@rowa-pharma.ie