Revlimid (lenalidomide) – Risk of second primary malignancies in authorised indication

Revlimid (lenalidomide) is an immunomodulating agent first licensed via a European assessment procedure in 2007, subject to a number of risk minimisation measures including a pregnancy prevention plan to ensure its safe use. Structurally related to thalidomide, Revlimid is authorised for use in combination with dexamethasone for the treatment of multiple myeloma in patients who have received at least one prior therapy.

Based on an observation of a 4-fold higher incidence of second primary malignancies (SPM) in newly diagnosed multiple myeloma patients treated with lenalidomide compared to controls, a review of the benefit-risk balance of Revlimid in the authorised indication was undertaken by the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency (See IMB Drug Safety Newsletters 42 and 44, available on www.imb.ie).

In the authorised indication (in previously treated multiple myeloma patients), an increase of second primary malignancies was observed (3.98 per 100 patient-years in lenalidomide treated group versus 1.38 per 100 patient-years in the control group). Non-invasive second primary malignancies comprise basal cell or squamous cell skin cancers. Most invasive second primary malignancies were solid tumour malignancies.

Based on these data, the risk of occurrence of second primary malignancies should be taken into account before initiating treatment with Revlimid. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as indicated.

This information was communicated via a Direct Healthcare Professional Communication (DHPC) by the manufacturing authorisation holder in agreement with the IMB and is available on www.imb.ie. *

Advice for Healthcare Professionals

• The risk of occurrence of second primary malignancies should be taken into account before initiating treatment with Revlimid.
• Physicians should carefully evaluate patients before and during treatment using standard cancer screening for the occurrence of second primary malignancies and institute treatment as indicated.
• Suspected adverse reactions, especially the occurrence of new cancers associated with the use of Revlimid should be reported to the IMB via the usual routes, see www.imb.ie for further details.

Key Message

A higher incidence of second primary malignancies has been observed in patients treated with Revlimid compared to controls, within the authorised indication.

The benefit-risk balance for Revlimid remains positive within its approved patient population however prescribers should be aware of the risk of new cancers as a result of treatment with lenalidomide.

*Information on the risk of arterial and venous thromboembolic events associated with use of Revlimid was previously highlighted in a DHPC and in the 41st edition of the IMB’s DSN, and subsequently in MIMS Ireland Oncology Reference May 2011.

Aliskiren – New contraindications and warnings due to the risks of cardiovascular and renal adverse reactions (Brands include Rasilez, Rasilez HCT, Rasilamlo)

Aliskiren is an antihypertensive agent which inhibits the renin-angiotensin-aldosterone system through a direct effect on renin, blocking the conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and angiotensin II. It has been licensed for use across the EU since 2007 either alone, or in combination with other antihypertensive medicines.

A review of aliskiren-containing medicines was initiated by the European Medicines Agency (EMA) in December 2011 after the ALTITUDE study was terminated early on the basis of preliminary interim analyses. The ALTITUDE study (Aliskiren Trial In Type 2 diabetes Using cardiovascular and renal Disease Endpoints) was a 4-year, randomised, placebo-controlled trial that included patients with type II diabetes and renal impairment and/or cardiovascular disease. The study was designed to evaluate the effect of aliskiren on the risk of cardiovascular and renal events in these high-risk patients, and participants received aliskiren or placebo in addition to either an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

The interim analysis showed that study patients were unlikely to benefit from aliskiren and there was a higher incidence of non-fatal strokes, renal complications (including acute renal failure), hyperkalaemia and hypotension in patients in the aliskiren group. In December 2011, healthcare professionals were informed of the interim results of the trial and advised that aliskiren use in combination with an ACE inhibitor or an ARB was contraindicated in all diabetic patients. Further review of analyses from the ALTITUDE study, alongside data from other studies and spontaneous reports, confirmed the risk of adverse outcomes (hypotension, syncope, stroke, hyperkalaemia, and changes in renal function including acute renal failure) when aliskiren is combined with ACE inhibitors or ARBs, especially in diabetic patients and those with impaired renal function. Although less evidence is available for other patient groups, adverse outcomes cannot be excluded and therefore the combination is not recommended for any patient.

In addition, the use of aliskiren is no longer recommended in any patient with severe renal impairment (GFR <30ml/min per 1.73m²) irrespective of whether it is used in combination with an ACE inhibitor or an ARB, another antihypertensive, or as monotherapy. This recommendation is based on an analysis of postmarketing surveillance data that showed an increased risk of renal adverse events and hyperkalaemia with aliskiren in this patient group.

This information was recently communicated to healthcare professionals, a copy of which is available on www.imb.ie.

Advice for healthcare professionals

• Prescribers should review the treatment of all patients taking aliskiren in combination with an ACE inhibitor or an ARB at a routine appointment.
• Treatment with aliskiren-containing medicines should be discontinued (or not initiated) in diabetic patients, or non-diabetic patients with renal impairment (GFR <60ml/min per 1.73m²) who are taking an ACE inhibitor or an ARB.
• Aliskiren in combination with ACE inhibitors or ARBs is not recommended in any other patient groups.
• Use of aliskiren (either as monotherapy or in combination) is no longer recommended in patients with severe renal impairment (GFR <30ml/min per 1.73m²).
• The benefits and risks of continuing aliskiren treatment should be considered carefully at the individual patient level.
• Alternative antihypertensive treatment should be considered as necessary.

Key Message

Use of aliskiren in combination with ACE inhibitors or ARBs is contraindicated in:

– diabetic patients (type I or type II); and

– non-diabetic patients with an estimated glomerular filtration rate (GFR) <60ml/min per 1.73m².

In all other patient groups, the combination is not recommended.

Any use of aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended in any patient with severe renal impairment.

Suggested treatment algorithm for patients with metastatic neuroendocrine tumours

Reference: Öberg KE. Management of neuroendocrine tumours: Current and future therapies. Expert Rev Endocrinol Metab. 2011;6(1):49-62. [adapted]. MIMS Ireland Copyright®

Table 1 - Histological classification of neuroendocrine tumours (NET)^1,3

a: GI NET; b: Pancreatic NET.

HPF: High powered fields; ENETS: European NETs Society; WHO: World Health Organisation

Table 2 – Clinical presentation of pancreatic NET²

Table 3 – Randomised trials of biologically targeted therapies in pancreatic NET²

References

1- Kulke MH, Chan JA, and Bergsland EK. New treatment options for advanced neuroendocrine tumours. American Society of Clinical Oncology (ASCO). 2011 137-43, available at http://www.asco.org

2- Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumours. J Hematol Oncol. 2011; 4: 29.

3- Öberg KE. Management of neuroendocrine tumours: Current and future therapies. Expert Rev Endocrinol Metab. 2011;6(1):49-62. 

MIMS Ireland Copyright®

Evolving Strategies for the Management of Neuroendocrine tumours^1,2,3

Neuroendocrine tumours (NETs) are a genetically diverse group of malignant solid tumours arising from neuroendocrine cells throughout the body (including in the thymus, lung, pancreas, GI tract and less common sites). They can be either clinically symptomatic (i.e., ‘functioning’), producing peptides causing characteristic hormonal syndromes, or silent, (i.e., ‘nonfunctioning’). Functioning NETs are characterised by the hormones they produce and the symptoms they cause. The clinical symptoms of functioning NETs typically appear after the tumour has metastasised to the liver.

NETs can be broadly classified into well-differentiated tumours (more indolent) and poorly differentiated ones (far more aggressive) (see Table 1 for histological classification of NET). Well-differentiated tumours are traditionally further subdivided into either carcinoid or pancreatic NETs. Carcinoid tumours have a similar histological appearance to pancreatic NETs, but generally originate in the bronchi, small intestine, appendix or rectum.*

Neuroendocrine tumours have demonstrated an increase in incidence over past decades, partly due to increased awareness and improved diagnosis.

*Based on embryological origin, NETs were traditionally classified in 1963 as foregut (thymus, oesophagus, lung, stomach, duodenum and pancreas), midgut (appendix, ileum, caecum and ascending colon) and hindgut (distal large bowel and rectum) tumours, but this system is now considered outdated as it does not distinguish biologically relevant differences.

DIAGNOSIS

The diagnosis of NETs is multimodal, based on clinical symptoms, hormone levels (for functioning NETs), radiological and nuclear imaging, and histological confirmation. However, a large proportion of NETs are non-functioning and diagnosed incidentally during imaging for other indications. Most patients with NETs have metastatic disease at diagnosis, with regional or distant metastasis observed in 50% of patients (in regional lymph nodes, then liver, then distant sites such as bone).

Biomarkers

A number of biochemical tests are available, which can assist with the initial diagnosis and assessment of required treatment. The most common are:

Chromogranin A (CgA) is present in the chromaffin granules of neuroendocrine cells. CgA measurement via a blood test can be used to diagnose both functioning and nonfunctioning NETs¹ and plays an important role in the assessment of treatment response and monitoring of recurrence. However CgA may be elevated in a number of non-malignant conditions therefore the use of CgA as a diagnostic or screening test for NET should be discouraged.¹

Ki-67, a protein found in the nucleus during cell division, can be used in NET as a marker of tumour proliferation. Low Ki-67 levels indicate lower proliferation which correlates with longer survival.

As a general rule, aggressive malignancies are tumours with: ¹

• a high grade (grade 3),
• a mitotic count > 20 per 10 high powered fields,
• or a Ki-67 proliferation index > 20%

5-hydroxyindoleacetic Acid (5-HIAA) is a serotonin metabolite can be used to predict the presence of a midgut NET.

Specific hormones

While most pancreatic NETs are considered ‘non-functional’, with no symptoms of hypersecretion, the functional tumours on the other hand can present with various and sometimes puzzling symptoms (Kurke pNET) (see Table 2 for clinical presentation of pancreatic NETs). Specific hormones related to clinical syndromes are:

• gastrin (Zollinger–Ellison syndrome)
• insulin/proinsulin (hypoglycemia symptoms)
• glucagon for glucagonomas
• vasoactive intestinal peptide (VIP) (VIP-omas).

Imaging

Imaging techniques can be used to determine the location of the primary tumour and assess tumour extent (localisation and metastases). Common imaging techniques include computed tomography (CT) or MRI scans. As pancreatic NETs and carcinoid tumours both frequently over-express somatostatin receptors, somatostatin-receptor scintigraphy (SRS, Octreoscan) has been commonly used to localise and stage NET. SRS is also the diagnostic test of choice for locating secondaries as whole-body imaging enables the identification of distant metastases. Also, over the past decade, PET tracers for somatostatin receptor imaging led to better results and should improve staging and follow-up.³

THERAPEUTIC STRATEGIES

Surgery is the only curative approach, and as such represents the traditional first line therapy for localised NETs. However, it is not always possible as most patients with NETs are diagnosed after metastases have occurred.

Evidence increasingly shows that pancreatic NETs are more responsive to therapeutic agents, most agents being associated with higher response rates in pancreatic compared to carcinoid NETs.

Traditionally, therapeutic approaches for patients with advanced, unresectable NETs have included  hepatic-directed therapies ( e.g. surgical resection and hepatic artery embolisation) and systemic treatment options including the use of somatostatin analogues or interferon for control of hormonal hypersecretion, as well as alkylating chemotherapy. In addition, biologically targeted therapies may play an increasing role in patients with progressive advanced pancreatic NETs.

Somatostatin analogues

In patients with advanced NETs symptoms of hormone hypersecretion can usually be treated effectively with somatostatin analogues (e.g., octreotide, lanreotide), which will continue to be main therapies for functioning neuroendocrine tumours over the next few years.

• In midgut carcinoid, treatment with somatostatin analogues is also associated with improved time to tumour progression (results from PROMID with octreotide LAR).^1,3
• Pasireotide, a new panreceptor analogue, might control clinical symptoms and hormone release in patients resistant to standard somatostatin analogue therapy.^1,3

Interferons

Interferon alpha is generally recommended as a second-line approach in patients with functioning NETs and low proliferation. Though their effect on symptom control is similar to that of somatostatin analogues and they may have greater antiproliferative activity, they do not act as rapidly and have a less favourable safety profile (fever, fatigue, anorexia and weight loss commonly reported).³

Chemotherapy

• In contrast to carcinoid tumours, pancreatic NETs are clearly responsive to cytotoxic chemotherapy.^1,2
• Streptozocin- or temozolomide-based chemotherapy is likely to continue to play a role, particularly in patients with pancreatic NETs and a high tumour burden for whom tumour response is a priority.¹

In phase II studies in pancreatic NETs, temozolomide has been combined with thalidomide, bevacizumab, or everolimus, with response rates ranging from 24% to 45%. The most promising response rates (70%) have been reported in studies of temozolomide combined with capecitabine. Altogether, these studies suggest that temozolomide-based regimens are at least comparable with streptozocin-based regimens in pancreatic NETs, and have a more favourable toxicity profile.¹

Radiotherapy

Although the response rate of NETs to external beam radiation is limited, the introduction of systemic receptor-targeted therapy (peptide receptor radiotherapy [PRRT]) has provided beneficial effects in patients with high tumour content of somatostatin type 2 receptors.³

Biologically targeted therapies

Both the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways have emerged as an attractive target in NETs.^1,2,3 Biologically targeted therapies thus involve agents such as TOR and VEGF inhibitors (including anti-VEGF receptor antibodies and tyrosine kinase inhibitors).

• NETs are highly vascular and characterised by upregulated VEGF and VEGF receptor (VEGFR) expression, which correlates with angiogenesis, metastases, and decreased progression free survival (PFS) among patients with low-grade NETs.
• mTOR is a central regulator of protein synthesis, promoting cell growth and proliferation, as well as cell metabolism and angiogenesis (in part by mediating VEGF and insulin growth factor (IGF)-1 signalling)
• For advanced pancreatic NETs, treatment with either mTOR inhibitor everolimus or VEGFR tyrosine kinase inhibitor sunitinib has been shown to prolong progression-free survival in randomised studies (see Table 3 for randomised trials of biologically targeted therapies in pancreatic NETs).

References

1- Kulke MH, Chan JA, and Bergsland EK. New treatment options for advanced neuroendocrine tumours. American Society of Clinical Oncology (ASCO). 2011 137-43, available at http://www.asco.org

2- Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumours. J Hematol Oncol. 2011; 4: 29.

3- Öberg KE. Management of neuroendocrine tumours: Current and future therapies. Expert Rev Endocrinol Metab. 2011;6(1):49-62. 

MIMS Ireland Copyright®

Company: Rowex Ltd.
Legal category: Prescription. GMS. Sport permitted.
Active ingredient: Atorvastatin 10mg, 20mg, 40mg, 80mg.
Description: Yellow, biconvex film-coated tablets marked HLA10, HLA20, HLA40 or HLA80 respectively. 10mg, 20mg, 40mg: Round. 80mg: Oval.
Presentation: 10mg-28, €14.66; 20mg-28, €27.51; 40mg-28, €28.30; 80mg-28, €32.50.
Indications: Adjunct to diet in primary hypercholesterolaemia (HC), heterozygous familial HC or mixed hyperlipidaemia. Homozygous familial HC (as adjunct to other lipid-lowering treatments or if unavailable). Prevention of cardiovascular events in patients at high risk for first cardiovascular event, as adjunct to correction of other risk factors.
Pharmacology: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
Dosage: Adult: Initially 10mg once daily, increase as necessary at 4 week intervals; maximum 80mg once daily. Elderly: As per adults. Children: Homozygous familial HC, 4-17 years: 10mg daily with titration up to 80mg daily according to response and tolerability (under specialist supervision only).
Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active liver disease, persistent raised liver enzymes (> 3xULN). Inadequate contraception. Pregnancy, lactation.
Special precautions: Caution: Hepatic impairment. Perform liver function tests before treatment and periodically thereafter. History of alcohol abuse or liver disease. Prior hemorrhagic stroke or lacunar infarct (assess risk/benefit of 80mg dose). Myalgia, myositis and myopathy reported. Pre-disposing factors for rhabdomyolysis (see SPC); measure creatine kinase (CK) levels before therapy. Discontinue if rhabdomyolosis or interstitial lung disease develops, or CK levels > 10xULN.
Drug interactions: Not recommended: CYP3A4 inhibitors (e.g. erythromycin, diltiazem, ciclosporin, clarithromycin, itraconazole and HIV protease inhibitors including ritonavir, lopinavir, darunavir, tipranavir, saquinavir, fosamprenavir), CYP3A4 inducers (e.g. rifampin, efavirenz, St. John’s Wort), transport protein inhibitors, gemfibrozil / fibric acid derivatives, niacin, ezetimibe, colestipol, fusidic acid, digoxin, oral contraceptives, warfarin, grapefruit juice, fenofibrate.
Adverse drug reactions: Nasopharyngitis, allergic reactions, hyperglycaemia, headache, pharyngolaryngeal pain, epistaxis, GI disorders, myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain, abnormal liver function test, increased blood CK levels.
Full prescribing information and references available from Rowex Ltd. Telephone: 1800 304400. Fax: (027) 50417. E-mail: rowex@rowa-pharma.ie

Company: Dexcel Pharma Ltd.
Legal category: Prescription. GMS. Sport permitted.
Active ingredient: Atorvastatin 10mg, 20mg, 40mg.
Description: White round film-coated tablets marked 10, 20 or 40 on one side respectively.
Presentation: 10mg-28, €14.66; 20mg-28, €27.51; 40mg-28, €28.30.
Indications: Adjunct to diet in primary hypercholesterolaemia (HC), heterozygous familial HC or mixed hyperlipidaemia. Homozygous familial HC (as adjunct to other lipid-lowering treatments or if unavailable). Prevention of cardiovascular events in patients at high risk for first cardiovascular event, as adjunct to correction of other risk factors.
Pharmacology: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
Dosage: Adult: Initially 10mg once daily, increase as necessary at 4 week intervals; maximum 80mg once daily. Elderly: As per adults. Children: HC, 10 years and above: 10mg daily with titration up to 20mg daily according to response and tolerability (under specialist supervision only).
Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active liver disease, persistent raised liver enzymes (> 3xULN). Inadequate contraception. Pregnancy, lactation.
Special precautions: Caution: Hepatic impairment. Perform liver function tests before treatment and periodically thereafter. History of alcohol abuse or liver disease. Prior hemorrhagic stroke or lacunar infarct (assess risk/benefit of 80mg dose). Myalgia, myositis and myopathy reported. Pre-disposing factors for rhabdomyolysis (see SPC); measure creatine kinase (CK) levels before therapy. Discontinue if rhabdomyolosis or interstitial lung disease develops, or CK levels > 10xULN. Contains lactose.
Drug interactions: Not recommended: CYP3A4 inhibitors (e.g. erythromycin, diltiazem, ciclosporin, clarithromycin, itraconazole and HIV protease inhibitors including ritonavir, lopinavir, darunavir, tipranavir, saquinavir, fosamprenavir), CYP3A4 inducers (e.g. rifampin, efavirenz, St. John’s Wort), transport protein inhibitors, gemfibrozil / fibric acid derivatives, niacin, ezetimibe, colestipol, fusidic acid, digoxin, oral contraceptives, warfarin, grapefruit juice, fenofibrate.
Adverse drug reactions: Nasopharyngitis, allergic reactions, hyperglycaemia, headache, pharyngolaryngeal pain, epistaxis, GI disorders, myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain, abnormal liver function test, increased blood CK and ALT levels.
Full prescribing information and references available from Pinewood Healthcare. Telephone: (052) 6186000.

Company: Pfizer Healthcare Ireland.
Legal category: Prescription. GMS. Sport permitted.
Active ingredient: Atorvastatin 10mg, 20mg, 40mg, 80mg.
Description: White round film-coated tablets marked ATV on one side and 10, 20, 40 or 80 on reverse respectively.
Presentation: 10mg-30, €15.60; 20mg-30, €29.40; 40mg-30, €30.30; 80mg-30, €34.80.
Indications: Adjunct to diet in primary hypercholesterolaemia (HC), heterozygous familial HC or mixed hyperlipidaemia. Homozygous familial HC (as adjunct to other lipid-lowering treatments or if unavailable). Prevention of cardiovascular events in patients at high risk for first cardiovascular event, as adjunct to correction of other risk factors.
Pharmacology: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.
Dosage: Adult: Initially 10mg once daily, increase as necessary at 4 week intervals; maximum 80mg once daily. Elderly: As per adults. Children: HC, 10 years and above: 10mg daily with titration up to 20mg daily according to response and tolerability (under specialist supervision only).
Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active liver disease, persistent raised liver enzymes (> 3xULN). Inadequate contraception. Pregnancy, lactation.
Special precautions: Caution: Hepatic impairment. Perform liver function tests before treatment and periodically thereafter. History of alcohol abuse or liver disease. Prior hemorrhagic stroke or lacunar infarct (assess risk/benefit of 80mg dose). Myalgia, myositis and myopathy reported. Pre-disposing factors for rhabdomyolysis (see SPC); measure creatine kinase (CK) levels before therapy. Discontinue if rhabdomyolosis or interstitial lung disease develops, or CK levels > 10xULN. Contains lactose.
Drug interactions: Not recommended: CYP3A4 inhibitors (e.g. erythromycin, diltiazem, ciclosporin, clarithromycin, itraconazole and HIV protease inhibitors including ritonavir, lopinavir, darunavir, tipranavir, saquinavir, fosamprenavir), CYP3A4 inducers (e.g. rifampin, efavirenz, St. John’s Wort), transport protein inhibitors, gemfibrozil / fibric acid derivatives, niacin, ezetimibe, colestipol, fusidic acid, digoxin, oral contraceptives, warfarin, grapefruit juice, fenofibrate.
Adverse drug reactions: Nasopharyngitis, allergic reactions, hyperglycaemia, headache, pharyngolaryngeal pain, epistaxis, GI disorders, myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain, abnormal liver function test, increased blood CK and ALT levels.
Full prescribing information and references available from Pfizer Healthcare Ireland. Telephone: (01) 4676500.

Company: Clonmel Healthcare Ltd.
Legal category: Prescription. GMS. Sport permitted.
Active ingredient: Candesartan cilexetil 4mg, 8mg, 16mg.
Description: White biconvex tablets scored and marked C4, C8 or C16 respectively. Can be divided into equal halves.
Presentation: 4mg-28, €13.60; 8mg-28, €17.29; 16mg-28, €23.34.
Indications: Essential hypertension. Treatment of patients with heart failure and left ventricle systolic dysfunction (LVEF ≤40%) as add-on therapy to angiotensin converting enzyme (ACE)-inhibitors or when ACE-inhibitors are not tolerated.
Pharmacology: Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor.
Dosage: Adult: Hypertension: Initially 8mg once daily. Usual maintenance dose: 8mg, may be increased to 16mg; maximum 32mg once daily. Renal impairment (including haemodialysis), mild to moderate hepatic impairment, risk of hypotension due to intravascular volume depletion: 4mg initially. Heart failure: Initially 4mg once daily. Titrate up to 32mg once daily by doubling dose at intervals of at least 2 weeks. Elderly: As per adults. Children: Safety and efficacy not established.
Contraindications: Hypersensitivity to candesartan cilexetil or to any of the excipients. Severe hepatic impairment and/or cholestasis. Pregnancy, lactation.
Special precautions: Not recommended: Primary hyperaldosteronism. Caution: Aortic mitral valve stenosis, obstructive hypertrophic cardiomyopathy, severe congestive heart failure, underlying renal disease (including renal artery stenosis), ischaemic cardiopathy, ischaemic cerebrovascular disease, haemodialysis (monitor blood pressure), anaesthesia and surgery. Monitor renal function, serum potassium and creatinine levels (heart failure, elderly, renal impairment, concomitant ACE inhibitor). Hypotension may occur. Kidney transplant (no experience). Driving/using machines. Contains lactose.
Drug interactions: Not recommended: Lithium. K+ -sparing diuretics, supplements or salts, other drugs that may increase K+ levels, NSAIDs, other antihypertensives.
Adverse drug reactions: Hypertension: Respiratory infection, dizziness/vertigo, headache. Heart failure: Hyperkalaemia, hypotension, renal impairment.
Full prescribing information and references available from Clonmel Healthcare. Telephone: (052) 6177777. Fax: (052) 6177791. E-mail: medicalinformation@clonmel-health.ie

Company: Clonmel Healthcare Ltd.
Legal category: Prescription. GMS. Sport prohibited.
Active ingredients: Candesartan cilexetil/hydrochlorothiazide 16mg/12.5mg.
Description: White biconvex tablets scored and marked CH16.
Presentation: 16mg/12.5mg-28, €23.34.
Indication: Essential hypertension, where monotherapy with candesartan cilexetil or hydrocholorothiazide (HCTZ) is not sufficient.
Pharmacology: Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. HCTZ inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and promotes the excretion of sodium, chloride and water. It decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure.
Dosage: Adult: One tablet once daily. Dose titration with the individual components recommended. Intravascular volume depletion, mild-moderate renal/hepatic impairment: Dose titration of candesartan recommended; initially 4mg candesartan. Elderly: As per adults. Children: Safety and efficacy not established.
Contraindications: Hypersensitivity to the active substances or excipients. Severe hepatic impairment and/or cholestasis. Severe renal impairment. Refractory hypokalaemia and hypercalcaemia. Gout. Driving/using machines. Pregnancy, lactation.
Special precautions: Not recommended: Primary aldosteronism. Renal impairment: Monitor potassium, creatinine and uric acid levels. Recent kidney transplant (no experience). Caution: Renal artery stenosis, impaired hepatic function or progressive liver disease, aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy, anaesthesia and surgery. Correct intravascular volume and/or sodium depletion before starting treatment. Monitor serum electrolytes. Parathyroid function tests. May impair glucose tolerance. Hypersensitivity reactions to HCTZ may occur (especially if history of allergy or bronchial asthma). Exacerbation or activation of SLE reported. Contains lactose.
Drug interactions: Not recommended: Lithium. Caution: NSAIDs, metformin. Drugs associated with K+ loss and hypokalaemia. K+-sparing diuretics, supplements or salts, other drugs that may increase K+ levels, digitalis glycosides. Drugs that may induce torsades de pointes such as class Ia or class III antiarrhythmics, some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperiodol) and others (e.g. bepridil, cisapride, diphemanil, erythromycin iv, halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine iv), colestipol or cholestyramine. Skeletal muscle relaxants, calcium supplements, vitamin D, beta-blockers, diazoxide, anticholinergic agents, amantadine, cytotoxic drugs (e.g. cyclophosphamide, methotrexate), alcohol, barbiturates, anaesthetics, antidiabetics (including insulin), pressor amines, iodinated contrast media, ciclosporin, baclofen, amifostin, tricyclic antidepressants, neuroleptics.
Adverse drug reactions: Respiratory infection, dizziness/vertigo, headache, hyperglycaemia, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), glycosuria, weakness, increases in cholesterol and triglycerides.
Full prescribing information and references available from Clonmel Healthcare. Telephone: (052) 6177777. Fax: (052) 6177791. E-mail: medicalinformation@clonmel-health.ie