Lisinopril 40 mg tablets

1. Name Of The Medicinal Product

Lisinopril 40 mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 40 mg anhydrous lisinopril (as lisinopril dihydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

40 mg tablets are light yellow coloured, capsule shaped, biconvex, uncoated tablets, debossed with 'L' on one side and on other side with '40'.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypertension

Treatment of hypertension.

4.2 Posology And Method Of Administration

Lisinopril should be administered orally in a single daily dose. As with all other medication taken once daily, Lisinopril should be taken at approximately the same time each day. The absorption of Lisinopril tablets is not affected by food.

The dose should be individualised according to patient profile and blood pressure response (see section 4.4).

Hypertension

Lisinopril may be used as monotherapy or in combination with other classes of antihypertensive therapy.

Starting dose

In patients with hypertension the usual recommended starting dose is 10 mg. Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt and /or volume depletion, cardiac decompensation, or severe hypertension) may experience an excessive blood pressure fall following the initial dose. A starting dose of 2.5-5 mg is recommended in such patients and the initiation of treatment should take place under medical supervision. A lower starting dose is required in the presence of renal impairment (see Table 1 below).

Maintenance dose

The usual effective maintenance dosage is 20 mg administered in a single daily dose. In general if the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks on a certain dose level, the dose can be further increased. The maximum dose used in long-term, controlled clinical trials was 80 mg/day.

Diuretic-Treated Patients

Symptomatic hypotension may occur following initiation of therapy with Lisinopril. This is more likely in patients who are being treated currently with diuretics. Caution is recommended therefore, since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Lisinopril. In hypertensive patients in whom the diuretic cannot be discontinued, therapy with Lisinopril should be initiated with a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Lisinopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed (see section 4.4 and section 4.5).

Dosage Adjustment In Renal Impairment

Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table 1 below.

Table 1 Dosage adjustment in renal impairment.

Creatinine Clearance (ml/min)	Starting Dose (mg/day)
Less than 10 ml/min (including patients on dialysis)	2.5 mg*
10-30 ml/min	2.5-5 mg
31-80 ml/min	5-10 mg

* Dosage and/or frequency of administration should be adjusted depending on the blood pressure response.

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

Use in Hypertensive Paediatric Patients aged 6-16 years

The recommended initial dose is 2.5 mg once daily in patients 20 to <50 kg, and 5 mg once daily in patients

In children with decreased renal function, a lower starting dose or increased dosing interval should be considered.

Heart Failure

In patients with symptomatic heart failure, Lisinopril should be used as adjunctive therapy to diuretics and, where appropriate, digitalis or beta-blockers. Lisinopril may be initiated at a starting dose of 2.5 mg once a day, which should be administered under medical supervision to determine the initial effect on the blood pressure. The dose of Lisinopril should be increased:

- By increments of no greater than 10 mg

- At intervals of no less than 2 weeks

- To the highest dose tolerated by the patient up to a maximum of 35 mg once daily

Dose adjustment should be based on the clinical response of individual patients.

Patients at high risk of symptomatic hypotension e.g. patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy should have these conditions corrected, if possible, prior to therapy with Lisinopril. Renal function and serum potassium should be monitored (see section 4.4).

Acute Myocardial Infarction

Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Intravenous or transdermal glyceryl trinitrate may be used together with Lisinopril.

Starting dose (first 3 days after infarction)

Treatment with Lisinopril may be started within 24 hours of the onset of symptoms. Treatment should not be started if systolic blood pressure is lower than 100 mm Hg. The first dose of Lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily. Patients with a low systolic blood pressure (120 mm Hg or less) when treatment is started or during the first 3 days after the infarction should be given a lower dose - 2.5 mg orally (see section 4.4).

In cases of renal impairment (creatinine clearance <80 ml/min), the initial Lisinopril dosage should be adjusted according to the patient's creatinine clearance (see Table 1).

Maintenance dose

The maintenance dose is 10 mg once daily. If hypotension occurs (systolic blood pressure less than or equal to 100 mm Hg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mm Hg for more than 1 hour) Lisinopril should be withdrawn.

Treatment should continue for 6 weeks and then the patient should be re-evaluated. Patients who develop symptoms of heart failure should continue with Lisinopril (see section 4.2).

Renal Complications of Diabetes Mellitus

In hypertensive patients with type 2 diabetes mellitus and incipient nephropathy, the dose is 10 mg Lisinopril once daily which can be increased to 20 mg once daily, if necessary, to achieve a sitting diastolic blood pressure below 90 mm Hg.

In cases of renal impairment (creatinine clearance <80 ml/min), the initial Lisinopril dosage should be adjusted according to the patient's creatinine clearance (see Table 1).

Paediatric Use

There is limited efficacy and safety experience in hypertensive children >6 years old, but no experience in other indications (see section 5.1). Lisinopril is not recommended in children in other indications than hypertension.

Lisinopril is not recommended in children below the age of 6, or in children with severe renal impairment (GFR <30ml/min/1.73m²)(see section 5.2).

Use In The Elderly

In clinical studies, there was no age-related change in the efficacy or safety profile of the drug. When advanced age is associated with decrease in renal function, however, the guidelines set out in Table 1 should be used to determine the starting dose of Lisinopril. Thereafter, the dosage should be adjusted according to the blood pressure response.

Use in kidney transplant patients

There is no experience regarding the administration of Lisinopril in patients with recent kidney transplantation. Treatment with Lisinopril is therefore not recommended.

4.3 Contraindications

- Hypersensitivity to Lisinopril, to any of the excipients or any other angiotensin converting enzyme (ACE) inhibitor.

- History of angioedema associated with previous ACE inhibitor therapy

- Hereditary or idiopathic angioedema.

- Second and third trimester of pregnancy (see sections 4.4 and 4.6).

4.4 Special Warnings And Precautions For Use

Symptomatic Hypotension

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving Lisinopril, hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see section 4.5 and section 4.8). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Lisinopril. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Lisinopril may be necessary.

Hypotension In Acute Myocardial Infarction

Treatment with Lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100 mm Hg or lower or those in cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mm Hg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour) then Lisinopril should be withdrawn.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, Lisinopril should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

Renal Function Impairment

In cases of renal impairment (creatinine clearance <80 ml/min), the initial Lisinopril dosage should be adjusted according to the patient's creatinine clearance (see Table 1 in section 4.2) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.

In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral renal artery stenosis or with a stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of Lisinopril therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril may be required.

In acute myocardial infarction, treatment with Lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/l and/or proteinuria exceeding 500 mg/24 h. If renal dysfunction develops during treatment with Lisinopril (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril.

Hypersensitivity/Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported uncommonly in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril. This may occur at any time during therapy. In such cases, Lisinopril should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

Anaphylactoid reactions in Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Desensitisation

Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product.

Hepatic failure

Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving Lisinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue Lisinopril and receive appropriate medical follow-up.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Lisinopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Lisinopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Race

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.

As with other ACE inhibitors, Lisinopril may be less effective in lowering blood pressure in black patients than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Lisinopril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see 4.5 Interaction with other medicinal products and other forms of interaction).

Lithium

The combination of lithium and Lisinopril is generally not recommended (see section 4.5).

Pregnancy and lactation

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Use of lisinopril is not recommended during breast-feeding (see section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Diuretics

When a diuretic is added to the therapy of a patient receiving Lisinopril the antihypertensive effect is usually additive.

Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when Lisinopril is added. The possibility of symptomatic hypotension with Lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with Lisinopril (see section 4.4 and section 4.2).

Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes

Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.

If Lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of Lisinopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Non steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.

Gold

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

Other antihypertensive agents

Concomitant use of these agents may increase the hypotensive effects of Lisinopril. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.

Tricyclic antidepressants / Antipsychotics /Anaesthetics

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates.

4.6 Pregnancy And Lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4).The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitors therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of Lisinopril during breastfeeding, Lisinopril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.

4.8 Undesirable Effects

The following undesirable effects have been observed and reported during treatment with Lisinopril and other ACE inhibitors with the following frequencies: Very common (

Blood and the lymphatic system disorders:
rare:	decreases in haemoglobin, decreases in haematocrit.
very rare:	bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease.
Metabolism and nutrition disorders
very rare:	hypoglycaemia
Nervous system and psychiatric disorders:
common:	dizziness, headache
uncommon:	mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances.
rare:	mental confusion, olfactory disturbance
frequency not known:	depressive symptoms, syncope
Cardiac and vascular disorders:
common:	orthostatic effects (including hypotension)
uncommon:	myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see section 4.4), palpitations , tachycardia. Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders:
common:	cough
uncommon:	rhinitis
very rare:	bronchospasm, sinusitis. Allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal disorders:
common:	diarrhoea, vomiting
uncommon:	nausea, abdominal pain and indigestion
rare:	dry mouth
very rare:	pancreatitis, intestinal angioedema, hepatitis - either hepatocellular or cholestatic, jaundice and hepatic failure (see section 4.4)
Skin and subcutaneous tissue disorders:
uncommon:	rash, pruritus, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4)
rare:	urticaria, alopecia, psoriasis
very rare:	diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma.

A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Renal and urinary disorders:
common:	renal dysfunction
rare:	uraemia, acute renal failure
very rare:	oliguria/anuria
Endocrine disorders:
Frequency not known:	inappropriate antidiuretic hormone secretion.
Reproductive system and breast disorders:
uncommon:	impotence
rare:	gynaecomastia
General disorders and administration site conditions:
uncommon:	fatigue, asthenia
Investigations:
uncommon:	increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia.
rare:	increases in serum bilirubin, hyponatraemia.

Safety data from clinical studies suggest that lisinopril is generally well tolerated in hypertensive paediatric patients, and that the safety profile in this age group is comparable to that seen in adults.

4.9 Overdose

Limited data are available for overdose in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

The recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, take measures aimed at eliminating Lisinopril (e.g., emesis, gastric lavage, administration of absorbents and sodium sulphate). Lisinopril may be removed from the general circulation by haemodialysis (see 4.4 special warning and precautions for use). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors, ATC code: C09A A03.

Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may result in an increase in serum potassium concentration.

Whilst the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.

The effect of lisinopril on mortality and morbidity in heart failure has been studied by comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or 5 mg once daily). In a study of 3164 patients, with a median follow up period of 46 months for surviving patients, high dose lisinopril produced a 12% risk reduction in the combined endpoint of all-cause mortality and all-cause hospitalisation (p = 0.002) and an 8% risk reduction in all-cause mortality and cardiovascular hospitalisation (p = 0.036) compared with low dose. Risk reductions for all-cause mortality (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a post-hoc analysis, the number of hospitalisations for heart failure was reduced by 24% (p=0.002) in patients treated with high-dose lisinopril compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of lisinopril.

The results of the study showed that the overall adverse event profiles for patients treated with high or low dose lisinopril were similar in both nature and number. Predictable events resulting from ACE inhibition, such as hypotension or altered renal function, were manageable and rarely led to treatment withdrawal. Cough was less frequent in patients treated with high dose lisinopril compared with low dose.

In the GISSI-3 trial, which used a 2x2 factorial design to compare the effects of lisinopril and glyceryl trinitrate given alone or in combination for 6 weeks versus control in 19,394, patients who were administered the treatment within 24 hours of an acute myocardial infarction, lisinopril produced a statistically significant risk reduction in mortality of 11% versus control (2p=0.03). The risk reduction with glyceryl trinitrate was not significant but the combination of lisinopril and glyceryl trinitrate produced a significant risk reduction in mortality of 17% versus control (2p=0.02). In the sub-groups of elderly (age > 70 years) and females, pre-defined as patients at high risk of mortality, significant benefit was observed for a combined endpoint of mortality and cardiac function. The combined endpoint for all patients, as well as the high-risk sub-groups, at 6 months also showed significant benefit for those treated with lisinopril or lisinopril plus glyceryl trinitrate for 6 weeks, indicating a prevention effect for lisinopril. As would be expected from any vasodilator treatment, increased incidences of hypotension and renal dysfunction were associated with lisinopril treatment but these were not associated with a proportional increase in mortality.

In a double-blind, randomised, multicentre trial which compared lisinopril with a calcium channel blocker in 335 hypertensive Type 2 diabetes mellitus subjects with incipient nephropathy characterised by microalbuminuria, lisinopril 10 mg to 20 mg administered once daily for 12 months, reduced systolic/diastolic blood pressure by 13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a similar reduction in blood pressure, those treated with lisinopril showed a significantly greater reduction in urinary albumin excretion rate, providing evidence that the ACE inhibitory action of lisinopril reduced microalbuminuria by a direct mechanism on renal tissues in addition to its blood pressure lowering effect.

Lisinopril treatment does not affect glycaemic control as shown by a lack of significant effect on levels of glycated haemoglobin (HbA_1c).

In a clinical study involving 115 paediatric patients with hypertension, aged 6-16 years, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or 20 mg of lisinopril once a day, and patients who weighed 50 kg or more received either 1.25 mg, 5 mg or 40 mg of lisinopril once a day. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with a consistent antihypertensive efficacy demonstrated at doses greater than 1.25 mg.

This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mm Hg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and race.

5.2 Pharmacokinetic Properties

Lisinopril is an orally active non-sulphydryl-containing ACE inhibitor.

Absorption

Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25% with interpatient variability of 6-60% over the dose range studied (5-80 mg). The absolute bioavailability is reduced approximately 16% in patients with heart failure. Lisinopril absorption is not affected by the presence of food.

Distribution

Lisinopril does not appear to be bound to serum proteins other than to circulating angiotensin converting enzyme (ACE). Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

Elimination

Lisinopril does not undergo metabolism and is excreted entirely unchanged into the urine On multiple dosing lisinopril has an effective half-life of accumulation of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 ml/min. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose.

Hepatic impairment

Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about 30% as determined by urinary recovery) but an increase in exposure (approximately 50%) compared to healthy subjects due to decreased clearance.

Renal impairment

Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 ml/min. In mild to moderate renal impairment (creatinine clearance 30-80 ml/min) mean AUC was increased by 13% only, while a 4.5- fold increase in mean AUC was observed in severe renal impairment (creatinine clearance 5-30 ml/min).

Lisinopril can be removed by dialysis. During 4 hours of haemodialysis, plasma lisinopril concentrations decreased on average by 60%, with a dialysis clearance between 40 and 55 ml/min.

Heart failure

Patients with heart failure have a greater exposure of lisinopril when compared to healthy subjects (an increase in AUC on average of 125%), but based on the urinary recovery of lisinopril, there is reduced absorption of approximately 16% compared to healthy subjects.

Paediatrics

The pharmacokinetic profile of

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• Ask your pharmacist if you need more information or advice.


• You must contact a doctor if your symptoms worsen or do not improve after 3 days.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What LIQUIFILM TEARS is and what it is used for


• 2. Before you use LIQUIFILM TEARS


• 3. How to use LIQUIFILM TEARS


• 4. Possible side effects


• 5. How to store LIQUIFILM TEARS


• 6. Further information

What Liquifilm Tears Is And What It Is Used For

LIQUIFILM TEARS is a substitute for tears and contains a lubricant called polyvinyl alcohol. It is an eye drops solution used for the relief of the symptoms of dry eye (such as soreness, burning, irritation or dryness) caused by your eyes not producing enough tears.

Before You Use Liquifilm Tears

Do NOT use LIQUIFILM TEARS:

• 
  if you are allergic (hypersensitive) to polyvinyl alcohol or any of the other ingredients of LIQUIFILM TEARS listed in Section 6, “What LIQUIFILM TEARS contains”.


• 
  while you are wearing soft contact lenses: you must remove them before using LIQUIFILM TEARS eye drops. After using LIQUIFILM TEARS, wait at least 15 minutes before putting your lenses back in. See also in Section 2, “Important information about some of the ingredients of LIQUIFILM TEARS”.

Take special care with LIQUIFILM TEARS:

Stop using LIQUIFILM TEARS and contact your doctor if:

• you experience long-lasting redness or irritation of the eye, eye pain, changes in vision


• your condition worsens or has not improved 3 days after having started treatment with LIQUIFILM TEARS.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

If you have to use any other eye medicine during treatment with LIQUIFILM TEARS: first use the other eye medicine, wait 15 minutes, then use LIQUIFILM TEARS.

Pregnancy and breast-feeding

You can use LIQUIFILM TEARS if you are pregnant and when you are breast-feeding.

Driving and using machines

Your sight may become blurred for a short time just after using LIQUIFILM TEARS. You should not drive or use machines until your sight is clear again.

Important information about some of the ingredients of LIQUIFILM TEARS

If you wear soft contact lenses you must remove them before using LIQUIFILM TEARS eye drops. After using LIQUIFILM TEARS, you have to wait at least 15 minutes before putting your lenses back in.

This is important because one of the ingredients of LIQUIFILM TEARS, called benzalkonium chloride, may cause eye irritation and can change the colour of soft contact lenses.

How To Use Liquifilm Tears

If LIQUIFILM TEARS has been recommended for you then use it exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The usual dose of LIQUIFILM TEARS is 1 or 2 drops in each eye that needs treatment as often as you feel the need.

Instructions for use

Do not use the bottle if the seal around the cap is broken before you first open it.

Wash your hands before opening the bottle. Tilt your head back and look at the ceiling.

• 1. Gently pull down the lower eyelid of the eye that needs treatment until there is a small “pocket”.


• 2. Turn the bottle upside down. Squeeze it to release 1 drop into the “pocket”.


• 3. Let go of the lower lid, and blink your eyes a few times. For a second drop repeat the steps 2 and 3.


• 4. Repeat the steps 1 to 3 for the other eye, if it also needs treatment.

If a drop misses your eye, try again.

To help prevent infection, do not let the tip of the bottle touch your eye, the surrounding tissue or anything else. Put the screw-cap back on to close the bottle, straight after you have used it. Once you have opened the bottle, you must not use it longer than 28 days; please see also Section 5, “How to store LIQUIFILM TEARS”.

If you use more LIQUIFILM TEARS than you should

Using more drops of LIQUIFILM TEARS than you should will not cause you any harm.

If you forget to use LIQUIFILM TEARS

If you have missed a dose of LIQUIFILM TEARS continue with your next dose as normal.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Liquifilm Tears Side Effects

Like all medicines, LIQUIFILM TEARS can cause side effects, although not everybody gets them.

Stop using LIQUIFILM TEARS and contact your doctor if:

• you experience long-lasting redness or irritation of the eye, eye pain, changes in vision


• your condition worsens or has not improved 3 days after having started treatment with LIQUIFILM TEARS.

If you experience any of the following side effects just after putting in the drops, talk to your doctor if they worry you:

• eye pain, eye irritation or feeling of burning in the eye, redness of the eyes, an excess of tears, feeling of something in the eye, an allergic reaction in the eye.

The above mentioned side effects are known to occur, but the number of people likely to be affected can vary.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Liquifilm Tears

Keep out of the reach and sight of children.

Do not use LIQUIFILM TEARS after the expiry date which is stated on the bottle label and the carton after ‘EXP.’. The expiry date refers to the last day of that month.

Do not store above 25°C. Do not refrigerate or freeze.

You must throw away the bottle 28 days after you first opened it, even if there are still some drops left.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What LIQUIFILM TEARS contains

• The active ingredient is polyvinyl alcohol 1.4% w/v.


• The other ingredients are benzalkonium chloride, sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic, edetate disodium, hydrochloric acid or sodium hydroxide (to adjust pH) and purified water.

What LIQUIFILM TEARS looks like and contents of the pack

LIQUIFILM TEARS is a solution in a plastic bottle with a screw-cap. Each bottle contains 15 ml of solution.

Each pack contains 1 bottle.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Allergan Ltd

Marlow International

The Parkway

Marlow

Bucks

SL7 1YL

UK

Tel:01628 494026

Fax:01628 494057

Email:uk_medinfo@allergan.com

Manufacturer:

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

County Mayo

Ireland

This leaflet was last approved in July 2009.

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge: 0800 198 5000 (UK only).

Please be ready to give the following information: Polyvinyl alcohol 1.4% w/v reference number PL 00426/0009R.

This is a service provided by the Royal National Institute of the Blind.

Laxido Orange, powder for oral solution, sugar-free

1. Name Of The Medicinal Product

Laxido Orange, powder for oral solution.

2. Qualitative And Quantitative Composition

Each sachet contains the following quantitative composition of active ingredients:

Macrogol 3350 13.125g

Sodium Chloride 350.7mg

Sodium Hydrogen Carbonate 178.5mg

Potassium Chloride 46.6mg

The content of electrolyte ions per sachet following reconstitution in 125ml of water is equivalent to:

Sodium 65mmol/l

Chloride 53mmol/l

Hydrogen Carbonate (Bicarbonate) 17mmol/l

Potassium 5.4mmol/l

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for oral solution. Single-dose sachet containing a free flowing white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of chronic constipation. Laxido Orange is also effective in resolving faecal impaction, defined as refractory constipation with faecal loading of the rectum and/or colon.

4.2 Posology And Method Of Administration

Laxido Orange is for oral use.

Chronic Constipation:

A course of treatment for chronic constipation with Laxido Orange does not normally exceed 2 weeks, although this can be repeated if required. As for all laxatives, prolonged use is not usually recommended. Extended use may be necessary in the care of patients with severe chronic or resistant constipation, secondary to multiple sclerosis or Parkinson's Disease, or induced by regular constipating medication in particular opioids and antimuscarinics.

Adults, adolescents and the elderly: 1-3 sachets daily in divided doses, according to individual response. For extended use, the dose can be adjusted down to 1 or 2 sachets daily.

Children below 12 years old: Not recommended.

Faecal Impaction:

A course of treatment for faecal impaction with Laxido Orange does not normally exceed 3 days.

Adults, adolescents and the elderly: 8 sachets daily, all of which should be consumed within a 6 hour period.

Children below 12 years old: Not recommended.

Patients with impaired cardiovascular function: For the treatment of faecal impaction the dose should be divided so that no more than 2 sachets are taken in any one hour.

Patients with renal insufficiency: No dosage change is necessary for the treatment of constipation or faecal impaction.

Administration:

Each sachet should be dissolved in 125 ml water. For use in faecal impaction, 8 sachets may be dissolved in 1 litre of water.

4.3 Contraindications

Laxido Orange is contraindicated in intestinal obstruction or perforation caused by functional or structural disorder of the gut wall, ileus and in patients with severe inflammatory conditions of the intestinal tract (e.g. ulcerative colitis, Crohn's disease and toxic megacolon).

Hypersensitivity to the active substances or any of the excipients.

4.4 Special Warnings And Precautions For Use

The faecal impaction diagnosis should be confirmed by appropriate physical or radiological examination of the rectum and abdomen.

Mild adverse drug reactions are possible as indicated in Section 4.8. If patients develop any symptoms indicating shifts of fluids/electrolytes (e.g. oedema, shortness of breath, increasing fatigue, dehydration, cardiac failure) Laxido Orange should be stopped immediately and electrolytes measured and any abnormality should be treated appropriately.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no known interactions of Laxido Orange with other medicinal products. However, macrogol 3350 raises the solubility of medicinal products that are soluble in alcohol and mainly insoluble in water. It is a theoretical possibility that absorption of these drugs could be reduced transiently. Therefore, other medicines should not be taken orally for one hour before and for one hour after taking Laxido Orange.

4.6 Pregnancy And Lactation

There is no experience with the use of Laxido Orange during pregnancy and lactation and it should not be used during pregnancy and lactation unless clearly necessary.

4.7 Effects On Ability To Drive And Use Machines

Laxido Orange has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

Immune System Disorders:

Allergic reactions are possible.

Gastro-intestinal Disorders:

Potential gastro-intestinal effects that may occur include abdominal distension and pain, borborygmi and nausea. Mild diarrhoea may also occur, but normally resolves after dose reduction.

4.9 Overdose

Severe distension or pain can be treated using nasogastric aspiration. Vomiting or diarrhoea may induce extensive fluid loss, possibly leading to electrolyte disturbances that should be treated appropriately.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Osmotically acting laxatives.

ATC code: A06A D65

Macrogol 3350 induces a laxative effect through its osmotic action in the gut. This product also contains electrolytes to ensure that there is no overall gain or loss of water, potassium or sodium.

Clinical studies using the listed active substances for the treatment of chronic constipation have shown that the dose required to produce normally formed stools tends to decrease over time. For most patients, the maintenance dose will be one to two sachets per day (adjusted according to individual response).

Comparative studies in faecal impaction using active controls (e.g. enemas) have not been performed. However, results from a non-comparative study have shown that, from a population of 27 adult patients, the listed combination of active substances cleared faecal impaction in 12/27 (44%) patients after one day's treatment, increasing to 23/27 (85%) following two days' treatment and 24/27 (89%) recovered at the end of three days.

5.2 Pharmacokinetic Properties

Macrogol 3350 is virtually unabsorbed from the gastro-intestinal tract and is excreted, unaltered, in faeces. Any macrogol 3350 that enters the systemic circulation is excreted in urine.

5.3 Preclinical Safety Data

Preclinical studies provide evidence that macrogol 3350 has no significant systemic toxicity potential, although no tests of its effects on reproduction or genotoxicity have been conducted.

There are no long-term animal toxicity or carcinogenicity studies involving macrogol 3350, although there are toxicity studies using high levels of orally administered high-molecular weight macrogols that provide evidence of safety at the recommended therapeutic dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Acesulfame Potassium (E950)

Orange Flavour

(Orange flavour contains the following constituents: natural flavouring substances and preparations, maltodextrin and propylene glycol [E1520])

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Sachet: Two years.

Reconstituted solution: Six hours.

6.4 Special Precautions For Storage

Sachet: Store below 25°C.

Reconstituted solution: Store covered in a refrigerator (2°C to 8°C).

6.5 Nature And Contents Of Container

The sachet is composed of paper, low density polyethylene and aluminium.

Sachets are packed in cartons of 2, 8, 10, 20, 30, 50 and 100.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Galen Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

UK

8. Marketing Authorisation Number(S)

PL 21590/0087.

9. Date Of First Authorisation/Renewal Of The Authorisation

01 May 2008.

10. Date Of Revision Of The Text

10 February 2010

Lemsip Max Cold and Flu Capsules

1. Name Of The Medicinal Product

Lemsip Max Cold & Flu Capsules

2. Qualitative And Quantitative Composition

Active ingredients	mg/capsule	Specification
Paracetamol	500	Ph Eur
Caffeine	25	Ph.Eur
Phenylephrine hydrochloride	6.1	Ph Eur

3. Pharmaceutical Form

Red/yellow hard gelatine capsules

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of symptoms associated with the common cold and influenza, including relief of aches and pains, sore throat, headache, fatigue and drowsiness, nasal congestion, and lowering of temperature.

4.2 Posology And Method Of Administration

Adults and children 12 years and over:

Two capsules every 4-6 hours to a maximum of 4 doses in any 24 hours.

Do not exceed 8 capsules in any 24 hours.

Swallow whole with water. Do not chew.

Do not give to children under 12 years.

4.3 Contraindications

Paracetamol: Hypersensitivity to paracetamol or any of the other constituents.

Caffeine: Should be given with care to patients with a history of peptic ulcer.

Phenylephrine hydrochloride: Severe coronary heart disease and cardiovascular disorders. Hypertension. Hyperthyroidism. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors.

4.4 Special Warnings And Precautions For Use

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Use with caution in patients with Raynaud's Phenomenon and diabetes mellitus.

Phenylephrine

Phenylephrine should be used with care in patients with cardiovascular disease, diabetes mellitus, closed angle glaucoma, prostatic enlargement and hypertension.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paracetamol

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Medicinal products which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdose.

Phenylephrine hydrochloride

Monoamine oxidase inhibitors (including moclobemide): hypertensive interactions occur between sympathomimetic amines such as phenylephrine and monoamine oxidase inhibitors (see section 4.3).

Sympathomimetic amines: concomitant use of phenylephrine with other sympathomimetic amines can increase the risk of cardiovascular side effects.

Beta-blockers and other antihypertensives (including debrisoquine, guanethidine, reserpine, methyldopa): phenylephrine may reduce the efficacy of beta-blockers and antihypertensives. The risk of hypertension and other cardiovascular side effects may be increased (see section 4.3).

Tricyclic antidepressants (e.g. amitriptyline): may increase the risk of cardiovascular side effects with phenylephrine (see section 4.3).

Digoxin and cardiac glycosides: concomitant use of phenylephrine may increase the risk of irregular heartbeat or heart attack.

Caffeine

Caffeine undergoes extensive metabolism by hepatic microsomal cytochrome P450, factors known to alter the activity of this enzyme system may influence caffeine clearance. Thus, caffeine elimination is enhanced in cigarette smokers and inhibited by cimetidine, disulfiram, and oral contraceptive steroids.

4.6 Pregnancy And Lactation

Paracetamol

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breastfeeding.

Caffeine

Taken during pregnancy it appears that the half-life of caffeine is prolonged. This is a possible contributing factor in hyperemesis gravidarum.

Phenylephrine hydrochloride

The safety of this medicine during pregnancy and lactaction has not been established but in view of a possible association of foetal abnormalities with first trimester exposure to phenylephrine, the use of the product during pregnancy should be avoided. In addition, because phenylephrine may reduce placental perfusion, the product should not be used in patients with a history of pre-eclampsia. In view of the lack of data on the use of phenylephrine during lactation, this medicine should not be used during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Lemsip Max Cold & Flu Capsules has no or negligible influence on ability to drive or use machinery.

4.8 Undesirable Effects

Paracetamol

Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur. There have been a few reports of blood dyscrasias including thrombocytopenia, leucopenia, pancytopenia, neutropenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Acute pancreatitis after ingestion of above normal amounts.

Phenylephrine hydrochloride

High blood pressure with headache and vomiting, probably only in overdose. Rarely, palpitations. Also, rare reports of allergic reactions and occasionally urinary retention in males.

Caffeine

The most commonly reported adverse events following dosing with caffeine are GI irritation and CNS stimulation. Adverse CNS effects include insomnia, restlessness, nervousness and mild delirium; adverse GI effects include nausea, vomiting and gastric irritation

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g of more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors

If the patient:

(a) Is on long-term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

(b) Regularly consumes ethanol in excess of recommended amounts.

Or

(c) Is likely to be glutathione depleted, e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines. See BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit.

Caffeine

Symptoms - emesis and convulsions may occur. No specific antidote. However, treatment is usually fluid therapy. Fatal poisoning is rare. If symptoms become apparent or overdose is suspected, consult a doctor immediately.

Phenylephrine hydrochloride

Features of severe overdose of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression. Treatment includes early gastric lavage and symptomatic and supportive measures. Hypertensive effects may be treated with an i.v. alpha-receptor blocking agent.

Phenylephrine overdose is likely to result in: nervousness, headache, dizziness, insomnia, increased blood pressure, nausea, vomiting, mydriasis, acute angle closure glaucoma (most likely to occur in those with closed angle glaucoma), tachycardia, palpitations, allergic reactions (e.g. rash, urticaria, allergic dermatitis), dysuria, urinary retention (most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy).

Additional symptoms may include, hypertension, and possibly reflex bradycardia. In severe cases confusion, hallucinations, seizures and arrhythmias may occur. However the amount required to produce serious phenylephrine toxicity would be greater than that required to cause paracetamol-related liver toxicity.

Treatment should be as clinically appropriate. Severe hypertension may need to be treated with alpha blocking medicinal products such as phentolamine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol: Paracetamol has both analgesic and antipyretic activity which is believed to be mediated principally through its inhibition of prostaglandin synthesis within the central nervous system.

Caffeine: Caffeine is a central nervous system stimulant. It inhibits the enzyme phosphodiesterase and has an antagonistic effect at central adenosine receptors. Its action on the central nervous system is mainly on the higher centres and it produces a condition of wakefulness and increased mental activity.

Phenylephrine hydrochloride: Phenylephrine is a post-synaptic *-receptor agonist with low cardioselective *-receptor affinity and minimal central stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

5.2 Pharmacokinetic Properties

Paracetamol: Paracetamol is absorbed rapidly and completely mainly from the small intestine, producing peak plasma levels after 15-20 minutes following oral dosing. The systemic availability is subject to first-pass metabolism and varies with dose between 70% and 90%. The drug is rapidly and widely distributed throughout the body and is eliminated from plasma with a T_½ of approximately 2 hours. The major metabolites are glucuronide and sulphate conjugates (>80%) which are excreted in urine.

Caffeine: Caffeine is absorbed readily from oral, rectal or parenteral administration, but absorption from the gastrointestinal tract may be erratic. There is little evidence of accumulation in any particular tissue. Caffeine passes readily into the central nervous system and into saliva. Concentrations have also been detected in breast milk. It is metabolised almost completely and is excreted in the urine as 1-methyluric acid, 1-methylxanthine and other metabolites, with only about 1% unchanged.

Phenylephrine hydrochloride: Phenylephrine is absorbed from the gastrointestinal tract, but has reduced bioavailability by the oral route due to first-pass metabolism. It retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of the nasal mucosa. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Starch

croscarmellose sodium

sodium lauryl sulphate

magnesium stearate

talc

gelatine

titanium dioxide (E171)

quinoline yellow (E104)

patent blue V (E131)

erythrosin (E127)

shellac

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store up to 25°C.

6.5 Nature And Contents Of Container

250 micron opaque uPVC blister with foil/paper laminate, 35 gsm paper/9 micron soft-temper foil and heat-seal coated, contained in an outer cardboard carton.

Pack sizes: 4, 6, 8, 10, 12, 14 and 16 capsules.

6.6 Special Precautions For Disposal And Other Handling

The capsules are to be taken orally, with water if preferred, and swallowed whole without being chewed.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited,

Dansom Lane,

Hull,

HU8 7DS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00063/0104.

9. Date Of First Authorisation/Renewal Of The Authorisation

16/03/2009

10. Date Of Revision Of The Text

10/08/2011

Letrozole 2.5mg film-coated tablets (Zentiva)

1. Name Of The Medicinal Product

Letrozole 2.5 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each tablet contains 2.5 mg letrozole.

Excipient: each tablet contains 61.5 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Yellow film-coated round biconvex tablets, debossed with L9OO on one side and 2.5 on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

• Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

• Extended adjuvant treatment of hormone-dependent early breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy for 5 years.

• First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer.

• Advanced breast cancer in women with natural or artificially induced postmenopausal status after relapse or disease progression, who have previously been treated with anti-oestrogens.

Efficacy has not been demonstrated in patients with hormone-receptor negative breast cancer.

4.2 Posology And Method Of Administration

Adults and elderly patients

The recommended dose of letrozole is 2.5 mg once daily. No dose adjustment is required for elderly patients.

In the adjuvant setting, it is recommended to treat for 5 years or until tumour relapse occurs. In the adjuvant setting, clinical experience is available for 2 years (median duration of treatment was 25 months).

In the extended adjuvant setting, clinical experience is available for 4 years (median duration of treatment).

In patients with advanced or metastatic disease, treatment with letrozole should continue until tumour progression if evident.

Children

Not applicable.

Patients with hepatic and/or renal impairment

No dosage adjustment is required for patients with renal insufficiency with creatinine clearance greater than 30 ml/min.

Insufficient data are available in cases of renal insufficiency with creatinine clearance lower than 30 ml/min or in patients with severe hepatic insufficiency (see sections 4.4 and 5.2).

4.3 Contraindications

Letrozole is contraindicated in:

• Patients with known hypersensitivity to letrozole or to any of the excipients.

• Premenopausal endocrine status; pregnancy; lactation (see sections 4.6 and 5.3).

4.4 Special Warnings And Precautions For Use

In patients whose postmenopausal status seems unclear, LH, FSH and/or oestradiol levels must be assessed before initiating treatment in order to clearly establish menopausal status.

Renal impairment

Letrozole has not been investigated in a sufficient number of patients with a creatinine clearance lower than 10 ml/min. The potential risk/benefit to such patients should be carefully considered before administration of letrozole.

Hepatic impairment

Letrozole has only been studied in a limited number of non-metastatic patients with varying degrees of hepatic function: mild to moderate, and severe hepatic insufficiency. In non-cancer male volunteers with severe hepatic impairment (liver cirrhosis and Child-Pugh score C), systemic exposure and terminal half-life were increased 2-3 fold compared to healthy volunteers. Thus, letrozole should be administered with caution and after careful consideration of the potential risk/benefit to such patients (see section 5.2).

Bone effects

Letrozole is a potent oestrogen-lowering agent. In the adjuvant and extended adjuvant setting the median follow-up duration of 30 and 49 months respectively is insufficient to fully assess fracture risk associated with long term use of letrozole. Women with a history of osteoporosis and/or fractures or who are at increased risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry prior to the commencement of adjuvant and extended adjuvant treatment and be monitored for development of osteoporosis during and following treatment with letrozole. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored (see section 4.8).

Letrozole tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.

Additionally, a review of the clinical trial database indicated no evidence of clinically relevant interactions with other commonly prescribed drugs.

There is no clinically experience to date on the use of letrozole in combination with other anticancer agents.

In vitro, letrozole inhibits the cytochrome P450 isoenzyme 2A6 and, moderately, 2C19. Thus, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow.

4.6 Pregnancy And Lactation

Women of perimenopausal status or child-bearing potential

The physician needs to discuss the necessity of a pregnancy test before initiating letrozole and of adequate contraception with women who have the potential to become pregnant (i.e. women who are perimenopausal or who recently became postmenopausal) until their postmenopausal status is fully established (see sections 4.4 and 5.3).

Pregnancy

Letrozole is contraindicated during pregnancy (see sections 4.3 and 5.3).

Lactation

Letrozole is contraindicated during lactation (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Fatigue and dizziness have been observed with the use of letrozole and somnolence has been reported uncommonly. Therefore, caution is advised when driving or using machines.

4.8 Undesirable Effects

Letrozole was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer and as adjuvant treatment of early breast cancer. Up to approximately one third of the patients treated with letrozole in the metastatic setting, up to approximately 70-75% of the patients in the adjuvant setting (both letrozole and tamoxifen arms), and up to approximately 40% of the patients treated in the extended adjuvant setting (both letrozole and placebo arms) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature. Most adverse reactions can be attributed to normal pharmacological consequences of oestrogen deprivation (e.g hot flushes).

The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia, nausea, and fatigue. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g hot flushes, alopecia and vaginal bleeding).

After standard adjuvant tamoxifen, based on median follow-up of 28 months, the following adverse events irrespective of causality were reported significantly more often with letrozole than with placebo- hot flushes (50.7% vs. 44.3%), arthralgia/arthritis (28.5% vs. 23.2%) and myalgia (10.2%vs. 7.0%). The majority of these adverse events were observed during the first year of treatment. There was a higher but non significant incidence of osteoporosis and bone fractures in patients who received letrozole than in patients who received placebo (7.5% vs. 6.3% and 6.7% vs. 5.9%, respectively).

In an updated analysis in the extended adjuvant setting conducted at a median treatment duration of 47 months for letrozole and 28 months for placebo, the following adverse events irrespective of causality were reported significantly more often with letrozole than with placebo: hot flushes (60.3% vs. 52.6%), arthralgia/arthritis (37.9% vs. 26.8%) and myalgia (15.8% vs. 8.9%). The majority of these adverse events were observed during the first year of treatment. In the patients in placebo arm who switched to letrozole a similar pattern of general events was observed. There was a higher incidence of osteoporosis and bone fractures, any time after randomisation, in patients who received letrozole than in patients who received placebo (12.3% vs. 7.4% and 10.9% vs. 7.2%, respectively). In patients who switched to letrozole, newly diagnosed osteoporosis, any time after switching, was reported in 3.6% of patients while fracture were reported in 5.1% of patients any time after switching.

In the adjuvant setting, irrespective of causality, the following adverse events occurred any time after randomization in the letrozole and tamoxifen groups respectively: thromboembolic events (1.5% vs. 3.2%, P<0.001), angina pectoris (0.8% vs. 0.8%,), myocardial infarction (0.7% vs. 0.4%) and cardiac failure (0.9% vs 0.4%, p=0.006).

The following adverse drug reactions, listed in Table 1 were reported from clinical studies and from post marketing experience with letrozole.

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention:

very common (

Table 1:

Infections and infestations
Uncommon:	Urinary tract infection
Neoplasms, benign, malignant and unspecified (including cysts and polyps)
Uncommon:	Tumour pain (not applicable in the adjuvant and extended adjuvant setting)
Blood and the lymphatic system disorders
Uncommon:	Leukopenia
Metabolism and nutrition disorders
Common:	Anorexia, appetite increase, hypercholesterolaemia
Uncommon:	General oedema
Psychiatric disorders
Common:	Depression
Uncommon:	Anxiety (including nervousness), irritability
Nervous system disorders
Common:	Headache, dizziness
Uncommon:	Somnolence, insomnia, memory impairment, dysesthesia (including paresthesia and hypoesthesia), taste disturbance, cerebrovascular accident
Eye disorders
Uncommon:	Cataract, eye irritation, blurred vision
Cardiac disorders
Uncommon:	Palpitations, tachycardia
Vascular disorders
Uncommon:	Thrombophlebitis (including superficial and deep thrombophlebitis), hypertension, ischemic cardiac events
Rare:	Pulmonary embolism, arterial thrombosis, cerebrovascular infarction
Respiratory, thoracic and mediastinal disorders
Uncommon:	Dyspnoea, cough
Gastrointestinal disorders
Common:	Nausea, vomiting, dyspepsia, constipation, diarrhoea
Uncommon:	Abdominal pain, stomatitis, dry mouth
Hepatobiliary disorders
Uncommon:	Increased hepatic enzymes
Not known:	hepatitis
Skin and subcutaneous tissue disorders
Very common:	Increased sweating
Common:	Alopecia, rash (including erythematous, macullopapular, psoriaform, and vesicular rash)
Uncommon:	Pruritus, dry skin, urticaria
Not known:	Anaphylactic reaction, Angioedema, toxic epidermal necrolysis, erythema multiform
Musculoskeletal and connective tissue disorders
Very common:	Arthralgia
Common:	Myalgia, bone pain, osteoporosis, bone fractures
Uncommon:	Arthritis
Renal and urinary disorders
Uncommon:	Increased urinary frequency
Reproductive system and breast disorders
Uncommon:	Vaginal bleeding, vaginal discharge, vaginal dryness, breast pain
General disorders and administration site conditions
Very common:	Hot flushes, fatigue including asthenia
Common:	Malaise, peripheral oedema
Uncommon:	Pyrexia, mucosal dryness, thirst
Investigations
Common:	Weight increase
Uncommon:	Weight loss

4.9 Overdose

Isolated cases of overdosage with letrozole have been reported.

No specific treatment for overdosage is known. Treatment should be symptomatic and supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: enzyme inhibitors

ATC Code: L02B G04

Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent.

Pharmacodynamic effects

The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primary androstenedione and testosterone - to oestrone and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting aromatase enzyme.

Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all tissues where present.

In healthy postmenopausal women, single doses of 0.1, 0.5 and 2.5 mg letrozole suppresses serum oestrone and oestradiol by 75-78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78h.

In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress plasma concentration of oestradiol, oestrone, and oestrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of oestrone and oestrone sulphate are below the limit of detection in the assays, indicating that higher oestrogene suppression is achieved with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17- hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5 and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T4, and T3 uptake test.

Adjuvant treatment

A multicenter, double-blind study randomized over 8000 postmenopausal women with resected receptor-positive early breast cancer, to one of the following option:

Option 1:

A. tamoxifen for 5 years

B. letrozole for 5 years

C. tamoxifen for 2 years followed by letrozole for 3 years

D. letrozole for 2 years followed by tamoxifen for 3 years

Option 2:

A. tamoxifen for 5 years

B letrozole for 5 years

Data in Table 2 reflect results based on data from the monitoring arms in each randomization option and data from the two switching arms up to 30 days after the data of switch. The analysis of monotherapy vs sequencing of endocrine treatments will be conducted when the necessary number of events has been achieved.

Patients have been followed for a median of 26 months, 76% of the patients for more than 2 years, and 16% (1252 patients) for 5 years or longer.

The primary endpoint of the trial was disease-free survival (DFS) which was assessed as the time from randomization to the earliest event of loco-regional or distant recurrence (metastases) of the primary disease, development of invasive contralateral breast cancer, appearance of a second non-breast primary or death from any cause without a prior cancer event. Letrozole reduced the risk of recurrence by 19% compared with tamoxifen (hazard ratio 0.81; P=0.003). The 5-year DFS rates were 84.0% for letrozole and 81.4% for tamoxifen. The improvement in DFS with letrozole is seen as early as 12 months and is maintained beyond 5 years. Letrozole also significantly reduced the risk compared to tamoxifen whether prior adjuvant chemotherapy was given (hazard ratio 0.72; P=0.018) or not (hazard ratio 0.84; p=0.044).

For the secondary endpoint overall survival a total of 358 deaths were reported (166 on letrozole and 192 on tamoxifen). There was no significant difference between treatments in overall survival (hazard ratio 0.86; P=0.15). Distant disease-free survival (distant metastases), a surrogate for overall survival, differed significantly overall (hazard ratio 0.73; P=0.001) and in pre-specified stratification subsets. Letrozole significantly reduced the risk of systemic failure by 17% compared with tamoxifen (hazard ratio 0.83; P=0.02).

However, although in favour of letrozole non significant difference was obtained in the occurrence of contralateral breast cancer (hazard ratio 0.61; P=0.09). An explanatory analysis of DFS by nodal status showed that letrozole was significantly superior to tamoxifen in reducing the risk of recurrence in patients with node positive disease (HR 0.71; 95% CI 0.59, 0.85; P=0.0002) while no significant difference between treatments was apparent in patients with node negative disease (HR 0.98; 95% CI 0.77, 1.25; P=0.89). This reduced benefit in node negative patients was confirmed by an explanatory interaction analysis (p=0.03).

Patients receiving letrozole, compared to tamoxifen, had fewer second malignancies (1.9% vs. 2.4%). Particularly the incidence of endometrial cancer was lower with letrozole compared to tamoxifen (0.2% vs. 0.4%).

See Tables 2 and 3 that summarize the results. The analyses summarized in Table 4 omit the 2 sequential arms from randomization option 1, i.e. take account only of the monotherapy arms.

Table 2: Disease free and overall survival (ITT population)

	letrozole n=4003	tamoxifen n=4007	hazard ratio (95% CI)1	P -value2
Disease-free survival (primary) - events (protocol definition, total)	351	428	0.81 (0.70, 0.93)	0.0030
Distant disease-free survival (metastases) (secondary)	184	249	0.73 (0.60, 0.88)	0.0012
Overall survival (secondary) - number of deaths (total)	166	192	0.86 (0.70, 1.06)	0.1546
Systemic disease-free survival (secondary)	323	383	0.83 (0.72, 0.97)	0.0172
Contralateral breast cancer (invasive) (secondary)	19	31	0.61 (0.35, 1.08)	0.0910

¹ CI: confidence interval

² Logrank test, stratified by randomization option and use of prior adjuvant chemotherapy

Table 3: Disease-free and overall survival by nodal status and prior adjuvant chemotherapy (ITT population)

	hazard ratio (95% CI)1	p-value2
Disease-free survival:
Nodal status - Positive - Negative	0.71 (0.59, 0.85) 0.98 (0.77, 1.25)	0.0002 0.8875
Prior adjuvant chemotherapy - Yes - No	0.72 (0.55, 0.95) 0.84 (0.71, 1.00)	0.0178 0.0435
Overall survival:
Nodal status - Positive - Negative	0.81 (0.63, 1.05) 0.88 (0.59, 1.30)	0.1127 0.5070
Prior adjuvant chemotherapy - Yes - No	0.76 (0.51, 1.14) 0.90 (0.71, 1.15)	0.1848 0.3951
Distant disease-free survival:
Nodal status - Positive - Negative	0.67 (0.54, 0.84) 0.90 (0.60, 1.34)	0.0005 0.5973
Prior adjuvant chemotherapy - Yes - No	0.69 (0.50, 0.95) 0.75 (0.60, 0.95)	0.0242 0.0184

¹ CI: confidence interval

² Cox model significance level

Table 4: Primary Core Analysis: Efficacy endpoints according to randomization option monotherapy arms (ITT population)

endpoint	option	statistic	letrozole	tamoxifen
Disease free survival (primary, protocol definition)	1	Events / n	100/ 1546	137/ 1548
		HR1 (95% CI2 ), P3	0.73 (0.56, 0.94), 0.0159
	2	Events / n	177 / 917	202/ 911
		HR (95% CI), P	0.85 (0.69, 1.04), 0.1128
	Overall	Events/ n	277 / 2463	339 / 2459
		HR (95% CI), P	0.80 (0.68, 0.94), 0.0061
Disease free survival (excluding second malignancies)	1	Events/ n	80/ 1546	110 / 1548
		HR (95% CI), P	0.73 (0.54, 0.97), 0.0285
	2	Events/ n	159 / 917	187 / 911
		HR (95% CI), P	0.82 (0.67, 1.02) 0.0753
	Overall	Events/ n	239 / 2463	297 / 2459
		HR (95% CI), P	0.79 (0.66, 0.93), 0.0063
Distant disease free survival (secondary)	1	Events/ n	57 / 1546	72 / 1548
		HR (95% CI), P	0.79 (0.56, 1.12) 0.1913
	2	Events/ n	98 / 917	124 / 911
		HR (95% CI), P	0.77 (0.59, 1.00), 0.0532
	Overall	Events/ n	155 / 2463	196 / 2459
		HR (95% CI), P	0.78 (0.63, 0.96), 0.0195
Overall survival (secondary)	1	Events/ n	41 / 1546	48 / 1548
		HR (95% CI), P	0.86 (0.56, 1.30), 0.4617
	2	Events/ n	98 / 917	116 / 911
		HR (95% CI), P	0.84 (0.64, 1.10), 0.1907
	Overall	Events/ n	139 / 2463	164 / 2459
		HR (95% CI), P	0.84 (0.67, 1.06), 0.1340

¹ HR = hazard ratio

² CI = confidence interval

³P-value given is based on logrank test, stratified by adjuvant chemotherapy for each randomization option, and by randomization option and adjuvant chemotherapy for overall analysis

The median duration of treatment (safety population) was 25 months, 73% of the patients were treated for more than 2 years, 22% of the patients for more than 4 years. The median duration of follow-up was 30 months for