Letrozole 2.5mg film-coated Tablets.

Each film-coated tablet contains 2.5 mg letrozole.

Each tablet contains 61.500 mg of lactose monohydrate. For a full list of excipients, see section 6.1

Film-coated tablet

Yellow, round, biconvex, film coated tablets plain on both sides.

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

• Treatment of early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy.

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

• Advanced breast cancer in postmenopausal women in whom tamoxifen or other anti-oestrogen therapy has failed.

• Pre-operative therapy in postmenopausal women with localised hormone receptor positive breast cancer, to allow subsequent breast-conserving surgery in women not originally considered candidates for breast-conserving surgery. Subsequent treatment after surgery should be in accordance with standard of care.

Adult and elderly patients

The recommended dose of letrozole is 2.5 mg once daily. In the adjuvant setting, treatment with letrozole should continue for 5 years or until tumour relapse occurs, whichever comes first. Following standard adjuvant tamoxifen therapy, treatment with letrozole should continue for 4 years or until tumour relapse occurs, whichever comes first. Currently there is a lack of long-term data, therefore the optimal duration of therapy has not yet been established. In patients with metastatic disease, treatment with letrozole should continue until tumour progression is evident. Regular monitoring to observe progression during the pre-operative treatment period is recommended (see Section 5.1 “Pharmacodynamic properties”). No dose adjustment is required for elderly patients.

Children

Not recommended for use in children.

Patients with hepatic and/or renal impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh grade A and B) or renal impairment (creatinine clearance 10 mL/min.), (see section 5.2 "Pharmacokinetic properties").

• Hypersensitivity to the active substance or to any of the excipients.

• Premenopausal, pregnant or lactating women (see section 4.6 Pregnancy and Lactation).

• Patients with severe hepatic impairment (Child-Pugh grade C).

• Pre-operative use of letrozole is contraindicated if the receptor status is negative or unknown.

letrozole is not recommended for use in children as efficacy and safety in this patient group have not been assessed in clinical studies. There are no efficacy data to support the use of letrozole in men with breast cancer.

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

As letrozole is a potent oestrogen lowering agent, reductions in bone mineral density can be anticipated. The impact of letrozole on long-term fracture risk remains undetermined. During adjuvant treatment with letrozole, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by letrozole are not available, treatment for osteoporosis should be initiated as appropriate and patients treated with letrozole should be carefully monitored.

Lactose: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions, even though cimetidine is a known inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising letrozole in vitro (see section 5.2, “Metabolism and elimination”).

There was no evidence of other clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac sodium, ibuprofen; paracetamol; furosemide; omeprazole).

There is no clinical experience to date on the use of Letrozole in combination with other anti-cancer agents.

Letrozole inhibits in vitro the cytochrome P450-isoenzymes 2A6 and moderately 2C19, however, CYP2A6 does not play a major role in drug metabolism. In in vitro experiments letrozole was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 100-fold higher than those observed in plasma at steady-state. Thus, clinically relevant interactions with CYP2C19 are unlikely to occur. 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.

Pregnancy

Letrozole is contraindicated during pregnancy (see section 4.3 Contraindications).

Lactation

Letrozole is contraindicated during lactation (see section 4.3 Contraindications)

Women of child–bearing potential

The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who have recently become postmenopausal, until their postmenopausal status is fully established.

There are no adequate data from the use of letrozole in pregnant women.

Embryotoxicity and foetotoxicity were seen in pregnant rats following oral administration of letrozole, and there was an increase in the incidence of foetal malformation among the animals treated. However, it is not known whether this was an indirect consequence of the pharmacological activity of letrozole (inhibition of oestrogen biosynthesis) or a direct drug effect.

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

Letrozole was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer, as adjuvant treatment of early breast cancer as well as in the treatment of women who have received prior standard tamoxifen therapy. Approximately one third of the patients treated with letrozole in the metastatic and neoadjuvant settings, approximately 70-75% of the patients in the adjuvant setting (both letrozole and tamoxifen arms), and approximately 40% of the patients treated following standard adjuvant tamoxifen (both letrozole and placebo arms) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with oestrogen deprivation.

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, 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 the placebo arm who switched to letrozole, a similar pattern of general adverse events was observed. The incidence of self-reported osteoporosis, any time after randomisation was higher in patients who received letrozole than in patients who received placebo (12.3 % vs. 7.4 %). The incidence of clinical fractures, at any time after randomisation, was higher in patients who received letrozole than for placebo patients (10.9 % vs. 7.2 %). In patients who switched to letrozole, newly diagnosed osteoporosis, any time after switching, was reported in 3.6 % of patients while fractures were reported in 5.1 % of patients any time after switching.

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

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10000 to < 1/1000); very rare ( 1/10,000), not known (cannot be estimated from the available data).

*Including:

(1) including nervousness, irritability

(2) including paraesthesia, hypoaesthesia

(3) including superficial and deep thrombophlebitis

(4) including erythematous, maculopapular, psoriaform and vesicular rash

(5) including aesthenia and malaise

(6) in metastatic/neoadjuvant setting only

(7) in the adjuvant setting, irrespective of causality, the following adverse events occurred in the letrozole and tamoxifen groups respectively: thromboembolic events (1.2% vs. 3.0%), angina pectoris (0.8% vs. 0.8%), myocardial infarction (0.5% vs. 0.4%), cardiac failure (0.8% vs. 0.3%).

Table 2 presents the frequency of pre-specified adverse events grades 1-5 in the BIG 1-98 study, irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.

¹ Based on number of patients with normal serum cholesterol levels at baseline and developing at least one value greater than 1.5 times the upper limit of normal in the laboratory measuring total serum cholesterol. Approximately 90% of the measured values were non-fasting measurements.

² Denominator is number of patients with baseline measurements of total serum cholesterol – letrozole, n=3207; tamoxifen, n=3228

³ Denominator is number of patients not having undergone hysterectomy at baseline –letrozole, n=3090; tamoxifen, n=3157

There is no clinical experience of overdosage. In animal studies, letrozole exhibits only a slight degree of acute toxicity. In clinical trials, the highest single and multiple dose tested in healthy volunteers was 30 mg and 5 mg, respectively, the latter also being the highest dose tested in postmenopausal breast cancer patients. Each of these doses was well tolerated. There is no clinical evidence for a particular dose of letrozole resulting in life-threatening symptoms.

There is no specific antidote to letrozole. In general, supportive care, symptomatic treatment and frequent monitoring of vital signs is appropriate.

Pharmacotherapeutic group:

ATC Code: L02B G04

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

Pharmacodynamic effects

The elimination of oestrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to oestrone (E1) and oestradiol (E2). The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

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

In healthy postmenopausal women, single doses of 0.1, 0.5, and 2.5 mg letrozole suppress 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 oestrogen 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-hydroxy-progesterone, 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.

Adjuvant treatment

A multicentre, double-blind study randomised over 8000 postmenopausal women with resected receptor-positive early breast cancer, to one of the following arms:

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.

Data in Table 3 reflect results from non-switching arms (arms A and B) together with data truncated 30 days after the switch in the two switching arms (arms C and D). 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 randomisation 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 tumour or death from any cause. 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 of recurrence compared with tamoxifen whether prior adjuvant chemotherapy was given (hazard ratio 0.72; P=0.018) or not (hazard ratio 0.84; P=0.044) and in node positive patients (hazard ratio 0.71; P=0.0002). A significant benefit of letrozole over tamoxifen is not yet evident in node negative patients (hazard ratio 0.98; P=0.888).

There was no significant difference between treatments in overall survival (hazard ratio 0.86; P=0.155).

Table 3 summarises the results.

Table 3 Disease-free survival and overall survival (ITT population)

Treatment after standard adjuvant tamoxifen

In a multicentre, double-blind, randomised, placebo-controlled study, performed in over 5100 postmenopausal patients with receptor-positive or unknown primary breast cancer, patients who had remained disease-free after completion of adjuvant treatment with tamoxifen (4.5 to 6 years) were randomly assigned either letrozole or placebo.

The primary analysis conducted at a median follow-up of around 28 months (25% of the patients being followed-up for up to 38 months) showed that letrozole reduced the risk of recurrence by 42% compared with placebo (hazard ratio 0.58; P=0.00003), an absolute reduction of 2.4%. This statistically significant benefit in DFS in favour of letrozole was observed regardless of nodal status or prior chemotherapy.

For the secondary endpoint overall survival (OS) a total 113 deaths were reported (51 letrozole, 62 placebo). Overall, there was no significant difference between treatments in OS (hazard ratio 0.82; P=0.29). Table 4 summarises the results:

Table 4 Disease-free and overall survival (Modified ITT population)

Updated analyses were conducted at a median follow-up of 49 months. In the letrozole arm at least 30% of the patients had completed 5 years and 59% had completed at least 4 years of follow-up. After the unblinding of the study, 56% of the patients in the placebo arm opted to switch to letrozole.

In this analysis of DFS, letrozole significantly reduced the risk of breast cancer recurrence compared with placebo (HR 0.68; 95% CI 0.55, 0.83; P=0.0001). letrozole also significantly reduced the odds of a new invasive contralateral cancer by 41% compared with placebo (OR 0.59; 95% CI 0.36, 0.96; P=0.03). There was no significant difference in distant disease-free survival or overall survival.

The clinical interpretation of these updated analyses should take into account that over half of the patients in the placebo arm switched to letrozole. Therefore, analyses were conducted to evaluate the effect of the switch. In one exploratory analysis comparing letrozole with placebo until switch, letrozole reduced the risk of breast cancer recurrence (HR 0.55; 95% CI 0.45,0.68; p<0.001).

After unblinding, patients who switched to letrozole from placebo had been off adjuvant tamoxifen for a median 31 months (range 14 to 79 months). Other analyses were performed within the placebo arm taking account of the switch to letrozole. Acknowledging the varying times of the switch after the completion of prior tamoxifen therapy and the known limitations of non-randomised comparison, results suggested a consistent reduction in the risk of breast cancer recurrence in those patients who switched to letrozole (HR 0.31; 95% CI 0.20, 0.49, p<0.001).

The efficacy of letrozole was not assessed in women who discontinued tamoxifen therapy more than 3 months earlier.

There was no difference in safety and efficacy between patients aged < 65 versus 65 years.

Updated results (median follow-up was 40 months) from the bone mineral density (BMD) sub-study (n=226) demonstrated that, at 2 years, compared to baseline, patients receiving letrozole had a median decrease of 3.8% in hip BMD compared to 2.0% in the placebo group (P=.0.018). There was no significant difference in changes in lumbar spine BMD at any time.

Concomitant calcium and vitamin D supplementation was mandatory in the BMD substudy.

Updated results (median follow-up was approximately 50 months) from the lipid sub-study (n=347) showed no significant difference between the letrozole and placebo groups at any time. In the core study the incidence of cardiovascular ischemic events for letrozole versus placebo until switch was 11.1 % vs. 8.6 %.

First-line treatment

One large well-controlled double-blind trial was conducted comparing letrozole 2.5 mg to tamoxifen 20 mg daily as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. In this trial of 907 women, letrozole was superior to tamoxifen in time to progression (primary endpoint) and in overall objective response, time to treatment failure and clinical benefit (CR+PR+NC24 weeks).

Letrozole treatment in the first line therapy of advanced breast cancer patients is associated with an early survival advantage over tamoxifen. A significantly greater number of patients were alive on letrozole versus tamoxifen throughout the first 24 months of the study. As the study design allowed patients to cross-over upon progression to the other therapy the long-term survival could not be evaluated.

Pre-operative treatment:

A double blind trial was conducted in 337 postmenopausal breast cancer patients randomly allocated either letrozole 2.5mg for 4 months or tamoxifen for 4 months. At baseline all patients had tumours stage T2-T4c, N0-2, M0, ER and/or PgR positive and none of the patients would have qualified for breast-conserving surgery. There were 55% objective responses in the letrozole treated patients versus 36% for the tamoxifen treated patients (p<0.001) based on clinical assessment. This finding was consistently confirmed by ultrasound (p=0.042) and mammography (p<0.001) giving the most conservative assessment of response. This response was reflected in a statistically significantly higher number of patients in the letrozole group who became suitable for and underwent breast-conserving therapy (45% of patients in the letrozole group versus 35% of patients in the tamoxifen group, p=0.022). During the 4 month pre-operative treatment period, 12% of patients treated with L letrozole and 17% of patients treated with tamoxifen had disease progression on clinical assessment.

Absorption

Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median t_max: 1 hour fasted versus 2 hours fed; and mean C_max: 129 ± 20.3 nmol/L fasted versus 98.7 ± 18.6 nmol/L fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken without regard to mealtimes.

Distribution

Plasma protein binding of letrozole is approximately 60%, mainly to albumin (55%). The concentration of letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg ¹⁴C-labelled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87 ± 0.47 L /kg.

Metabolism and elimination

Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of letrozole (CL_m= 2.1 L/h) but is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite in vitro, but their individual contributions to letrozole clearance in vivo have not been established. In an interaction study co-administration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in letrozole clearance suggesting that in vivo the 2A6 isoenzyme plays an important part in total clearance. In this study a slight decrease in AUC and increase in Cmax were observed.

Formation of minor unidentified metabolites and direct renal and faecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg ¹⁴C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in urine and 3.8 ± 0.9% in faeces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7 ± 7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged letrozole.

The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.

Age had no effect on the pharmacokinetics of letrozole.

Special populations

In a study involving volunteers with varying degrees of renal function (24 hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of letrozole or the urinary excretion of the glucoronide of its carbinol metabolite was found after a single dose of 2.5 mg. The Cmax, AUC and half-life of the metabolite have not been determined. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment was 37 % higher than in normal subjects, but still within the range seen in subjects without impaired function.

Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs letrozole caused signs of moderate toxicity at 100 mg/kg.

In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings can be attributed to the pharmacological action of the compound. Effects on the liver (increased weight, hepatocellular hypertrophy, fatty changes) were observed, mainly at high dose levels. Increased incidences of hepatic vacuolation (both sexes, high dose) and necrosis (intermediate and high dose females) were also noted in rats treated for 104 weeks in a carcinogenicity study. They may have been associated with the endocrine effects and hepatic enzyme-inducing properties of Letrozole. However, a direct drug effect cannot be ruled out.

In a 104-week mouse carcinogenicity study, dermal and systemic inflammation occurred, particularly at the highest dose of 60 mg/kg, leading to increased mortality at this dose level. Again it is not known whether these findings were an indirect consequence of the pharmacological activity of Letrozole (i.e. linked to long-term oestrogen deprivation) or a direct drug effect.

The pharmacological effects of letrozole resulted in skeletal, neuroendocrine and reproductive findings in a juvenile rat study at doses between 0.003 mg/kg/day and 0.3 mg/kg/day. Bone growth and maturation were decreased from the lowest dose (0.003 mg/kg/day) in males and increased from the lowest dose (0.003 mg/kg) in females. In addition, bone mineral density (BMD) was decreased at that dose in females. In the same study, decreased fertility at all doses was accompanied by hypertrophy of the hypophysis, testicular changes which included a degeneration of the seminiferous tubular epithelium, ovarian cysts and atrophy of the female reproductive tract. Effects on bone size in females at 0.3 mg/kg/day and males at 0.03 mg/kg/day and morphological changes in the testes were not reversible. All other effects were at least partially reversible at 0.003 and 0.03 mg/kg/day.

Both in vitro and in vivo investigations on letrozole's mutagenic potential revealed no indication of any genotoxicity.

In the carcinogenicity studies no treatment-related tumours were noted in male animals. In female animals, treatment-related changes in genital tract tumours (a reduced incidence of benign and malignant mammary tumours in rats, an increased incidence of benign ovarian stromal tumours in mice) were secondary to the pharmacological effect of the compound.

Tablet core:

Lactose monohydrate

Maize starch

Hypromellose Type 2910

Cellulose microcrystalline

Sodium starch glycolate Type A

Colloidal anhydrous silica

Magnesium stearate

Coating (Opadry 03B82927 yellow):

Hypromellose 6 cp E464

Titanium dioxide E171

Iron oxide yellow E172

Macrogol 400

Talc E553b

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Blister composed of clear 250µ polyvinyl chloride (PVC) film coated with 90 gsm polyvinylidene chloride (PVdC) and plain 25µ aluminum foil.

Letrozole tablets are packed in blisters in pack of 10 tablets , 14 tablets 28 tablets , 30 tablets , 50 tablets , 60 tablets , 84 tablets , 90 tablets , 98 tablets or 100 tablets

Not all packs may be marketed

Any unused product or waste material should be disposed of in accordance with local requirements.

Accord Healthcare Limited

Sage House

319, Pinner Road

North Harrow

Middlesex HA1 4 HF

United Kingdom

PL 20075/0076

21/10/2008

07/06/2011

IF APPLICABLE

IF APPLICABLE