Please Scroll Down to See Forums Below 
.jpg "Research Chemical Sciences")
.png "Research Chemical Sciences")
Possible alternative to Nolva or Arimidex, please read and tell me what you think; kind of long.
Data Sheet
Data Sheet
<< FEMARA>> Letrozole Qualitative and Quantitative Composition
Active substance: 4, 4'-[(1H-1, 2, 4-triazol-1-yl)-methylene]bis-benzonitrile (INN/USAN= letrozole).
Each film-coated tablet contains 2.5 mg letrozole.
Pharmaceutical Form
Film-coated tablets.
Clinical Particulars Therapeutic Indications
Treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status, who have previously been treated with antiestrogens.
Dosage and Method of Administration Adult and elderly patients
The recommended dose of << Femara>> is 2.5 mg once daily. Treatment with << Femara>> should continue until tumour progression is evident. No dose adjustment is required for elderly patients.
Children
Not applicable.
Patients with hepatic and/or renal impairment
No dosage adjustment is required for patients with hepatic impairment or renal impairment (creatinine clearance 10 mL/min.). However, patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision (see "Pharmacokinetic Properties").
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Premenopausal endocrine status; pregnancy, lactation.
Special Warnings and Special Precautions for Use
<< Femara>> 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 << Femara>> . In patients with severe hepatic impairment (Child-Pugh score C), systemic exposure and terminal half-life were approximately doubled compared to healthy volunteers. Such patients should therefore be kept under close supervision (see 'Pharmacokinetic properties').
Interaction with Other Medicaments and Other Forms of Interactions
Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of << Femara>> with these drugs does not result in clinically significant drug interactions.
A review of the clinical trial database indicated no evidence of other clinically relevant interaction with other commonly prescribed drugs.
There is no clinical experience to date on the use of << Femara>> in combination with other anti-cancer agents.
Letrozole inhibits in vitro the cytochrome P450-isozymes 2A6 and moderately 2C19. 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. However, 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 and Lactation
<< Femara>> is contraindicated during pregnancy and lactation.
Effects on the Ability to Drive and Use Machines
<< Femara>> is unlikely to impair the ability of patients to drive or to operate machinery. However, fatigue and dizziness have been observed with the use of << Femara>> . Patients should be advised that their physical and/or mental abilities required for operating machinery or driving a car may be impaired.
Adverse Effects
In clinical trials, adverse experiences (AEs) were generally mild to moderate and rarely severe enough to require discontinuation of treatment. Many AEs can be attributed to either the underlying disease or the normal pharmacological consequences of estrogen deprivation (e.g. hot flushes, hair thinning).
The table below shows in decreasing order of frequency the AEs - possibly related to trial drug according to the investigator - that have been reported with an incidence of more than 2.0% (whether for << Femara>> or for megestrol acetate) in a controlled clinical trial with << Femara>> (2.5 mg daily) and megestrol acetate (160 mg daily) for up to 33 months.
Adverse experience << Femara>> N = 174 % Megestrol acetate N = 189 % Headache 6.9 4.8 Nausea 6.3 4.2 Peripheral oedema 6.3 3.7 Fatigue 5.2 6.3 Hot flushes 5.2 3.7 Hair thinning 3.4 1.1 Rash (1) 3.4 0.5 Vomiting 2.9 1.6 Dyspepsia 2.9 1.6 Weight increase 2.3 8.5 Musculoskeletal pain (2) 2.3 1.1 Anorexia 2.3 1.1 Vaginal bleeding 1.7 3.2 Leukorrhoea 1.7 2.6 Constipation 1.7 2.1 Dizziness 1.1 3.7 Increased appetite 1.1 3.7 Increased sweating 1.1 2.1 Dyspnoea 0.6 5.8 Thrombophlebitis (3) 0.6 3.7 Vaginal spotting 0.6 2.1 Hypertension 0 2.6 Pruritus 0 2.6
Including: erythematous rash, maculopapular rash.
Including: arm pain, back pain, leg pain, skeletal pain.
Including: superficial and deep thrombophlebitis.
Other adverse experiences considered to be possibly drug-related and reported in at least 3 patients treated with << Femara>> , with a frequency below 2.0 %, included weight loss, and generalised oedema.
Overdose
There is no experience of overdosage with << Femara>> . No specific treatment for overdosage is known; treatment should be symptomatic and supportive.
Pharmacological Properties Pharmacodynamic Properties Pharmacotherapeutic group
ATC Code: L02B G
Non-steroidal aromatase inhibitor (inhibitor of estrogen biosynthesis); antineoplastic agent.
Pharmacodynamic effects
The elimination of estrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of estrogens. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to estrone (E1) and estradiol (E2). The suppression of estrogen 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 estrogen biosynthesis in all tissues.
In healthy postmenopausal women, single doses of 0.1, 0.5, and 2.5 mg letrozole suppress serum estrone and estradiol by 75-78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 h.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress plasma concentration of estradiol, estrone, and estrone sulphate by 75 - 95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of estrone and estrone sulphate are below the limit of detection in the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen 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 estrogen 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.
Two well-controlled clinical trials were conducted comparing two letrozole doses (0.5 mg and 2.5 mg) to megestrol acetate and to aminoglutethimide, respectively, in postmenopausal women with advanced breast cancer previously treated with antiestrogens.
Statistically significant differences were observed in favour of letrozole 2.5 mg compared to megestrol acetate in overall objective tumour response rate (24% vs 16%, p=0.04), and in time to treatment failure (p=0.04). Time to progression was not significantly different between letrozole 2.5 mg and megestrol acetate (p=0.07). Overall survival was not significantly different between the 2 arms (p=0.2).
In the second study, letrozole 2.5 mg was statistically superior to aminoglutethimide for time to progression (p=0.008), time to treatment failure (p=0.003) and overall survival (p=0.002). The response rate was not significantly different between letrozole 2.5 mg and aminoglutethimide (p=0.06).
Pharmacokinetics Properties Absorption
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median tmax: 1 hour fasted versus 2 hours fed; and mean Cmax: 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 (CLm= 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. 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 was found after a single dose of 2.5 mg. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh score B) was 37 % higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of letrozole after a single oral dose in eight subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh score C) to those in healthy volunteers (N=8), AUC and t½ increased by 95 and 187%, respectively. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. However, since in patients dosed at 5 or 10 mg/day no increase in toxicity was observed, a dose reduction in patients with severe hepatic impairment appears not to be warranted, although such patients should be kept under close supervision. In addition, in two well-controlled studies involving 359 patients with advanced breast cancer, no effect of renal impairment (calculated creatinine clearance: 20-50 mL/min) or hepatic dysfunction was found on the letrozole concentration.
Preclinical Safety Data
In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of systemic or target organ toxicity.
Letrozole showed a low degree of acute toxicity in rodents exposed to 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 observed can be attributed to the pharmacological action of the compound. The no-adverse effect level was 0.3 mg/kg in both species.
Both in vitro and in vivo investigations on letrozole's mutagenic potential revealed no indications of any genotoxicity.
In a 104-week rat carcinogenicity study no treatment related tumours were noted in male rats. In female rats, a reduced incidence of benign and malignant mammary tumours at all the doses of letrozole was found.
Oral administration of letrozole to gravid rats resulted in a slight increase in the incidence of foetal malformation among the animals treated. However, it was not possible to show whether this was an indirect consequence of the pharmacological properties (inhibition of estrogen biosynthesis) or a direct effect of letrozole in its own right.
Preclinical observations were confined to those associated with the recognised pharmacological action, which is the only safety concern for human use derived from animal studies.
These results reinforce the proposed contraindications in 'Contraindications' and 'Pregnancy and lactation'.
Pharmaceutical Particulars List of Excipients
Colloidal anhydrous silica, microcrystalline cellulose, lactose monohydrate, magnesium stearate, maize starch, sodium starch glycollate, hydroxypropyl methylcellulose, polyethylene glycol 8000, talc, titanium dioxide, iron oxide yellow.
Incompatibilities
None known.
Shelf Life
Three years.
Special Precautions for Storage
Do not store above 30°C.
Nature and Contents of Container
PVC/PE/PVDC blister packs.
Instructions for Use / Handling
No specific instructions for use/handling.
Medicine Classification
Prescription Medicine
------------------
Good things come to those who wait.
Data Sheet
Data Sheet
<< FEMARA>> Letrozole Qualitative and Quantitative Composition
Active substance: 4, 4'-[(1H-1, 2, 4-triazol-1-yl)-methylene]bis-benzonitrile (INN/USAN= letrozole).
Each film-coated tablet contains 2.5 mg letrozole.
Pharmaceutical Form
Film-coated tablets.
Clinical Particulars Therapeutic Indications
Treatment of advanced breast cancer in women with natural or artificially induced postmenopausal status, who have previously been treated with antiestrogens.
Dosage and Method of Administration Adult and elderly patients
The recommended dose of << Femara>> is 2.5 mg once daily. Treatment with << Femara>> should continue until tumour progression is evident. No dose adjustment is required for elderly patients.
Children
Not applicable.
Patients with hepatic and/or renal impairment
No dosage adjustment is required for patients with hepatic impairment or renal impairment (creatinine clearance 10 mL/min.). However, patients with severe hepatic impairment (Child-Pugh score C) should be kept under close supervision (see "Pharmacokinetic Properties").
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Premenopausal endocrine status; pregnancy, lactation.
Special Warnings and Special Precautions for Use
<< Femara>> 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 << Femara>> . In patients with severe hepatic impairment (Child-Pugh score C), systemic exposure and terminal half-life were approximately doubled compared to healthy volunteers. Such patients should therefore be kept under close supervision (see 'Pharmacokinetic properties').
Interaction with Other Medicaments and Other Forms of Interactions
Clinical interaction studies with cimetidine and warfarin indicated that the co-administration of << Femara>> with these drugs does not result in clinically significant drug interactions.
A review of the clinical trial database indicated no evidence of other clinically relevant interaction with other commonly prescribed drugs.
There is no clinical experience to date on the use of << Femara>> in combination with other anti-cancer agents.
Letrozole inhibits in vitro the cytochrome P450-isozymes 2A6 and moderately 2C19. 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. However, 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 and Lactation
<< Femara>> is contraindicated during pregnancy and lactation.
Effects on the Ability to Drive and Use Machines
<< Femara>> is unlikely to impair the ability of patients to drive or to operate machinery. However, fatigue and dizziness have been observed with the use of << Femara>> . Patients should be advised that their physical and/or mental abilities required for operating machinery or driving a car may be impaired.
Adverse Effects
In clinical trials, adverse experiences (AEs) were generally mild to moderate and rarely severe enough to require discontinuation of treatment. Many AEs can be attributed to either the underlying disease or the normal pharmacological consequences of estrogen deprivation (e.g. hot flushes, hair thinning).
The table below shows in decreasing order of frequency the AEs - possibly related to trial drug according to the investigator - that have been reported with an incidence of more than 2.0% (whether for << Femara>> or for megestrol acetate) in a controlled clinical trial with << Femara>> (2.5 mg daily) and megestrol acetate (160 mg daily) for up to 33 months.
Adverse experience << Femara>> N = 174 % Megestrol acetate N = 189 % Headache 6.9 4.8 Nausea 6.3 4.2 Peripheral oedema 6.3 3.7 Fatigue 5.2 6.3 Hot flushes 5.2 3.7 Hair thinning 3.4 1.1 Rash (1) 3.4 0.5 Vomiting 2.9 1.6 Dyspepsia 2.9 1.6 Weight increase 2.3 8.5 Musculoskeletal pain (2) 2.3 1.1 Anorexia 2.3 1.1 Vaginal bleeding 1.7 3.2 Leukorrhoea 1.7 2.6 Constipation 1.7 2.1 Dizziness 1.1 3.7 Increased appetite 1.1 3.7 Increased sweating 1.1 2.1 Dyspnoea 0.6 5.8 Thrombophlebitis (3) 0.6 3.7 Vaginal spotting 0.6 2.1 Hypertension 0 2.6 Pruritus 0 2.6
Including: erythematous rash, maculopapular rash.
Including: arm pain, back pain, leg pain, skeletal pain.
Including: superficial and deep thrombophlebitis.
Other adverse experiences considered to be possibly drug-related and reported in at least 3 patients treated with << Femara>> , with a frequency below 2.0 %, included weight loss, and generalised oedema.
Overdose
There is no experience of overdosage with << Femara>> . No specific treatment for overdosage is known; treatment should be symptomatic and supportive.
Pharmacological Properties Pharmacodynamic Properties Pharmacotherapeutic group
ATC Code: L02B G
Non-steroidal aromatase inhibitor (inhibitor of estrogen biosynthesis); antineoplastic agent.
Pharmacodynamic effects
The elimination of estrogen-mediated stimulatory effects is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of estrogens. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to estrone (E1) and estradiol (E2). The suppression of estrogen 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 estrogen biosynthesis in all tissues.
In healthy postmenopausal women, single doses of 0.1, 0.5, and 2.5 mg letrozole suppress serum estrone and estradiol by 75-78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 h.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 to 5 mg suppress plasma concentration of estradiol, estrone, and estrone sulphate by 75 - 95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of estrone and estrone sulphate are below the limit of detection in the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen 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 estrogen 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.
Two well-controlled clinical trials were conducted comparing two letrozole doses (0.5 mg and 2.5 mg) to megestrol acetate and to aminoglutethimide, respectively, in postmenopausal women with advanced breast cancer previously treated with antiestrogens.
Statistically significant differences were observed in favour of letrozole 2.5 mg compared to megestrol acetate in overall objective tumour response rate (24% vs 16%, p=0.04), and in time to treatment failure (p=0.04). Time to progression was not significantly different between letrozole 2.5 mg and megestrol acetate (p=0.07). Overall survival was not significantly different between the 2 arms (p=0.2).
In the second study, letrozole 2.5 mg was statistically superior to aminoglutethimide for time to progression (p=0.008), time to treatment failure (p=0.003) and overall survival (p=0.002). The response rate was not significantly different between letrozole 2.5 mg and aminoglutethimide (p=0.06).
Pharmacokinetics Properties Absorption
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median tmax: 1 hour fasted versus 2 hours fed; and mean Cmax: 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 (CLm= 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. 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 was found after a single dose of 2.5 mg. In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh score B) was 37 % higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of letrozole after a single oral dose in eight subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh score C) to those in healthy volunteers (N=8), AUC and t½ increased by 95 and 187%, respectively. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients without severe hepatic dysfunction. However, since in patients dosed at 5 or 10 mg/day no increase in toxicity was observed, a dose reduction in patients with severe hepatic impairment appears not to be warranted, although such patients should be kept under close supervision. In addition, in two well-controlled studies involving 359 patients with advanced breast cancer, no effect of renal impairment (calculated creatinine clearance: 20-50 mL/min) or hepatic dysfunction was found on the letrozole concentration.
Preclinical Safety Data
In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of systemic or target organ toxicity.
Letrozole showed a low degree of acute toxicity in rodents exposed to 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 observed can be attributed to the pharmacological action of the compound. The no-adverse effect level was 0.3 mg/kg in both species.
Both in vitro and in vivo investigations on letrozole's mutagenic potential revealed no indications of any genotoxicity.
In a 104-week rat carcinogenicity study no treatment related tumours were noted in male rats. In female rats, a reduced incidence of benign and malignant mammary tumours at all the doses of letrozole was found.
Oral administration of letrozole to gravid rats resulted in a slight increase in the incidence of foetal malformation among the animals treated. However, it was not possible to show whether this was an indirect consequence of the pharmacological properties (inhibition of estrogen biosynthesis) or a direct effect of letrozole in its own right.
Preclinical observations were confined to those associated with the recognised pharmacological action, which is the only safety concern for human use derived from animal studies.
These results reinforce the proposed contraindications in 'Contraindications' and 'Pregnancy and lactation'.
Pharmaceutical Particulars List of Excipients
Colloidal anhydrous silica, microcrystalline cellulose, lactose monohydrate, magnesium stearate, maize starch, sodium starch glycollate, hydroxypropyl methylcellulose, polyethylene glycol 8000, talc, titanium dioxide, iron oxide yellow.
Incompatibilities
None known.
Shelf Life
Three years.
Special Precautions for Storage
Do not store above 30°C.
Nature and Contents of Container
PVC/PE/PVDC blister packs.
Instructions for Use / Handling
No specific instructions for use/handling.
Medicine Classification
Prescription Medicine
------------------
Good things come to those who wait.
