ACCOLATE
ACCOLATE
Composition
Tablets containing 20 mg zafirlukast.
Properties
Pharmacodynamics The cysteinyl leukotrienes (LTC 4 , LTD 4 and LTE 4 ) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors found in the human airway.
Leukotriene production and receptor occupation has been implicated in the pathophysiology of asthma. Effects include smooth muscle contraction, airway oedema and altered cell activity associated with the inflammatory process, including eosinophil influx to the lung. Accolate is a competitive, highly selective and potent oral peptide leukotriene antagonist of LTC, b LTD 4 and LTE 4 components of slow reacting substance of anaphylaxis. In vitro studies have shown that Accolate antagonises the contractile activity of all three peptide leukotrienes (leukotriene C 4 , D 4 , and E 4 ) in human conducting airway smooth muscle to the same extent.
Animal studies have shown Accolate to be effective in preventing peptide leukotriene-induced increases in vascular permeability, which give rise to oedema in the airways, and to inhibit peptide leukotriene-induced influx of eosinophils into airways. The specificity of Accolate has been shown by its action on leukotriene receptors and not prostaglandin, thromboxane, cholinergic and histamine receptors.
In a placebo-controlled study where segmental bronchoprovocation with allergen was followed by bronchoalveolar lavage 48 hours later, zafirlukast decreased the rise in basophils, lymphocytes and histamine, and reduced the stimulated production of superoxide by alveolar macrophages.
Accolate attenuated the increase in bronchial hyperresponsiveness that follows inhaled allergen challenge. Further, methacholine sensitivity was diminished by long-term dosing with Accolate 20 mg twice daily.
Further, in clinical trials evaluating chronic therapy with Accolate, the lung function measured when plasma levels were at trough showed sustained improvements over baseline. Accolate shows a dose dependent inhibition of bronchoconstriction induced by UFACTURER SECTION APM ...ASTRAZENECA inhaled LTD 4 .
Asthmatic patients are approximately 10-fold more sensitive to the bronchoconstricting activity of inhaled LTD 4 . A single oral dose of Accolate can enable an asthmatic patient to inhale 100 times more LTD 4 and shows significant protection at 12 and 24 hours. Accolate inhibits the bronchoconstriction caused by several kinds of challenge, such as the response to sulphur dioxide, exercise and cold air. Accolate attenuates the early and late phase inflammatory reaction caused by various antigens such as grass, cat dander, ragweed and mixed antigens.
In asthmatic patients not adequately controlled by p-agonist therapy (given as required) Accolate improves symptoms (reducing daytime and nocturnal asthmatic symptoms), improves lung function, reduces the need for concomitant 0-agonist medication and reduces incidence of exacerbations.
Similar benefits have been seen in patients with more severe asthma receiving high dose inhaled steroids. In clinical studies, there was a significant first-dose effect on baseline bronchomotor tone observed within 2 hours of dosing, when peak plasma concentrations had not yet been achieved.
Initial improvements in asthma symptoms occurred within the first week, and often the first few days, of treatment with Accolate.
Pharmacokinetics
Peak plasma concentrations of zafirlukast are achieved approximately 3 hours after oral administration of Accolate. Administration of Accolate with food increased the variability in the bioavailability of zafirlukast and reduced bioavailability in most (75%) subjects. The net reduction was approximately 40%. Following twice-daily administration of Accolate (30 to 80 mg bd), accumulation of zafirlukast in plasma was low (not detectable-2.9 times first dose values; mean 1.45; median 1.27).
The terminal half-life of zafirlukast is approximately 10 hours. Steady-state plasma concentrations of zafirlukast were proportional to the dose and predictable from single-dose pharmacokinetic data. Zafirlukast is extensively metabolised. Following a radiolabelled dose the urinary excretion accounts for approximately 10% dose and faecal excretion for 89%. Zafirlukast is not detected in urine.
The metabolites identified in human plasma were found to be at least 90-fold less potent than zafirlukast in a standard in vitro test of activity. Zafirlukast is approximately 99% protein bound to human plasma proteins, predominantly albumin, over the concentration range 0.25 to 4.0 pg/ml. Pharmacokinetic studies in special populations have been performed in a relatively small number of subjects, and the clinical significance of the following kinetic data is not established.
Pharmacokinetics
of zafirlukast in adolescents and adults with asthma were similar to those of healthy adult males. When adjusted for body weight, the pharmacokinetics of zafirlukast are not significantly different between men and women. Elderly subjects and subjects with stable alcoholic cirrhosis demonstrated an approximately two-fold increase in C maM and AUC compared to normal subjects given the same doses of Accolate. There are no significant differences in the pharmacokinetics of zafirlukast in patients with mild renal impairment and in normal subjects. However, there are no conclusive data available in patients with moderate or severe renal impairment, hence the recommendation for caution is used in this patient population. Pre-Clinical Safety Data Relevant to the Prescriber After multiple doses of greater than 40 mg/kg/day for up to 12 months, liver enlargement associated with degenerative/ fatty change or glycogen deposition was seen in rats, mice and dogs.
Histiocytic aggregates were seen in a number of tissues of dogs. Male mice given 300 mg/kg zafirlukast daily had an increased incidence of hepatocellular adenomas compared to control animals. Rats given 2000 mg/kg zafirlukast daily had an increased incidence of urinary bladder papilloma compared to control animals. Zafirlukast was not mutagenic in a range of tests. The clinical significance of these findings during the long term use of Accolate in man is uncertain. There were no other notable findings from the pre-clinical testing.
Indications
Accolate is indicated for the treatment of asthma.
Contraindications
Accolate should not be given to patients who have previously experienced hypersensitivity to the product or any of its ingredients.
Accolate is contraindicated in patients with hepatic impairment or cirrhosis; it has not been studied in patients with hepatitis or in long term studies of patients with cirrhosis. Accolate is contraindicated in children under 12 years of age until safety information is available.
Side Effects
The following have been reported in association with the administration of Accolate:
Gastrointestinal: nausea, vomiting, abdominal pain, hepatitis (rare)
General: lower limb oedema (rare)
Musculoskeletal: arthralgia (rare), myalgia (rare) - Skin: rash (including blistering), hypersensitivity reactions including urticaria and angioedema (rare)
- Neurological: headache
Haematologic: bruising (rare), bleeding disorders, including menorrhagia (rare), thrombocytopenia (rare), and agranulocytosis (very rare).
The above events have usually resolved following cessation of therapy. Headache and gastrointestinal disturbance are usually mild and do not necessitate withdrawal from therapy. In placebo-controlled clinical trials, an increased incidence of infection has been observed in elderly patients given Accolate.
Infections were usually mild, predominantly affecting the respiratory tract.
Warnings
and
Precautions
Accolate should be taken regularly to achieve benefit, even during symptom free periods. Accolate therapy should normally be continued during acute exacerbations of asthma. Accolate does not allow a reduction in existing steroid treatment.
As with inhaled steroids and cromones (disodium cromoglycate, nedocromil sodium), Accolate is not indicated for use in the reversal of bronchospasm in acute asthma attacks.
Accolate has not been evaluated in the treatment of labile (brittle) or unstable asthma. Cases of eosinophilic conditions, including Churg-Slrauss Syndrome have been reported in association with Accolate usage. A causal relationship has neither been confirmed nor refuted.
If a patient develops an eosinophilic condition or a Churg-Strauss Syndrome type illness Accolate should be stopped, a rechallenge test should not be performed and treatment should not be restarted. Elevations in serum transaminases can occur during treatment with Accolate. These are usually asymptomatic and transient but could represent early evidence of hepatotoxicity, and have very rarely been associated with more severe hepa tocellular injury and liver failure. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g. anorexia, nausea, vomiting, right upper quadrant pain, fatigue, lethargy, flu-like symptoms, enlarged liver, pruritus and jaundice), Accolate should be discontinued.
The serum transaminases, in particular serum ALT, should be measured immediately and the patient managed accordingly. Patients in whom Accolate was withdrawn because of hepatotoxicity with no other attributable cause should not be reexposed to Accolate. Accolate is not recommended for patients with hepatic impairment including hepatic cirrhosis.
Pregnancy and Lactation The safety of Accolate in human pregnancy has not been established. In animal studies, zafirlukast did not have any apparent effect on fertility and did not appear to have any teratogenic or selective toxic effect on the foetus.
The potential risks should be weighed against the benefits of continuing therapy during pregnancy and Accolate should be used during pregnancy only il clearly needed. Zalirlukast is excreted in human breast milk. Accolate should not be administered to mothers who are breast-feeding. Effect on Ability to Drive and Operate Machinery There is no evidence that Accolate affects the ability to drive and use machinery. Pharmaceutical Particulars Storage Do not store above 30°C. Shelf life Please refer to expiry date on the blister strip or outer carton. Overdosage No information exists with regard to the effects of overdosage of Accolate in humans. Management should be supportive. Removal of excess medication by gastric lavage may be helpful.
Drug Interactions
Accolate may be administered with other therapies routinely used in the management of asthma and allergy. Inhaled steroids, inhaled and oral bronchodilator therapy, antibiotics and antihistamines are examples of agents which have been coadministered with Accolate without adverse interaction. Accolate may be administered with oral contraceptives without adverse interaction. Co-administration with warfarin results in an increase in maximum prothrombin time by approximately 35%. It is, therefore, recommended that if Accolate is coadministered with warfarin, prothrombin time should be closely monitored.
The interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. In clinical trials co-administration with theophylline resulted in decreased plasma levels of zalirlukast, by approximately 30%, but with no effect on plasma theophylline levels. However, during post-marketing surveillance, there have been rare cases of patients experiencing increased theophylline levels when co-administered Accolate.
Co-administration with terfenadine resulted in a 54% decrease in AUC for zafirlukast, but with no effect on plasma terfenadine levels.
Co-administration with acetylsalicylic acid ("aspirin”, 650 mg four times a day) may result in increased plasma levels of zafirlukast. by approximately 45%. Co-administration with erythromycin will result in decreased plasma levels of zafirlukast, by approximately 40%.
The clearance of zafirlukast in smokers may be increased by approximately 20%. At concentrations of 10 pg/ml and above, zafirlukast causes increases in the assay value for bilirubin in animal plasma. However, zafirlukast has not been shown to interfere with the 2,5-dichlorophenyl diazonium salt method of bilirubin analysis of human plasma.
Dosage and Administration
Accolate should be taken continuously.
Adults and children aged 12 years and over The dosage is one 20 mg tablet twice daily. This dosage should not be exceeded. Higher doses may be associated with elevations of one or more liver enzymes consistent with hepatotoxicity. As food may reduce the bioavailability of zafirlukast, Accolate should not be taken with meals. Elderly The clearance of zafirlukast is significantly reduced in elderly patients (over 65 years old), and and AUC are approximately double those of younger adults. However, accumulation ol zafirlukast is no greater than that seen in multiple-dose trials conducted in adult subjects with asthma, and the consequences of the altered kinetics in the elderly are unknown. Clinical experience with Accolate in the elderly (over 65 years) is limited and caution is recommended until further information is available. Children There is no clinical experience of the use of Accolate in children under 12 years of age. Until safety information is available, the use of Accolate in children is contraindicated. Renal Impairment No dosage adjustment is necessary in patients with mild renal impairment. However, experience is limited in patients with moderate to severe renal impairment (see Pharmacokinetics) so clear dose recommendations cannot be given; Accolate should be used with caution in this patient group
Packaging
Please refer to the outer carton for pack size. II/JB/000-029-748.2.0 ARIMIDEX
Composition
Arimidex is presented as white, biconvex, film-coated tablets containing 1 mg of anastrozole. A logo is impressed on one side and a tablet strength marking on the other side.
Properties
Pharmacodynamics Arimidex is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily from the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral 5. 74 ROC 4UFA ASTRAZENECA tissues. Oestrone is subsequently converted to oestradiol. Reducing circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer. In post-menopausal women, Arimidex at a daily dose of 1 mg produced oestradiol suppression of greater than 80% using a highly sensitive assay. Arimidex does not possess any progestogenic, androgenic or oestrogenic activity. Daily doses of Arimidex up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed. In a large phase III study conducted in 9366 post-menopausal women with early invasive breast cancer, adjuvant treatment with anastrozole following surgery showed statistical superiority over tamoxifen for the primary end point time to disease recurrence. Due to the immaturity of the data it is not possible to state the degree of this benefit in the long-term or whether this will translate into a survival advantage for anastrozole. Currently it is not known whether anastrozole adds a survival benefit to chemotherapy as it is known for tamoxifen. The long-term safety of anastrozole treatment is not yet known. When Arimidex and tamoxifen were coadministered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of oestradiol suppression produced by Arimidex. Pharmacokinetics Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steadystate plasma concentrations during once daily dosing of Arimidex tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters. Anastrozole pharmacokinetics are independent of age in post-menopausal women. Pharmacokinetics have not been studied in children. Anastrozole is only 40% bound to plasma proteins. Anastrozole is extensively metabolised by post-menopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase. The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers. Pre-Clinical Safety Data Acute toxicity In acute toxicity studies in rodents the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog the median lethal dose was greater than 45 mg/kg/day. Chronic toxicity Multiple dose toxicity studies utilised rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low dose (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme inducing properties of anastrozole, and were unaccompanied by significant toxic or degenerative changes. Mutagenicity Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen. Reproductive toxicology Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound. The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole. Carcinogenici ty A two year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrazole. A two year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.
Indications
Adjuvant treatment of postmenopausal women with oestrogen receptor positive early invasive breast cancer who are unable to take tamoxifen therapy because of high risk of thromboembolism or endometrial abnormalities. Treatment of advanced breast cancer in post-menopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.
Contraindications
Arimidex is contraindicated in: - pre-menopausal women. - pregnant or lactating women. - patients with severe renal impairment (creatinine clearance less than 20 ml/min). - patients with moderate or severe hepatic disease. - patients with known hypersensitivity to anastrozole or to any of the excipients as referenced on the carton. Oestrogen-containing therapies should not be co-administered with Arimidex as they would negate its pharmacological action. Concurrent tamoxifen therapy (see Drug Interactions).
Side Effects
(see tablel)
Warnings
and
Precautions
Arimidex is not recommended for use in children as safety and efficacy have not been established in this group of patients. The menopause should be defined biochemically in any patient where there is doubt about hormonal status. There are no data to support the safe use of Arimidex in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min). 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 and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials. Pregnancy and Lactation Arimidex is contraindicated in pregnant or lactating women.
(Arimidex) Table 1: Possible Adverse Drug Reactions VERY COMMON (> 10%) Vascular: Hol Hushes, mainly mild or moderate in nature.
COMMON General: Asthenia, mainly mild or moderate (> 1% and < 10%) in nature.
Musculoskeletal, connective Joint pain/sliffness, mainly mild or tissue and bone: moderate in nature.
Reproductive system and breast: moderate in nature. V
aginal dryness, mainly mild or Skin and subcutaneous tissue:
Hair thinning, mainly mild or moderate in nature.
Rash, mainly mild or moderate in nature.
Gastrointestinal: Nausea, mainly mild or moderate in nature.
Diarrhoea, mainly mild or moderate in nature.
Nervous system: Headache, mainly mild or moderate in nature.
UNCOMMON Reproductive system and breast: Vaginal bleeding, mainly mild or (> 0.1% and < 1%) moderale in nature*.
Metabolism and nutrition: Anorexia, mainly mild in nature.
Hypercholesterolaemia, mainly mild or moderate in nature.
Gastrointestinal: Vomiting, mainly mild or moderate in nature.
Nervous system: Somnolence, mainly mild or moderate in nature.
VERY RARE Skin and subcutaneous tissue: Erythema multiformae (< 0.01%) Stevens-Johnson syndrome 'Vaginal bleeding has been reported uncommonly, mainly in patients with advanced breast cancer during the first few weeks aflor changing from existing hormonal therapy to treatment with Arimidex.
If bleeding persists, further evaluation should be considered. Elevated y-GT and alkaline plwsphntase have boon reported uncommonly (> 0.1% and < 1%).
A causal relationship for these changes has not been established, Effects on Ability to Drive and Operate Machinery Arimidex is unlikely to impair the ability of patients to drive and operate machinery.
However, asthenia and somnolence have been reported with the use of Arimidex and caution should be observed when driving or operating machinery while such symptoms persist.
Pharmaceutical Particulars Storage Do not store above 30°C. Shelflife Please refer to expiry date on the blister strip or outer carton. Overdosage There is limited clinical experience of accidental overdosage.
In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of Arimidex, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to post-menopausal women with advanced breast cancer; these dosages were well tolerated.
A single dose of Arimidex that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic.
In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because Arimidex is not highly protein bound.
General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Drug Interactions
Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of Arimidex with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450.
A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with Arimidex who also received other commonly prescribed drugs. Oestrogen-containing therapies should not be co-administered with Arimidex as they would negate its pharmacological action. Tamoxifen should not be co-administered with Arimidex, as this may diminish its pharmacological action (see
Contraindications
).
Dosage and Administration
Adults including the elderly One 1 mg tablet to be taken orally once a day. Children Not recommended for use in children. Renal Impairment No dose change is recommended in patients with mild or moderate renal impairment Hepatic Impairment No dose change is recommended in patients with mild hepatic disease. For early disease, the recommended duration of treatment shouid be 5 years.
Packaging
Please refer to the outer carton for pack size. t: 1 mg. ONC.000-107-912.1.0