INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
KESSAR™ 10 (TABLETS)
KESSAR™ 20 (TABLETS)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

KESSAR™ 10 (TABLETS)
KESSAR™ 20 (TABLETS)

COMPOSITION:
Each 10 mg tablet contains tamoxifen citrate equivalent to 10 mg tamoxifen.
Each 20 mg tablet contains tamoxifen citrate equivalent to 20 mg tamoxifen.

PHARMACOLOGICAL CLASSIFICATION:
A 21.12 Hormone inhibitors

PHARMACOLOGICAL ACTION:
KESSAR exhibits anti-oestrogenic activity by competing with oestrogen for binding sites in the target organs. When bound to the receptor, tamoxifen induces changes in the receptor shape inhibiting its binding to the oestrogen responsive element on DNA.
KESSAR also has weak oestrogenic effects.
After oral administration tamoxifen is readily absorbed with peak concentrations within 4 to 7 hours.
Steady state concentration (about 300 ng/mL) can be achieved after 4 weeks of treatment with 40 mg daily.
Tamoxifen is highly bound to serum proteins (>98%).
Tamoxifen is metabolised predominantly to N-desmethyltamoxifen and to the minor metabolites, e.g. 4-hydroxytamoxifen.
Tamoxifen has a half-life of 7 days, while the half-life of N-desmethyltamoxifen is 14 days.
Tamoxifen and/or its metabolites undergo extensive enterohepatic circulation which can be accountable for prolongation of serum levels and primary faecal excretion.

INDICATIONS:
Therapy for advanced disease:
KESSAR is indicated for the palliative treatment of certain types of advanced breast tumours.
Adjuvant therapy:
KESSAR is effective in delaying recurrence following total mastectomy and axillary dissection or segmented mastectomy, axillary dissection and breast irradiation in women with axillary node-negative breast cancer. Data are insufficient to predict which women are most likely to benefit and to determine if KESSAR provides any benefit in women with tumours of less than 1 cm. KESSAR is effective in delaying recurrence following total mastectomy and axillary dissection in postmenopausal women with breast cancer. In some adjuvant studies most of the benefit to date has been in the subgroup with 4 or more positive axillary nodes. The estrogen and progesterone receptor values may help to predict whether adjuvant KESSAR therapy is likely to be beneficial.

CONTRA-INDICATIONS:
KESSAR must not be given during pregnancy or to breast feeding women and should be used with caution in women with functioning ovaries.
KESSAR is contra-indicated in patients with known hypersensitivity to any of the tablets’ingredients.

WARNINGS:
Endometrial changes: An increased incidence of endometrial changes, including hyperplasia, polyps and cancer has been reported in association with tamoxifen treatment. Any patients receiving or having previously received tamoxifen, who report vaginal bleeding, should be promptly investigated.
These events are likely to be related to the oestrogenic properties of KESSAR.
In addition, it is recommended that a complete gynaecological examination be performed before initiating tamoxifen therapy to detect any pre-existing endometrial abnormalities, and to repeat such examinations during tamoxifen treatment on a yearly basis.

DOSAGE AND DIRECTIONS FOR USE:
The usual dosage is 20 - 40 mg/day given either in two divided doses (morning and evening) or as a single daily dose. In the management of advanced disease, KESSAR treatment is to be continued until disease progression. The optimum duration of adjuvant therapy has not been established, but at least 2 years of treatment is advisable. However, recent data seem to suggest that no further therapeutic advantage is gained if the treatment is prolonged past 5 years.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Severe adverse reactions may sometimes be controlled by reduction of dosage.
The most frequent adverse effects are hot flushes, nausea and vomiting, menstrual irregularities, vaginal bleeding or discharge, pruritus vulvae, rashes and dry skin .
Patients with bone metastases can experience a transient, sometimes severe increase in bone or tumour pain, often combined with hypercalcemia, which may occur shortly after starting therapy. Local disease flare may also occur but generally subsides rapidly. These events may require temporary interruption of tamoxifen treatment, with subsequent resumption of therapy at a reduced dosage, with gradual increase to the full dose.
Other adverse effects associated with KESSAR therapy include:

•	possibly an increased tendency to thromboembolism and pulmonary embolism.
•	oedema and fluid retention,
•	weight gain
•	musculoskeletal pain
•	gastro-intestinal intolerance including abdominal cramps and diarrhoea
•	neuro-psychiatric symptoms - dizziness, lightheadedness, headache, depression, fatigue, confusion
•	ocular disturbances - blurred vision and loss of visual acuity, corneal opacities, and retinopathies.
•	alterations of liver function parameters and very rarely, severe hepatic abnormalities - including hepatic necrosis, hepatic failure and hepatocellular cancer
•	alopecia
•	leukopenia
•	thrombocytopenia
•	serum lipid changes

Precautions:
Changes in calcium metabolism: hypercalcemia may occur in some breast cancer patients with bone metastases within a few weeks of starting treatment with KESSAR. Patients with bone metastases should be closely monitored during the first weeks of herapy; if hypercalcemia does occur appropriate measures should be taken and the product should be withdrawn.
Thromboembolic disorders: these have been reported to occur occasionally in patients receiving KESSAR; therefore, the use of tamoxifen in patients at a high risk of thromboembolism has to be weighed against the clinical benefits of therapy.
Premenopausal patients: must be examined before treatment to exclude the possibility of pregnancy. Moreover, Tamoxifen may occasionally increase oestradiol plasma concentrations and may induce ovulation, exposing patients at risk of pregnancy. In pre-menopausal woman, KESSAR completely suppresses menstruation and cystic ovarian swelling may develop.
Tamoxifen was genotoxic in some in-vitro and in-vivo genotoxicity tests in rodents.
Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long term studies. The clinical relevance of these findings has not been established.
Interactions:
When KESSAR is used concurrently with coumarin-like anticoagulants (e.g. warfarin), a significant increase in the anticoagulant effect may occur leading to bleeding risks. KESSAR and coumarin-like agents should be used concomitantly with caution, and under these conditions the prothrombin time should be closely monitored.
Medicines that are known to decrease renal calcium excretion (e.g. thiazide diuretics) may increase the risk of hypercalcemia and should be used with caution in patients with bone metastases and who are receiving tamoxifen.
The serum levels of tamoxifen and its metabolites are markedly reduced after aminoglutethimide administration due to increased tamoxifen clearance.
Concurrent use of bromocriptine may result in increased serum levels of tamoxifen and metabolites.
Various degrees of oestrogen effects on Papanicolau smears have been reported in postmenopausal patients who are receiving tamoxifen.
Increased serum thyroxine levels, likely due to an increase in thyroxine-binding globulin, may occur in patients who are receiving tamoxifen, but are not accompanied by clinical hyperthyroidism.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See “SIDE-EFFECTS”.
There is no specific antidote and treatment must be symptomatic and supportive.

IDENTIFICATION:
KESSAR™ 10 Tablets - a white, round, convex, uncoated tablet, 6 mm in diameter embossed with "10" on the one side.
KESSAR™ 20 Tablets - a white, round, convex, uncoated tablet, 9 mm in diameter embossed with "20" on the one side.

PRESENTATION:
Aluminium/aluminium blister pack of 10 tablets in 30's and 250's.

STORAGE INSTRUCTIONS:
Store below 25°C and protect from light.
Keep out of reach of children.

REGISTRATION NUMBERS:
KESSAR™ 10 Tablets: S/21.12/358
KESSAR™ 20 Tablets: S/21.12/359

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Limited
Alphen West G
George Street
Midrand
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
July 1997
New addition to this site: February 2005
Source: Pharmaceutical Industry
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