INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DIVA-35 (tablets)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DIVA-35 (tablets)

COMPOSITION:
The 28-day pack (every day pack) contains 21 hormonal tablets each with 2 milligrams cyproterone acetate and 35 micrograms of ethinylestradiol. It also contains 7 non-hormonal tablets

PHARMACOLOGICAL CLASSIFICATION:
A 21.8.2 Progesterone with estrogens.
PHARMACOLOGICAL ACTION:
Cyproterone acetate blocks the effect of endogenously produced and exogenously administered androgens at the target organs by means of competitive inhibition. The stimulating effect of male sex hormones on androgen-dependent structures and functions is weakened or abolished by cyproterone acetate.
Excessive sebaceous gland function is decreased.
Apart from the described anti-androgen effect, cyproterone acetate also has a progestational action. The ethinylestradiol in the combination inhibits ovulation and changes the cervical mucus and the endometrium rendering them unfavourable for sperm penetration and nidation of a fertilized ovum, respectively.

INDICATIONS:
Androgen-dependent acne, especially those forms which are accompanied by seborrhea or by inflammation or formation of nodes (acne papulopustulosa, acne nodulocystica), androgen-dependent alopecia and mild forms of hirsutism.
Oral contraception in women requiring anti-androgen therapy.

CONTRA-INDICATIONS:

1.	Pregnancy and lactation.
2.	Severe disturbances of liver function; recurrent cholestatic jaundice; jaundice or persistent itching during a previous pregnancy; the Dubin-Johnson or Rotor syndromes; previous or existing liver tumours.
3.	Existing or previous arterial or venous thrombotic or embolic processes, conditions which predispose to them (e.g. disorders of the clotting system with a tendency towards thrombosis and certain heart diseases).
4.	Sickle-cell anaemia.
5.	Existing or treated breast or endometrial cancer.
6.	Severe diabetes mellitus with vascular changes.
7.	Disturbances of lipid metabolism.
8.	History of herpes of pregnancy.
9.	Deterioration of otosclerosis during pregnancy.
10.	Undiagnosed vaginal bleeding.
11.	Hypersensitivity of any of the components of DIVA-35.
12.	Severe or focal migraine or cerebrovascular insufficiency.

Strict medical supervision is required in patients with diabetes or a tendency to diabetes, high blood pressure, varicose veins, a history of phlebitis, otosclerosis, multiple sclerosis, epilepsy, porphyria, tetany, chorea minor, asthma, depression, or conditions influenced by fluid retention.

Reasons for immediate discontinuation of DIVA-35:

1.	Occurrence, or exacerbation of migraines, headaches or unusually frequent or severe headaches.
2.	Sudden disturbances of vision or hearing or other perceptual disorders.
3.	First signs of thrombophlebitis or thromboembolic symptoms (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Pain and tightness in the chest.
4.	Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilization, e.g. after accidents or surgery. DIVA-35 should not be restarted until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin.
5.	Onset of jaundice, hepatitis or itching of the whole body.
6.	Increase in epileptic seizures.
7.	Significant rise in blood pressure.
8.	Onset of severe depression.
9.	Severe upper abdominal pain or liver enlargement.
10.	Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy.
11.	Pregnancy.

WARNINGS:
DIVA-35 is not for use in men and should not be used in children.
The combination of cyproterone acetate and ethinylestradiol has been found to cause an increase in the incidence of tumours (including carcinoma) in the liver of rats, when given in very high doses and for the majority of the animal’s life-span. The relevance of this finding to human is unknown.
In rare cases benign and, in even rarer cases, malignant liver tumours leading to life-threatening intra-abdominal haemorrhage in isolated cases, have been observed after use of hormonal substances such as those contained in DIVA-35. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis.
The incidence of diseases of the circulatory system in women using combined oral contraceptives is significantly greater than those of controls, and the mortality is slightly increased. Coronary thrombosis, cerebrovascular accidents and venous thrombosis are more likely to occur in women aged 35 years or over, particularly if they have used the contraceptive for longer than 5 years, if they smoke, if they are obese or if they are hypertensive. Additional risk factors are diabetes, hypercholesterolaemia and familial hyperlipoproteinaemia. However the risk of mortality due to oral contraceptives in women under 35 who are in the high-risk group is in general far less than the risk of mortality due to pregnancy.

INTERACTIONS:
Interactions with other medicines and efficacy:
Hepatic enzyme inducers such as barbiturates, primidone, phenobarbitone, phenytoin, phenylbutazone, rifampicin, carbamazepine and griseofulvin can impair the contraceptive efficacy of DIVA-35. For women receiving long-term therapy with hepatic enzyme reducers, another method of contraception should be used.
Oral contraceptive failure may occur with concomitant antibiotic therapy. For maximal protection, additional non-hormonal contraception should be recommended for the duration of antibiotic therapy and for seven days afterwards. Those on long-term therapy need only take extra precaution for the first two weeks of antibiotic therapy.
Spotting and breakthrough bleeding are possible signs of diminished contraceptive effectiveness.
With vomiting or diarrhoea, the absorption of oral contraceptives may be diminished and women should be advised to use additional methods of contraception at the time of such disorders in order to prevent a possible pregnancy, which would be a compelling reason for the discontinuation of this product.
The requirements for oral antidiabetics or insulin can change as a result of the effect on glucose tolerance.
The herbal remedy St John’s Wort (Hypericum perforatum) should not be taken concomitantly with DIVA-35 as this could potentially lead to a loss of contraceptive effect.
The effectiveness of anticoagulants, antidepressant, antihypertensives, beta-blockers and diuretics, may be reduced if administered with DIVA-35. The plasma concentrations of ciclosporin and theophylline may be increased with concomitant use.
Large supplements of Vitamin C may increase serum ethinylestradiol concentration. Withdrawal of high doses of Vitamin C may lead to breakthrough bleeding.

Effects on laboratory tests:
Oral contraceptives may interfere with some laboratory estimations, in particular hormones, glucose tolerance, thyroid function, blood coagulation, serum triglycerides and liver function tests.

PREGNANCY AND LACTATION:
DIVA-35 is contra-indicated during pregnancy and lactation. See Contra-Indications and Warnings above.

DOSAGE AND DIRECTIONS FOR USE:
Before starting DIVA-35, a thorough gynaecological examination (including the breasts and a cytological smear of the cervix) should be carried out and the family case history carefully noted. In addition, disturbances of the clotting system must be ruled out if any members of the family have suffered from thromboembolic diseases (e.g. deep vein thrombosis, stroke, myocardial infarction) already at a young age. Pregnancy must be excluded. If the hirsutism has only recently appeared or has lately intensified to a considerable extent, an androgen-producing tumour or an adrenal enzyme defect must be excluded in the differential diagnosis.
Initial course:
One tablet daily for 28 days, starting on the first day of the menstrual cycle (the first day of menstruation counting as Day 1).
Subsequent course:
After the last tablet has been taken from the first pack, tablet-taking is continued from a new pack the very next day.
Length of use:
The length of use depends on the severity of the clinical picture. In general, treatment should be carried out over several months. It is recommended that DIVA-35 be taken for at least another 3 to 4 cycles after the signs have subsided. Should there be a recurrence weeks or months after discontinuation, treatment with DIVA-35 may be resumed.
When changing from an oral contraceptive and relying on the contraceptive action of DIVA-35, the instructions given below should be followed:
Changing from 21-day combined oral contraceptives:
The first tablet of DIVA-35 should be taken on the first day immediately after the end of the previous oral contraceptive course. Additional contraceptive precautions are not required.
Changing from a combined Every Day Pill (28 day tablets):
The first DIVA-35 tablet should be taken the day after the last active tablet from the Every Day Pill pack. Additional contraceptive precautions are not then required.
Changing from a progesterone-only pill (POP):
The first tablet of DIVA-35 should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining progesterone-only pills should be discarded.
Post-partum and post-abortum use:
After pregnancy, DIVA-35 can be started 21 days after a vaginal delivery, provided the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of pill taking. Since the first post-partum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets.
After a first-trimester abortion, DIVA-35 may be started immediately and no additional contraceptive precautions are required.
Special circumstances requiring additional contraception:
If a patient forgets to take her tablet at the usual time, she must take it within the next 12 hours at the latest. If more than 12 hours elapse from the time that she normally takes her tablet, and also in the case of vomiting or diarrhoea, she must continue to take the other tablets in the pack at the usual time in order to avoid premature withdrawal bleeding during the cycle. At the same time, however, an additional, non-hormonal method of contraception (with the exception of the rhythm and temperature methods) must be employed in order to prevent a pregnancy which would be a compelling reason for the discontinuation of DIVA-35.
If tablet(s) have been missed during the last 7 days of a pack, there should be no break before the next pack is started. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on tablet taking days, but this is not clinical significant. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Gastro-intestinal system:
Frequent: Gastro-intestinal irritation, nausea and abdominal cramps.
Less frequent: Vomiting.
Urogenital:
Frequent: Breast tenderness.
Less frequent: Amenorrhoea, menstrual irregularities such as spotting, breakthrough bleeding, changes in menstrual flow, changes in cervical erosion and cervical secretions, amenorrhoea during and after treatment and anovulation post treatment can occur. There may be a slight increase in the risk of cervical cancer (other factors may be involved) and breast cancer.
Vaginal candidiasis has been reported.
Metabolic and nutritional:
Less frequent: Cholestatic jaundice, gall disease, reduced glucose tolerance and changes in lipid metabolism have been reported. Liver function may be impaired although jaundice is rare. Water retention and weight gain may occur.
In rare cases benign, and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage, have been observed after the use of hormonal substances such as those contained in DIVA-35. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnostic considerations.
Central nervous system:
Less frequent: Changes in libido, mild dizziness, headache, migraine, depressive moods, mood changes, drowsiness and changes in appetite may occur.
Skin and appendages:
Frequent: Skin irritation and redness, pruritus.
Less frequent: Poor tolerance of contact lenses, alopecia, chloasma (melasma), allergic rash, photosentivity and haemorrhagic eruption may occur.
Circulatory/Cardiovascular system:
The incidence of disease of the circulatory system in women using combined oral contraceptives is significantly greater than those on controls, and the mortality is slightly increased. Increased mortality from myocardial infarction is much greater in women aged 35 years or over, particularly if they used the contraceptive for longer than 5 years and if they smoke. Other risk factors include a family history of arterial disease, hypercholesterolaemia, familial hyperlipoproteinaemia, diabetes mellitus, hypertension, obesity and migraine. Specific risk factors for venous thrombo-embolism include a family history of venous thrombo-embolism, varicose veins and, again, obesity. However, the risk of mortality due to oral contraceptives in women under 35 who are in the high-risk group is in general far less than the risk of mortality due to pregnancy. Hypertension may occur in association with the use of oral contraceptives. Regular blood pressure checks, including a pre-treatment level, are advisable.
Special Precautions:
See Warnings and Dosage and Directions for use.
Hypertension may occur in association with the use of oral contraceptives. Regular blood-pressure checks, including a pretreatment level, are advisable.
Prolonged amenorrhoea following the use of oral contraceptives may occur. Caution is advised where oligomenorrhoea or amenorrhoea have occurred in the past.
The use of ultraviolet lamps, for the treatment of acne, or prolonged exposure to sunlight, increases the risk of the deterioration of chloasma.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See Side-effects and Special Precautions above.
Treatment is symptomatic and supportive.

IDENTIFICATION:
21 round, biconvex, yellow sugar-coated tablets with a 5.7 mm nominal diameter and 7 round, biconvex, white sugar-coated tablets with a 6.85 mm nominal diameter.

PRESENTATION:
Each PVC/PVDC blister and aluminium foil contains 28 tablets. Each carton contains either 1 or 3 blister strips.

STORAGE INSTRUCTIONS:
Store in original packs below 25ºC. Protect from light.
STORE ALL MEDICINES OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
38/21.8.2/0055

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Dr Reddy’s Laboratories (Pty) Ltd
PO Box 2064
Parklands
2121

DATE OF PUBLICATION OF THE PACKAGE INSERT:
June 2005

New addition to this site: February 2007
Source: Pharmaceutical Industry
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