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Logo TRIPHASIL® tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

TRIPHASIL® tablets

COMPOSITION:
The six brown tablets of TRIPHASIL contain 30 µg
ethinyl oestradiol and 50 µg levonorgestrel.
The five white tablets contain 40 µg ethinyl oestradiol and 75 µg levonorgestrel
The ten yellow tablets contain 30 µg ethinyl oestradiol and 125 µg levonorgestrel.
The seven red tablets are inert.

PHARMACOLOGICAL CLASSIFICATION:
Category A, 18.8 Ovulation controlling agents.

PHARMACOLOGICAL ACTION:
TRIPHASIL has a three-phase dosage regimen which conforms with physiological pattern of the normal cycle. The oestrogen/progestogen ratio varies during the cycle, the dosage ratios being administered as a 6-day/5-day/10-day regimen in order to ensure good cycle control and to bring about distinct cyclical changes at the level of the vaginal epithelium and the endometrium for less likelihood of implantation.
Ovulation is inhibited by suppression of gonadotropin release particularly the mid-cycle peaks, and the viscosity of the cervical mucous increased, impairing sperm penetration and an endometrium less receptive for implantation is formed.
Sebaceous glands are androgen dependent and excessive androgen activity of the skin may exacerbate acne. Oestrogens may exhibit androgen antagonism and suppress sebaceous gland activity.
Pharmacokinetics:
Ethinyl oestradiol and levonorgestrel are well absorbed from the gastrointestinal tract. Ethinyl oestradiol is subject to considerable first-pass metabolism with a mean bioavailability of 40-45%.
Levonorgestrel does not undergo first-pass metabolism and is therefore completely bioavailable.
Levonorgestrel is extensively plasma protein bound both to sex hormone binding globulin (SHBG) and albumin. Ethinyl oestradiol, however, is bound in plasma only to albumin and enhances the binding capacity of SHBG. Following oral administration, peak plasma levels of each drug occur within 1 to 4 hours.
The elimination half-life of ethinyl oestradiol is approximately 25 hours. It is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present both free and as conjugates with glucuronide and sulphate. Conjugated ethinyl oestradiol is excreted in bile and subject to enterohepatic recirculation. About 40% of the drug is excreted in the urine and 60% is eliminated in the faeces.
The elimination half-life for levonorgestrel is approximately 24 hours. The medicine is primarily metabolized by reduction of the A ring followed by glucuronidation. About 60% of levonorgestrel is excreted in the urine and 40% is eliminated in the faeces.

INDICATIONS:
TRIPHASIL is indicated for fertility control in women and for the control of cases of dysfunctional uterine bleeding and symptomatic treatment of primary dysmenorrhoea where contraception is also desired.

TRIPHASIL may benefit women on contraception with coincidental acne.

CONTRA-INDICATIONS:
(a) Oral contraceptives are contra-indicated in patients with recurrent cholestatic jaundice, or impaired liver function, known or suspected oestrogen-dependent neoplasia, thrombophlebitis, or thromboembolic disorders, or a history thereof, severe migraine, cerebrovascular insufficiency coronary-artery disease and undiagnosed vaginal bleeding. Medication should be discontinued immediately if migraine becomes focal or there is a loss of vision or if there is an onset of unexplained chest pain.
(b) Relative contra-indications include a history of diabetes mellitus, epilepsy, asthma, hypertension depression, porphyria, or states in which fluid retention occur.
(c) Oral contraceptives must be avoided in known or suspected pregnancy.
(d) Known or suspected carcinoma of the breast.
(e) Benign or malignant liver tumours which developed during the use of oral contraceptives or oestrogen-containing products.

WARNINGS:
CIGARETTE SMOKING
CIGARETTE SMOKING INCREASES THE RISK OF SERIOUS CARDIOVASCULAR SIDE-EFFECTS FROM THE USE OF ORAL CONTRACEPTIVES. THE RISK INCREASES WITH AGE AND WITH HEAVY SMOKING (15 OR MORE CIGARETTES PER DAY) AND IS QUITE MARKED IN WOMEN OVER 35 YEARS OF AGE. WOMEN WHO USE ORAL CONTRACEPTIVES SHOULD BE STRONGLY ADVISED NOT TO SMOKE.

Ocular Lesions
Discontinue oral contraceptives and institute appropriate diagnostic and therapeutic measures if there is a gradual or sudden, partial or complete loss of vision proptosis or diplopia papilloedema or any evidence of retinal vascular lesions or optic neuritis.
Carcinoma
Long-term continuous administration of either natural or synthetic oestrogen in certain animal species increases the frequency of carcinoma of the breast, cervix, vagina and liver.
At present, there is no confirmed evidence from human studies which would indicate that an increased risk of cancer is associated with the use of oral contraceptives. Close clinical surveillance is nevertheless essential in all women taking these preparations. In all cases of undiagnosed, persistent, or recurrent vaginal bleeding, appropriate diagnostic measures should be taken to eliminate the possibility of malignancy. Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms should be monitored with particular care.
Headache
The onset or exacerbation of migraine or development of headache of a new pattern which is recurrent, persistent, or severe, requires discontinuation of the oral contraceptive and evaluation of the cause.
Carbohydrate and Lipid Metabolic Effects
A decrease in glucose tolerance has been observed in a significant percentage of patients on oral contraceptives. For this reason prediabetic and diabetic patients should be carefully observed while receiving the oral contraceptive. An increase in triglycerides and total phospholipids has been observed in patients receiving oral contraceptives.
Use During or Immediately Preceding Pregnancy
Foetal abnormalities, including heart defects and limb defects, have been reported in offspring of women who have taken oral contraceptives in early pregnancy. Pregnancy should be ruled out before an oral contraceptive regimen is begun and considered in women who have missed two consecutive menstrual periods. The possibility of pregnancy should be considered at the first missed menstrual period in a patient who has not adhered to the prescribed regimen. Further oral contraceptive use should be withheld until pregnancy has been ruled out.
Oral contraceptives have not been shown to have any deleterious effects on the foetus or to increase the incidence of miscarriage in women who discontinue their use PRIOR to conception. However, in women who discontinue oral contraceptives with the intent of becoming pregnant a nonhormonal method of contraception is recommended for a period of three months before attempting to conceive.
Female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is considerable evidence that oestrogens are ineffective for these indications, and there is no evidence from well-controlled studies that progestins are effective for these uses.
The administration of progestin-only or oestrogen- progestin combinations to induce withdrawal bleeding should not be used as a test of pregnancy.
Use during lactation: See “Side-effects and Special Precautions”, Precaution 10.
Bleeding Irregularities
Breakthrough bleeding, spotting and amenorrhoea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, non-functional causes should be borne in mind. In undiagnosed persistent or recurrent bleeding from the vagina, appropriate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to a regimen with a higher oestrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary, since this may increase the risk of thromboembolic disease.
Women with a history of oligomenorrhoea or secondary amenorrhoea or young women without regular cycles may have a tendency to remain anovulatory or to become amenorrhoeic after discontinuation of oral contraceptives. Women with these pre-existing problems should be advised of this possibility and encouraged to use another method of contraception. Post-use anovulation, possibly prolonged, may also occur in women without previous irregularities.
Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
Thromboembolic Disorders
An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The physician should be alert to the earliest manifestations of those disorders (e.g. thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, cerebral haemorrhage, cerebral thrombosis, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Should any of these occur or be suspected, the medicine should be discontinued immediately. A four- to six-fold increased risk of thromboembolic complications following surgery has been reported in users of oral contraceptives. If feasible, oral contraceptives should be discontinued at least 4 weeks before surgery associated with an increased risk of thromboembolism or prolonged immobilisation.
Myocardial Infarction and Coronary Artery Disease
An increased risk of myocardial infarction associated with the use of oral contraceptives has been reported. Studies found that the greater the number of underlying risk factors for coronary artery disease (cigarette smoking, hypertension, hypercholesterolaemia, obesity, diabetes history of pre-eclampsia) the higher the risk of developing myocardial infarction, regardless of whether or not the patient used an oral contraceptive. Oral contraceptives, however, were found to be a clear additional risk factor.
Hepatic Tumours
Benign hepatic adenomas have been found to be associated with the use of oral contraceptives. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal haemorrhage. This has been reported in short- and long-term users of oral contraceptives. Such lesions may present as an abdominal mass or with signs and symptoms of an acute abdomen and should be considered if the patient has abdominal pain and tenderness or evidence of intra-abdominal bleeding.
Elevated Blood Pressure
An increase in blood pressure has been reported in patients receiving oral contraceptives. In some women hypertension may occur within a few months of beginning use. In the first year of use, the prevalence of women with hypertension is low but the incidence increases with increasing exposure. Age is also strongly correlated with the development of hypertension in oral contraceptive users. Women who previously have had hypertension during pregnancy may be more likely to develop an elevation of blood pressure when given oral contraceptives. If blood pressure rises markedly, the drug should be discontinued. Hypertension that develops as a result of taking oral contraceptives usually returns to normal after discontinuing the medicine.
Gallbladder Disease
Studies report an increased risk of surgically confirmed gallbladder disease in users of oestrogens and oral contraceptives.

DOSAGE AND DIRECTIONS FOR USE:
FOR CONTRACEPTION
To achieve maximum effectiveness, TRIPHASIL tablets must be taken exactly as directed and at intervals not exceeding 24 hours. Patients should be instructed to take the tablets at the same time every day, preferably after the evening meal or at bedtime.
First Cycle:
The patient is instructed to take the first TRIPHASIL tablet on the first day of the menstrual cycle (first day of bleeding). The first tablet should be selected from those in the red area of the pack marked with the appropriate day of the week. Thereafter, one tablet is taken daily, following the arrows marked on the package until all the tablets have been taken. Withdrawal bleeding should occur within 2 to 4 days after the patient has taken the last yellow tablet.
NOTE:
1. During this first cycle where treatment with TRIPHASIL tablets is started after the first day of the menstrual cycle, contraceptive reliance should not be placed on TRIPHASIL tablets and a mechanical, i.e. barrier, method of contraception should be supplemented for the first 14 consecutive days of administration. If the tablets are begun after Day 5 or postpartum, it must be considered that ovulation and conception may have occurred before the tablets were started.
2. New patients with a history of short menstrual cycles (i.e. less than 25 days) should also use a supplementary, nonsteroidal method of contraception (e.g. mechanical) until they have taken a tablet daily for 14 consecutive days.
Subsequent Cycles:
A new pack should be started the day after completion of the previous pack by taking the tablet in the red area of the new pack indicated with the appropriate day of the week. There must be no interruption of treatment, i.e. the new pack is started immediately after completion of the previous pack and each new pack is started with the same tablet in the red area of the pack even if withdrawal bleeding has not occurred or is still in progress. This method should continue for as long as contraception is desired. Each cycle or pack will begin on the same day of the week.
The patient who is changing from another oral contraceptive product will begin TRIPHASIL tablets on the day she would usually start a new package of the other product. During the first TRIPHASIL tablet cycle, a mechanical, i.e. barrier, method of contraception should be used until 14 consecutive daily tablets have been taken.
If transient spotting or breakthrough bleeding occurs, the patient is instructed to continue the regimen since such bleeding is usually without significance. It the bleeding is persistent or prolonged, the patient is advised to consult her doctor.
In the nonlactating mother, use of TRIPHASIL tablets may be instituted immediately after delivery or at the first postpartum examination, whether or not menstruation has resumed.

Missed Tablets:
The patient should be instructed to take a missed tablet as soon as it is remembered. If two consecutive tablets are missed, they should both be taken as soon as remembered. The next tablet should be taken at the usual time. If at any time the patient misses one or two tablets she should also use a supplementary, nonsteroidal method of contraception (e.g. mechanical) until she has taken a tablet daily for 14 consecutive days or until the package is finished if less than 14 tablets remain. If the patient misses one or more inert tablets, she is still protected against pregnancy, provided she begins the active tablets on the proper day. If three consecutive tablets are missed, all medication has to be discontinued and the remainder of the package discarded. A new tablet cycle is started on the eighth day after the last tablet was taken and a supplementary nonsteroidal means of contraception (e.g. mechanical) should be used for the remaining days without tablets and until the patient has taken a tablet daily for 14 consecutive days.
If withdrawal bleeding does not occur and TRIPHASIL tablets have been taken according to directions, it is unlikely that the patient has conceived. She should be instructed to begin a second course of TRIPHASIL tablets on the usual day. If bleeding does not occur at the end of this second cycle, TRIPHASIL tablets should not be taken until diagnostic procedures to exclude the possibility of pregnancy have been performed. If the patient has not adhered to the prescribed regimen (missed one or more active tablets or started taking them on a day later than recommended) the probability of pregnancy should be considered at the time of the first missed period before TRIPHASIL is resumed.

FOR THE SYMPTOMATIC TREATMENT OF PRIMARY DYSMENORRHOEA AND CASES OF DYSFUNCTIONAL UTERINE BLEEDING - Dosage as for Contraception.

FOR THE TREATMENT OF ANDROGEN-DEPENDENT ACNE - Dosage as for Contraception.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
1. The following side-effects may occur:
  Nausea and/or vomiting
  Headache
  Temporary slight intermenstrual bleeding
  Change in libido
  Change in menstrual flow
  Depressive moods
  Chloasma
  Breast changes including tenderness, enlargement and secretion
  Increase or decrease in mass
2. The following should be considered potential side-effects of TRIPHASIL tablets:
  Change in cervical erosion or cervical secretion
  Rash (allergic)
  Vaginal candidiasis
  Changes in corneal curvature (steepening)
  Intolerance to contact lenses
  Gastrointestinal disturbances such as bloating and abdominal cramps
3. The following side-effects have been reported in users of oral contraceptives:
  Premenstrual-like syndrome         Dizziness
  Cataracts         Hirsutism
  Chorea         Loss of scalp hair
  Changes in appetite         Erythema multiforme
  Cystitis-like syndrome         Erythema nodosum
  Nervousness         Haemorrhagic eruption
  Vaginitis         Precipitation of acute
  Haemolytic uremic syndrome         attack of porphyria

4. The incidence of disease of the circulatory system in women using combined oral contraceptives is significantly greater than that of controls, and the mortality is slightly increased. Coronary thrombosis, cerebrovascular incidents 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 five years, if they smoke, if they are obese or it 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.
5. Hypertension may occur in association with the use of oral contraceptives. Regular blood pressure checks including a pretreatment level, are advisable.
6. Prolonged amenorrhoea following the use of oral contraceptives may occur. The incidence is in the order of 1% of users. Caution is advised where oligomenorrhoea or amenorrhoea have occurred in the past.
7. Mood changes, headache, mass gain, skin pigmentation, vaginal candidiasis, breast tenderness, gallbladder disease, gastrointestinal irritation and fluid retention may occur.
8. Case reports have been published of benign hepatic tumours in women on oral contraceptives for a prolonged time, but a causal relationship has not been established. The preparation should be discontinued if persistent upper abdominal pain develops.
9. Interactions with other medicines and efficacy:
  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 longterm antibiotic therapy need only take extra precautions for the first two weeks of antibiotic therapy. Spotting and breakthrough bleeding are possible signs of diminished contraceptive effectiveness.
  The efficacy of the contraceptive pill may be decreased when it is administered concomitantly with other medicines such as antiepileptic agents, rifampicin, phenylbutazone, ampicillin, penicillin V, tetracycline, neomycin, chloramphenicol, sulphonamides, nitrofurantoin, barbiturates, meprobamate, phenacetin and pyrazolone containing analgesics chlorpromazine, chlordiazepoxide, and dihydroergotamine.
  Combination oral contraceptives have been reported to antagonize the effectiveness of oral anti-coagulants anti-hypertensive agents, anticonvulsants, and hypoglycaemic agents.
  Patients should be carefully monitored for decreased response to these medicines.
  Oral contraceptives may interfere with the oxidative metabolism of diazepam and chlordiazepoxide, resulting in plasma accumulation of the parent compound. Patients receiving these benzodiazepines on a longterm basis should be monitored for increased sedative effects.
  The effects of benzodiazepines on oral contraceptive metabolism have not been determined.
  Oestrogen therapy may decrease the antidepressant response to tricyclic antidepressants and increase their incidence of toxic side effects.
  Oestrogens may enhance the effects of glucocorticoids. With vomiting and 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.
10. 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:-
  a. Increased prothrombin and Factors VII, VIII, IX and X; decreased anti-thrombin 3; increased norepinephrine-induced platelet aggregability.
  b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI). T4 by radioimmuno assay Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
  c. Decreased pregnanediol excretion.
  d. Reduced response to metyrapone test.
  e. Increased sulphobromophthalein retention.
    The results of these tests should not be regarded as reliable until oral contraceptive use has been discontinued for 1 to 2 months. Abnormal tests should then be repeated.
    Oral contraceptives may produce false positive results when neutrophil alkaline phosphatase activity is evaluated for the early diagnosis of pregnancy. A decrease in glucose tolerance has been observed in a significant percentage of patients on oral contraceptives. For this reason diabetic patients should be carefully observed while on TRIPHASIL therapy.
11. Surgery is more likely to be associated with an increased incidence of thrombotic side-effects. Adequate precaution should be taken.
PRECAUTIONS:
1. A thorough history and physical examination should be performed before prescribing an oral contraceptive and periodically during its administration. Special attention should be given to blood pressure, breasts, abdomen, and pelvic organs.
2. Oral contraception may cause mental depression. Patients with a history of mental depression should be carefully observed and this product discontinued if depression recurs to a serious degree.
3. These agents may cause some degree of fluid retention. Women with cardiac or renal dysfunction, convulsive disorders, migraine, or asthma require careful observation since these conditions may be exacerbated by the fluid retention which may occur in users of oral contraceptives.
4. Cholestatic jaundice has been reported in users of oral contraceptives. If this occurs, this product should be discontinued. Patients with a history of jaundice during pregnancy should be carefully observed during TRIPHASIL therapy.
5. Steroid hormones may be poorly metabolized in patients with impaired liver function and should be administered with caution to such patients.
6. Users of oral contraceptives may have disturbances in normal tryptophan metabolism which may result in a relative pyridoxine deficiency. The clinical significance of this is yet to be determined.
7. Serum folate levels may be depressed by oral contraceptives use. Women who become pregnant shortly after discontinuing these agents may have a greater chance of developing folate deficiency and its complications.
8. Laboratory tests:
  Papanicolaou smears should be performed before prescribing oral contraceptives and periodically during their administration. Baseline and periodic blood glucose determinations should be performed in patients predisposed to diabetes mellitus.
9. Use during pregnancy - See “Warnings" - Use During or Immediately Preceding Pregnancy.
10. Use during lactation:
Oestrogen Containing oral contraceptives given in the postpartum period may interfere with lactation. There may be a decrease in the quantity and quality of the breast milk. Furthermore, a small fraction of the hormonal components of such oral contraceptives has been identified in the milk of mothers receiving them. The effects if any, on the breast-fed infant have not been determined. If feasible, the use of oestrogen-containing oral contraceptives should be deferred until the infant has been weaned.
11. Under the influence of oestrogen-progestogen preparations, pre-existing uterine leiomyomata may increase in size.
12. Carcinogenesis, Mutagenesis, Impairment of Fertility - See "WARNINGS" - Carcinoma, and Use During or Immediately Preceding Pregnancy.
13. Omitted tablets - See “Dosage and directions for use”.
UNDER NO CIRCUMSTANCES SHOULD THE ORAL CONTRACEPTIVE TABLET BE STOPPED WITHOUT HAVING ADOPTED A SATISFACTORY ALTERNATIVE METHOD OF CONTRACEPTION.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Treatment is symptomatic and supportive.

CONDITIONS OF REGISTRATION:
Advertising to the professions only.

IDENTIFICATION:
The TRIPHASIL package contains 28 sugar-coated tablets (6 brown, 5 white, 10 yellow and 7 red).

PRESENTATION:
TRIPHASIL is available in blister packs of 28 tablets comprising of 6 brown, 5 white, 10 yellow and 7 red tablets.

STORAGE DIRECTIONS:
Store in a cool (below 25 °C), dry place. Keep out of reach of children.

REGISTRATION NUMBER:
N/18.8/40

NAME AND BUSINESS ADDRESS OF APPLICANT:
AKROMED PRODUCTS (Pty) Ltd.
Co. Reg. No.: 05/13586/07
20 Spanner Road, Clayville, Olifantsfontein 1666
Trademark and product under
licence to WYETH-AYERST
LABORATORIES, U.S.A.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
l4 February 1992

24940 QC708
Davbar Dbn.

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