Modern contraceptive methods represent more than a technical advance; they are the instrument of a true social revolution - the "first reproductive revolution" in the history of humanity, and an achievement of the second part of the 20th century, when modern, effective methods became available. The human population, which had more than tripled from 1.8 to more than 6 billion in just one century, is today being brought under control. At the turn of the millennium, all over the world, more than 600 million married women are using contraception, with nearly 500 million in developing countries. Among both married and unmarried, sexually active women, contraceptive use has risen.

Hormonal contraception, the best known method, first made available as a daily pill, can today be administered through seven different routes: intramuscular, intranasal, intrauterine, intravaginal, oral, subcutaneous, and transdermal.

New oral contraceptives are being developed in order to improve tolerance while ensuring efficacy and good cycle control. Two approaches are commonly being investigated: (1) to lower the steroid dose of both the oestrogen and progestogen components and (2) to utilize new progestogens with a more favourable pharmacological profile. Combined low-dose oral contraceptive pills now commonly contain 30 mg, or less, of ethinyl estradiol in combination with one of a number of established synthetic progestogens. However, almost all synthetic progestogens currently in clinical use lack certain characteristics of natural progesterone and, therefore, there remains some potential for a better oestrogen/progestogen combination to be developed.

In particular, none of the currently available progestogens display clinically relevant levels of antimineralocorticoid activity, as does natural progesterone. Therefore, in some women, the use of conventional oral contraceptives can result in fluid retention and associated symptoms such as oedema and weight gain. This aspect of oral contraceptive use is particularly important, since, along with cycle control, weight gain is a major reason for women discontinuing, or not initiating, oral contraceptive use, especially in adolescent girls.

Development of new progestogens with improved pharmacological activity is, therefore, an important aspect of current research. One such new progestogen is drospirenone, which is being developed for use in combined oral contraceptive preparations. This novel progestogen differs in important ways from other currently available progestogens and has a pharmacological profile that is very similar to natural progesterone.

CRISANTA, which contains drospirenone (DRSP) 3 mg and ethinylestradiol (EE) 0.03mg (together, termed as DEE), is a combined oral contraceptive (COC) for the prevention of pregnancy in women of reproductive age, which acts by suppression of gonadotropins. This combination is well tolerated, demonstrating good cycle control and a beneficial effect on skin conditions and well-being (including some premenstrual and menstrual symptoms). The frequency and type of adverse events reported in clinical trials are typical of those observed with other COCs.

Receptor-Binding

The in vitro receptor-binding affinity and pharmacological profile of DRSP are similar to those of progesterone; both have progestogenic, antiandrogenic and antimineralocorticoid activity.

Oestrogenic Activity

Oestrogen acts synergistically with drospirenone in suppressing the cyclic pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH); in addition, oestrogen maintains the endometrium and helps to prevent breakthrough bleeding. The EE-induced increase in the levels of the sex -hormone-binding globulin (SHBG; 3- to 4-fold) and corticosteroid-binding globulin (CBG; 2- to 2.5-fold) were not affected when women were given DEE. DRSP had no effect on the oestrogen-stimulated increase in plasma renin substrate levels over 3 cycles of DEE (DRSP 2 or 3 mg/EE 30 mcg).

Progestogenic Activity

DRSP inhibits follicular stimulation and ovulation by suppressing LH. It also helps to prevent fertilization by changing the cervical mucus, thereby slowing sperm transport and affects ovum implantation through atrophy of the endometrium during treatment. DRSP inhibits ovulation in a dose-dependent manner; the optimal oral dosage is 3mg. Irrespective of the dose of DRSP, DEE inhibits cervical function as well as reduced spinnbarkeit and crystallization of the cervical mucus; the effect on spinnbarkeit is partially reversed. Long-term treatment (13 cycles) with DEE had a marked antiproliferative effect on the endometria of healthy, menstruating women.

Antimineralocorticoid Activity

In a normal menstrual cycle, urinary sodium and aldosterone excretion, and PRA (plasma renin activity) and plasma aldosterone levels are significantly higher in the luteal phase of the cycle than in the follicular phase. This physiological natriuresis is due to the antimineralocorticoid activity of progesterone.

Like endogenous progesterone, DRSP has an antimineralocorticoid effect on the renin-angiotensin-aldosterone system. It causes natriuresis when given as a single agent or in combination with EE. Unlike cyproterone acetate (CPA), desogestrel (DSG) or levonorgestrel (LNG), which have no antimineralocorticoid activity, DRSP affects the physiologic natriuresis observed in the normal menstrual cycle by significantly increasing urinary aldosterone and sodium excretion in the follicular phase.

The effect of DRSP on plasma renin angiotensin and plasma aldosterone is reversible, generally returning to baseline values by the fifth treatment-free day of a cycle. A small increase in serum potassium levels was noted when DEE (DRSP 3 mg/EE 1 mg) was co-administered with enalapril maleate in hypertensive women; however, this increase was not statistically or clinically significant, and clinical hyperkalaemia was not observed.

No significant changes were observed in serum sodium, creatinine, or potassium levels when women were given DEE (DRSP 3 mg/EE 15-30 mcg), or EE 30 mcg/LNG 150 mcg. Nevertheless, because of the antimineralocorticoid activity of DRSP (comparable to a 25 mg dose of spironolactone), there is potential for hyperkalaemia to develop in high-risk women (particularly those with renal impairment) who take an oral contraceptive (OC) containing DRSP, or when DEE is co-administered with potassium-sparing agents.

Antiandrogenic Activity

DRSP, CPA, and dienogest are the only progestogens demonstrating antiandrogenic activity at therapeutic dosages. Anti-androgenic activity occurs due to competitive androgen receptor-binding. DEE directly reduces the production of testosterone and its precursors by inhibition of steroidogenic enzymatic activities, resulting in a decrease in seborrhoea, acne, and hirsutism in women.

Ethinyl Estradiol

EE is absorbed within 2 hours of oral administration of DEE. Steady-state maximum serum concentrations Cmax and area under the curves (AUC) of drug concentration versus time values are achieved during the second half of a treatment cycle. The absolute bioavailability is approximately 40%, and the apparent volume of distribution is 4-5 L/kg. EE is rapidly metabolized, primarily by conjugation and aromatic hydroxylation, via the hepatic cytochrome P450 (CYP) 3A4 isoenzyme, and is excreted in the urine and the faeces.

Drospirenone¹

DRSP is absorbed within 2 hours of oral administration of DEE, and Cmax and AUC increased in a dose-related fashion after single doses. The absolute bioavailability is 76%. Absorption is slowed by food.

Steady-state Cmax values were achieved by day 7 to day 10 of the first treatment cycle when young women were given DEE. Steady-state AUC values demonstrated a slight accumulation (12% versus 17%) during the first 6 treatment cycles. Serum DRSP concentrations were increased in women with moderate renal impairment; DEE is contraindicated in women with renal impairment.

Although drospirenone is extensively bound to serum albumin (95-97%), it does not bind to SHBG or CBG and the apparent volume of distribution is 4 L/kg.

Prior to elimination (which is both faecal and renal), DRSP is extensively metabolized in the liver; the two main metabolites found in the plasma (the acid form of DRSP and 4, 5-dihydrodrospirenone-3-sulphate) are pharmacologically inactive. Although the CYP isoenzyme CYP2C19 is inhibited in vitro by DRSP, the clearance of concomitant omeprazole was not affected. Elimination is moderately slow and biphasic; the terminal disposition half-life after single or multiple doses is approximately 30 hours.

Special Populations

Women with Renal Impairment¹

The pharmacokinetics of DRSP 3 mg/day for 14 days was minimally affected in women aged 30-60 years with mild renal impairment [CLCR >3-4.8 L/h (>50-80 ml/min)] receiving a low potassium diet. However, serum DRSP concentrations in women with moderate renal impairment [CLCR >1.8-3 L/h (>30-50 ml/min)] were approximately 37% higher than those observed in women with normal renal function [CLCR >4.8 L/h (>80 ml/min)]. No clinically significant changes in potassium concentration were reported in any treatment group, although five of the seven women who concomitantly received potassium-sparing drugs had increased serum potassium levels by day 14 (mean increase of 0.33 mEq/L).

The efficacy of DEE as an OC has been assessed in over 31,000 monthly cycles in more than 2,400 healthy women of reproductive age. The table below includes two large, multicentre, randomized (but non-blind) trials (13-cycle, and 26-cycle) in which DEE (n = 2,099) was compared with EE 30 mcg/DSG 150 mcg (DSGEE) (n = 857), and a multicentre, non-comparative study (n = 326; 13 cycles). When used correctly, the efficacy of OCs is greater than 99%; however, typical rates of efficacy range between 92% and 97%, indicating that non-compliance is the main reason for 'failure' of OCs.

Studies comparing DEE with an established OC (DSGEE) reported relative contraceptive efficacy by using a comparison of Pearl index outcomes. The oral DEE combination was highly effective in preventing pregnancy in young healthy women who required contraceptive protection. Pregnancy rates of 0.3-0.7%, corrected Pearl indices (i.e., those derived from data excluding cycles where condoms were used) of 0.41-0.71 and pregnancy ratios (the number of women who became pregnant divided by the number of women who completed 13 cycles without other contraception multiplied by 100) of 0.3-0.84 were recorded in clinical trials of DEE for 13 and 26 monthly cycles in 326-1,657 women (total, 3,192-18,418 cycles).

The Pearl index, taking only the method failure into consideration, is 0.07 for DEE. One pregnancy due to a method failure occurred during the use of DSGEE; the resulting Pearl index was 0.28.

Cycle control (measured by the incidence of intermenstrual bleeding) in women receiving DEE appears to be good, with a low incidence of intermenstrual bleeding after the first cycle, which is maintained for up to 26 cycles.

In clinical trials, the incidence of intermenstrual bleeding was greatest in the first cycle, and decreased over the study period. The median cycle length from cycle 2 onwards for both new users of DEE and women switching from other OCs was 28 days; withdrawal bleeding was generally of 4-7 days duration and was described by most women as normal.

Intermenstrual bleeding was characterized as spotting (scanty bleeding) or breakthrough bleeding (normal/heavy bleeding).

In the three clinical trials, 25-66% of women receiving DEE reported breakthrough bleeding and/or spotting in the first cycle; this had become 9-18% by cycle 2; 5-8% by cycle 13; and remained at 6% in cycle 26. Spotting alone occurred in 20-44% of women receiving DEE in cycle 1; 4-6% in cycle 13; and 5% in cycle 26.

As with other OCs, spotting may occur more often in women using DEE for the first time than in those switching from another OC. About half of the women using DEE reported no intermenstrual bleeding.

The impact of the new progestogen, DRSP, on self-perception women have regarding their menstrual health has been evaluated in many studies. Treatment with DEE improves subjective feelings of well-being in women. Women have reported that symptoms of water retention, negative affect, and increased appetite significantly improved after treatment.

In one survey where the participants were questioned about their premenstrual symptoms (PMS), almost all of the respondents had experienced some PMS in the days preceding their menses, prior to initiating DEE. Only approximately 4% of respondents stated that they did not suffer from any symptoms in the days preceding their menses. Overall, depressed mood, irritability, breast tenderness or pain, abdominal bloating or swelling, or skin and hair problems were reported by 52-66% of the respondents prior to initiating treatment. Swelling of the extremities such as the hands and the ankles was reported by 37% of the respondents. The mean individual symptom scores were significantly reduced with DEE, compared with the time before its use. The greatest improvements occurred for skin and hair problems, abdominal bloating or swelling, breast tenderness or pain, and swelling of the extremities.

In another study conducted with DEE, the occurrence of menstrual-related symptoms was evaluated by a questionnaire at baseline and at the end of cycle 6 for three phases of the menstrual cycle. These phases were the 4-day period before menstruation (premenstrual), the first through last day of menstruation (menstrual), and the remainder of the cycle (post-menstrual). The questionnaire consisted of 23 items.

Statistically significant decreases from baseline to cycle 6 were observed for all subjects and in all menstrual phases for negative affect and water retention. In the premenstrual and menstrual phases, the severity level of increased appetite was significantly lower at cycle 6 compared with baseline. The results of this health assessment questionnaire showed that DEE had an impact on the perception of the severity of some common menstrual cycle symptoms. Symptoms of water retention, negative affect, and increased appetite were less severe by cycle 6. The subjects' perceptions that their symptoms of water retention and increased appetite were lessened are consistent with the observed loss of weight at cycle 6.

The low rate of discontinuation of DEE could result, in part, from the positive effect it had on perceptions of water retention and negative affect.

Progesterone has a high affinity to the mineralocorticoid receptor, for which it is an antagonist. Almost all synthetic progestogens are devoid of this antimineralocorticoid effect. They are unable to antagonize the salt-retaining effect of oestrogens. This could be one cause of the weight gain and increase in blood pressure that is seen with the use of COCs and, in some susceptible women, with postmenopausal oestrogen/ (progestogen) treatment. A frequent finding in COC users is the occurrence of various degrees of oedema and other symptoms related to fluid retention, which cause poor compliance.

A non-randomized study conducted was aimed to evaluate body weight and composition during the menstrual cycle and during oral contraception with DEE. A multifrequency bioelectrical impedance analysis was carried out in 38 women with normal cycles at baseline during the follicular phase (FP) and the luteal phase (LP) of the menstrual cycle, and after 3 and 6 cycles of DEE to evaluate total body water (TBW), intracellular water (ICW), extracellular water (ECW), fat mass and fat-free mass. Body weight, waist-to-hip ratio, blood pressure, and the plasma concentrations of electrolytes were also determined at each visit.

TBW and ECW increased in the LP. With DEE, TBW and ECW were significantly lower than in the LP, but similar to the values measured in the FP. No significant variations in ICW or in the other parameters were observed.

DEE maintained the same concentrations in TBW and ECW observed in the FP. This effect is likely due to the antimineralocorticoid activity of DRSP, which counteracts the water retention elicited by the oestrogen.

DEE appears to cause little change in mean body weight during treatment. Most women who took DEE for up to 26 cycles either maintained their baseline body weight or experienced a small body weight loss over the majority of cycles. Women receiving DSGEE also had small reductions in body weight in the early stages of treatment, a tendency that was reversed from cycles 3 to 9, resulting in a net gain in body weight (+1.4%) by cycle 26.

At the 3-month follow-up after 26 cycles, there were mean body weight gains from baseline of 0.4 kg and 0.98 kg in the DEE and DSGEE groups. In extended treatment in both groups, there were statistically significant differences overall between the treatment groups in both comparative trials, with DEE being associated with greater body weight loss or less gain after 13 cycles and 26 cycles. A meta-analysis of body weight change in women from both the comparative trials indicated a slight decrease in body weight with DEE after 13 cycles and a slight increase with DSGEE.

In one survey, the participants were questioned about their satisfaction with their current body weight while receiving treatment.

Of the women who used the DEE for up to 6 months, 33% lost weight and of those who used DEE for up to 1 year, 37% lost weight. Some weight gain was reported by 17% of the women.

Thereafter, the proportion of women who reported weight loss decreased gradually with every subsequent year of use. Moreover, 61% of the respondents, who had switched to DEE because of weight problems associated with their previous OC method, stated that they had lost weight while using it, whereas 43% new starters lost weight.

Prolonged use of hormonal OCs containing an oestrogen and a progestogen may lead to slight mean increases in body weight and blood pressure. In this regard, there is no significant difference among various preparations containing 50 mcg or 30 mcg EE. In rare instances, OC use may lead to severe or 'malignant' hypertension.

A comparative study of DEE (3 mg DRSP/30 mcg EE) versus 150 mcg LNG/30 mcg EE in Thai women showed that DEE has a more favourable effect on body weight and blood pressure than LNGEE. A statistically significant difference was found in body weight changes between the two groups at the sixth cycle.

While there was an increase in mean body weight in the LNGEE group, the mean body weight in the DEE group was below the baseline value throughout the study. DEE had a more favourable effect on the blood pressure than LNGEE, with the mean systolic and diastolic blood pressures remaining lower in the DEE group (the difference between the two preparations being statistically significant at the end of the study), which may result from the antimineralocorticoid properties.

DRSP does not appear to have a clinically significant effect on systolic or diastolic blood pressures; mean blood pressure recordings in young, healthy women taking DEE remained within normal limits in clinical trials.

The simultaneous, slight reduction in body weight and blood pressure suggests that it is due to a reduction in extracellular volume.

Seborrhoea and Acne

COCs are a highly effective treatment option for acne in women, particularly in those with symptoms of hyperandrogenism. The beneficial effects of COCs on acne are partly due to their ability to reduce androgen secretion by the ovaries and to increase the levels of theSHBG. Moreover, some progestins, such as DRSP, CPA, and dienogest, have marked antiandrogenic activity, thereby partially counteracting the effects of endogenous androgens. Furthermore, DRSP has antiandrogenic properties through direct actions at the androgen receptor site, which, when combined with EE in an OC, make it a suitable option in the treatment of acne and other skin-related conditions, in addition to other hyperandrogenic disorders such as hirsutism.

In a survey conducted in 10,947 users of DEE, about one-third (37%; n = 4,098) of respondents stated that they had acne or related skin problems before starting DEE; of these, 3,050 (74%) reported that their skin condition had improved since they started treatment. Moreover, 90% of the respondents were satisfied or very satisfied with the current appearance of their skin while receiving this COC. In other studies, DEE reduced sebum production and hair growth on the upper lip and chin, as well as increased SHBG levels and decreased androgen levels. DEE has also been shown to be at least as effective as an OC containing CPA, but superior to a triphasic contraceptive containing norgestimale (NGM), making it a good option for women with acne and other skin-related problems who require contraception.

A double-blind study compared DEE with a triphasic preparation containing 35 mcg EE and 0.180 mg, 0.215 mg, or 0.250 mg NGM, also used in the treatment of mild to moderate acne vulgaris. DEE was shown to be superior to EE/NGM in the reduction in total lesion count (-3.3% in favour of DEE) and in the investigators' assessment of therapeutic effect on facial acne (-3.6% in favour of DEE). Sebum production was reduced at cycle 6 compared with baseline; median sebum production decreased from 137 mcg/cm2 to 96 mcg/cm².

DEE increased the level of the SHBG by a greater extent than EE/NGM and correspondingly reduced the levels of total and free testosterone (T), androstenedione (A), and dehydroepiandrosterone sulphate (DHEAS); these changes usually are associated with decreased sebum production and improvement of acne. Greater reductions in DHEAS levels were observed with DEE treatment, but both treatments reduced A levels by a similar extent.

As the antimineralocorticoid activity of DRSP may reduce follicular wall oedema during the second half of the menstrual cycle, it may result in the additional efficacy of DEE on inflammatory lesions at this cycle phase.

Hirsutism^{13, 14}

COCs are considered the first-line treatment for women with hirsutism. They diminish androgen release from the ovaries and decrease plasma free T levels by increasing the SHBG concentrations. COCs containing CPA and DRSP have been proved effective for the treatment of acne and facial hirsutism. Their progestational activity lowers LH secretion and, hence, the release of LH-mediated ovarian androgen. However, the increase in plasma SHBG concentration is blunted by the androgenic activity of the progestin. Therefore, it is preferable, to select a COC containing a progestin with low androgenic activity. DRSP has antimineralocorticoid and antiandrogenic activity and its pharmacological and biochemical profiles are similar to those of endogenous progesterone. Its important feature is that it does not attenuate the EE-induced increase in the SHBG; neither does it interfere with androgen binding to the SHBG.

In a study assessing long-term clinical and biochemical results and the response of different body parts to medical therapy with the DEE combination for 12 cycles in hirsute patients with or without polycystic ovarian syndrome (PCOS) 50 women with moderate to severe hirsutism were recruited. Hirsutism was assessed at 6-month intervals using the Ferriman-Gallwey (F-G) scoring system. Serum FSH, LH, total and free T, A, DHEAS, estradiol (E2), and the SHBG levels at 6 and 12 months of therapy were compared with baseline values.

Improvement was most prominent on the chest and abdomen, followed by the upper lip and chin. The least effect was observed on the back and arms. Serum levels of total and free T and A decreased, whereas SHBG levels increased significantly after 6 and 12 months, when compared with baseline levels. DEE exerts significant antiandrogenic activity and is effective in improving facial hirsutism. The beneficial effect is most obvious after 6 cycles and continues thereafter at a slower rate.

In another study in 48 patients with hirsutism, DEE achieved a significant reduction in hair growth in patients with moderate to severe hirsutism over 12 months. There was a significant increase in serum SHBG and a significant decrease in serum total T, free T, and A during the treatment period8. There was a statistically significant decrease in the total hirsutism score, as well as a significant decrease in hair growth on all body parts after 6 and 12 months of therapy, when compared with baseline values. After 6 months, diminished hair growth was more evident on the chest, waist, thighs, and arms.

Hyperandrogenism itself, as well as progestins with androgenic activity, counteracts the beneficial effect of oestrogen on serum SHBG concentration. Thus, treating hirsute patients with COCs containing high doses of oestrogen together with progestins devoid of androgenic activity (i.e., CPA or DRSP) has much less effect on the SHBG concentration and they should, therefore, be more effective for the treatment of hirsutism.

For women who require ongoing contraception, poor tolerability is the most frequent reason to discontinue OCs. The hormonal components of OCs, as in oestrogens (usually EE) and progestogens, are known to have various metabolic effects, including effects on lipid and carbohydrate metabolism and, therefore, potentially increasing the risks of cardiovascular disease. The two components of COCs, EE and the progestogen, have different effects on the major lipoprotein classes - high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL).

Slight decreases in glucose tolerance and increases in insulin resistance have been reported for some OCs by means of oral or intravenous glucose tolerance tests (OGTTs, IVGTTs) or glucose clamps, but evidence for an increased risk to develop diabetes has never been provided. However, a further investigation of the long-term consequences of OC use on carbohydrate metabolism is important because any chronic, hyperglycaemia (even if mild) and/or hyperinsulinaemia in the fasting state as well as during a glucose load may contribute to ischaemic vascular diseases and to the metabolic syndrome (or Syndrome X).

Although the specific contributions of the oestrogen and the progestin to the metabolic effects of OCs are not fully understood, it is evident that the dose of EE and the dose and type of the progestin, particularly its androgenic properties, affect the metabolic influence of OCs.

In a study, the effect of DEE on carbohydrate metabolism was assessed. The absolute change of the natural logarithm of the AUC for glucose and insulin from pre-treatment to treatment cycle 13 were the target variables in the study and it showed the following results:

DEE did not cause any major changes in the fasting blood levels of the carbohydrate variables, even during long-term use. All blood glucose and insulin levels were within normal ranges and well below the threshold of impaired glucose tolerance. There was no shift towards an impaired glucose tolerance. The changes were similar to the changes during the physiological menstrual cycle and not sufficient to induce an increase incidence of diabetes mellitus.

In a study, the relative changes by DEE on the cholesterol content of the total HDL fraction and the HDL2 and LDL sub-fractions were assessed. The results were as follows:

There was a favourable change seen in the lipid profile, as there was an increase in mean HDL cholesterol with stable mean LDL cholesterol levels. This increased HDL/LDL ratio was clinically beneficial with respect to cardiovascular disease risk. Mean triglycerides levels increased, but were within the normal range.

An extensive assessment of the VTE risk associated with DEE has been undertaken by reviewing data from the clinical development programme, postmarketing surveillance and spontaneous worldwide reporting, as well as information from other sources.

The VTE rate with DEE does not highlight any safety concerns. Furthermore, the risk of VTE with DEE or other OCs is far less than those associated with pregnancy and delivery (up to 800/100,000 women-years) or other risks of daily living.

The 3-year interim results from a large, controlled, prospective postmarketing surveillance study suggest a VTE rate of:cycle

DEE does not increase the rate of thromboembolic events compared with other Ocs

In addition to ovulation inhibition, the contraceptive effect by OCs is attained by induced changes of the endometrium, thereby hampering ovum implantation. The administration of an OC produces variable histological pictures, but in general, results in an underdevelopment of endometrial stroma and glands, whereas the effect on the endometrial glands are often more pronounced. The endometrium becomes scanty and contains only a few glands with empty and narrow-lined lumina. On long term OC intake, the height of the epithelium decreases, the glands become atrophic and pseudo-decasualization of the stroma can be detected. Moreover, the development of the spiral arteries does not take place to the same extent as in a normal menstrual cycle.

These induced changes in the endometrium are to be considered to avoid hyperplasia and to minimize the long-term risk of endometrial cancer; moreover, they could also lead to less menstrual bleeding.

A study was conducted to assess the degree to which DEE affects the endometrium in healthy women. The main aim was to evaluate endometrial morphology in comparison to an untreated cycle.

After 13 cycles of DEE, the endometrium had an atrophic appearance in 63% of the subjects. The size of the glands, the glandular epithelial height, and the number of glands per square millimetre were already significantly reduced after 3 months. Histological and ultrasonographical evaluation of the endometrium indicated a suppression of the proliferative activity of the endometrium.

There was increasing endometrium atrophy, resulting in small glands with single layers of inactive epithelium, without mitotic figures and secretory activity, and no evidence of decidual changes. Under treatment, from a mean baseline value of 376 vacuolated cells, the number of vacuolated cells per 1,000 glandular cells was suppressed to zero. Overall, there was good suppression of endometrial activity, with the histological markers for antiproliferative activity and induced atrophic changes comparing well with other modern low-dose COCs.

DRSP is an analogue of spironolactone. Consequently, there is a theoretical potential for hyperkalaemia to develop in some women who take an oral formulation containing DRSP, particularly when DRSP-containing formulations are co-administered with potassium-sparing agents in women with severe renal impairment.

Information on the safety of DRSP and DRSP-containing formulations with regard to hyperkalaemia (and associated subsequent arrhythmia) has been obtained from several sources. These include the U.S. Phase IV Study, the EURAS Study and the EE/DRSP Clinical Trial (assessment) Programme.

No cases of hyperkalaemia in women on DEE were detected, compared to 15/100,000 women-years in other OC groups. The reporting rate of arrhythmia was similar for DEE compared with other OC users. There were fewer reports of events related to hyperkalaemia (electrolyte disturbances, syncope) with DEE versus other OCs (U.S. Phase IV Study).

The results of the entire clinical Phase I-III for DEE showed a lack of effect on potassium levels. In Phase III studies, 98.2% potassium measurements were within the normal range (97.4% for EE/DSG). There is no increased risk of hyperkalaemia with DEE in high-risk populations (e.g. taking co-medication or with renal impairment) (EE/DRSP Clinical Assessment Programme).

Available data indicate that DEE is a SAFE OC, with no effect on the impairment of carbohydrate and lipid metabolism, no increased risk of VTE, and results in effective suppression of endometrial activity.

CRISANTA is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.

To achieve maximum contraceptive effectiveness, CRISANTA must be taken exactly as directed at intervals not exceeding 24 hours. CRISANTA consists of 21 tablets of a monophasic combined hormonal preparation.

The dosage of CRISANTA is one tablet daily for 21 consecutive days, followed by 7 pill- free days. A patient should begin to take CRISANTA on the first day (day 1) of her menstrual period.

During the first cycle of CRISANTA use, the patient should be instructed to take one tablet daily, beginning on day 1 of her menstrual cycle for 21 consecutive days, followed by 7-pill free days. Withdrawal bleeding could occur during this period. Each subsequent course is started after 7 pill-free days have followed the preceding course.

It is recommended that CRISANTA be taken at the same time each day, preferably after the evening meal or at bedtime.

If CRISANTA is taken for the first time later than the first day of the menstrual cycle, it should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient should begin a new pack of CRISANTA, taking her tablets on the next day after 7-pill free days, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of CRISANTA is started later than the day following 7-pill free days, the patient should use another method of contraception until she has taken a tablet daily for 7 consecutive days.

When switching from another OC, CRISANTA should be started on the same day that a new pack of the previous OC would have been started.

Withdrawal bleeding usually occurs within 7-pill free days. If spotting or breakthrough bleeding occurs while taking CRISANTA, the patient should be instructed to continue taking CRISANTA as instructed and as per the regimen described above. She should be instructed that this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient should consult the physician.

Although the occurrence of pregnancy is unlikely if CRISANTA is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed dosing schedule (missed one or more tablets or started taking them a day later than she should have), the possibility of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures should be taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraception should be discontinued if pregnancy is confirmed.

Missed Pill

If the patient forgets to take a tablet at the usual time, the tablet may be taken within the next 12 hours. If more than 12 hours have elapsed from the time of usual administration, the patient must discard the missed tablet and continue to take the remaining tablets in the pack at the usual time in order to avoid premature withdrawal bleeding during this cycle. A supplementary non-hormonal method of contraception must be employed until the pack is empty to prevent pregnancy. If pregnancy occurs, CRISANTA has to be stopped immediately.

Drospirenone and Ethinyl Estradiol Tablets

Each film-coated tablet contains:

Ethinyl Estradiol IP …........ 0.03 mg

Drospirenone ….........3.0 mg

Oral tablet

CRISANTA, a combination of drospirenone (DRSP) and ethinyl estradiol (EE), is a combined oral contraceptive (COC), which acts by suppression of gonadotropins

Although the primary mechanism of action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of ovum implantation).

DRSP is a spironolactone analogue with antimineralocorticoid activity. Pre-clinical studies in animals and in vitro have shown that DRSP has no androgenic, oestrogenic, glucocorticoid, and antiglucocorticoid activity. Pre-clinical studies in animals have also shown that DRSP has antiandrogenic activity.

Absorption

The absolute bioavailability of DRSP from a single entity tablet is about 76%. The absolute bioavailability of EE is approximately 40% because of presystemic conjugation and first-pass metabolism. The absolute bioavailability of the combination tablet of DRSP plus EE (DEE) has not been evaluated

Serum concentrations of DEE reach peak levels within 1-3 hours after administration of DEE. After a single dose of DEE, the relative bioavailability, compared to a suspension, is 107% and 117% for DRSP and EE, respectively.

The pharmacokinetics of DRSP is dose proportional following single doses ranging from 1-10 mg. Following daily dosing of DEE, steady-state DRSP concentrations are observed after 10 days. There is about 2- to 3-fold accumulation in serum Cmax and area under the curve (AUC, 0-24 hours) values of DRSP following multiple-dose administration of DEE.

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of DEE, serum Cmax and AUC (0-24 hours) values of EE accumulate by a factor of about 1.5 to 2.0.

Effect of Food

The rate of absorption of DRSP and EE, following single administration of two DEE tablets, is slower under fed conditions, with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remains unchanged. In contrast, the extent of absorption of EE is reduced by about 20% under fed conditions.

Distribution

DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4-5 L/kg.

DRSP does not bind to the sex hormone-binding globulin (SHBG) or corticosteroidbinding globulin (CBG), but binds about 97% to other serum proteins. Multiple dosing over 3 cycles results in no change in the free fraction (as measured at trough levels). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of both the SHBG and CBG. EE-induced effects on the SHBG and CBG are not affected by variation of the DRSP dosage in the range of 2-3 mg.

Metabolism

The two main metabolites of DRSP found in human plasma are identified to be the acid form of DRSP, generated by the opening of the lactone ring, and the 4, 5-dihydrodrospirenone-3-sulphate. These metabolites are not pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent, mainly by cytochrome P450 3A4 (CYP3A4).

EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulphate. CYP3A4 in the liver is responsible for the 2-hydroxylation, which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation, prior to urinary and faecal excretion.

Excretion

DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP is nearly complete after 10 days and amounts excreted are slightly higher in the faeces compared to the urine. DRSP is extensively metabolized and only trace amounts of unchanged DRSP is excreted in the urine and the faeces. At least twenty different metabolites were observed in the urine and the faeces. About 38-47% of the metabolites in the urine are glucuronide and sulphate conjugates. In the faeces, about 17-20% of the metabolites are excreted as glucuronides and sulphates.

For EE, the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is excreted in the urine and the faeces as glucuronide and sulphate conjugates and undergoes enterohepatic circulation.

CRISANTA is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive (OC). For the majority of women, OCs can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening, or may cause temporary or permanent disability, or even death.

To achieve maximum contraceptive effectiveness, CRISANTA must be taken exactly as directed at intervals not exceeding 24 hours. CRISANTA consists of 21 tablets of a monophasic combined hormonal preparation.

The dosage of CRISANTA is one tablet daily for 21 consecutive days followed by 7 pill free days. A patient should begin to take CRISANTA on the first day (day 1) of her menstrual period.

During the first cycle of CRISANTA use, the patient should be instructed to take onetablet daily, beginning on day 1 of her menstrual cycle for 21 consecutive days, followed by 7 pill-free days. Withdrawal bleeding could occur during this period. Each subsequent course is started after 7 tablet-free days have followed the preceding course.

It is recommended that CRISANTA be taken at the same time each day, preferably after the evening meal or at bedtime.

If CRISANTA is first taken later than the first day of the menstrual cycle, it should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient should begin a new pack of CRISANTA, taking her tablets on the next day after 7-pill free days, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of CRISANTA is started later than the day following 7-pill free days, the patient should use another method of contraception until she has taken a tablet daily for 7 consecutive days.

When switching from another OC, CRISANTA should be started on the same day that a new pack of the previous OC would have been started.

Withdrawal bleeding usually occurs within 7-pill free days. If spotting or breakthrough bleeding occurs while taking CRISANTA, the patient should be instructed to continue taking CRISANTA as instructed and by the regimen described above. She should be instructed that this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient should be advised to consult the physician.

Although the occurrence of pregnancy is unlikely if CRISANTA is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed dosing schedule (missed one or more tablets or started taking them on a day later than she should have), the possibility of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraception should be discontinued if pregnancy is confirmed.

If the patient forgets to take a tablet at the usual time, the tablet may be taken within the next 12 hours. If more than 12 hours have elapsed from the time of usual administration, the patient must discard the missed tablet and continue to take the remaining tablets in the pack at the usual time in order to avoid premature withdrawal bleeding during this cycle. A supplementary non-hormonal method of contraception must be employed until the pack is empty to prevent pregnancy. If pregnancy occurs, CRISANTA has to be stopped immediately.

CRISANTA should not be used in women who have the following:

Patients should be counselled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Cigarette smoking increases the risk of serious cardiovascular side effects from OC use. This 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 OCs should be strongly advised not to smoke.

Physical Examination and Follow-up

It is good medical practice for all women to have annual history and physical examinations, including women using OCs. The physical examination, however, may be deferred until after initiation of OCs if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

Hyperkalaemia

CRISANTA contains 3 mg of the progestin, DRSP, which has antimineralocorticoid activity, including the potential for hyperkalaemia in high-risk patients, comparable to a 25 mg dose of spironolactone. CRISANTA should not be used in patients with conditions that predispose to hyperkalaemia (i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the first treatment cycle. Drugs that may increase serum potassium include ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, and NSAIDs.

The use of OCs is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidaemias, obesity, and diabetes.

The information contained in this prescribing information is based principally on studies carried out in patients who used OCs with higher formulations of oestrogens and progestogens than those in common use today. The effect of the long-term use of OCs with lower formulations of both oestrogens and progestogens remains to be determined.

Thromboembolic Disorders and Other Vascular Problems

Carcinoma of the Reproductive Organs and Breasts

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation, the increased risk disappears. The risk does not appear to increase with duration of use and no consistent relationships have been found with the dose, or type of steroid. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history. Some studies have found a small increase in risk for women who first use COCs before age 20. Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in non-users. Women who currently have or have had breast cancer should not use OCs, because breast cancer is a hormonally-sensitive tumour. Some studies suggest that OC use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behaviour and other factors. In spite of many studies of the relationship between OC use and breast and cervical cancers, a cause-and-effect relationship has not been established.

Hepatic Neoplasia

Benign hepatic adenomas are associated with OC use. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after 4 or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal haemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) OC users.

Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of OCs. OCs should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilloedema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used OCs prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed dosing schedule, the possibility of pregnancy should be considered at the time of the first missed period. OC use should be discontinued if pregnancy is confirmed.

Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of OCs and oestrogens. Recent studies, however, have shown that the relative risk of developing gallbladder disease among OC users may be minimal. These findings of minimal risk may be related to the use of OC formulations containing lower hormonal doses of oestrogens and progestogens.

Carbohydrate and Lipid Metabolic Effects

OCs have been shown to cause glucose intolerance in a significant percentage of users. OCs containing greater than 75 mcg of oestrogens causes hyperinsulinism, while lower doses of oestrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the non-diabetic woman, OCs appears to have no effect on fasting blood glucose. Because of these demonstrated effects, pre-diabetic and diabetic women should be carefully observed while taking OCs. A small proportion of women will have persistent hypertriglyceridaemia while on the pill. Changes in serum triglycerides and lipoprotein levels have been reported in OC users.

Women who are being treated for hyperlipidaemia should be followed closely if they elect to use OCs. Some progestogens may elevate low-density lipoprotein (LDL) levels and may render the control of hyperlipidaemia more difficult.

Liver Function

If jaundice develops in any woman receiving OCs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

Fluid Retention

OCs may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention.

Emotional Disorders

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

Elevated Blood Pressure

An increase in blood pressure has been reported in women taking OCs and this increase is more likely in older OC users and with continued use. The incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use OCs, they should be monitored closely, and if a significant elevation of blood pressure occurs, OCs should be discontinued. For most women, elevated blood pressure will return to normal after stopping OCs, and there is no difference in the occurrence of hypertension among ever-users and never-users.

Headache

The onset or exacerbation of migraine or the development of headaches with a new pattern, which is recurrent, persistent or severe, requires discontinuation of OCs and evaluation of the cause.

Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on OCs, especially during the first 3 months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, letting some time lapse before re-treatment, or a change to another formulation may solve the problem. In the event of amenorrhoea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhoea or oligomenorrhoea, especially when such a condition was pre-existent.

Rifampin: Metabolism of EE and some progestins (e.g., norethindrone) is increased by rifampin. A reduction in contraceptive effectiveness and an increase in menstrual irregularities have been associated with concomitant use of rifampin.

Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine have been shown to increase the metabolism of EE and/or some progestins, which could result in a reduction of contraceptive effectiveness.

Antibiotics: Pregnancy while taking COCs has been reported when these contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effects of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Atorvastatin: Co-administration of atorvastatin and an OC increased AUC values for norethindrone and EE by approximately 30% and 20%, respectively.

St. John's Wort: Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and reduce the effectiveness of OCs and emergency contraceptive pills. This may also result in breakthrough bleeding.

Others: Ascorbic acid and acetaminophen may increase plasma concentrations of some synthetic oestrogens, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and an increased incidence of menstrual irregularities has been suggested with phenylbutazone.

Metabolic Interactions

Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated via in vitro and in vivo studies (see Pharmacokinetics, Metabolism). In in vitro studies, DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4, with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetics study, using omeprazole as a marker substrate. In this study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype], the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose). Based on the available results of in vivo and in vitro studies, it can be concluded that, at a clinical dose level, DRSP shows little propensity to interact to a significant extent with cytochrome P450 enzymes.

Interactions with Drugs That Have the Potential to Increase Serum Potassium There is a potential for an increase in serum potassium in women taking CRISANTA with other drugs. Of note, occasional or chronic use of NSAID medication was not restricted in any of the CRISANTA clinical trials.

COCs containing EE may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of OCs. In addition, OCs may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance on temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with OCs.

CRISANTA is contraindicated in patients with renal insufficiency

CRISANTA is contraindicated in patients with hepatic dysfunction. The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Pregnancy Category X

Oestrogens and progestins should not be used during pregnancy.

Small amounts of OC steroids have been identified in the milk of nursing mothers, and a few adverse effects on the infants have been reported, including jaundice and breast enlargement. In addition, OCs given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use OCs, but to use other forms of contraception until she has completely weaned her child.

After oral administration of DEE and , about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg DRSP in an infant.

Safety and efficacy of CRISANTA have been established in women of reproductive age. Safety and efficacy are expected to be the same for post-pubertal adolescents below the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

An increased risk of the following serious adverse reactions has been associated with the use of OCs:

Thrombophlebitis; arterial thromboembolism; pulmonary embolism; myocardial infarction; cerebral haemorrhage; cerebral thrombosis; hypertension; gallbladder disease; hepatic adenomas or benign liver tumours.

There is evidence of an association between the following conditions and the use of OCs, although additional confirmatory studies are needed:

Mesenteric thrombosis and retinal thrombosis.

The following adverse reactions have been reported in patients receiving OCs and are believed to be drug-related:

Nausea; vomiting; gastrointestinal symptoms (such as abdominal cramps and bloating); breakthrough bleeding; spotting; change in menstrual flow; amenorrhoea; temporary infertility after discontinuation of treatment; oedema; melasma (which may persist); breast changes - tenderness, enlargement, secretion, change in weight (increase or decrease); change in cervical erosion and secretion; diminution in lactation when given immediately postpartum; cholestatic jaundice; migraine; rash (allergic); mental depression; reduced tolerance to carbohydrates; vaginal candidiasis; change in corneal curvature (steepening); intolerance to contact lenses.

The following adverse reactions have been reported in users of OCs and a causal association has been neither confirmed nor refuted: Acne; Budd-Chiari syndrome; cataracts; changes in appetite; changes in libido; colitis; cystitis-like syndrome; dizziness; erythema multiforme; erythema nodosum; headache; haemolytic uraemic syndrome; haemorrhagic eruption; hirsutism; impaired renal function; loss of scalp hair; nervousness; porphyria; pre-menstrual syndrome; vaginitis.

The following are the most common adverse events reported with the use of DEE during the clinical trials, occurring in >1% of subjects and which may or may not be drug-related: Headache; menstrual disorders; breast pain; abdominal pain; nausea; leucorrhoea; flu syndrome; acne; vaginal moniliasis; depression; diarrhoea; asthenia; dysmenorrhoea; back pain; infection; pharyngitis; intermenstrual bleeding; migraine; vomiting; dizziness; nervousness; vaginitis; sinusitis; cystitis; bronchitis; gastroenteritis; allergic reactions; urinary tract infection; pruritus; emotional lability; rash; upper respiratory infection.

Serious ill effects have not been reported following acute ingestion of large doses of other OCs by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. DRSP, however, is a spironolactone analogue, which has antimineralocorticoid properties. Serum concentrations of potassium and sodium, and evidence of metabolic acidosis should be monitored in cases of overdose.

Store in a cool, dry place.

CRISANTA Tablets Pack of 21 tablets