CRISANTA LS Tablets (Drospirenone + Ethinylestradiol)

Table of Content

Warning: Cigarette Smoking and Serious Cardiovascular Events

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke.

Composition

Each film-coated tablet contains:
Drospirenone    ………. 3 mg

Ethinylestradiol ………. 0.02 mg

Dosage Form

Tablets for oral use.

Description

CRISANTA-LS is an oral contraceptive. Each pack consists of 24 tablets, and each tablet contains 3 mg of drospirenone (DRSP) and 0.02 mg of ethinylestradiol (EE).

Pharmacology

Pharmacodynamics 

Drospirenone is a spironolactone analogue with anti-mineralocorticoid and anti-androgenic activity. The oestrogen in crisanta-LS is ethinylestradiol.

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and the endometrial changes that reduce the likelihood of implantation.

Contraception

Two studies evaluated the effect of 3 mg DRSP / 0.02 mg EE combinations on the suppression of ovarian activity as assessed by measurement of follicle size via transvaginal ultrasound and serum hormone (progesterone and estradiol) analyses during two treatment cycles (21-day active tablet period plus 7-day pill-free period). More than 90% of subjects in these studies demonstrated ovulation inhibition.

Acne

Acne vulgaris is a skin condition with a multifactorial aetiology, including androgen stimulation of sebum production. While the combination of EE and DRSP increases sex hormone-binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the anti-androgenic activity of DRSP on acne is not known.

Pharmacokinetics

Absorption

The absolute bioavailability of DRSP from a single entity tablet is about 76%. The absolute bioavailability of EE is approximately 40% as a result of presystemic conjugation and first-pass metabolism. Serum concentrations of DRSP and EE reached peak levels within 1-2 hours after the administration.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of DRSP and EE, steady-state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC(0-24h) values of DRSP following multiple-dose administration of DRSP and EE.

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of DRSP and EE, serum Cmax and AUC(0–24h) values of EE accumulate by a factor of about 1.5-2.

Table 1: Pharmacokinetic Parameters of DRSP 3 mg and EE 0.02 mg

DRSP

Cycle/day

No. of subjects

Cmaxa (ng/ml)

Tmaxb (h)

AUC (0-24h)a (ng·h/ml)

t1/2a (h)

1/1

23

38.4 (25)

1.5

(1-2)

268 (19)

NA

1/21

23

70.3 (15)

1.5

(1-2)

763 (17)

30.8 (22)

EE

Cycle/day

No. of subjects

Cmaxa (pg/ml)

Tmaxb (h)

AUC (0-24h)a (pg·h/ml)

t1/2a (h)

1/1

23

32.8 (45)

1.5

(1-2)

108 (52)

NA

1/21

23

45.1 (35)

1.5

(1-2)

220 (57)

NA

NA = Not available

a: geometric mean (geometric coefficient of variation)

b: median (range)

Effect of Food

The rate of absorption of DRSP and EE following single administration of a formulation similar to DRSP and EE was slower under fed (high fat meal) conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.

Distribution

DRSP and EE serum concentrations 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 SHBG or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough concentrations). 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 SHBG and CBG. EE induced effects on SHBG and CBG were 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 were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4, 5-dihydrodrospirenone-3-sulphate formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active.  Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.

EE has been reported to be subject to significant gut and the liver hepatic first-pass metabolism. Metabolism of EE and its oxidative metabolites occur primarily by conjugation 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 concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single- and multiple- dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in faeces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and faeces. At least 20 different metabolites were observed in urine and faeces. About 38-47% of the metabolites in urine were glucuronide and sulphate conjugates. In faeces, about 17-20% of the metabolites were excreted as glucuronides and sulphates.

For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and faeces as glucuronide and sulphate conjugates and undergoes enterohepatic circulation.

Special Populations

Renal Impairment

DRSP+EE is contraindicated in patients with renal impairment. Steady-state serum DRSP levels in women with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those of women with normal renal function (CLcr > 80 ml/min). The serum DRSP levels were on average 37 % higher in women with moderate renal impairment (CLcr, 30 - 50 mL/min) compared to those in women with normal renal function. DRSP treatment was also well tolerated by women with mild and moderate renal impairment. DRSP treatment did not show any clinically significant effect on serum potassium concentration.

Hepatic Impairment

DRSP+EE is contraindicated in patients with hepatic disease. The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. DRSP and EE have not been studied in women with severe hepatic impairment.

Paediatric Population
Safety and efficacy of DRSP+EE has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

Geriatric Population
DRSP+EE has not been studied in postmenopausal women and is not indicated in this population.

Indications

CRISANTA-LS is indicated for:

  • Use as oral contraceptive in women
  • Treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. It should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.
  • Treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women.

The effectiveness of DRSP and EE for PMDD when used for more than three menstrual cycles has not been evaluated. DRSP and EE has not been evaluated for the treatment of premenstrual syndrome.

The decision to prescribe CRISANTA-LS should take into consideration the individual woman's current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with DRSP and EE compares with other Combine Hormonal Contraceptives (CHCs)

Dosage and Administration

CRISANTA-LS consists of 24 tablets of a monophasic combined hormonal preparation. The dosage of CRISANTA-LS is one tablet daily for 24 consecutive days followed by 4 pill-free days per menstrual cycle.

How to Take CRISANTA-LS

Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly. To achieve maximum effectiveness, CRISANTA-LS must be taken exactly as directed, in the order directed on the pack. Single missed pills should be taken as soon as remembered.

How to Start CRISANTA-LS

During the first cycle of CRISANTA-LS use, instruct the patient to take one tablet of CRISANTA-LS daily, beginning on Day 1 of her menstrual cycle (the first day of menstruation is Day 1).

She should take one tablet daily for 24 consecutive days followed by 4 pill-free days. CRISANTA-LS should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. CRISANTA-LS can be taken without regard to meals. If CRISANTA-LS 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. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.

Instructions for Patients

Subsequent Packs of CRISANTA-LS

The patient should begin her next and all subsequent 24-day regimens of CRISANTA-LS on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her tablets on the next day after the 4 pill-free days, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of CRISANTA-LS is started later than the day following the 4 pill-free days, the patient should use another method of contraception until she has taken CRISANTA-LS daily for 7 consecutive days.

Switching

When Switching from a Different Birth Control Pill

When switching from another birth control pill, CRISANTA-LS should be started on the same day that a new pack of the previous oral contraceptive would have been started.

When Switching from a Method other than a Birth Control Pill

When switching from a transdermal patch or vaginal ring, CRISANTA-LS should be started preferably on the day of removal, but at the latest when the next application would have been due.

When switching from an injection, CRISANTA-LS should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, CRISANTA-LS should be started on the day of removal. The woman should, in all of these cases, be advised to additionally use a barrier method for the first 7 days of tablet-taking.

Withdrawal bleeding usually occurs within 3 days following the last tablet. If spotting or breakthrough bleeding occurs while taking CRISANTA-LS, instruct the patient to continue taking CRISANTA-LS by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider.

Following first-trimester abortion, the woman may start CRISANTA-LS immediately. When doing so, she need not take additional contraceptive measures.

For postpartum women who do not breastfeed or after a second trimester abortion, start CRISANTA-LS no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on CRISANTA-LS postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken CRISANTA-LS for 7 consecutive days.

Although the occurrence of pregnancy is low if CRISANTA-LS 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. CRISANTA LS should be discontinued if pregnancy is confirmed.

The risk of pregnancy increases with each tablet missed. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence.

Missed Pill

If the user is less than 24 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time. If she is more than 24 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1. The recommended hormone-free tablet interval is 4 days, tablet-taking must never be discontinued for longer than 7 days

2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian axis.

The risk of pregnancy increases with each tablet missed.

If she MISSES one tablet:

  • Ask her to take it as soon as she remembers. Ask her to take the next tablet at her regular time. This means she may take two tablets in one day.
  • She does not need to use a back-up birth control method if she has sex.

If she MISSES two tablets in a row in WEEK 1 OR WEEK 2 of the pack:

  • Ask her to take two tablets on the day she remembers and two tablets the next day.
  • Then ask her to take one tablet a day until she finishes the pack.
  • She could become pregnant if she has sex in the 7 days after she restarts her tablets. She must use another birth control method (such as condoms or spermicides) as a back-up for those 7 days.

If she MISSES two tablets in a row in WEEK 3 or Week 4 of the pack:

  • Ask her to throw out the rest of the pack and start a new pack that same day.
  • She could become pregnant if she has sex in the 7 days after she restarts her tablets. She must use another birth control method (such as condoms or spermicides) as a back-up for those 7 days.
  • She may not have her period this month but this is expected. However, if she misses her period 2 months in a row, ask her to contact her doctor or clinic because she might be pregnant.

If she MISSES three OR more tablets in a row during ANY Week:

  • Ask her to throw out the rest of the pack and start a new pack that same day.
  • She could become pregnant if she has sex in the 7 days after she restarts her tablets. She must use another birth control method (such as condoms or spermicides) as a back-up for those 7 days.
  • She may not have her period this month but this is expected. However, if she misses her period 2 months in a row, ask her to contact her doctor or clinic because she might be pregnant.

Finally, if she is still not sure what to do about the tablets she has missed:

  • Ask her to use a back-up method (such as condoms or spermicides) anytime she has sex.
  • Ask her to continue taking 1 tablet each day until she contacts her doctor.

Advice in Case of Gastrointestinal Disturbances

In case of severe gastrointestinal disturbances (e.g.  vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3–4 hours after tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 24 hours of the usual time of tablet-taking if possible. If more than 24 hours elapse, the advice concerning missed tablets is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack.

How to Postpone a Withdrawal Bleed

To delay a period the woman should continue with another blister pack of CRISANTA-LS. The extension can be carried on for as long as wished until the end of the active tablets in the second pack. During the extension, the woman may experience breakthrough-bleeding or spotting. Regular intake of CRISANTA-LS is then resumed after the pill-free days. To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming placebo tablet phase by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

Contraindications

Do not prescribe DRSP+EE to women who are known to have the following conditions. Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.

  • Renal impairment - severe renal insufficiency or acute renal failure
  • Adrenal insufficiency
  • Presence or high risk of arterial or venous thrombotic diseases / thromboembolism. Examples include women who are known to:
    • Smoke, if over age 35
    • Have deep vein thrombosis or pulmonary embolism, now (on anticoagulants) or in the past
    • Current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
    • Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
    • Major surgery with prolonged immobilization
    • Have cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
    • Have coronary artery disease
    • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
    • Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
    • Have inherited or acquired hypercoagulopathies
    • Have severe or uncontrolled hypertension
    • Have diabetes mellitus with vascular disease
    • Have severe dyslipoproteinaemia
    • Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35
  • Undiagnosed abnormal uterine bleeding
  • Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts)
  • Presence or history of liver tumours, benign or malignant, or liver disease
  • Presence or history of severe hepatic disease as long as liver function values have not returned to normal
  • Pregnancy, because there is no reason to use COCs during pregnancy
  • Hypersensitivity to any component of this product
  • Use of Hepatitis C drug combinations containing ombitasvir / paritaprevir / ritonavir, with or without dasabuvir due to the potential for ALT elevations

Warnings and Precautions

If any of the conditions or risk factors mentioned below is present, the suitability of DRSP+EE should be discussed with the woman.

In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of DRSP+EE should be discontinued.

In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case anticoagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

General

Thromboembolic Disorders and Other Vascular Problems

Stop DRSP+EE if an arterial or venous thrombotic event occurs.

Based on presently available information on DRSP-containing COCs with 0.03 mg EE, DRSP containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a 3-fold increase. Before initiating use of DRSP+EE in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk for VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs.

Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-pregnant, non-users (1-5 per 10,000 woman-years), the rates during pregnancy (5-20 per 10,000 woman-years) are even greater, especially during the postpartum period (40-65 per 10,000 woman-years). The risk of VTE in women using COCs has been estimated to be 3-9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared with that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC.

The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

If feasible, stop DRSP+EE at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start DRSP+EE no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and haemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop DRSP+EE if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

Risk of Venous Thromboembolism (VTE)

The use of any combined hormonal contraceptive (CHC) increases the risk of VTE compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as DRSP+EE may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with DRSP+EE, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

Risk Factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

DRSP+EE is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.

In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

It is estimated that out of 10,000 women who use a CHC containing drospirenone between 9 and 12 women will develop a VTE in one year; this compares with about 6 in women who use a levonorgestrel-containing CHC. In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

VTE may be fatal in 1-2% of the cases.

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Table 2: Risk Factors for VTE

Risk factor

Comment

Obesity

(body mass index over 30 kg/m2)

Risk increases Substantially as BMI rises. Particularly important to consider if other risk factors also present.

Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma

 

 

 

 

Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors

In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another

method of contraception should be used to avoid unintentional pregnancy.

 

Antithrombotic treatment should be considered if DRSP+EE has not

been discontinued in advance.

Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).

If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use

           

Other medical conditions associated with VTE

Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease

Increasing age

Particularly above 35 years

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of the puerperium, must be considered.

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:

  • unilateral swelling of the leg and/or foot or along a vein in the leg;
  • pain or tenderness in the leg which may be felt only when standing or walking,
  • increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:

  • sudden onset of unexplained shortness of breath or rapid breathing;
  • sudden coughing which may be associated with haemoptysis;
  • sharp chest pain;
  • severe light headedness or dizziness;
  • rapid or irregular heartbeat.

Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discolouration of an extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of Arterial Thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for ATE (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk Factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). DRSP+EE is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.

Table 3: Risk factors for ATE

Risk factor

Comment

Increasing age

Particularly above 35 years

Smoking

Women should be advised not to smoke if they wish to use a CHC.

Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.

Hypertension

 

Obesity (body mass index over 30 kg/m2)

Risk increases substantially as BMI increases.

Particularly important in women with additional risk factors

Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).

If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use

Migraine

An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation

Other medical conditions associated with adverse vascular events

 

Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus

Symptoms of ATE

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:

  • sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
  • sudden trouble walking, dizziness, loss of balance or coordination;
  • sudden confusion, trouble speaking or understanding;
  • sudden trouble seeing in one or both eyes;
  • sudden, severe or prolonged headache with no known cause;
  • loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) can include:

  • pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
  • discomfort radiating to the back, jaw, throat, arm, stomach;
  • feeling of being full, having indigestion or choking;
  • sweating, nausea, vomiting or dizziness;
  • extreme weakness, anxiety, or shortness of breath;
  • rapid or irregular heartbeats.

Hyperkalaemia

The progestin DRSP is an aldosterone antagonist with potassium sparing properties. It has anti-mineralocorticoid activity, including the potential for hyperkalaemia in high risk patients, comparable to a 25 mg dose of spironolactone. DRSP+EE is contraindicated in patients with conditions that predispose to hyperkalaemia (i.e. renal impairment, hepatic impairment and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists and NSAIDs. Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g. indinavir, boceprevir), and clarithromycin.

In most cases, no increase of potassium levels is to be expected. In a clinical study, however in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products serum potassium levels slightly, but not significantly, increased during drospirenone intake. Therefore, it is recommended to check serum potassium during the first treatment cycle in patients presenting with renal insufficiency and a pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products.

Carcinoma of the Breasts and Reproductive Organs

Women who currently have or have had breast cancer should not use DRSP+EE because breast cancer is a hormonally-sensitive tumour. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some epidemiological studies suggest that long-term use of COCs (> 5 years) are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behaviour and other factors such as human papilloma virus.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

With the use of the higher-dosed COCs (50 μg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed COCs remains to be confirmed.

Liver Disease

Discontinue DRSP+EE if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use. In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. An estimate of the attributable risk is 3.3 cases/100,000 COC users. In isolated cases, rupture of hepatic adenomas may cause death through intra-abdominal haemorrhage. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials in patients treated for hepatitis C virus infections with the Hepatitis C combination drug regimen containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinylestradiol-containing medications, such as COCs. Discontinue DRSP+EE and switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. DRSP+EE can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

High Blood Pressure

For women with well-controlled hypertension, monitor blood pressure and stop DRSP+EE if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. If, during the use of a COC in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the COC must be withdrawn. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking DRSP+EE. COCs may decrease glucose intolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidaemias. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed, particularly in the early stage of COC use.

Headache

If a woman taking DRSP+EE develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue DRSP+EE if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

Bleeding Irregularities/ Reduced cycle control

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles. If bleeding irregularities persist or occur after previously regular cycles, non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Based on patient diaries from two contraceptive clinical trials of DRSP+EE, 8 to 25% of women experienced unscheduled bleeding per 28-day cycle. A total of 12 subjects out of 1,056 (1.1%) discontinued due to menstrual disorders including intermenstrual bleeding, menorrhagia, and metrorrhagia.

Women who use DRSP+EE may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from contraception trials for up to 13 cycles, 6 to 10% of women experienced cycles with no withdrawal bleeding. Some women may encounter post-pill amenorrhoea or oligomenorrhoea, especially when such a condition was pre-existent.

In some women withdrawal bleeding may not occur during the pill free days. If the COC has been taken according to the directions, it is unlikely that the woman is pregnant. 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), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy before COC use is continued.

COC Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives 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.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy.

Depression

Women with a history of depression should be carefully observed and DRSP+EE discontinued if depression recurs to a serious degree.

Interference with Laboratory Tests

The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.

Monitoring

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

Other Conditions

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstones; porphyria; systemic lupus erythematosus; haemolytic uremic syndrome; sydenham's chorea; herpes gestationis; otosclerosis related hearing loss.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus which previously occurred during pregnancy or during previous use of sex steroids necessitates the discontinuation of COCs.

In women with hereditary angio-oedema, exogenous oestrogens may induce or exacerbate symptoms of angio-oedema.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis has been reported during COC use.

Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g. missed active tablets, gastrointestinal disturbances during tablet taking or concomitant medication.

Medical Examination/Consultation

Prior to the initiation or reinstitution of DRSP+EE a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications and warnings. It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of DRSP +EE compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Drug Interactions

Consult the labelling of all concurrently-used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations.

Effects of Other Drugs on Combined Hormonal Contraceptives (DRSP+EE)  

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

Management

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

Short-term treatment

Women on treatment with enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the tablets in the COC pack, the next COC pack should be started right away.

Long-term treatment

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.

Substances Increasing the Clearance of COCs (Diminishing the Efficacy of COCs by Enzyme Induction)

Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, primidone, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate; HIV medication ritonavir, nevirapine and efavirenz, and products containing St. John’s wort (hypericum perforatum). Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Substances Increasing the Plasma Concentrations of COCs (Decreasing the Clearance of COCs)

Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as etoricoxib, azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the oestrogen or the progestin or both. The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

The clinical impact for a patient taking a DRSP-containing COC concomitantly with chronic use of a CYP3A4/5 inhibitor is unknown.

Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors

Significant changes (increase or decrease) in the plasma concentrations of oestrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Antibiotics

There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

Effects of COCs on Other Drugs

COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

COCs may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin or midazolam as marker substrate, an interaction of drospirenone at doses of 3 mg with the cytochrome P450 mediated metabolism o other active substances is unlikely.

COCs Increasing the Plasma Concentrations of CYP450 Enzymes

In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase.

Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.

Potential to Increase Serum Potassium Concentration

There is a potential for an increase in serum potassium concentration in women taking DRSP+EE with other drugs that may increase serum potassium concentration. A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. No patient in either treatment group developed hyperkalemia (serum potassium concentrations > 5.5 mEq/L).

In patients without renal insufficiency, the concomitant use of DRSP and ACE-inhibitors or NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of DRSP +EE with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle.

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer DRSP + EE with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations.

Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier/binding) proteins, e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions, glucose tolerance, lipids, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis.

Changes generally remain within the normal laboratory range. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

Renal Impairment

DRSP+EE is contraindicated in patients with renal impairment.

In subjects with creatinine clearance (CLcr) of 50–79 mL/min, serum DRSP levels were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30–49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalaemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs

Hepatic Impairment

DRSP+EE is contraindicated in patients with hepatic disease. The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. DRSP+ EE has not been studied in women with severe hepatic impairment.

Pregnancy

Pregnancy Category X

DRSP+EE is not indicated during pregnancy.

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed may start COCs no earlier than 4 weeks postpartum.

If pregnancy occurs during use of with DRSP+EE, the preparation should be withdrawn immediately. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy.

Animal studies have shown undesirable effects during pregnancy and lactation. Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual adverse effect in humans.

The available data regarding the use of DRSP+EE during pregnancy are too limited to permit conclusions concerning negative effects of DRSP+EE on pregnancy, health of the foetus or neonate. To date, no relevant epidemiological data are available. The increased risk of VTE during the postpartum period should be considered when re-starting DRSP+EE

Lactation

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Oestrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk during COC use. These amounts may affect the child. Therefore, the use of COCs should generally not be recommended until the breastfeeding mother has completely weaned her child.

After oral administration of 3 mg DRSP/0.03 mg EE tablets, 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 0.003 mg DRSP in an infant.

Paediatric Use

Safety and efficacy of DRSP+EE has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 years and for users aged 18 years and older. Use of this product before menarche is not indicated.

Geriatric Use

DRSP+EE has not been studied in postmenopausal women and is not indicated in this population.

Undesirable Effects

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labelling:

  • Serious cardiovascular events and stroke
  • Vascular events
  • Liver disease

Adverse reactions commonly reported by COC users are:

  • Irregular uterine bleeding
  • Nausea
  • Breast tenderness
  • Headache

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Contraception and Acne Clinical Trials

The data provided reflect the experience with the use of DRSP and EE in the adequate and well-controlled studies for contraception (N=1,056) and for moderate acne vulgaris (N=536).

The adverse reactions seen across the two indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (> 2% of users) were: Headache/migraine (6.7%), menstrual irregularities (including vaginal haemorrhage and metrorrhagia (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4%) and mood changes (2.2%).

PMDD Clinical Trials

Safety data from two trials for the indication of PMDD are reported separately due to differences in study design and setting in the Contraception and Acne studies as compared with the PMDD clinical program.

Common adverse reactions (> 2% of users) were: menstrual irregularities (including vaginal haemorrhage and metrorrhagia) (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%).

Adverse Reactions (> 1%) Leading to Study Discontinuation

Contraception Clinical Trials

Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1.0%).

Acne Clinical Trials

Of 536 women, 5.4% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was menstrual irregularities (including menometrorrhagia, menorrhagia, metrorrhagia and vaginal haemorrhage; 2.2%).

PMDD Clinical Trials

Of 285 women, 11.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were: nausea/vomiting (4.6%), menstrual irregularity (including vaginal haemorrhage, menorrhagia, menstrual disorder, menstruation irregular and metrorrhagia; 4.2%), fatigue (1.8%), breast tenderness (1.4%), depression (1.4%), headache (1.1%), and irritability (1.1%).

Serious Adverse Reactions

Contraception Clinical Trials: migraine and cervical dysplasia

Acne Clinical Trials: none reported in the clinical trials

PMDD Clinical Trials: cervical dysplasia

Adverse drug reactions which have been associated with the use of DRSP+EE as oral contraceptive or in the treatment of moderate acne vulgaris

System Organ

Class

Common

(≥1/100 to <1/10)

uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Not known (cannot be

estimated from the

available data)

Infections and

infestations

 

 

Candidiasis

 

Blood and

lymphatic system

disorders

 

 

Anemia

Thrombocythemia

 

Immune system

disorders

 

 

Allergic reaction

Hypersensitivity

Endocrine

disorders

 

 

Endocrine disorder

 

Metabolism and

nutrition disorders

 

 

Increased appetite

Anorexia Hyperkalemia

Hyponatremia

 

 

Psychiatric

disorders

Emotional lability

Depression

Nervousness

Somnolence

Anorgasmia

Insomnia

 

Nervous system

disorders

Headache

Dizziness

Paresthesia

Vertigo

Tremor

 

Eye disorders

 

 

Conjunctivitis

Dry eye

Eye disorder

 

Cardiac disorders

 

 

Tachycardia

 

Vascular disorders

 

Migraine

Varicose vein Hypertension

Phlebitis

 

Vascular disorder

Epistaxis

Syncope

Venous

thromboembolism

(VTE)

Arterial

thromboembolism

(ATE)

 

Gastrointestinal

disorders

Nausea

Abdominal pain

Vomiting

Dyspepsia

Flatulence

Gastritis

Diarrhea

Abdomen enlarged

Gastrointestinal

disorder

Gastrointestinal fullness

Hiatus hernia

Oral candidiasis

Constipation

Dry mouth

 

Hepatobiliary

disorders

 

 

Biliary pain

Cholecystitis

 

Skin and

subcutaneous

tissue disorders

 

Acne

Pruritus

Rash

Chloasma

Eczema

Alopecia

Dermatitis acneiform

Dry skin

Erythema nodosum

Hypertrichosis

Skin disorder

Skin striae

Contact dermatitis

Photosensitive

dermatitis

Skin nodule

Erythema multiforme

Musculoskeletal

and connective tissue disorders

 

Back pain

Pain in extrremity

Muscle cramps

 

 

 

 

 

Reproductive

system and breast

disorders

Breast pain

Metrorrhagia*

Amenorrhea

Vaginal candidiasis

Pelvic pain

Breast enlargement

Fibrocystic breast

Uterine / Vaginal

bleeding*

Genital discharge

Hot flushes

Vaginitis

Menstrual disorder

Dysmenorrhea

Hypomenorrhea

Menorrhagia

Vaginal dryness

Papanicolaou smear

suspicious

Libido decreased

Dyspareunia

Vulvovaginitis

Postcoital bleeding

Withdrawal bleeding

Breast cyst

Breast hyperplasia

Breast neoplasm

Cervical polyp

Endometrial atrophy

Ovarian cyst

Uterine enlargement

 

General disorders

and administration

site conditions

 

Asthenia

Sweating increased

Oedema

(Generalized oedema,

Peripheral oedema,

Face oedema)

Malaise

 

Investigations

 

Weight increase

Weight decrease

 

* bleeding irregularities usually subside during continued treatment

Description of Selected Adverse Reactions

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs.

The following serious adverse events have been reported in women using COCs:

  • Venous thromboembolic disorders;
  • Arterial thromboembolic disorders;
  • Hypertension;
  • Liver tumours;
  • Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn's disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;
  • Chloasma;
  • Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.
  • In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown.

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives.

Post Marketing Experience

The following adverse reactions have been identified during post approval use of DRSP and EE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions are grouped into System Organ Classes, and ordered by frequency.

Vascular Disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, retinal thrombosis, myocardial infarction and stroke), hypertension (including hypertensive crisis)

Hepatobiliary Disorders: Gallbladder disease, liver function disturbances, liver tumours

Immune System Disorders: Hypersensitivity (including anaphylactic reaction)

Metabolism and Nutrition Disorders: Hyperkalaemia, hypertriglyceridaemia, changes in glucose tolerance or effect on peripheral insulin resistance (including diabetes mellitus)

Skin and Subcutaneous Tissue Disorders: Chloasma, angio-oedema, erythema nodosum, erythema multiforme

Gastrointestinal Disorders: Inflammatory bowel disease

Musculoskeletal and Connective Tissue Disorders: Systemic lupus erythematosus

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024. 

By reporting side effects you can help provide more information on the safety of this product.

Overdosage

There have been no reports of serious ill effects from overdose, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

DRSP is a spironolactone analogue having anti-mineralocorticoid properties. Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.

There has not yet been any experience of overdose with DRSP +EE. On the basis of general experience with combined oral contraceptives, symptoms that may possibly occur in case of taking an overdose of active tablets are nausea, vomiting and withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product. There are no antidotes and further treatment should be symptomatic.

Storage and Handling Instructions

Store in a cool, dry place.

Packaging Information

CRISANTA-LS is available in a pack of 24 tablets.

 

Last updated: October 2018

Last reviewed: October 2018