Synfonia

Drospirenone, ethinylestradiol.

The active tablet is round, peach film-coated tablet, plain on both sides.
The inactive tablet is round, white film-coated tablet, plain on both sides.
24 peach (active) film-coated tablets: Each film-coated tablet contains 2 active substances of drospirenone 3 mg and ethinylestradiol 0.02 mg.
Excipient: Lactose 44 mg.
4 white (inactive) film-coated tablets: The tablet does not contain active substance.
Excipient: Lactose 89.5 mg.
Excipients/Inactive Ingredients: Active film-coated tablets (peach): Lactose monohydrate, Pregelatinized starch, Povidone K-30, Croscarmellose sodium, Polysorbate 80, Magnesium stearate, Opadry II Pink.
Inactive film-coated tablets (white): Lactose anhydrous, Povidone K-30, Magnesium stearate, Opadry II White.

Pharmacology: Pharmacodynamics: The contraceptive effect of combined oral contraceptives is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion and endometrium.
Drospirenone has beneficial properties in addition to contraception. Drospirenone has antimineralocorticoid activity that can prevent weight gain and other symptoms caused by fluid retention. It counteracts the estrogen-related sodium retention, providing for a very good tolerance and has positive effects on the premenstrual syndrome (PMS). Drospirenone 3 mg and ethinylestradiol 0.02 mg 24+4 tablets, a shortened hormone free interval, was studied in premenstrual dysphoric disorder (PMDD). PMDD is a severe form of PMS. It showed clinical superiority in relief of symptoms of PMDD in comparison with placebo.
In combination with ethinylestradiol, drospirenone displays a favorable lipid profile with an increase in HDL. Drospirenone exerts antiandrogenic activity leading to a positive effect on the skin and toa reduction in acne lesions and sebum production, reduction in greasiness of the skin and hair.
In addition, drospirenone does not counteract the ethinylestradiol-related sex hormone binding globulin (SHBG) increase which is useful for binding and inactivation of the endrogenous androgens. Drospirenone has no androgenic, estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Bioavailability is between 76 and 85%. Concomitant ingestion of food has no influence on the bioavailability of drospirenone.
Distribution: After oral administration, serum drospirenone levels decrease with a terminal half-life approximately 30 hours. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG).
Metabolism: Drospirenone is extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4.
Elimination: Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine, the half-life of metabolite excretion with the urine and feces is about 40 hours.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is absorbed rapidly and completely. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%.
Distribution: Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%), and induces an increase in the serum concentrations of sex hormone binding globulin (SHBG) and corticoid binding globulin (CBG).
Metabolism: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized as free metabolites and as conjugates with glucuronides and sulfate.
Elimination: Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.
Toxicology: Preclinical safety data: In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those associated with the recognised pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and fetotoxic effects in animals which are considered as species specific.

Synfonia is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.
Synfonia is indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive as their method of contraception. Synfonia is also indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and achieved menarche. Synfonia should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.

Route of administration: Oral use.
The tablets must be taken every day at about the same time, if necessary with a little liquid, with or without food, in the order shown on the blister pack. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack. Withdrawal bleeding usually starts on day 2-3 after starting the inactive tablets (last row) and may not have finished before the next pack is started. Do not leave a gap between packs, i.e. start taking the next pack on the day after the patient has finished the current one, even if her period continues. This means that she will always start new pack on the same day of the week, and also that she has her withdrawal bleed on about the same days, each month.
How to start Synfonia (24+4 film-coated tablets): No preceding hormonal contraceptive use (in the past month): Start taking Synfonia on day 1 of the patient's cycle, i.e. the first day of menstrual bleeding. Then follow the days in order. Synfonia will work immediately, it is not necessary to use an additional contraceptive method. Patient may also start on days 2-5 of her cycle, but in that case make sure she also use an additional contraceptive method (barrier method) for the first 7 days of tablet-taking in the first cycle.
Changing from another combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch): Patient should start Synfonia preferably on the day after the last active tablet (the last tablet containing the active substances) of the previous COC, but at the latest on the day following the usual tablet-free or inactive tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, she should start using Synfonia preferably on the day of removal, but at the latest when the next application would have been due. If she follow these instructions, it is not necessary to use an additional contraceptive method.
Changing from a progestogen-only-method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS): Patient may switch any day from the progestogen-only pill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method (i.e. condom) for the first 7 days of tablet-taking when having intercourse.
After having a baby: If patient has just had a baby, a doctor may tell to wait until after her first normal period before she starts taking Synfonia. Sometimes it is possible to start sooner. A doctor will advise the patient. If patient is breast-feeding and wants to take Synfonia, she should discuss this first with a doctor.
After a miscarriage or an abortion: A doctor will advise the patient.
What to do if the patient forget tablets: If the patient forgot to take the last 4 tablets from ROW 4 OF HER BLISTER, she is still protected against pregnancy because they do not contain any active ingredients. However, to make sure that she does not change her pill taking rhythm, which is important for the contraceptive reliability of her pill, she should proceed with her next tablet at the normal time and discard the forgotten inactive tablets to avoid any confusion. If she forgot the last tablet from row 4 of her current pack it is important that she still take the first tablet from the next pack at the correct time.
The following advice refers to missing active tablets (tablets 1-24 of her blister): If the patient is less than 12 hours late in taking a tablet, the reliability of the pill is maintained. Take the tablet as soon as she remembers and take the next tablets at the usual times.
If the patient is more than 12 hours late in taking any active tablet, the reliability of the pill may be reduced. The more consecutive active tablets she has missed the higher the risk that the contraceptive effect is decreased. There is a particularly high risk of becoming pregnant if the patient misses tablets at the beginning of the pack or at the end (the last of the 24 active tablets). Therefore, she should follow the rules given as follows (see also the diagram as follows).
More than one tablet forgotten in a pack: Ask a doctor for advice.
1 tablet missed during day 1-7: Take the missed tablet as soon as patient remembers (even if this means taking two tablets at the same time) and take the next tablets at the usual time. Use extra contraceptive precautions (barrier method) for the next 7 days.
If she had sexual intercourse in the week before missing the tablet, there is a possibility of becoming pregnant. So tell a doctor immediately.
1 tablet missed during day 8-14: Take the missed tablet as soon as patient remembers (even if this means taking two tablets at the same time) and take the next tablets at the usual time. The reliability of the pill is maintained. She need not use extra contraceptive precautions.
1 tablet missed during day 15-24: The patient may choose either of the following options, without the need for extra contraceptive precautions: 1. Take the missed tablet as soon as she remembers (even if this means taking two tablets at the same time) and take the next tablets at the usual time. Discard current pack as soon as the 3 active tablets in row 4 are finished (the remaining 4 inactive tablets in row 4 must not be taken) and start the next pack so that NO GAP IS LEFT BETWEEN PACKS. She may not have a withdrawal bleed until the end of the active tablets of the second pack but she may have spotting or breakthrough bleeding on tablet-taking days. Or;
2. Stop taking tablets from her current pack, have a tablet-free break of 4 days or less (ALSO COUNT THE DAY SHE MISSED HER TABLET) and continue with the next pack.
3. If she has forgotten many tablets and do not have a withdrawal bleed while taking the last 4 inactive tablets in row 4, she may be pregnant. Consult a doctor before she starts the next pack. (See figure.)

Click on icon to see table/diagram/image

WHAT TO DO IF: The patient suffers from gastro-intestinal disturbances (e.g. vomiting, severe diarrhea): If the patient vomits, or has severe diarrhea after taking any of the 24 active tablets of Synfonia, the active ingredients may not have been completely absorbed. If she vomits within 3 to 4 hours after taking the tablets, this is like missing a tablet. Therefore, follow the active for missed tablets.
If patient has severe diarrhea, contact a doctor. Vomiting or diarrhea while taking the last 4 inactive tablets from row 4 does not have an influence on the contraceptive reliability.
The patient wants to delay a period: The patient can delay her period if she starts with her next pack of Synfonia immediately after finishing the 3 active tablets in row 4 of her current pack (do not take the last 4 inactive tablets from row 4). She can continue with this pack for as long as she wishes, e.g. until this pack is empty to get a period approx. 3 weeks later than usual. When she wishes her period to begin earlier than that, just stop taking active tablets, discard the pack and have a pill-free interval of a maximum of 4 days and then start a new pack. In this case, approx. 2-3 days after she took the last tablet she should get her period. While using the second pack she may have some breakthrough bleeding or spotting on tablet-taking days.
The patient wants to change the starting day of her period: If the patient takes her tablets as directed, she will have her period on about the same day every 4 weeks. If she wants to change this, do not use up the inactive tablets from the last row (row 4) before she starts the next pack. For example, if her period usually starts on a Friday and in future she wants it to start on Tuesday (3 days earlier) she should now start her next pack 3 days sooner than she usually does, discard the 3 remaining tablets of her previous pack and then continue with the next pack without having a break between the packs. The less inactive tablets from row 4 she takes, the higher is the probability that she will not have a bleeding. She may have some breakthrough bleeding or spotting during the use of the next pack.
The patient has unexpected bleeding: With all pill, for the first few months, she can have irregular vaginal bleeding (spotting or breakthrough bleeding) between her periods. She may need to use sanitary protection, but continue to take her tablets as normal. Irregular vaginal bleeding usually stops once the body has adjusted to the pill (usually after about 3 tablet-taking cycles). If it continues, becomes heavy or starts again, tell a doctor.
The patient has missed a period: If the patient has taken all of her tablets at the right time, and she has not vomited, nor had severe diarrhea while taking any of the 24 active pills, or used other medicines then she is very unlikely to be pregnant. Continue to take Synfonia as usual.
If the patient misses her period twice in a row, she may be pregnant. Tell a doctor immediately. Do not start the next pack of Synfonia until a doctor has checked that the patient is not pregnant.
More about the Pill: The combined pill may also have non-contraceptive health benefits.
The patient's period may be lighter and shorter. As a result, the risk of anemia may be lower. Her period pains may become less severe or may completely disappear.
In addition, some serious disorders have been reported to occur less frequently in users of the pills containing 50 micrograms of ethinylestradiol ('high-dose pills'). These are benign breast disease, ovarian cysts, pelvic infections (pelvic inflammatory disease or PID), ectopic pregnancy (pregnancy in which the embryo implants outside the womb) and cancer of the endometrium (lining of the womb) and ovaries. This may also be the case for low-dose pills but so far this has only been confirmed for endometrial and ovarian cancer.
One of the hormones in Synfonia, drospirenone, has special properties leading to beneficial effects in addition to contraception. Drospirenone can prevent weight-gain, and other symptoms like bloating and swelling, related to fluid retention caused by hormones both in oral contraceptives and at certain times in the menstrual cycle. These special properties make drospirenone similar tothe natural progesterone hormone produces by the body. Drospirenone also has antiandrogenic activity which can help to reduce acne (pimples) and greasiness of the skin and hair.

There has not yet been any experience of overdose with Synfonia. 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 and vomiting. There are no antidotes and further treatment should be symptomatic.

This medication should not be used in the presence of any the conditions listed as follows. Should any of the conditions appear for the first time during use, the product should be stopped immediately: Renal insufficiency; Hepatic dysfunction; Adrenal insufficiency; Thrombophlebitis or thromboembolic disorders; A past history of deep-vein thrombophlebitis or thromboembolic disorders; Active or history of cerebrovascular disease or coronary artery disease; Valvular heart disease with thrombogenic complications; Severe hypertension; Diabetes with vascular involvement; Have or have had a pancreatitis associated with high levels of fatty substances in blood; Headaches with focal neurological symptoms; Major surgery with prolonged immobilization; Known or suspected breast carcinoma, or endometrium carcinoma; Known or suspected estrogen-dependent neoplasia; Cholestatic jaundice of pregnancy or jaundice with prior pill use; Known or suspected pregnancy; Undiagnosed vaginal bleeding; Liver tumor (benign or malignant) or active liver disease; Jaundice; Heavy smoking (≥15 cigarettes per day) and over age 35; Hypersensitivity to any component of this product.

1. Do not use in the presence of thrombosis and hepatic disease.
2. Should not use in women who have risk of thrombosis, such as a history of thrombophlebitis, obesity, diabetes, hypertension.
3. Should not use in presence or history of liver tumors, known or suspected sex hormones related cancer such as breast cancer or genital organs cancer.
4. Use carefully in cigarette smoking women, especially women older than 35 years of age should consult the physician before using this medication.
5. Use other than contraceptive, consult the physician.
6. Consult the physician if any abnormal symptoms occur while using this medication.

Prior to the initiation or reinstitution of Synfonia, 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 (see Contraindications) and warnings (see Warnings). The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given.
Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Use of combined oral contraceptives is associated with an increased risk of several conditions including thromboembolism, stroke, myocardial infarction, liver tumor, gallbladder disease, visual disturbances and hypertension. Cigarette smoking increases the risk of serious adverse cardiovascular effects during oral contraceptive use. The risk increases with age and with heavy smoking (15 or more cigarettes daily) and is markedly greater in women older than 35 years of age. Women who are receiving combined oral contraceptives should be strongly advised not to smoke. Women older than 35 years of age who smoke, and women with ischemic heart disease or a history of this disease, should not use combined oral contraceptives.
If any of the conditions/risk factors mentioned previously is present, the benefits of combined oral contraceptives use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether combined oral contraceptives use should be discontinued.
The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use. Should any of the following symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident occur, the product should be stopped and immediately contact the physician: unusual unilateral leg pain and/or swelling; sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; 'acute' abdomen.
The pill and cancer: Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This slight increase in the numbers of breast cancer diagnoses gradually disappears during the course of the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that the women were examined more often, so that the breast cancer was noticed earlier.
In rare cases benign liver tumors and even more rarely, malignant liver tumors have been reported in users of the pill. These tumors may lead to internal bleeding. Contact a doctor immediately if patient has severe pain in her abdomen.
The most important risk factor for cervical cancer is persistent human papilloma virus infection. Some studies have indicated that long-term use of the pill may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable toother factors, e.g., cervical screening and sexual behavior including use of barrier contraceptives.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
No effects on ability to drive and use machines have been observed in users of COCs.

Pregnancy: If the patient is pregnant, she should not take Synfonia. If the patient is pregnant when taking Synfonia, she should stop taking it immediately and contact a doctor.
Lactation: It is generally not recommended to take Synfonia when the patient is breast-feeding. If she wants to use the contraceptive while breast-feeding, she should consult a doctor.

The following undesirable effects have been reported by users of the pill, although they need not be caused by the pill. These undesirable effects may occur in the first few months that the patient is using the pill and usually lessen with time. (See table.)

Click on icon to see table/diagram/image

If the patient has hereditary angioedema; exogenous estrogens may induce or exacerbate symptoms of angioedema.
If the patient notices any side effects not mentioned in this monograph, inform a doctor or pharmacist.

Hepatic metabolism: Interactions can occur with drugs that reduce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, griseofulvin, rifampicin, HIV-medication (e.g. ritonavir, nevirapine) and possibly also and products containing the herbal remedy St. John's Wort (Hypericum perforatum).
Women on short-term treatment with any of the previously mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) should temporarily use a barrier method in addition to the combined oral contraceptives.
Influence of Synfonia on other medicinal products: Oral contraceptives 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).
Other interactions: In patients without renal insufficiency, the concomitant use of drospirenone and ACE-inhibitors or NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of Synfonia with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle.
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) proteins.

Incompatibilities: Not applicable.

Do not store above 30°C.
Shelf life: 2 years.

Oral Contraceptives

G03AA12 - drospirenone and ethinylestradiol ; Belongs to the class of progestogens and estrogens in fixed combinations. Used as systemic contraceptives.

D