Instructions for Siluet film-coated tablets 2.03 mg blister No. 63
Composition
active ingredients: dienogest, ethinylestradiol;
1 film-coated tablet contains dienogest 2 mg and ethinylestradiol 0.03 mg;
excipients: lactose monohydrate, corn starch, hypromellose (type 2910), talc, polacrilin potassium, magnesium stearate;
shell: Opadry II 85F18422 white (polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc).
Dosage form
Film-coated tablets.
Main physicochemical properties: white or almost white, round, biconvex tablets, film-coated, engraved with “G53” on one side, plain on the other side. Diameter approximately 5.5 mm.
Pharmacotherapeutic group
Sex hormones and modulators of the reproductive system. Progestogens and estrogens, fixed combinations. ATX code G03AA16.
Pharmacological properties
Pharmacodynamics
All hormonal contraceptive methods have a very low contraceptive failure rate when used as directed. Contraceptive failure rates may be higher if the drug is not used as directed (e.g., missing a pill).
During studies with the drug Silhouette®, the Pearl index was calculated:
unadjusted Pearl index - 0.454 (upper 95% confidence interval (CI): 0.701); adjusted Pearl index - 0.182 (upper 95% confidence interval: 0.358).
Silhouette®, film-coated tablets, is a combined oral contraceptive (COC) with antiandrogenic effect, containing ethinylestradiol and dienogest as a progesterone.
The contraceptive effect of Silhouette® pills is based on the interaction of various factors, the most important of which are the inhibition of ovulation and changes in cervical secretion.
The antiandrogenic effect of the combination of ethinylestradiol and dienogest is based mainly on a decrease in the level of androgens in the blood plasma.
Dienogest is a nortestosterone derivative with an in vitro affinity for progesterone receptors that is 10-30 times lower than that of other synthetic progestogens. In vivo animal data indicate strong progestogenic activity and antiandrogenic activity. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.
The dose of dienogest that leads to ovulation suppression is 1 mg/day.
The risk of endometrial and ovarian cancer is reduced with high-dose COCs (0.05 mg ethinylestradiol). Whether this also applies to low-dose COCs remains unclear.
Pharmacokinetics
Ethinylestradiol.
Absorption. Ethinylestradiol is rapidly and completely absorbed after oral administration. Peak serum concentrations are approximately 67 pg/mL and are reached within 1.5 to 4 hours. Ethinylestradiol is extensively metabolized during absorption and the first pass through the liver, resulting in a mean oral bioavailability of approximately 44%.
Distribution: Ethinylestradiol binds strongly but nonspecifically to serum albumin (approximately 98%) and induces an increase in serum concentrations of sex steroid binding globulin (SSGB). The apparent volume of distribution of ethinylestradiol is approximately 2.8-8.6 l/kg.
Biotransformation. Ethinylestradiol undergoes presystemic conjugation in the small intestinal mucosa and in the liver. Ethinylestradiol is metabolized mainly by aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are additionally formed, among which there are both free metabolites and conjugates with glucuronides and sulfates. Clearance is 2.3-7 ml / min / kg.
Elimination. Serum ethinylestradiol levels decline in a biphasic manner with half-lives of approximately 1 hour and 10-20 hours, respectively. Ethinylestradiol is not eliminated unchanged; its metabolites are excreted in the urine and bile in a ratio of 4:6. The half-life of the metabolites is approximately 1 day.
Steady state. Steady state is reached during the second half of the cycle, when the concentration of ethinylestradiol in the blood serum is approximately twice as high as after a single dose.
Dienogest.
Absorption. After oral administration, dienogest is rapidly and completely absorbed. The maximum concentration in blood plasma (51 ng/ml) is reached 2.5 hours after taking one tablet. Absolute bioavailability when used together with ethinylestradiol is 96%.
Biotransformation. Dienogest is metabolized mainly by hydroxylation and conjugation to form mainly endocrinologically inactive metabolites. These metabolites are very rapidly eliminated from plasma, so that no active metabolite is observed in the blood plasma, but only dienogest in unchanged form. The total clearance (CL/F) is 3.6 l/h after a single dose.
Excretion. The level of dienogest in the blood serum decreases with a half-life of about 9 hours. Only a small amount of dienogest is excreted unchanged by the kidneys. After an oral dose of 0.1 mg/kg body weight, the ratio of excretion with feces to urine is approximately 3.2. After oral administration, about 86% of the administered dose is excreted within 6 days, the majority, 42%, is excreted in the urine in the first 24 hours.
Steady state. The pharmacokinetics of dienogest are independent of the level of GSH. With daily use, the concentration of the substance in the blood serum increases by 1.5 times, reaching a steady state after 4 days of use.
Indication
Oral contraception.
Before prescribing Silhouette®, the woman should be assessed for individual risk factors, especially for venous thromboembolism (VTE), and the risk of venous thromboembolism when taking Silhouette® should be compared with the risk when taking other combined hormonal contraceptives (CHCs) (see sections “Contraindications” and “Special Instructions for Use”).
Contraindication
Combined hormonal contraceptives (CHCs) should not be used if any of the following conditions are present. If any of these conditions appear for the first time during CHC use, the drug should be discontinued immediately.
Presence or risk of venous thromboembolism (VTE):
current or history of venous thromboembolism (use of anticoagulants) (e.g. deep vein thrombosis (DVT) or pulmonary embolism (PE)); known hereditary or acquired predisposition to venous thromboembolism, such as resistance to activated protein C (including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency;
major surgery with prolonged immobilization (see section "Special instructions for use");
high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use");
presence or risk of arterial thromboembolism (ATE):
Arterial thromboembolism, including a history (e.g. myocardial infarction), or the presence of prodromal symptoms (e.g. angina); cerebrovascular disease, including a history of stroke, or the presence of prodromal symptoms (e.g. transient ischemic attack (TIA)); known hereditary or acquired predisposition to the development of arterial thromboembolism, such as hyperhomocysteinemia and the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); migraine with focal neurological symptoms in history;
high probability of arterial thromboembolism due to the presence of multiple risk factors (see section "Special precautions for use") or due to the presence of one of the following serious risk factors:
diabetes mellitus with vascular complications; severe arterial hypertension; severe dyslipoproteinemia; pancreatitis present or in history, if associated with severe hypertriglyceridemia; severe liver disease present or in history, until liver function tests have returned to normal; presence or in history of liver tumors (benign or malignant); known or suspected malignant tumors (e.g., genital or breast) that are dependent on sex hormones; established or suspected pregnancy; vaginal bleeding of unknown etiology; hypersensitivity to the active substances or to any of the components of the drug.
The simultaneous use of Silhouette® and medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir is contraindicated (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Note: The information for the concomitant medicinal product should be consulted for potential interactions.
Pharmacodynamic interactions
Concomitant use of ethinylestradiol-containing medicinal products with direct-acting antiviral medicinal products containing ombitasvir, paritaprevir or dasabuvir and their combinations increases the risk of alanine aminotransferase (ALT) elevations greater than 20 times the upper limit of normal in healthy patients and in patients with hepatitis C virus (see section "Contraindications").
Therefore, women taking Siluet® should use an alternative method of contraception (e.g. progestogen-only contraceptives or non-hormonal methods) before starting therapy with this combination of drugs. Siluet® can be resumed 2 weeks after completing therapy with this combination.
Pharmacokinetic interactions
The effect of other drugs on Silhouette®.
Interactions are possible with drugs that induce microsomal enzymes. This leads to an increase in the clearance of sex hormones, which, in turn, changes the pattern of menstrual bleeding and/or causes a loss of contraceptive effectiveness.
Therapy
Enzyme induction may be detected after a few days of treatment. Maximum enzyme induction is generally observed after a few weeks. After discontinuation of treatment, enzyme induction may persist for about 4 weeks.
Short-term treatment
Women taking enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the combined oral contraceptive (COC). The barrier method should be used throughout the duration of treatment with the drug and for 28 days after stopping its use.
If therapy with an inducer drug is started during the period of taking the last COC tablets from the current package, then taking the tablets from the next COC package should be started immediately after the end of the tablets in the previous package without the usual break.
Long-term treatment
For women on long-term therapy with active substances that induce liver enzymes, a barrier or other reliable non-hormonal method of contraception is recommended.
Active substances that increase the clearance of COCs (reduced COC efficacy due to enzyme induction), e.g. barbiturates, carbamazepine, phenytoin, primidone, rifampicin; also possibly oxcarbazepine, topiramate, felbamate, griseofulvin and medicinal products containing St. John's wort extract (Hypericum perfiratum).
Active substances with inconsistent effects on CHC clearance
When used concomitantly with COCs, a large number of combinations of HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of estrogen or progestins. The cumulative effect of such changes may be clinically significant in some cases.
Therefore, the prescribing information for the concomitant HIV/HCV medicinal product should be consulted to identify potential interactions. If in doubt, women should additionally use a barrier method of contraception during treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
Active substances that reduce the clearance of PDA (enzyme inhibitors)
The clinical significance of the potential interaction with enzyme inhibitors remains unclear.
Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both.
Etoricoxib at doses of 60 to 120 mg/day has been shown to increase plasma concentrations of ethinyl estradiol by 1.4- to 1.6-fold, respectively, when co-administered with a combined hormonal contraceptive containing 0.035 mg ethinyl estradiol.
The effect of Silhouette® on other medicines.
Oral contraceptives may affect the metabolism of other drugs. Accordingly, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). However, in vitro data suggest that inhibition of CYP enzymes by dienogest at therapeutic doses is unlikely.
Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, which in turn causes a slight (e.g., when using theophylline) or moderate (e.g., when using tizanidine) increase in their plasma concentrations.
Other types of interactions
Laboratory tests
The use of contraceptive steroids may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, as well as levels of plasma transport proteins such as corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and parameters of coagulation and fibrinolysis. Usually these changes are within normal limits.
Application features
Warning: If any of the conditions or risk factors listed below are present, the appropriateness of using Silhouette® should be discussed with the woman.
If any of the following conditions or risk factors worsen or occur for the first time, the woman is advised to consult a doctor who may decide to discontinue the use of the drug.
In case of suspected or confirmed VTE or ATE, COC use should be discontinued. If anticoagulant therapy is initiated, alternative adequate contraception should be provided due to the teratogenic effects of anticoagulants (coumarins).
Circulatory disorders.
The use of any CHC increases the risk of venous thromboembolism (VTE) in women compared with non-users. Products containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. Other products such as Siluet® may increase this risk by 1.6 times. The decision to use a product other than those with the lowest risk of VTE should only be made after discussion with the woman. It is necessary to ensure that she is aware of the risk of VTE associated with the use of Siluet®, the extent of her existing risk factors and the fact that the risk of VTE is highest during the first year of use. There is some evidence that the risk of VTE may increase when CHC use is resumed after a break of 4 weeks or more.
In women who are not using CHCs and are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, the risk for any individual woman may be much higher depending on her risk factors (see below).
According to epidemiological studies in women, when using low-dose combined oral contraceptives (< 50 μg ethinylestradiol), 6-12 out of 10,000 women will develop VTE within 1 year.
It is estimated that among 10,000 women who use a CHC containing levonorgestrel, about 61 will develop VTE in one year.
It is estimated2 that 8-11 out of 10,000 women who use CHCs containing dienogest and ethinylestradiol will develop VTE in one year.
The number of VTE cases per year was lower than expected during pregnancy or in the postpartum period.
VTE can be fatal in 1-2% of cases.
Risk factors for developing VTE.
The risk of developing venous thromboembolic complications in women using CHCs may be significantly increased in the presence of additional risk factors, especially multiple ones (see Table 1).
Siluet® is contraindicated in women with multiple risk factors that may increase the risk of developing venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk of developing VTE should be taken into account. CHCs should not be prescribed if the benefit/risk ratio is negative (see section "Contraindications").
Table 1. Risk factors for VTE development.
| Risk factor | Note |
Obesity (body mass index exceeding 30 kg/m2). | The risk increases significantly as the patient's body mass index increases. It especially requires attention in the presence of other risk factors. |
Prolonged immobilization, major surgery, any surgery on the lower extremities or pelvic organs, neurosurgery, or extensive trauma. Note: temporary immobilization, including air travel, is more 4 hours, may also be a risk factor for VTE, especially in women with other risk factors. | In such situations, it is recommended to stop using the drug/patch/ring (in the case of elective surgery at least 4 weeks before it) and not resume use earlier than 2 weeks after full recovery of motor activity. In order to avoid unwanted pregnancy, other methods of contraception should be used. Antithrombotic treatment may be appropriate if Silhouette® has not been discontinued in advance. |
| Family history (venous thromboembolism in a relative or parent, especially at a relatively early age, for example under 50). | If a hereditary predisposition to VTE is suspected, women are advised to consult a specialist before using any CHC. |
| Other medical conditions associated with VTE | Cancer, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), and sickle cell anemia. |
| Increasing age | Especially over 35 years old. |
There is no consensus on the possible influence of varicose veins and superficial thrombophlebitis on the occurrence or progression of venous thrombosis.
Attention should be paid to the increased risk of thromboembolism during pregnancy and especially in the first 6 weeks after delivery (for information on pregnancy and lactation, see the section "Use during pregnancy or breastfeeding").
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
If the following symptoms occur, a woman should seek medical help immediately and inform her doctor that she is taking CHCs.
Symptoms of deep vein thrombosis (DVT) may include:
Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as more common or less severe conditions (e.g., respiratory tract infections).
Other signs of vascular occlusion may include: sudden pain, swelling, and slight blueness of the limb.
In the case of occlusion of the vessels of the eye, the initial symptom may be blurred vision, which is not accompanied by pain, and may progress to loss of vision. Sometimes the loss of vision develops almost instantly.
Risk of arterial thromboembolism (ATE).
Epidemiological studies have shown that the use of CHCs is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (transient ischemic attack, stroke). Arterial thromboembolic complications can be fatal.
Risk factors for the development of ATE.
The risk of arterial thromboembolic complications or cerebrovascular events with CHC use is increased in women with the risk factors described in Table 2. Silhouette® is contraindicated if a woman has one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increased risk may be greater than the sum of the risks associated with each individual factor, so the overall risk should be taken into account. CHCs should not be prescribed if the benefit/risk ratio is unfavorable (see section "Contraindications").
Table 2. Risk factors for the development of ATE
| Risk factor | Note |
| Increasing age | Especially over 35 years old. |
| Smoking | Women should be advised to quit smoking if they wish to use CHCs. Women over the age of 35 who continue to smoke should be strongly advised to use another method of contraception. |
| Arterial hypertension | |
Obesity (body mass index exceeding 30 kg/m2) | The risk increases significantly with increasing body mass index. It especially requires attention if women have other risk factors. |
| Family history (arterial thromboembolism in a relative or parent, especially at a relatively early age, such as before 50) | If a hereditary predisposition to developing ATE is suspected, women are advised to consult a specialist before using any CHC. |
| Migraine | An increase in the frequency or severity of migraine during CHC use (which may be a prodromal condition before the development of cerebrovascular events) may be a reason for immediate discontinuation of the drug. |
| Other medical conditions associated with adverse vascular reactions | Diabetes mellitus, hyperhomocysteinemia, heart valve defects and atrial fibrillation, dyslipoproteinemia, systemic lupus erythematosus. |
Symptoms of ATE
If the following symptoms occur, a woman should seek urgent medical attention and inform her doctor that she is taking CHCs.
Symptoms of a cerebrovascular accident may include:
sudden numbness or weakness of the face, arm or leg, especially on one side; sudden trouble walking, dizziness, loss of balance or coordination; sudden confusion, trouble speaking or understanding; sudden loss of vision in one or both eyes; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting, with or without seizures.
The temporary nature of the symptoms may indicate a transient ischemic attack (TIA).
Symptoms of myocardial infarction (MI) may include:
pain, discomfort, pressure, heaviness, a feeling of squeezing or fullness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, throat, arm, abdomen; a feeling of fullness in the stomach, indigestion or heartburn; increased sweating, nausea, vomiting or dizziness; severe weakness, anxiety or shortness of breath; fast or irregular heartbeat.
Tumors.
The results of some epidemiological studies indicate an additional increase in the risk of developing cervical cancer with long-term use of COCs (more than 5 years), but this statement remains controversial, since it is not yet clear to what extent the results of the studies take into account concomitant risk factors, such as sexual behavior and other factors, in particular human papillomavirus infection.
In rare cases, benign and even more rarely malignant liver tumors have been observed in women using COCs. In some cases, these tumors have caused life-threatening intra-abdominal bleeding. In the event of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis in women using COCs.
Neoplasms can be life-threatening or fatal.
Other states.
Depressed mood and depression are common adverse reactions with hormonal contraceptives (see section 4.8). Depression can be severe and is a known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood swings and symptoms of depression, even if they occur soon after starting treatment.
Women with hypertriglyceridemia and those with a family history of this disorder are at risk of developing pancreatitis when using COCs.
Although a slight increase in blood pressure has been reported in many women taking COCs, a clinically significant increase in blood pressure is rare. However, if clinically significant hypertension develops during COC use, it is advisable to discontinue the COC and treat the hypertension. If appropriate, COC use can be resumed after normotensive status has been achieved with antihypertensive therapy. COC use should be discontinued if, during their use for hypertension diagnosed before COC use, persistently high blood pressure persists despite adequate antihypertensive therapy.
The following conditions have been reported to occur or worsen during pregnancy and CHC use, but the relationship to CHC use is not conclusive: jaundice and/or pruritus associated with cholestasis; gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
In women with a hereditary predisposition to angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
In acute or chronic liver dysfunction, it may be necessary to discontinue COC use until liver function tests return to normal. In the event of recurrence of cholestatic jaundice and/or pruritus associated with cholestasis, which first occurred during pregnancy or previous use of sex hormones, COC use should be discontinued.
Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence that women with diabetes mellitus taking low-dose COCs (<0.05 mg ethinylestradiol) need to change their treatment regimen. However, diabetic patients should be closely monitored during COC use, especially at the beginning of treatment.
Cases of exacerbation of endogenous depression, epilepsy, Crohn's disease and ulcerative colitis have also been observed during the use of COCs.
Chloasma may occasionally occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid direct sunlight and ultraviolet radiation while taking COCs.
Medical examination/consultation.
Before initiating or reinstituting SiluetÒ, a careful history, including family history, a physical examination and pregnancy should be taken. Blood pressure should be measured and a physical examination should be performed, taking into account the contraindications (see section 4.3) and the specific features of use (see section 4.4). The woman should be made aware of the information on venous and arterial thrombosis, including the risk associated with SiluetÒ compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and the actions to be taken if thrombosis is suspected.
Patients are advised to carefully read the instructions for medical use of the medicinal product and follow the recommendations contained therein. The frequency and nature of medical examinations should depend on the established treatment protocols and be adapted to each individual woman.
Patients should be advised that hormonal contraceptives do not protect against HIV infection (AIDS) or any other sexually transmitted disease.
Decreased efficiency
The effectiveness of COCs may be reduced in the event of missed tablets, gastrointestinal disorders (see section “Method of administration and dosage”) or concomitant use of other medicines (see section “Interaction with other medicines and other types of interactions”).
Cycle disruption.
If irregular bleeding persists or occurs after several regular cycles, non-hormonal causes of bleeding should be considered and appropriate diagnostic measures should be taken, including examination to exclude tumors or pregnancy. Diagnostic measures may include curettage.
Some women may not have a withdrawal bleed during the tablet-free interval. If the COC has been taken according to the instructions described in section 4.2, pregnancy is unlikely. However, if the contraceptive was used irregularly before the first missed withdrawal bleed or if withdrawal bleed is absent for two cycles, pregnancy must be ruled out before COC use is continued.
Increased alanine transaminase (ALT) activity
In studies of patients treated for hepatitis C virus infection with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed significantly more frequently in women taking ethinylestradiol-containing products, such as CHCs (see sections 4.3 and 4.5).
This medicinal product contains 47.66 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies on the effects on the ability to drive or use machines have been conducted. Women using COCs have no effect on the ability to drive or use machines.
Use during pregnancy or breastfeeding
Pregnancy. The drug is contraindicated for use during pregnancy.
If pregnancy occurs while taking Siluet®, the drug should be discontinued immediately. Extensive epidemiological studies do not indicate an increased risk of birth defects in children whose mothers used COCs before pregnancy, nor does they indicate a teratogenic effect in the event of inadvertent use of COCs during pregnancy.
Animal studies have shown adverse effects during pregnancy and lactation. Based on animal studies, adverse effects due to hormonal effects of the active substances cannot be excluded. However, general experience with COC use during pregnancy does not indicate any adverse effects in humans.
When resuming the use of the drug Silhouette®, the increased risk of developing VTE in the postpartum period should be taken into account (see sections “Method of administration and dosage”, “Special instructions for use”).
Breastfeeding. COCs may affect breastfeeding, as they may reduce the amount of breast milk and change its composition. Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use. These amounts may affect the child. Therefore, Siluet® is not recommended for use until the breastfeeding period is complete.
Method of administration and doses
Method of application.
For oral use.
Dosage.
How to take Silhouette®
The tablets should be taken at about the same time each day, if necessary with a little liquid, in the order indicated on the blister pack. You should take 1 tablet per day for 21 consecutive days. The first tablet from each subsequent pack should be taken after a 7-day break, during which withdrawal bleeding usually occurs, which usually begins 2-3 days after taking the last tablet and may not end before the start of the next pack.
How to start treatment with Silhouette®
If hormonal contraceptives were not used in the previous period (last month). Taking the tablets should be started on the first
