Instructions / Instruction for use: Levonorgestrel + Ethinylestradiol (Levonorgoestrelum+Aethinyloestradiolum)I want this, give me price
Estrogens, gestagens; Their homologues and antagonists
Nosological classification (ICD-10)
Z30 Monitoring contraceptive use
Local Contraception, Contraception oral, Local contraception, Episodic prevention of pregnancy, Hormonal Contraception, Contraception, Prevention of Pregnancy, Prevention of unwanted pregnancy, Contraceptive intrauterine, Contraception in women with androgenization phenomena, Installation and removal of the intrauterine device, Prevention of pregnancy (contraception)
Z30.0 General advice and advice on contraception
Safe sex, Intrauterine device contraception, Contraception, Contraceptive intrauterine, Oral contraception, Oral contraception during lactation and with estrogen contraindications, Postcoital contraception, Prevention of Pregnancy, Prevention of unwanted pregnancy, Emergency Contraception, Episodic prevention of pregnancy, Contraception in adolescents, Prevention of pregnancy (contraception)
Characteristics of Levonorgestrel + Ethinylestradiol
Low-dose monophasic oral combined estrogen-gestagen contraceptive.
The pharmacological action is estrogen-gestagenic, contraceptive.
The contraceptive effect is carried out by means of complementary mechanisms, the most important of which are suppression of ovulation and an increase in the viscosity of the secretion of the cervix, as a result of which it becomes impenetrable for spermatozoa.
In women taking COC, the cycle becomes more regular, the pain and intensity of menstrual-like bleeding decreases, which reduces the risk of iron deficiency anemia. In addition, there is evidence that the use of COC reduces the risk of developing endometrial cancer and ovarian cancer.
When properly applied, the Perl index (an indicator that reflects the frequency of pregnancy in 100 women during the year of use of the contraceptive) is less than 1. If the admission is missed or the application is incorrect, the Pearl index may increase.
Absorption. After ingestion, levonorgestrel is rapidly and completely absorbed, Cmax in plasma, equal to 3-4 ng / ml, is reached after approximately 1 hour. The bioavailability of levonorgestrel with oral administration is almost complete.
Distribution. Levonorgestrel binds to plasma albumin and GSHG. In the free form, only about 1.3% of the total concentration of levonorgestrel is in the blood plasma; About 64% - are specifically associated with SHBG and about 35% are nonspecifically associated with albumin. Induction with ethinylestradiol synthesis of SHBG affects the binding of levonorgestrel to plasma proteins, causing an increase in the fraction associated with SHBG and a decrease in the fraction associated with albumin. The apparent Vd of levonorgestrel is about 184 liters after a single application.
Metabolism. Levonorgestrel undergoes extensive metabolism. The main metabolites in the blood plasma are unconjugated and conjugated forms of 3α, 5β-tetrahydrollevorgestrel. According to in vitro and in vivo studies, the main enzyme involved in the metabolism of levonorgestrel is CYP3A4. The clearance from the blood plasma is 1.3-1.6 ml / min / kg.
Excretion. Concentration of levonorgestrel in blood plasma is reduced biphasic. T1 / 2 in the terminal phase is 20-23 hours. Levonorgestrel is not excreted unchanged, metabolites are excreted by the kidneys and through the intestine in a ratio of approximately 1: 1 with T1 / 2 about 24 hours.
Css (equilibrium concentration). With daily intake, the concentration of levonorgestrel in the blood plasma increases approximately 3-4 times, reaching Css in the second half of the application cycle. The pharmacokinetics of levonorgestrel is affected by the concentration of SHBG in the blood plasma, which, when levonorgestrel is used together with ethinyl estradiol, increases approximately 1.7-fold. With Css, the clearance speed is reduced to about 0.7 ml / min / kg.
Absorption. After ingestion, ethinylestradiol is rapidly and completely absorbed. Cmax in blood plasma, equal to about 95 pg / ml, is achieved in 1-2 hours. During absorption and first passage through the liver, ethinyl estradiol is metabolized, resulting in an average bioavailability of about 45% (individual differences within 20 -65%).
Distribution. Ethinyl estradiol is almost completely (approximately 98%), although non-specific, bound by albumin. Ethinyl estradiol induces synthesis of SHBG. The apparent Vd of ethinylestradiol is 2.8-8.6 l / kg.
Metabolism. Ethinyl estradiol undergoes presystemic conjugation in both the small intestine mucosa and the liver. The main pathway of metabolism is aromatic hydroxylation. The clearance rate from plasma is 2.3-7 ml / min / kg.
Excretion. Reduction of the concentration of ethinyl estradiol in blood plasma is biphasic; The first phase is characterized by T1 / 2 about 1 h, the second - 10-20 h. Unchanged from the body is not excreted. Metabolites of ethinyl estradiol are excreted by the kidneys and through the intestine in a ratio of 4: 6 with T1 / 2 for about 24 hours.
Css. With daily oral intake of ethinylestradiol in the blood plasma increases slightly, reaching Cmax 114 pg / ml at the end of the cycle. Given the volatile T1 / 2 in the terminal phase and the daily oral intake, Css is reached in about 1 week.
Use of Levonorgestrel + Ethinylestradiol
The combination of levonorgestrel + ethinyl estradiol is contraindicated in the presence of any of the conditions / diseases listed below. If any of these conditions / diseases develop for the first time against the background of this combination, then its application should be immediately canceled.
Thrombosis (venous and arterial); Thromboembolism (including deep vein thrombosis, pulmonary thromboembolism, myocardial infarction); Cerebrovascular disorders, incl. In the anamnesis; Identified acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C; Deficiency of antithrombin III; Protein C deficiency; Deficiency of protein S; Hyperhomocysteinemia; Antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant); States preceding thrombosis (including transient ischemic attacks, angina pectoris), incl. In the anamnesis; The presence of a high risk of venous or arterial thrombosis (see "Precautions"); Migraine with focal neurological symptoms, incl. In the anamnesis; Diabetes mellitus with vascular complications; Pancreatitis with severe hypertriglyceridemia, incl. In the anamnesis; Hepatic insufficiency and severe liver disease (until liver tests are normal); Liver tumors (benign or malignant), incl. In the anamnesis; Identified hormone-dependent malignant neoplasms (including genitals or mammary glands) or suspected of them; Bleeding from the vagina of unknown origin; Pregnancy or suspicion of it; breast-feeding; Hypersensitivity to any of the combination components; Deficiency of lactase, lactose intolerance, sugarase / isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption.
Restrictions for use
Risk factors for thrombosis and thromboembolism (smoking, thrombosis, myocardial infarction or cerebrovascular accident at a young age, someone from the next of kin; obesity with a BMI less than 30 kg / m2; dislipoproteinemia, controlled hypertension, migraine without focal neurological symptoms, diseases Heart valves, heart rhythm disturbances); diseases, which may occur when the peripheral circulatory disorders (diabetes without vascular complications; systemic lupus erythematosus; hemolytic-uremic syndrome, Crohn's disease and ulcerative colitis; sickle cell anemia; phlebitis superficial veins); Hypertriglyceridemia; Liver diseases not listed in the "Contraindications" section; Diseases that first appeared or worsened during pregnancy or against the background of previous administration of sex hormones (eg jaundice and / or itching associated with cholestasis, gallbladder disease, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham's chorea); Hereditary angioedema (exogenous estrogens can cause or exacerbate symptoms of angioedema).
pregnancy and lactation
The action category for fetus by FDA is X.
The combination of levonorgestrel + ethinyl estradiol is contraindicated during pregnancy and during breastfeeding.
If pregnancy is detected during the reception of this combination, it should be immediately canceled. Numerous epidemiological studies have found no increased risk of defects in children born to women treated with hormones before pregnancy, or the presence of teratogenic effect when sex hormones were taken inadvertently in early pregnancy.
Receiving combination levonorgestrel + ethinyl estradiol, as well as other KOC (combined oral contraceptives), can reduce the amount of breast milk and change its composition, so the use of this combination is counter to weaning. A small amount of sex hormones and / or their metabolites can penetrate into breast milk and influence the health of the child.
The most frequently described adverse events in patients receiving the combination of levonorgestrel + ethinyl estradiol are nausea, abdominal pain, weight gain, headache, depressed mood, mood changes, breast pain, breast engorgement. These phenomena occur in ≥1% of patients.
Serious adverse events are arterial and venous thromboembolism.
Adverse events (according to MedDRA classification), the connection of which with the reception of COC is not confirmed, but is not disproved, are given below.
From the side of the organ of vision: rarely - intolerance of contact lenses (unpleasant sensations when wearing them).
From the digestive tract (gastrointestinal tract): often - nausea, pain in the abdomen; Infrequently - vomiting, diarrhea.
From the immune system: rarely - hypersensitivity.
From the side of metabolism and eating disorders: infrequently - fluid retention.
From the nervous system: often - headache; Infrequently - a migraine.
Mental disturbance: often - decreased mood, mood swings; Infrequently - decreased libido; Rarely - increased libido.
From the genitals and the breast: often - soreness of the mammary glands, engorgement of the mammary glands; Infrequently, mammary gland hypertrophy; Rarely - discharge from the genital tract, discharge from the mammary glands.
From the skin and subcutaneous tissues: infrequently - rash, hives; Rarely erythema nodosum, erythema multiforme.
From the vessel seldom - venous and arterial thromboembolic complications (estimated frequency according to epidemiological studies in women using the COC), which are combined such nosological entities as occlusion of peripheral deep venous thrombosis and for thrombosis / occlusion of pulmonary vascular thrombosis, embolism and infarction / Myocardial infarction / cerebral infarction and stroke, not classified as hemorrhagic.
Common disorders: often - weight gain; Rarely - a decrease in body weight.
The following are undesirable events with very low frequency or delayed development of symptoms that are presumably associated with the administration of COCs (see also "Contraindications" and "Precautions").
- The frequency of detection of breast cancer has increased very slightly in women using COCs. Because breast cancer is rare in women younger than 40, the increase in cancer incidence in women using COC is insignificant in relation to the overall risk of breast cancer. A causal relationship with the use of COCs has not been identified.
- Liver tumors (benign and malignant).
- Women with hypertriglyceridemia (increased risk of pancreatitis when using COCs).
- Increased blood pressure (blood pressure).
- The onset or deterioration of conditions in which communication with the use of COCs is not undeniable - jaundice and / or pruritus associated with cholestasis; Formation of gallstones; Porphyria; Systemic lupus erythematosus; Hemolytic-uremic syndrome; chorea; Herpes during pregnancy; Hearing loss associated with otosclerosis.
- Women with hereditary Aigionevroticheskim edema - exogenous estrogens can cause or intensify the symptoms of angioedema.
- Dysfunction of the liver.
- Impairment of glucose tolerance or influence on peripheral insulin resistance.
- Crohn's disease, ulcerative colitis.
Results of drug interactions
- As a result of the interaction of oral contraceptives with other drugs (inducers of enzymes), breakthrough bleeding and / or a decrease in the contraceptive effect may occur (see "Interaction").
The effect of other drugs (drug) on a combination of levonorgestrel + ethinyl estradiol
Possible interaction combination with ethinyl estradiol levonorgestrel + PM inducing microsomal enzymes which may result in increased clearance of sex hormones, which in turn may lead to breakthrough uterine bleeding and / or reducing the contraceptive effect.
Women who receive treatment drugs that are inducers of microsomal enzymes, in addition to the combination of levonorgestrel + ethinylestradiol recommended temporarily use a barrier method of contraception or to select non-hormonal contraception. The barrier method of contraception should be used throughout the period of taking concomitant drugs and for another 28 days after their withdrawal. If the use of drugs, which is an inductor of microsomal liver enzymes, is planned to continue, the combination of levonorgestrel + ethinyl estradiol should be administered without a normal interruption in admission.
Drugs that increase clearance of the combination of levonorgestrel + ethinylestradiol (attenuating efficiency by enzyme induction): phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and drugs containing St. John's wort.
Drugs with different effects on the clearance of levonorgestrel + ethinylestradiol combination: the combined use of a combination of ethinyl estradiol levonorgestrel + many HIV protease inhibitors or HCV and NNRTIs can both increase and decrease the concentration of estrogen or progestin in the blood plasma. In some cases, such an effect may be clinically significant.
Drugs that reduce the clearance of the components of the combination levonorgestrel + ethinyl estradiol (enzyme inhibitors): strong and moderate inhibitors of CYP3A4, such as azole antifungal drugs (eg itraconazole, voriconazole, fluconazole), verapamil, macrolides (eg clarithromycin, erythromycin), diltiazem and grapefruit juice can Increase plasma concentrations of estrogen or progestin, or both components.
It is shown that etoricoxib at doses 60 and 120 mg / day when used together with COC containing 0.035 mg of ethinyl estradiol, ethinyl estradiol increases the concentration in plasma of 1.4 and 1.6 times, respectively.
Effect of COC on other drugs
COCs can affect the metabolism of other drugs, leading to an increase (eg, cyclosporine) or a decrease (eg lamotrigine) in their plasma and tissue concentrations.
In vitro, ethinyl estradiol is a reversible inhibitor of CYP2C19 (cytochrome P450 isoenzyme), CYP1A1 (cytochrome P450 isoenzyme) and CYP1A2 (cytochrome P450 isoenzyme), as well as irreversible inhibitor of CYP3A4 (cytochrome P450 isoenzyme), CYP2C8 (cytochrome P450 isoenzyme) and CYP2J2 (isoenzyme Cytochrome P450). In clinical studies, the administration of a hormonal contraceptive containing ethinyl estradiol did not lead to any increase or resulted only in a slight increase in the concentrations of CYP3A4 substrates in the blood plasma (eg midazolam), whereas the concentrations of CYP1A2 substrates in blood plasma may increase slightly (for example, theophylline ) Or moderately (eg melatonin and tizanidine).
Symptoms: nausea, vomiting, spotting spotting.
There is no specific antidote; symptomatic treatment should be performed.
Routes of administration
If any condition, disease or risk factor is observed from the following, careful consideration should be given to the potential risk and expected benefits of using COCs, incl. Combinations of levonorgestrel + ethinyl estradiol, in each individual case and discuss them with the patient before she decides to start using this combination. In case of weighting, strengthening, or the first manifestation of any of the following conditions or risk factors, the patient should consult with the attending physician to decide whether to discontinue this combination.
The results of epidemiological studies indicate the existence of a relationship between the use of COCs and an increase in the incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis, PE, myocardial infarction, cerebrovascular disorders). These diseases are rare.
The risk of VTE (venous thromboembolism) is maximal in the first year of COC use; It is increased both after the initial application and after the resumption of the use of the same or different COCs (after a break of 4 weeks or more). The data of a large prospective study with the participation of 3 groups of patients showed that an increased risk is observed mainly during the first 3 months.
The overall risk of VTE in patients taking low-dose COCs (containing less than 0.05 mg of ethinylestradiol) is 2-3 times higher than in non-pregnant patients who do not take COC; Nevertheless, this risk remains lower in comparison with the risk of VTE during pregnancy and childbirth.
VTE may be life-threatening or fatal (1-2% of cases).
VTE, manifested as deep vein thrombosis or PE, can occur with any COCs.
Very rarely, with the use of COCs, thrombosis occurs in other blood vessels, for example, liver, mesenteric, renal, cerebral veins and arteries or retinal vessels.
Symptoms of deep vein thrombosis include unilateral edema of the lower limb or along the vein on the lower limb; Pain or discomfort in the lower limb only in an upright position or when walking; Local increase in temperature; Redness or discoloration of the skin in the affected lower limb.
Symptoms of pulmonary embolism include difficulty breathing or rapid breathing; Sudden cough, incl. With hemoptysis; Acute pain in the chest, which can intensify with a deep inspiration; sense of anxiety; Severe dizziness; Rapid or irregular heartbeat. Some of these symptoms (eg, dyspnea, cough) are non-specific and can be misinterpreted as signs of other more or less severe complications (eg, respiratory tract infection).
Arterial thromboembolism can lead to stroke, vascular occlusion or myocardial infarction. Symptoms of a stroke include sudden weakness or loss of sensitivity in the face, limbs, especially on one side of the body; Sudden confusion; Problems with speech and understanding; Sudden one- or two-sided vision loss; Sudden gait disturbance; dizziness; Loss of balance or coordination of movements; Sudden strong or prolonged headache for no apparent reason; Loss of consciousness or fainting with or without epileptic seizure. Other signs of vessel occlusion can be sudden pain; Puffiness and weak blueing of the limbs; An acute abdomen.
Symptoms of myocardial infarction include pain, discomfort, pressure, heaviness, a feeling of contraction or bursting in the chest or behind the breastbone with irradiation in the back, jaw, upper limb, epigastric region; Cold sweats, nausea, vomiting or dizziness, severe weakness, anxiety, or shortness of breath; Rapid or irregular heartbeat.
Arterial thromboembolism can be life threatening or fatal.
In women with a combination of several risk factors or high severity of one of them, the possibility of their mutual reinforcement should be considered. In such cases, the degree of risk increase may be higher than with a simple summation of factors. In this case, the combination of levonorgestrel + ethinyl estradiol is contraindicated (see "Contraindications").
Factors of increased risk of thrombosis (venous and / or arterial) and thromboembolism or cerebrovascular disorders are age; Smoking (in smokers with an increase in the number of cigarettes smoked or increased in age, the risk increases, especially in women older than 35 years); Family history (eg venous or arterial thromboembolism in close relatives or parents at a relatively young age); Obesity (BMI> 30); Dyslipoproteinemia; arterial hypertension; migraine; Heart valve diseases; atrial fibrillation; prolonged immobilization, major surgery, any surgery in the lower extremities or vast trauma (in these cases it is recommended to cease the use of COCs - in case the intended operation of at least 4 weeks to it and not to resume reception within 2 weeks after immobilization); Temporary immobilization (for example, an air travel of more than 4 hours may also be a risk factor for the development of VTE, especially if there are other risk factors).
The question of the possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.
An increased risk of thromboembolism in the postpartum period should be considered.
Peripheral circulatory disorders as may occur in diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn's disease or ulcerative colitis) and sickle cell anemia.
An increase in the frequency and severity of migraine (which may precede cerebrovascular disorders) during the use of COCs may be grounds for the immediate cessation of the use of these drugs.
By biochemical parameters indicating the inherited or acquired predisposition to venous or arterial thrombosis include resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein deficit S, antiphospholipid antibodies (antibodies to cardiolipin, lupus anticoagulant).
In assessing the relationship between risk and benefit, it should be borne in mind that adequate treatment of the relevant condition can reduce the risk of thrombosis associated with it. It should also be taken into account that the risk of thrombosis and thromboembolism in pregnancy is higher than when taking low-dose COCs (containing less than 0.05 mg of ethinylestradiol).
The most significant risk factor for developing cervical cancer is persistent papillomavirus infection. There are reports of a slight increase in the risk of developing cervical cancer with prolonged use of COCs. Communication with the reception of the COC has not been proved. Reserved controversy as to the extent to which these data are associated with screening for cervical abnormalities or features with sexual behavior (less frequent use of barrier methods of contraception).
A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of breast cancer diagnosed in women taking COCs now (relative risk 1.24). The increased risk gradually disappears within 10 years after cessation of application of COC. Due to the fact that breast cancer is rare in women under 40 years, increasing the number of breast cancer cases in women taking COCs are currently taking or have recently, it is insignificant in relation to the total risk of the disease. His connection with the use of COC is not proven. The observed increase in risk may also be the result of earlier detection of breast cancer in women using COC (they are diagnosed earlier clinical forms of breast cancer than women do not apply CCO), the biological action of COC or a combination of both these factors.
In rare cases on the background of the development of benign COCs were observed, and in rare - malignant tumors of the liver, which in some cases lead to life-threatening intraabdominal bleeding. In the case of severe pain in the abdominal region, enlarged liver, or signs of intra-abdominal bleeding, this should be taken into account when making a differential diagnosis.
In women with hypertriglyceridemia (or the presence of this condition in a family history) during the administration of COC may increase the risk of developing pancreatitis.
Despite the fact that a slight increase in blood pressure was described in many women taking COC, a clinically significant increase was noted rarely. Nevertheless, if a persistent clinically significant increase in blood pressure develops during the administration of COC, these drugs should be discontinued and the treatment of hypertension should begin. Reception of COCs can be continued if normal blood pressure values are achieved with the help of antihypertensive therapy.
The following states have been reported to develop or worsen both during pregnancy and while taking COCs, but their association with COC use is not proven: cholestatic jaundice and / or pruritus related to cholestasis; Formation of stones in the gallbladder; Porphyria; Systemic lupus erythematosus; Hemolytic-uremic syndrome; chorea; Herpes during pregnancy; Hearing loss associated with otosclerosis. Also, cases of Crohn's disease and ulcerative colitis are described in the background of the use of COCs.
In women with hereditary forms of angioedema, exogenous estrogens can cause or worsen symptoms of angioedema.
Acute or chronic liver dysfunction may require cancellation of COC until liver function returns to normal. Recurrence of cholestatic jaundice, which developed for the first time during previous pregnancy or previous reception of sex hormones, requires discontinuation of COCs.
Although COCs may influence insulin resistance and glucose tolerance usually dose correction hypoglycemic drugs in patients with diabetes applying iizkodozirovannye COC (containing less than 0.05 mg ethinyl estradiol) is not required. Nevertheless, women with diabetes should be carefully observed while taking COC.
Sometimes chloasma can develop, especially in women with a history of pregnancy chloasma. Women with a tendency to chloasma while taking COC should avoid prolonged exposure to sunlight and exposure to UV radiation.
Application type levonorgestrel + ethinylestradiol combinations can affect the results of some laboratory tests, including biochemical liver function tests, thyroid, kidney and adrenal gland, the concentration of transport protein in plasma (e.g. binding globulin corticosteroids fraction lipid / lipoprotein parameters of carbohydrate metabolism, coagulation, and Fibrinolysis). These changes, as a rule, remain within the limits of normal physiological values.
Decrease in efficiency
The effectiveness of COCs can be reduced by skipping the dose, gastrointestinal disorders, or as a result of drug interactions.
Effect on the nature of bleeding
With the use of COC, irregular bleeding (spotting and / or breakthrough bleeding) can occur, especially during the first months of use. Therefore, any irregular bleeding should be assessed only after an adaptation period of approximately 3 cycles.
If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to exclude malignant neoplasms or pregnancy.
Some women may not develop withdrawal bleeding during an interruption in use. If a combination of levonorgestrel + ethinyl estradiol was taken as directed, it is unlikely that a woman is pregnant. However, if before the combination of levonorgestrel + ethinyl estradiol taken irregularly or missing two consecutive withdrawal bleeding, before continuing its use should be avoided pregnancy.
Before the start or resumption of use of the combination of levonorgestrel + ethinyl estradiol should be familiar with the history of life, a family history of women hold medical (including measurement of blood pressure, BMI definition) and gynecological examination (including breast examination and cytological examination of cervical epithelium), to exclude pregnancy. The frequency and nature of such surveys should be based on existing standards of medical practice, with the necessary consideration of the individual characteristics of each patient (but not less than once every 6 months).
It must be remembered that the combination of levonorgestrel + ethinyl estradiol does not protect against HIV (human immunodeficiency virus) -infection (AIDS (acquired immunodeficiency syndrome)) and other sexually transmitted diseases.
Conditions requiring medical advice include changes in health, especially the emergence of conditions listed in the "Contraindications" and "Precautions" sections; Local compaction in the mammary gland; Simultaneous reception of other drugs (see "Interaction"); Prolonged immobilization (for example, gypsum is applied to the lower limb), planned hospitalization or operation (at least 4 weeks before the proposed operation); Unusually heavy bleeding from the vagina; Admission failure in the first week of the combination of levonorgestrel + ethinyl estradiol and the presence of sexual contact seven or less days before; Absence of the next menstrualnopodobnogo a bleeding 2 times successively or suspicion on pregnancy.
The combination of levonorgestrel + ethinylestradiol should be discontinued and consult a doctor immediately if there are possible signs of thrombosis, myocardial infarction or stroke - an unusual cough; Unusually severe pain behind the sternum, giving to the left arm; Unexpected shortness of breath, unusual, severe and prolonged headache or migraine attack; Partial or complete loss of vision or double vision; Inarticulate speech; Sudden changes in hearing, smell or taste; Dizziness or fainting; Weakness or loss of sensitivity in any part of the body; Severe abdominal pain; Severe pain in the lower limb or a sudden onset of swelling in any of the lower extremities.
Impact on the ability to manage vehicles and mechanisms. Not found.