Dynamico, 50 mg 4 pcs.

AtCode: G04BE03

Pharmacological properties

Pharmacodynamics.

The erectile dysfunction drug restores impaired erectile function under sexual stimulation by increasing blood flow in the penis.

The physiological mechanism of erection involves the release of nitric oxide (NO) in the cavernous body due to sexual arousal. NO activates the enzyme guanylate cyclase, which leads to an increase in cyclic guanosine monophosphate (cGMP). In turn, cGMP causes the smooth muscles of blood vessels to relax and, consequently, the flow of blood into the cavernous body of the penis.

Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which causes the breakdown of cGMP in the cavernous body of the penis. It does not have a direct relaxing effect on the smooth muscles of the cavernous body, but increases the relaxing effect of nitric oxide on this tissue and increases blood flow in the

C penis. During activation of the NO – cGMP chain observed during sexual stimulation, inhibition of FDE5 leads to an increase of cGMP in the cavernous body. The pharmacological effect is achieved only in the presence of sexual stimulation.

The activity of sildenafil in relation to FDE5 is superior to other known phosphodiesterase isoenzymes: FDE6 – 10 times, FDE1 – more than 80 times; FDE2 – FDE4, FDE7-FDE11 – more than 700 times. Sildenafil is 4,000 times more selective against FDE5 compared to FDE3, which is important because FDE3 is one of the key enzymes regulating myocardial contractility.

Sildenafil has a mild and short-lived hypotensive effect, in most cases with no clinical manifestation when taken at recommended doses. The hypotensive effect is due to the vasodilatory effect of sildenafil due to an increase in cGMP in the vascular smooth muscle membrane.

Clinical data

Cardiology studies

The use of sildenafil in doses up to 100 mg did not result in clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after sildenafil administration at a dose of 100 mg was 8.3 mm Hg, and in diastolic blood pressure, 5.3 mm Hg. A more pronounced, but also transient effect on blood pressure (BP) was noted in patients taking nitrates (see “Contraindications” and “Interaction with other medications”).

In a study of the hemodynamic effects of sildenafil at a single dose of 100 mg in 14 patients with severe coronary heart disease (CHD) (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic BP decreased by 7% and 6%, respectively, and pulmonary systolic BP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenosed coronary arteries, and it also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until the severity of angina symptoms decreased. Exercise duration was significantly longer (19.9 seconds; 0.9 to 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of a variable dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and arterial hypertension taking more than two antihypertensive drugs. Sildenafil improved erections in 71% of men compared with 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in those taking more than three antihypergenic drugs.

Studies on visual impairment

In some patients, a mild and transient impairment in the ability to distinguish shades of color (blue/green) was detected 1 hour after taking sildenafil at a dose of 100 mg using the Farnsworth-Munsel 100 test. These changes were absent 2 hours after taking the drug. The color vision impairment is thought to be caused by inhibition of FDE6, which is involved in the transmission of light in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

In a placebo-controlled, crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil at a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision as assessed by specific visual tests (visual acuity, Amsler grid, color perception, color passage simulation, Humphrey perimeter, and photostress).

The efficacy and safety of sildenafil were evaluated in 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months in 3000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic, or mixed). Efficacy of the drug was evaluated globally using an erection diary, the International Erectile Function Index (a validated sexual function questionnaire), and a partner survey.

The efficacy of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, has been demonstrated in all studies conducted and has been confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients reporting that therapy improved their erections was 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose), compared with 25% in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improved erections, sildenafil treatment also improved the quality of orgasm, allowed to achieve satisfaction of intercourse and overall satisfaction.

The pooled data showed that 59% of patients who reported improved erections with sildenafil treatment were diabetic patients, 43% of patients who had undergone radical prostatectomy, and 83% of patients with spinal cord injury (versus 16%, 15%, and 12% in the placebo group, respectively).

Pharmacokinetics

The pharmacokinetics of sildenafil in the recommended dose range are linear.

Absorption. After oral administration, it is rapidly absorbed. Maximum plasma concentration (C_max) when taken on an empty stomach is reached within 0.5-2 hours, bioavailability is on average 41% (25-63%). In vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%. When taken in combination with fatty foods the absorption rate is reduced: C_max is reduced by an average of 29% and the time to reach maximum concentration (T_max) is increased by 60 minutes, but the degree of absorption is not significantly changed (the area under the pharmacokinetic curve of concentration-time (AUC) is reduced by 11%).

Distribution. The apparent volume of distribution in the equilibrium state is 105 liters. The binding of sildenafil and its main active metabolite to plasma proteins is 96% of the administered dose and is not dose-dependent. Less than 0.0002% of the sildenafil dose (188 ng on average) is detected in semen 90 min after drug administration.

Metabolism. Sildenafil is metabolized mainly by the liver microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (additional pathway). The main circulating active metabolite is N-desmethylmetabolite (N-desmethyl metabolite), whose activity against phosphodiesterase is 50% of sildenafil activity and its plasma concentration reaches 40% of sildenafil concentration. N-desmethylmetabolite undergoes further metabolism with a half-life of 4 hours.

Elimation. Total clearance of sildenafil is 41 l/h. The half-life (T_½) of sildenafil is 3-5 hours. Inactive metabolites are excreted through the intestine (80%) and the kidneys (13%).

Pharmacokinetics in special groups of patients.

In healthy patients over 65 years of age, the C_max of sildenafil and its active metabolite is increased by approximately 90% compared to younger patients (18-45 years) due to decreased sildenafil clearance. Plasma concentrations of free sildenafil are approximately 40% higher in older patients than in younger patients.

Age has no clinically significant effect on the incidence of side effects.

In patients with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil are not altered by taking 50 mg, and C_max and area under the concentration-time curve (AUC) for N-desmethylmetabolite are increased by 73% and 126%, respectively. In patients with severe renal impairment (creatinine clearance less than 30 mL/min), C_max and AUC are increased by 88% and 100%, respectively, C_max and AUC of N-desmethylmetabolite are increased by 79% and 200%, respectively.

In patients with cirrhosis (Child-Pugh grades A and B), C_max and AUC are increased by 47% and 84%, respectively.

The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Indications

Active ingredient

Composition

1 tablet contains: the active ingredient sildenafil citrate 35.12 mg, 70.24 mg or 140.48 mg (in terms of sildenafil 25.00 mg, 50.00 mg or 100.00 mg);

auxiliary substances: microcrystalline cellulose (PH 101) 102.88 mg, 205.76 mg or 411.52 mg; croscarmellose sodium 5.25 mg, 10.50 mg or 21.00 mg; hyprolose (hydroxypropyl cellulose) 4.50 mg, 9.00 mg or 18.00 mg; colloidal silica (colloidal anhydrous silica) 0.75 mg, 1.50 mg or 3.00 mg; magnesium stearate 1.50 mg, 3.00 mg or 6.00 mg; film coating: Opadray II 31F58914 white (hypromellose (E 464), lactose monohydrate, titanium dioxide (E 171), macrogol-4000, sodium citrate dihydrate (E 331)) 5.955 mg, 11.91 mg or 23.82 mg, indigo carmine (E 132) 0.045 mg, 0.09 mg or 0.18 mg.

How to take, the dosage

Ingestion.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily.

Renal dysfunction

In mild to moderate renal failure (CK 30-80 ml/min), no dose adjustment is necessary; in severe renal failure (CK <30 ml/min) the sildenafil dose should be reduced to 25 mg.

Hepatic disorders

As sildenafil excretion is impaired in patients with liver damage (particularly in cirrhosis), the dose of the drug should be reduced to 25 mg.

Combined use with other medicinal products

Combined use with ritonavir is not recommended. In any case, the maximum dose of sildenafil should not exceed 25 mg under any circumstances, and the frequency of use should be once every 48 hours (see “Interaction with other medicinal products”).

In co-administration with CYP3A4 isoenzyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole), the starting dose of sildenafil should be 25 mg (see section “Interaction with other medicinal products”).

In order to minimize the risk of postural hypotension in patients taking α-adrenoblockers, sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. It should also be considered to reduce the initial dose of sildenafil (see sections “Special Precautions” and “Interaction with other medicinal products”).

Elderly patients

There is no need to adjust the dose of the drug.

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance. There is a decrease in sildenafil clearance with concomitant use of inhibitors of CYP3A4 cytochrome isoenzyme (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a non-specific CYP3A4 cytochrome isoenzyme inhibitor, when taken with sildenafil (50 mg) increases sildenafil plasma concentrations by 56%.

Single administration of sildenafil 100 mg together with erythromycin (500 mg/day 2 times daily for 5 days), a moderate inhibitor of CYP3A4 cytochrome isoenzyme, against reaching a constant concentration of erythromycin in blood, leads to an increase of sildenafil AUC by 182 %.

When sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, are coadministered with saquinavir at a steady Cmax of sildenafil increased by 140%, and AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir.

The stronger CYP3A4 cytochrome isoenzyme inhibitors, such as ketoconazole and itraconazole, may also cause greater changes in the pharmacokinetics of sildenafil.

The concomitant use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and strong cytochrome P inhibitor450, against the background of achieving a constant concentration of ritonavir in the blood leads to an increase in Cmax sildenafil by 300% (4 times), a 1000% (11 times) AUC. After 24 hours, plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml). This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil has no effect on the pharmacokinetics of ritonavir. Given these data, concomitant administration of ritonavir and sildenafil is not recommended. In any case, the maximum dose of sildenafil should not exceed 25 mg for 48 hours under any circumstances.

If sildenafil is taken at the recommended doses in patients receiving concomitant strong CYP3A4 cytochrome isoenzyme inhibitors, the Cmax of free sildenafil does not exceed 200 nM and the drug is well tolerated.

A single administration of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

In studies involving healthy volunteers, concomitant use of an endothelin receptor antagonist, bosentan (an inducer of the CYP3A4 (moderate), CYP2C9 and possibly CYP2C19 isoenzymes) at equilibrium concentration (125 mg twice daily) and sildenafil at equilibrium concentration (80 mg three times daily) resulted in decreased AUC and Cmax of sildenafil by 62.6% and 52.4%, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It has been suggested that concomitant use of sildenafil with potent inducers of CYP3A4 isoenzyme, such as rifampicin, may lead to a greater reduction in plasma concentration of sildenafil.

. CYP2C9 cytochrome isoenzyme inhibitors (tolbutamide, warfarin), CYP2D6 cytochrome isoenzyme inhibitors (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect sildenafil pharmacokinetics. Azithromycin (500 mg/day for 3 days) has no effect on AUC, Cmax, Tmax, elimination rate constant and T1/2 of sildenafil or its major circulating metabolite.

Influence of sildenafil on other medications

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IR50 >150 μmol). When sildenafil is taken at the recommended doses, its Cmax is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effects of nitrates, both when used long-term and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated. When the α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered simultaneously in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic/diastolic BP in the supine position was 7/7 mm Hg, 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension, manifested as dizziness (without fainting), have been reported in these patients. In certain sensitive patients receiving α-adrenoblockers, concomitant use of sildenafil may result in symptomatic hypotension.

Significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by cytochrome isoenzyme CYP2C9, not detected.

Sildenafil (100 mg) has no effect on the pharmacokinetics of the HIV protease inhibitor, saquinavir, which is a substrate of the cytochrome CYP3A4 enzyme, at constant blood levels.

The concomitant use of sildenafil at equilibrium (80 mg three times daily) results in a 49.8% and 42% increase in the AUC and Cmah of bosentan (125 mg twice daily), respectively.

Sildenafil (50 mg) does not cause an additional increase in bleeding time with acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not increase the hypotensive effects of alcohol in healthy volunteers at a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with hypertension, there is no evidence of interaction between sildenafil (100 mg) and amlodipine. The mean additional BP reduction in the supine position is 8 mm Hg (systolic) and 7 mm Hg (diastolic). The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Special Instructions

To diagnose erectile dysfunction, determine its possible causes, and choose an adequate treatment, a complete medical history and a thorough physical examination must be taken. Erectile dysfunction treatments should be used with caution in patients with anatomic penile deformities (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see “Precautions.

In post-marketing studies, cases of prolonged erections and priapism have been reported. If an erection persists for more than 4 hours, immediate medical attention should be sought. If priapism therapy is not undertaken immediately, it may result in damage to penile tissue and permanent loss of potency.

Preventive medications intended to treat erectile dysfunction should not be prescribed for men for whom sexual activity is undesirable.

Sexual activity poses some risk if you have heart disease, so your doctor should refer you for a cardiovascular exam before starting any erectile dysfunction therapy. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke within last 6 months, life-threatening arrhythmias, hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg). Taking sildenafil in such patients is contraindicated (see section “Contraindications”). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular mortality rate (0.3 per 100 people per year) in patients receiving sildenafil compared to patients receiving placebo.

Cardiovascular Complications

In the postmarketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (includingincluding myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with sildenafil use. Most (but not all) of these patients had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity and some were noted after sildenafil administration without subsequent sexual activity. A direct correlation between the reported adverse events and these or other factors cannot be determined.

Hypotension

Sildenafil has a systemic vasodilator effect resulting in a transient decrease in BP, which is not clinically significant and does not result in any consequences in most patients. Nevertheless, before prescribing the drug, the physician should carefully evaluate the risk of possible adverse effects of vasodilatation in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy) as well as with rare syndrome of multiple systemic atrophy manifested by severe impairment of BP regulation by autonomic nervous system.

Since concomitant use of sildenafil and α-adrenoblockers may lead to symptomatic hypotension in some sensitive patients, caution should be exercised when prescribing the drug in patients taking α-adrenoblockers (see section “Interaction with other drugs”). In order to minimize the risk of postural hypotension in patients taking α-adrenoblockers, sildenafil should be started only after hemodynamic stabilization in these patients is achieved. It should also be considered whether it is reasonable to reduce the initial dose of sildenafil (see section “Dosage and administration”). The physician should inform patients about what actions should be taken if symptoms of postural hypotension occur.

Visual Impairment

In rare cases during post-registration use of all FDE5 inhibitors, including sildenafil, nonarteritic anterior ischemic optic neuropathy (NPINZN) was reported, a rare condition and cause of visual impairment or loss. Most of these patients had risk factors, including: decreased ratio of excavation and optic disc diameters (“stagnant disc”), age over 50 years, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, and smoking. The observational study evaluated whether recent use of drugs in the class of FDE5 inhibitors was associated with the acute onset of NSAIDs. Results indicated an approximately 2-fold increased risk of NPINZN within 5 half-lives of use of an FDE5 inhibitor. According to published literature, the annual incidence of NSAIDs is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population. Patients should be advised to discontinue sildenafil therapy in the event of sudden vision loss and immediately consult a physician. Individuals who have already had a history of NSAIDs have an increased risk of a recurrence of NSAIDs. Therefore, the physician should discuss this risk with such patients and also discuss with them the potential chance of adverse effects of FDE5 inhibitors. FDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefits outweigh the risks. Sildenafil is contraindicated in patients with episodes of NSAIDs with vision loss in one eye (see section “Contraindications”).

A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase function. There is no data on the safety of the drug in patients with pigmentary retinitis, so sildenafil should not be used in these patients (see section “Contraindications”).

Hearing impairment

Some postmarketing and clinical studies have reported cases of sudden hearing impairment or loss associated with all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or hearing loss. A causal relationship between the use of FDE5 inhibitors and sudden hearing impairment or hearing loss has not been established. Consult a physician immediately if there is sudden hearing impairment or hearing loss while taking sildenafil.

Bleeding

Sildenafil increases the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of sildenafil administration in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcer, therefore the drug should be used with caution in these patients (see section “Caution”). The incidence of nasal bleeding in patients with pulmonary hypertension associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary arterial hypertension (sildenafil 3.0%, placebo 2.4%). Patients who received sildenafil in combination with a vitamin K antagonist had a higher rate of nasal bleeding (8.8%) than patients who did not take a vitamin K antagonist (1.7%).

The use in combination with other erectile dysfunction treatments

The safety and effectiveness of sildenafil in combination with other FDE5 inhibitors or other pulmonary arterial hypertension drugs containing sildenafil or other erectile dysfunction treatments have not been studied, so such combinations are not recommended (see

Influence on driving and operating machinery

There has been no adverse effect on the ability to drive or operate machinery while taking sildenafil.

However, since taking sildenafil may cause dizziness, decreased blood pressure, chromatopsia, blurred vision, and other side effects, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and rapid psychomotor reactions. Also, the individual effect of the drug in the above situations should be carefully considered, especially at the beginning of treatment and when changing the dosing regimen.

The drug should be administered with caution.

Synopsis

Contraindications

Hypersensitivity to sildenafil or any other component of the drug; concomitant use of nitric oxide donors or organic nitrates or nitrates in any dosage form; concomitant use of ritonavir; patients for whom sexual activity is undesirable, including those with severe cardiovascular disease, such as unstable angina pectoris, severe heart failure, life-threatening arrhythmias; co-administration with guanylate cyclase stimulators such as riociguat – as this may lead to symptomatic hypotension; arterial hypotension (blood pressure (BP) less than 90/50 mm Hg. hypertension (BP greater than 170/100 mmHg), arterial hypertension (BP greater than 170/100 mmHg).): recent cerebrovascular events or myocardial infarction; patients with vision loss in one eye due to anterior ischemic optical neuropathy of nonarteritic genesis (whether it occurred due to FDE5 inhibitor use or not); hereditary degenerative retinal diseases, including retinitis pigmentosa (a small portion of such patients have retinal FDE genetic disease); severe hepatic insufficiency; female sex; age below 18 years.

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

The safety and effectiveness of sildenafil when used together with other drugs for treatment of erectile dysfunction have not been studied, so this combination is not recommended (see section “Cautions”).

Cautions

Anatomical deformity of the penis (angulation, cavernous fibrosis, or Peyronie’s disease) (see section “Special Precautions”).

Diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see section “Special Precautions”).

Diseases accompanied by bleeding.

Gastric and duodenal ulcer in the acute stage.

Liver function disorders.

Severe renal failure (CKR less than 30 ml/min).

Patients with a history of an episode of anterior nonarteritic ischemic optic neuropathy (see section “Special Precautions”).

Concomitant use of alpha-adrenoreceptor blockers.

Side effects

The most common side effects were headache and hot flashes.

In general, sildenafil side effects are mild to moderate and transient.

In fixed-dose studies, the incidence of some adverse events has been shown to increase with increasing dose.

The frequency of adverse reactions is represented by the following classification:

Very common

≥10%

Often

≥1%

Overdose

Pregnancy use

Similarities