Instructions for Moginin film-coated tablets 100 mg blister No. 1
Composition
active ingredient: sildenafil;
1 tablet contains sildenafil citrate equivalent to sildenafil 50 mg or 100 mg;
excipients: microcrystalline cellulose, dicalcium phosphate anhydrous, croscarmellose sodium, hypromellose, magnesium stearate; Opadry 03K80814 blue coating: hypromellose, titanium dioxide (E 171), triacetin, indigo carmine (E 132).
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex, smooth on both sides tablets, coated with a blue film coating.
Pharmacotherapeutic group
Drugs used for erectile dysfunction. Sildenafil. ATX code G04B E03.
Pharmacological properties
Pharmacodynamics.
Sildenafil is an oral therapeutic agent used to treat erectile dysfunction in men. In the natural state, particularly with sexual stimulation, it restores a disrupted erection by increasing blood flow to the penis.
The physiological mechanism of penile erection is the release of nitric oxide (NO) in the corpora cavernosa during sexual stimulation. NO activates the enzyme guanylate cyclase, which causes an increase in the level of cyclic guanosine monophosphate (cGMP), relaxation of the smooth muscles of the corpora cavernosa, and increased blood flow to them.
Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for the breakdown of cGMP. Sildenafil has a peripheral effect on erection. Sildenafil has no direct relaxing effect on the isolated human corpus cavernosum, but significantly enhances the relaxing effect of NO on this tissue.
When the NO/cGMP pathway is activated, as occurs with sexual stimulation, sildenafil inhibition of PDE5 leads to increased cGMP levels in the corpora cavernosa. Therefore, sexual arousal is required for sildenafil to exert its pharmacological effects.
Effect on pharmacodynamics.
In vitro studies have shown that sildenafil is selective for PDE-5, which is involved in the process of erection. Its effect on PDE-5 is stronger than on other known phosphodiesterases. This effect is 10 times stronger than the effect on PDE6, which is involved in the processes of photoconversion in the retina. When using the maximum recommended doses, the selectivity of sildenafil for PDE5 is 80 times higher than its selectivity for PDE1, 700 times higher than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10 and PDE11. In particular, the selectivity of sildenafil for PDE5 is 4000 times higher than its selectivity for PDE3 - a cGMP-specific isoform of phosphodiesterase involved in the regulation of heart contractions.
Pharmacokinetics.
Absorption.
Sildenafil is rapidly absorbed. The maximum observed plasma concentrations (Cmax) were reached within 30-120 minutes (mean 60 minutes) after oral administration in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%).
After oral administration of sildenafil, AUC and Cmax increase proportionally with increasing dose within the recommended dose range (25-100 mg). When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60 minutes and a mean decrease in Cmax of 29%.
Distribution.
The mean steady-state volume of distribution (Vd) for sildenafil is 105 L, indicating distribution into tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) are 96% bound to plasma proteins, this results in a mean maximum plasma concentration of free sildenafil of 18 ng/mL (38 nmol). Protein binding is independent of total drug concentration.
In healthy volunteers who took sildenafil (100 mg - single dose), less than 0.0002% (average 188 ng) of the administered dose was present in the ejaculate 90 minutes after its use.
Metabolism.
Sildenafil is mainly metabolized by the hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The main metabolite in the general circulation is formed by N-demethylation of sildenafil. The selectivity of the metabolite for PDE5 is comparable to that of sildenafil, and the activity of the metabolite for PDE5 is approximately 50% of the activity of the parent substance. The plasma concentration of this metabolite is approximately 40% of the plasma concentration of sildenafil. The N-demethylated metabolite undergoes further metabolism, and its half-life is approximately 4 hours.
Breeding.
The total body clearance of sildenafil is 41 l/h with a terminal half-life of 3-5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites, mainly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Pharmacokinetics in special patient groups
In healthy elderly volunteers (aged 65 years and older), a decrease in sildenafil clearance was observed, which resulted in an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by approximately 90% compared with the corresponding concentrations in healthy younger volunteers (18-45 years). Due to age-related differences in plasma protein binding, the corresponding increase in plasma concentrations of free sildenafil was approximately 40%.
Kidney failure.
In volunteers with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), sildenafil pharmacokinetics were unchanged after a single oral dose of 50 mg. The mean AUC and Cmax of the N-desmethyl metabolite increased by a maximum of 126% and 73%, respectively, compared with those in age-matched volunteers without renal impairment. However, due to high interindividual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax of 100% and 88%, respectively, compared with age-matched volunteers without renal impairment. In addition, the AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively.
Liver failure.
In volunteers with mild to moderate liver cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increased AUC (84%) and Cmax (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.
Indication
The drug Moginin® is recommended for use in men with erectile dysfunction, which is defined as the inability to achieve or maintain a penile erection necessary for successful sexual intercourse.
For the effective action of the drug Moginin®, sexual arousal is required.
Contraindication
- Hypersensitivity to the active substance or to any of the excipients of the drug.
- Concomitant use with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the NO/cyclic guanosine monophosphate (cGMP) metabolic pathways and potentiate the hypotensive effect of nitrates (see section 5.1).
- The concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated as it may lead to symptomatic hypotension (see section 4.5).
- Conditions in which sexual activity is not recommended (e.g. severe cardiovascular disorders such as unstable angina or severe heart failure).
- Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this pathology is associated with previous use of PDE5 inhibitors or not (see section "Special warnings and precautions for use").
- The presence of diseases such as severe liver dysfunction, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction and known hereditary degenerative retinal diseases such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), as the safety of sildenafil has not been studied in these subgroups of patients.
Interaction with other medicinal products and other types of interactions
Effects of other drugs on sildenafil
In vitro studies
Sildenafil is metabolized primarily by cytochrome P450 (CYP) isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers of these isoenzymes may increase sildenafil clearance.
In vivo studies
Sildenafil clearance has been shown to be reduced when co-administered with CYP3A4 inhibitors (ketoconazole, erythromycin, cimetidine). Although no increase in adverse events was observed when sildenafil was co-administered with CYP3A4 inhibitors, a starting dose of 25 mg sildenafil should be considered.
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a steady-state dose (1200 mg three times daily) with sildenafil (100 mg once daily) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil systemic exposure (AUC). Sildenafil had no effect on the pharmacokinetics of saquinavir (see section 4.2). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a greater effect.
When sildenafil (100 mg once) and erythromycin, a moderate CYP3A4 inhibitor, were administered at steady state (500 mg twice daily for 5 days), an increase in AUC of 182% was observed. In healthy male volunteers, there was no effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, and subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg when co-administered with sildenafil at a dose of 50 mg in healthy volunteers resulted in an increase in plasma concentrations of sildenafil by 56%.
Grapefruit juice is a weak inhibitor of CYP3A4 in the intestinal wall and may cause a modest increase in plasma levels of sildenafil.
Single administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
Although specific drug interaction studies have not been conducted, population pharmacokinetic analysis suggests that sildenafil pharmacokinetics were not altered by concomitant use of drugs belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitor group (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium antagonists, β-adrenoceptor antagonists, or inducers of CYP450 metabolism (such as rifampicin, barbiturates).
Co-administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19) at steady state (125 mg twice daily) with sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% decrease in sildenafil AUC and Cmax, respectively. Therefore, co-administration of potent CYP3A4 inducers such as rifampin may result in a more pronounced decrease in sildenafil plasma concentrations.
Nicorandil is a hybrid of a calcium channel activator and a nitrate. The nitrate component makes it possible for it to have a serious interaction with sildenafil.
Effect of sildenafil on other drugs
In vitro studies
Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μmol). Since peak plasma concentrations of sildenafil are approximately 1 μmol, the effect of Moginin® on the clearance of substrates of these isoenzymes is unlikely.
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.
In vivo studies
Since sildenafil is known to have an effect on NO/cGMP metabolism, sildenafil has been shown to potentiate the hypotensive effect of nitrates, therefore its concomitant use with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").
Riociguat. Preclinical studies have demonstrated an additive systemic blood pressure lowering effect when PDE5 inhibitors are co-administered with riociguat. Clinical studies have demonstrated that riociguat potentiates the hypotensive effect of PDE5 inhibitors. No beneficial clinical effect was observed in patients who participated in the study when PDE5 inhibitors were co-administered with riociguat.
The concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").
Concomitant use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most often occurred within 4 hours of sildenafil administration (see sections 4.4 and 4.2). In 3 specific drug interaction studies, the α-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia who were stabilised on doxazosin. In these populations, mean additional reductions in supine blood pressure of 7/7 mmHg, 9/5 mmHg and 8/4 mmHg and mean reductions in standing blood pressure of 6/6 mmHg were observed. 11/4 mm Hg, 4/5 mm Hg respectively.
Symptomatic orthostatic hypotension has occasionally been reported with concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin. These reports included dizziness and fainting, but without syncope.
Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at a mean maximum blood ethanol level of 80 mg/dl.
In patients taking sildenafil, no differences in the side effect profile were observed compared to placebo when using such classes of antihypertensive drugs as diuretics, β-adrenergic blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neurone blockers, calcium channel blockers and α-adrenergic blockers.
In a dedicated interaction study, co-administration of sildenafil (100 mg) and amlodipine in hypertensive patients resulted in an additional reduction in supine systolic blood pressure of 8 mm Hg. The corresponding reduction in diastolic blood pressure was 7 mm Hg. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section 5.1).
Sildenafil at a dose of 100 mg did not affect the pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, which are CYP3A4 substrates.
In healthy male volunteers, administration of sildenafil at steady state (80 mg 3 times daily) resulted in an increase in the AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.
The addition of a single dose of sildenafil to sacubitril/valsartan at steady state in hypertensive patients was associated with significantly greater blood pressure reductions compared with sacubitril/valsartan alone. Therefore, caution should be exercised when initiating sildenafil in patients receiving sacubitril/valsartan.
Application features
Before starting therapy, the patient's medical history should be collected and a physical examination should be performed to diagnose erectile dysfunction and determine its possible causes.
Risk factors for cardiovascular disease
Since sexual activity carries a certain cardiac risk, the physician should assess the patient's cardiovascular status before initiating any treatment for erectile dysfunction. Sildenafil has a vasodilating effect, which is manifested by a slight and transient decrease in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, the physician should carefully consider whether this effect may adversely affect patients with certain underlying diseases, especially in combination with sexual activity.
Patients with increased sensitivity to vasodilators include patients with obstruction of the left ventricular outflow tract (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare syndrome of multiple system atrophy, one of the manifestations of which is severe dysregulation of blood pressure by the autonomic nervous system.
Sildenafil potentiates the hypotensive effect of nitrates (see section "Contraindications").
Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, and hypotension, have been reported in association with sildenafil use. The majority of patients had cardiovascular risk factors. The majority of adverse reactions occurred during or immediately after sexual intercourse, with a few occurring shortly after drug use without sexual activity. Therefore, it is not possible to determine whether these adverse reactions are directly related to the risk factors or whether they are caused by other factors.
Priapism
Erectile dysfunction drugs, including sildenafil, should be prescribed with caution in patients with anatomical deformity of the penis (such as angulation, cavernous fibrosis, or Peyronie's disease) or in patients with conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
There is evidence of prolonged erection and priapism when taking sildenafil.
If an erection lasts more than 4 hours, patients should seek immediate medical attention. Without prompt treatment, priapism can lead to damage to penile tissue and permanent loss of potency.
Concomitant use with other PDE5 inhibitors or other drugs for the treatment of erectile dysfunction
The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other sildenafil-containing drugs for the treatment of pulmonary arterial hypertension, or with other drugs for the treatment of erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Effects on vision
Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study as associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be warned that in case of sudden visual impairment, the use of Moginin® should be discontinued and a doctor should be consulted immediately (see section "Contraindications").
Concomitant use with ritonavir
The simultaneous use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other types of interactions").
Concomitant use with α-adrenergic blockers
Sildenafil should be used with caution in patients taking α-adrenergic blockers, as the combination may lead to symptomatic hypotension in some susceptible patients (see section 4.5). Symptomatic hypotension usually occurs within 4 hours of sildenafil administration. To minimise the potential for postural hypotension in patients taking α-adrenergic blockers, patients should be stabilised on α-adrenergic blockers before starting sildenafil. A starting dose of 25 mg should also be considered (see section 4.2). Patients should also be advised how to respond to symptoms of orthostatic hypotension.
Effect on blood clotting
Studies in human platelets have shown that sildenafil potentiates the antiaggregatory effects of sodium nitroprusside in vitro. There is no information on the safety of sildenafil in patients with coagulation disorders or acute peptic ulcer. Therefore, the use of sildenafil in these patients should only be considered after careful consideration of the benefit-risk ratio.
Effect on sperm
After administration of a dose of 100 mg to healthy volunteers, no effect on sperm morphology or motility was observed (see section 5.1).
Hearing loss
Physicians should advise patients to discontinue use of PDE5 inhibitors, including Moginin®, and seek immediate medical attention if they experience sudden hearing loss or hearing loss. These events, which may also be accompanied by tinnitus and dizziness, have been reported in association with the use of PDE5 inhibitors, including sildenafil. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors or to other factors.
Concomitant use with antihypertensive drugs.
Sildenafil has a systemic vasodilator effect and may further reduce blood pressure in patients taking antihypertensive drugs. There is evidence that with the simultaneous use of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) orally, an average additional decrease in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg was observed.
Sexually transmitted diseases
Sildenafil does not protect against sexually transmitted diseases. Patients should be advised to take precautions to protect against sexually transmitted diseases, including human immunodeficiency virus (HIV).
Excipients
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
The drug Moginin® is not intended for use by women.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug Moginin® may have a minor influence on the ability to drive or use machines. Since dizziness and visual disturbances have been reported with sildenafil, patients should be advised to assess their individual response to sildenafil before driving or operating machinery.
Method of administration and doses
The medicine should be administered orally.
Adults
The recommended dose of sildenafil is 50 mg, taken as needed approximately one hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg*. The maximum recommended dose is 100 mg.
The frequency of use of the maximum recommended dose of the drug is 1 time per day. When using the drug Moginin® during meals, the effect of the drug may occur later than when used on an empty stomach (see the section "Pharmacokinetics").
Elderly patients (≥ 65 years)
There is no need for dose adjustment in elderly patients.
Patients with renal insufficiency
Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 ml/min), a dose of 25 mg should be considered.* Depending on efficacy and tolerability, the dose may be increased gradually to 50 mg and 100 mg if necessary.
Patients with hepatic insufficiency
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), a dose of 25 mg should be considered.* Depending on efficacy and tolerability, the dose may be increased gradually to 50 mg and 100 mg if necessary.
Patients taking other medications
If patients are concomitantly taking CYP3A4 inhibitors (see section 4.5), a starting dose of 25 mg* should be considered (except for ritonavir, the use of which with sildenafil is not recommended, see section 4.4).
To minimise the potential for postural hypotension in patients taking α-adrenergic blockers, their condition should be stabilised with α-adrenergic blockers before starting sildenafil. A starting dose of 25 mg* should also be considered (see sections 4.5 and 4.4).
* Use sildenafil at the appropriate dosage.
Children.
The drug Moginin® is not indicated for use in persons under the age of 18.
Overdose
In clinical trials in volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those observed with lower doses of sildenafil, but were more frequent and more severe.
The use of sildenafil at a dose of 200 mg did not lead to increased efficacy, but caused an increase in the number of cases of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).
In case of overdose, usual supportive measures should be employed as necessary. Acceleration of sildenafil clearance during hemodialysis is unlikely due to the high degree of binding of the drug to plasma proteins and the lack of elimination of sildenafil in the urine.
Adverse reactions
The safety profile of sildenafil is based on data from 74 double-blind, placebo-controlled clinical trials (9570 patients). The most common adverse reactions reported in clinical trials among patients taking sildenafil were headache, hot flushes, dyspepsia, nasal congestion, back pain, dizziness, nausea, visual disturbances, cyanopsia and blurred vision. Information on adverse reactions from post-marketing surveillance of sildenafil has been collected for more than 10 years.
Since not all adverse reactions have been reported and not all adverse reactions have been included in the sildenafil safety database, the frequency of such reactions cannot be reliably determined.
All clinically important adverse reactions that occurred in clinical trials at a frequency greater than placebo are listed below, by body system and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000).
The frequency of clinically important adverse reactions reported from post-marketing experience as unknown is also included.
Within each frequency grouping, side effects are listed in order of decreasing severity.
Infectious and invasive diseases
Uncommon: rhinitis.
On the part of the immune system
Uncommon: hypersensitivity.
From the nervous system
Very common: headache.
Common: dizziness.
Uncommon: drowsiness, hypoesthesia.
Rare: stroke, transient ischemic attack, seizures*, recurrent seizures*, syncope.
From the organs of vision
Common: color perception disorders**, visual disturbances, blurred vision.
Uncommon: lacrimation disorder***, eye pain, photophobia, photopsia, ocular hyperemia, visual acuity reduced, conjunctivitis.
Rare: non-arteritic anterior ischemic optic neuropathy*, retinal vascular occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, visual acuity reduced, myopia, asthenopia, floating vitreous opacities, iris disorders, mydriasis, halos, eye oedema, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal eye sensation, eyelid oedema, sclera discolouration.
From the side of the organs of hearing and vestibular apparatus
Uncommon: dizziness, tinnitus.
Rare: deafness.
From the heart
Uncommon: tachycardia, palpitations.
Rare: sudden cardiac death*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.
From the vascular side
Common: flushing, hot flushes.
Uncommon: hypertension, hypotension.
Respiratory, thoracic and mediastinal disorders
Common: nasal congestion.
Uncommon: epistaxis, sinus congestion.
Gastrointestinal tract
Common: nausea, dyspepsia.
Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.
Rare: oral hypoesthesia.
Skin and subcutaneous tissue disorders
Uncommon: rash.
Rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis*.
Musculoskeletal and connective tissue disorders
Uncommon: myalgia, pain in extremity.
From the urinary system
Uncommon: hematuria.
Reproductive system and breast disorders
Rare: penile bleeding, priapism*, hematospermia, prolonged erection.
General disorders and administration site conditions
Uncommon: chest pain, fatigue, feeling hot.
Rare: irritation.
Examination
Uncommon: increased heart rate.
*Reported only during post-marketing surveillance.
** Color perception disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.
*** Lacrimation disorders: dry eyes, lacrimation disorders and lacrimation increased.
The following events occurred in <2% of patients in controlled clinical trials; causality has not been established. Reports included events that had a probable relationship to drug use. Events that were not listed were mild and reports were too imprecise to be of significance.
General: Facial edema, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.
Cardiovascular system: angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.
Gastrointestinal: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.
From the blood and lymphatic system: anemia, leukopenia.
Metabolism and nutrition disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.
Nervous system: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.
From the respiratory system: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.
Skin: urticaria, herpes, itching, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.
Specific sensations: sudden decrease or loss of hearing, earache, hemorrhage in the eye, cataract, dry eyes.
From the urogenital system: cystitis, nocturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, swelling of the genitals, anorgasmia.
Post-marketing experience. The following adverse reactions have been identified during post-marketing experience. Because these reactions are reported voluntarily and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were reported because of their seriousness, frequency of reporting, lack of a clear alternative relationship, or a combination of these factors.
Cardiovascular and cerebrovascular events. Reported
