Sialdjuub

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CIALJUB (CIALJUB)

Composition:

Active substance: tadalafil;

1 tablet contains tadalafil 5 mg, 10 mg or 20 mg;

Excipients: lactose monohydrate, hydroxypropylcellulose, sodium croscarmellose, sodium lauryl sulfate, microcrystalline cellulose, magnesium stearate, purified water;

Tablet coating: Oparay II 32K580001 white (hypromellose, lactose monohydrate, titanium dioxide, triacetin, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 5 mg: white to almost white, oval-shaped, biconvex tablets, film-coated, engraved with "H2" on one side and "C" on the other;

Film-coated tablets, 10 mg: white to almost white, oval-shaped, biconvex tablets, film-coated, engraved with "H3" on one side and "C" on the other;

Film-coated tablets, 20 mg: white to almost white, oval-shaped, biconvex tablets, film-coated, engraved with "H4" on one side and "C" on the other.

Pharmacotherapeutic group.

Agents for the treatment of erectile dysfunction. ATC code G04BE08.

Pharmacological Properties

Pharmacodynamics

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 by tadalafil results in increased levels of cGMP in the corpus cavernosum. This leads to relaxation of smooth muscles and increased blood flow into penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.

In vitro studies have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in the smooth muscles of the corpus cavernosum, vascular and visceral smooth muscles, skeletal muscles, platelets, kidneys, lungs, and cerebellum. The effect of tadalafil on PDE5 is stronger than on other phosphodiesterases. The activity of tadalafil on PDE5 is 10,000 times greater than its effect on PDE1, PDE2, PDE4, and PDE7 enzymes present in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles, and other organs. Tadalafil is 10,000 times more potent against PDE5 than against PDE3, an enzyme present in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in myocardial contraction. Furthermore, tadalafil is approximately 700 times more potent against PDE5 than against PDE6, an enzyme present in the retina and responsible for phototransduction. Tadalafil is also 9,000 times more potent against PDE5 than against PDE8, PDE9, and PDE10, and 14 times more potent against PDE5 than against PDE11. Tissue distribution and physiological effects of PDE8 through PDE11 have not been fully characterized. The drug acts for up to 36 hours. The effect occurs as early as 16 minutes after dosing in the presence of sexual arousal.

Tadalafil administered to healthy volunteers did not cause significant differences compared to placebo in systolic and diastolic blood pressure in the supine position (mean maximum decrease 1.6/0.8 mmHg, respectively), systolic and diastolic blood pressure in the standing position (mean maximum decrease –0.2/4.6 mmHg, respectively), or in significant changes in heart rate.

Tadalafil does not impair color discrimination (blue/green), which is explained by the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no effects of tadalafil on visual acuity, electroretinogram, intraocular pressure, or pupil size have been observed.

A placebo-controlled study showed that tadalafil administration over 6 months had no clinically significant effect on sperm characteristics. In men, tadalafil did not affect levels of testosterone, luteinizing hormone, or follicle-stimulating hormone in blood.

Pharmacokinetics

Absorption

Tadalafil is well absorbed after oral administration. Cmax is reached on average within 2 hours after dosing.

The rate and extent of tadalafil absorption are not affected by food intake. Therefore, the drug can be taken regardless of meals. The time of dosing (morning or evening) has no clinically significant effect on the rate and extent of absorption.

Distribution

The mean volume of distribution is approximately 63 L. At therapeutic concentrations, 94% of tadalafil in blood plasma is protein-bound.

Less than 0.0005% of the administered dose was detected in the semen of healthy volunteers.

Metabolism

Tadalafil is primarily metabolized by the cytochrome P450 isoenzyme CYP3A4. The major circulating metabolite is methylcatechol glucuronide. This metabolite has PDE5 activity 13,000 times lower than that of tadalafil. Therefore, the metabolite is not expected to exhibit clinical activity at observed concentrations.

Elimination

The mean elimination half-life in healthy volunteers is 17.5 hours. Tadalafil is eliminated predominantly as inactive metabolites, mainly via feces (approximately 61% of the dose) and to a lesser extent via urine (approximately 36% of the dose).

Clinical characteristics.

Indications.

For the 5 mg dosage. Treatment of erectile dysfunction in adult men. The drug is effective for the treatment of erectile dysfunction in the presence of sexual stimulation.

Treatment of symptoms of benign prostatic hyperplasia in adult men.

For the 10 mg and 20 mg dosages. Treatment of erectile dysfunction in adult men. The drug is effective in the presence of sexual stimulation.

Contraindications.

Hypersensitivity to tadalafil or to any other component of the drug.

During clinical studies, tadalafil demonstrated the ability to potentiate the hypotensive effect of nitrates. This is considered to be a consequence of the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, tadalafil is contraindicated in patients receiving organic nitrates in any dosage form (see section "Interaction with other medicinal products and other forms of interaction").

The drug should not be administered to men with cardiovascular diseases for whom sexual activity is undesirable. Physicians should consider the potential cardiac risk of sexual activity in patients with a history of cardiovascular disease.

The following groups of patients with cardiovascular diseases were not included in clinical trials; therefore, the use of tadalafil is contraindicated in these patients:

 patients who have had myocardial infarction within the last 90 days;

 patients with unstable angina or angina occurring during sexual intercourse;

 patients with heart failure classified as NYHA class 2 or higher within the last 6 months;

 patients with uncontrolled arrhythmia, arterial hypotension ( 90/50 mm Hg), or uncontrolled arterial hypertension;

 patients who have had a stroke within the last 6 months.

The drug is contraindicated in patients who have experienced unilateral vision loss due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether it was associated with prior use of PDE5 inhibitors or not (see section "Special precautions for use").

Concomitant use of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators such as riociguat is contraindicated, as it may potentially lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clinically significant interactions with higher doses cannot be excluded if such interactions were observed with lower doses of the drug (10 mg).

Effect of other medicinal products on tadalafil.

Cytochrome CYP450 inhibitors.

Tadalafil is primarily metabolized by CYP3A4. The selective CYP3A4 inhibitor ketoconazole (200 mg daily) increases the area under the concentration-time curve (AUC) of tadalafil (10 mg) by 2-fold and the maximum plasma concentration (Cmax) by 15% compared to AUC and Cmax of tadalafil alone. Ketoconazole (400 mg daily) increases the AUC of tadalafil (20 mg) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increases the AUC of tadalafil (20 mg) by 2-fold without altering Cmax. Although specific interactions have not been studied, other protease inhibitors such as saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole, and grapefruit juice should be used with caution, as they are expected to increase plasma concentrations of tadalafil when used concomitantly. As a result, the frequency of adverse reactions may increase.

Transporters.

The effect of transporters, such as P-glycoprotein, on the distribution of tadalafil is unknown. Therefore, there is a possibility of drug interaction mediated by inhibition of transporters.

Cytochrome CYP450 inducers.

The CYP3A4 inducer rifampicin reduces the AUC of tadalafil by 88% compared to the AUC of tadalafil alone (10 mg). This reduction in concentration may lead to decreased efficacy of tadalafil. Concomitant use of other CYP3A4 inducers such as phenobarbital, phenytoin, and carbamazepine may also reduce plasma concentrations of tadalafil.

Effect of tadalafil on other medicinal products.

Nitrates.

Sialdzhub (5 mg, 10 mg, 20 mg) demonstrated the ability to potentiate the hypotensive effects of nitrates. Therefore, the use of the drug is contraindicated in patients receiving organic nitrates in any form (see section "Interaction with other medicinal products and other forms of interaction"). If nitrates are medically necessary in a patient receiving the drug at any dose (2.5–20 mg) due to a life-threatening condition, at least 48 hours must elapse after the last dose of the drug before administering nitrates. In such cases, nitrates should be administered under medical supervision with appropriate hemodynamic monitoring.

Antihypertensive agents (including calcium channel blockers).

Significant potentiation of the hypotensive effect of the α-adrenoreceptor blocker doxazosin (4–8 mg daily) was observed when co-administered with tadalafil (5 mg once daily or a single 20 mg dose). This effect lasts up to 12 hours and may manifest as individual symptoms, including dizziness. This combination is not recommended.

The aforementioned effects were not reported with concomitant use of alfuzosin or tamsulosin. Tadalafil should be prescribed with caution to patients receiving α-adrenoreceptor blockers, especially elderly patients. Treatment should be initiated at the lowest dose and gradually increased.

In patients receiving concomitant antihypertensive therapy, administration of tadalafil at a dose of 20 mg may lead to a reduction in blood pressure, which is generally mild and clinically insignificant (except in cases of concomitant use with α-adrenoreceptor blockers). Appropriate advice regarding the potential for blood pressure reduction should be provided to patients receiving antihypertensive drugs and tadalafil.

5-α-reductase inhibitors.

Tadalafil should be prescribed with caution to patients receiving 5-α-reductase inhibitors.

CYP1A2 substrates (e.g., theophylline).

A slight increase in heart rate was observed. The possibility of this effect should be considered when tadalafil is used concomitantly with theophylline, although it is not clinically significant.

Ethinylestradiol and terbutaline.

Tadalafil increased the bioavailability of oral formulations containing ethinylestradiol. Such an increase in bioavailability may be expected with concomitant use of terbutaline, although the clinical consequences of this combination are unknown.

Alcohol.

Alcohol (mean maximum concentration – 0.08%) did not affect the co-administration of tadalafil (10 or 20 mg). No changes in tadalafil concentration were observed during the 3 hours following simultaneous intake of alcohol and tadalafil. Alcohol was administered to achieve maximum alcohol absorption (rapid intake without food for 2 hours after administration). Administration of tadalafil (20 mg) did not result in a statistically significant reduction in blood pressure when combined with alcohol (0.7 g/kg), although postural dizziness and orthostatic hypotension were observed in some patients. Administration of tadalafil with lower doses of alcohol (0.6 g/kg) did not cause arterial hypotension, and dizziness occurred at the same frequency as with alcohol alone. The effect of alcohol on cognitive function was not enhanced by concomitant administration of tadalafil (10 mg).

Medicinal products metabolized by cytochrome P450.

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolized by CYP450 isoenzymes. Tadalafil does not inhibit or induce CYP450 isoenzymes, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19.

CYP2C9 substrates (e.g., R-warfarin).

Tadalafil (10 mg and 20 mg) did not show a clinically significant effect on the AUC of S-warfarin or R-warfarin (CYP2C9 substrates) and did not affect warfarin-induced prothrombin time.

Acetylsalicylic acid.

Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.

Antidiabetic medicinal products.

No specific studies on the interaction of tadalafil with antidiabetic medicinal products have been conducted.

Special precautions for use.

Before starting treatment with the medicine.

Before initiating treatment with the medicine, the physician should take a medical history and perform a physical examination to identify potential underlying causes of erectile dysfunction and benign prostatic hyperplasia, and initiate appropriate treatment.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, as there is a certain degree of cardiac risk associated with sexual activity. Tadalafil has a vasodilatory effect, which may lead to a slight and transient reduction in blood pressure (see section "Pharmacological properties") and may potentiate the hypotensive effect of nitrates (see section "Contraindications").

Before initiating tadalafil therapy for symptoms of benign prostatic hyperplasia, the patient should be examined to exclude possible prostate carcinoma and to carefully assess cardiovascular status (see section "Contraindications").

Evaluation of erectile dysfunction should include identification of potential underlying causes and appropriate medical management. It is unknown whether the medicine is effective in patients who have undergone pelvic surgery or nerve-sparing radical prostatectomy.

Cardiovascular system.

During the post-marketing period and/or clinical trials, serious adverse events related to the cardiovascular system have been reported, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, cerebrovascular accidents, transient ischemic attack, chest pain, palpitations, and tachycardia. Most patients who experienced such adverse reactions had pre-existing cardiovascular risk factors. However, it is currently not possible to definitively determine whether these events are related to underlying risk factors, the use of the medicine, patient sexual activity, or a combination of these or other factors.

In patients receiving concomitant antihypertensive therapy, tadalafil may potentiate the reduction in blood pressure. If daily treatment with the medicine is initiated, the clinical need for adjustment of antihypertensive therapy should be considered.

The medicine should be prescribed with caution to patients taking α1-blockers, as in some patients, concomitant use of these medicines may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction"). Combined use of tadalafil and doxazosin is not recommended.

Vision.

Cases of visual disturbances and NAION (non-arteritic anterior ischemic optic neuropathy) have been reported during treatment with the medicine and other PDE5 inhibitors. Physicians should inform patients about the necessity to immediately discontinue tadalafil and seek medical help in case of sudden vision loss (see section "Contraindications").

Hearing.

Cases of sudden hearing loss have been reported after administration of tadalafil. Although in some cases other risk factors were present (such as advanced age, diabetes, hypertension, and history of hearing loss), patients should seek immediate medical help in case of sudden decrease or loss of hearing.

Renal and hepatic impairment.

Daily administration of the medicine is not recommended in patients with severe renal impairment due to increased tadalafil AUC, limited clinical experience, and poor ability to affect its clearance by dialysis.

Clinical data on the use of the medicine for daily administration in patients with severe hepatic impairment (Child-Pugh class C) are limited.

Daily use of the medicine for the treatment of erectile dysfunction as well as for the treatment of benign prostatic hyperplasia has not been evaluated in patients with hepatic insufficiency. Before prescribing the medicine, the physician should carefully assess the individual benefit/risk ratio of therapy.

Priapism and anatomical deformity of the penis.

If a patient experiences an erection lasting 4 hours or longer, he should seek immediate medical help. If priapism is not treated promptly, it may lead to penile tissue damage and permanent loss of potency.

The medicine should be prescribed with caution to patients with anatomical deformities of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or to patients with conditions that may predispose to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).

Concomitant use with CYP3A4 inhibitors.

The medicine should be prescribed with caution to patients taking CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), as co-administration with tadalafil results in increased tadalafil AUC exposure (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with other medicinal products for erectile dysfunction.

The safety and efficacy of using the medicine in combination with other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied; therefore, patients should be informed not to take the medicine in such combinations.

Lactose.

The medicine contains lactose monohydrate; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

The medicine is not indicated for use in women.

Pregnancy. Data from studies on the use of tadalafil in pregnant women are limited. Animal studies did not reveal any direct or indirect harmful effects on pregnancy, embryonic or fetal development, delivery, or postnatal development. As a precautionary measure, it is advisable to avoid use of the medicine during pregnancy.

Breastfeeding period. Available pharmacodynamic/toxicological data in animals indicate excretion of tadalafil into milk. Risk to the breastfed infant should not be excluded. The medicine should not be used during breastfeeding.

Fertility. Effects indicating impaired fertility were observed in dogs. In two clinical studies, such an effect was not expected in humans, although decreased sperm concentration was observed in some individual men (see section "Pharmacological properties").

Ability to influence the speed of reactions when driving or operating machinery.

The influence of the medicine on the ability to drive or operate machinery is negligible. Although the frequency of reports of dizziness during clinical trials with placebo and with tadalafil was similar, patients should know how the medicine affects them before driving or operating machinery.

Administration and Dosage

For oral use. The tablets should be taken with the appropriate amount of active substance to achieve the recommended dose.

Erectile dysfunction in adult men.

The recommended dose is 10 mg taken prior to anticipated sexual activity, regardless of food intake. For patients in whom 10 mg of tadalafil does not produce an adequate effect, a dose of 20 mg may be used.

The medication should be taken at least 30 minutes prior to anticipated sexual activity.

The maximum recommended frequency of dosing is once per day.

Tadalafil 10 mg and 20 mg is intended for use prior to anticipated sexual activity and is not recommended for daily use.

If frequent use of the medication is anticipated (at least twice weekly), a daily regimen with lower doses may be more appropriate, based on patient preference and physician decision. For such patients, the recommended dose is 5 mg once daily, taken approximately at the same time each day. The dose may be reduced to 2.5 mg once daily (using appropriately dosed tadalafil tablets, since the tablet cannot be split), based on individual tolerability. The continued need for long-term daily treatment should be reviewed periodically.

Benign prostatic hyperplasia in adult men.

For daily use, the recommended dose is 5 mg once daily, taken approximately at the same time each day, regardless of food intake. For the treatment of adult men with both erectile dysfunction and symptoms of benign prostatic hyperplasia, the recommended dose for daily use is 5 mg once daily, taken approximately at the same time each day. For patients who do not tolerate 5 mg of tadalafil daily when being treated for benign prostatic hyperplasia, alternative therapy should be considered, as the efficacy of tadalafil 2.5 mg once daily for the treatment of benign prostatic hyperplasia has not been evaluated.

Special patient groups.

Elderly men. Dose adjustment is not required.

Patients with renal impairment. Dose adjustment is not necessary in patients with mild or moderate renal impairment. For patients with severe renal impairment, the maximum recommended dose is 10 mg (on-demand use). Daily administration of tadalafil 2.5 mg or 5 mg is not recommended for the treatment of patients with severe renal impairment and benign prostatic hyperplasia or erectile dysfunction (see sections "Pharmacological properties" and "Special precautions for use").

Patients with hepatic impairment.

For the treatment of erectile dysfunction, the recommended dose is 10 mg prior to anticipated sexual activity, regardless of food intake (on-demand use). Clinical data on the safety of tadalafil in patients with severe hepatic impairment (Child–Pugh class C) are limited; if prescribed, the physician should carefully assess the individual benefit/risk ratio. There are no data on the use of doses higher than 0 m g in patients with hepatic impairment. Daily administration of tadalafil, both for the treatment of benign prostatic hyperplasia and erectile dysfunction, has not been evaluated in patients with hepatic impairment; therefore, the physician should carefully evaluate the individual benefit/risks of such therapy (see sections "Pharmacological properties" and "Special precautions for use").

Men with diabetes mellitus. Dose adjustment is not required.

Children.

Not recommended for use in children.

Overdose.

Symptoms. In healthy volunteers, single doses of tadalafil up to 500 mg and multiple doses up to 100 mg/day were associated with adverse effects similar to those observed with lower doses.

Treatment. In case of overdose, standard symptomatic treatment should be initiated as needed. Hemodialysis has minimal effect on the elimination of tadalafil.

Adverse reactions.

Summary of the drug safety profile.

The most commonly reported adverse effects during treatment of erectile dysfunction or benign prostatic hyperplasia were headache, dyspepsia, back pain, and myalgia, with frequency increasing with higher doses of the drug. Adverse reactions were generally short-term and mild to moderate in severity. Most cases of headache with daily administration occurred within the first 10–30 days after initiation of treatment.

Tabulated data on adverse reactions.

The table below presents data on adverse reactions from spontaneous reports and placebo-controlled clinical trials (overall, 8022 patients receiving the drug and 4422 patients receiving placebo), with on-demand and daily use for the treatment of erectile dysfunction and daily use for the treatment of benign prostatic hyperplasia.

Very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from the available data).

1 Most of the patients in whom such adverse reactions were observed had cardiovascular risk factors in their medical history (see section "Special instructions").

2 Adverse reactions reported from post-marketing experience that were not observed during placebo-controlled clinical trials.

3 More frequently reported when tadalafil was used concomitantly with antihypertensive agents.

Individual adverse reactions. A slightly higher frequency of ECG abnormalities, primarily sinus bradycardia, was reported in patients receiving tadalafil once daily compared to patients receiving placebo. Most of these ECG abnormalities were not associated with clinical manifestations of adverse reactions.

Special patient groups. Data on the use of tadalafil in patients aged 65 years and older in clinical trials, both for the treatment of erectile dysfunction and for the treatment of benign prostatic hyperplasia, are limited. During clinical trials of on-demand tadalafil use (at a dose of 20 mg) for the treatment of erectile dysfunction, diarrhea occurred more frequently in patients aged 65 years and older. In clinical trials of tadalafil administered at a dose of 5 mg once daily for the treatment of benign prostatic hyperplasia, dizziness and diarrhea were reported more frequently in patients aged 75 years and older.

Shelf life.

2 years.

Storage conditions.

Keep out of the reach of children. Store at a temperature not exceeding 25 °C.

Packaging.

Prescription category.

By prescription.

Manufacturer.

Jubilant Generics Limited.

Manufacturer's location and address of its place of business.

Village Sikandarpur, Bhainswal, Roorkee-Dehradun Highway, Bhagwanpur, District Roorkee Haridwar, Uttarakhand, IN-247661, India