Dynamico Long, 5 mg 28 pcs

Indications

Erectile dysfunction.
Lower urinary tract symptoms in patients with benign prostatic hyperplasia (for a dosage of 5 mg).
Erectile dysfunction in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Pharmacological effect

Pharmacotherapeutic group: erectile dysfunction treatment – PDE-5 inhibitor.

ATX code: G04BE08

Pharmacological properties

Pharmacodynamics

Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (PDE-5) of cyclic guanosine monophosphate (cGMP). When sexual arousal causes local release of nitric oxide, inhibition of PDE5 by tadalafil leads to increased concentrations of cGMP in the corpus cavernosum of the penis. The consequence of this is the relaxation of the smooth muscles of the arteries and the flow of blood to the tissues of the penis, which causes an erection. Tadalafil has no effect in the absence of sexual arousal.

In vitro studies have shown that tadalafil is a selective PDE5 inhibitor. PDE-5 is an enzyme found in the smooth muscle of the corpus cavernosum, vascular smooth muscle of the internal organs, skeletal muscle, platelets, kidneys, lungs and cerebellum. The effect of tadalafil is more pronounced in relation to PDE-5 than in relation to other phosphodiesterases. Tadalafil is 10,000 times more potent at blocking PDE-5 than PDE-1, PDE-2, PDE-4 and PDE-7 enzymes, which are found in the heart, brain, blood vessels, liver, white blood cells, skeletal muscles and other organs. Tadalafil is 10,000 times more potent at blocking PDE-5 than the PDE-3 enzyme, which is found in the heart and blood vessels. This selectivity for PDE-5 over PDE-3 is important because PDE-3 is an enzyme involved in cardiac muscle contraction. In addition, tadalafil is approximately 700 times more potent at blocking PDE5 than the PDE6 enzyme, which is found in the retina and is responsible for phototransmission. Tadalafil is 9000 times more active in blocking PDE-5 than the enzymes PDE-8, PDE-9 and PDE-10, and 14 times more active in blocking PDE-5 than PDE-11. The tissue distribution and physiological effects of PDE-8 and PDE-11 inhibition have not yet been studied.

Tadalafil improves erection and increases the possibility of successful sexual intercourse.

Tadalafil in healthy volunteers does not cause significant changes in systolic and diastolic blood pressure compared to placebo in the supine position (mean maximum decrease is 1.6/0.8 mm Hg, respectively) and in the standing position (mean maximum decrease is 0.2/4.6 mm Hg, respectively). Tadalafil does not significantly change heart rate.

Tadalafil does not cause changes in color recognition (blue/green), which is explained by its low affinity for PDE-6. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.

Several studies have been conducted to evaluate the effect of daily tadalafil on spermatogenesis. No adverse effects on sperm morphology or motility were observed in any of the studies. One study found a decrease in mean sperm concentration compared to placebo. Decreased sperm concentration was associated with higher ejaculation frequency. In addition, no adverse effects were observed on mean concentrations of sex hormones, testosterone, luteinizing hormone, and follicle-stimulating hormone with tadalafil compared to placebo. The effectiveness and safety of tadalafil (in doses of 2.5 mg, 5.0 mg) was studied in clinical studies. An improvement in erection was noted in patients with erectile dysfunction of all degrees of severity when taking tadalafil once a day. In primary efficacy studies of 5 mg tadalafil, 62% and 69% of attempted intercourse were successful compared with 34% and 39% of patients taking placebo. Taking 5 mg of tadalafil significantly improved erectile function for 24 hours between doses.

Mechanism of action in patients with benign prostatic hyperplasia (BPH)

Inhibition of PDE5 by tadalafil, leading to increased concentrations of cGMP in the corpus cavernosum of the penis, is also observed in the smooth muscles of the prostate, bladder and the vessels that supply them. Relaxation of vascular smooth muscle leads to an increase in blood perfusion in these organs, and, as a result, to a decrease in the severity of BPH symptoms. Relaxation of prostate and bladder smooth muscle may further enhance the vascular effects.

Pharmacokinetics

Suction

After oral administration, tadalafil is rapidly absorbed. The average maximum concentration (Cmax) in blood plasma is achieved on average 2 hours after ingestion. The rate and degree of absorption of tadalafil do not depend on the time of food intake, so DYNAMICO LONG can be used regardless of food intake. Time of administration (morning or evening) did not have a clinically significant effect on the rate and extent of absorption.

The pharmacokinetics of tadalafil in healthy volunteers is linear with respect to time and dose. In the dose range from 2.5 to 20 mg, the area under the concentration-time curve (AUC) increases proportionally to the dose. Equilibrium concentration in blood plasma is achieved within 5 days when taking the drug once a day.

The pharmacokinetics of tadalafil in patients with erectile dysfunction are similar to the pharmacokinetics of the drug in patients without erectile dysfunction.

Distribution

The average volume of distribution is approximately 63 L, which indicates that tadalafil is distributed into the tissues of the body. At therapeutic concentrations, 94% of tadalafil in blood plasma is protein bound. Protein binding is not affected by impaired renal function.

In healthy volunteers, less than 0.0005% of the administered dose is found in semen.

Metabolism

Tadalafil is mainly metabolized with the participation of the cytochrome P450 isoenzyme CYP3A4. The main circulating metabolite is methylcatechol glucuronide. This metabolite is at least 13,000 times less active against PDE5 than tadalafil. Therefore, the concentration of this metabolite is not clinically significant.

Removal

In healthy volunteers, the average clearance of tadalafil when taken orally is 2.5 L/h, and the average half-life is 17.5 hours. Tadalafil is excreted primarily in the form of inactive metabolites, mainly through the intestines (about 61% of the dose) and, to a lesser extent, through the kidneys (about 36% of the dose).

Special patient groups

Age over 65

Healthy volunteers aged 65 years and older had lower oral clearance of tadalafil, resulting in a 25% increase in AUC compared to healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.

Kidney failure

In patients with mild (creatinine clearance 51 to 80 mL/min) and moderate renal impairment (creatinine clearance 31 to 50 mL/min) and in patients with end-stage renal disease on hemodialysis, tadalafil exposure (AUC) was approximately doubled. In hemodialysis patients, Cmax was 41% higher compared to healthy volunteers. Elimination of tadalafil by hemodialysis is negligible.

Liver failure

The pharmacokinetics of tadalafil in patients with mild to moderate hepatic impairment (Child-Pugh class A and B) are comparable to those in healthy volunteers. There is insufficient data for patients with severe hepatic impairment (Child-Pugh class C). When prescribing DINAMICO LONG to patients with severe liver failure, it is necessary to first assess the risks and benefits of using the drug.

Patients with diabetes

In patients with diabetes mellitus, when using tadalafil, the AUC was approximately 19% lower compared to healthy volunteers. This difference does not require dose adjustment.

Special instructions

Sexual activity has a potential risk for patients with cardiovascular diseases, therefore treatment of erectile dysfunction, including with DYNAMICO LONG, should not be carried out in men with heart diseases for which sexual activity is not recommended.

There are reports of priapism with the use of PDE5 inhibitors, including tadalafil. Patients should be informed to seek immediate medical attention if they experience an erection lasting 4 hours or more. Untimely treatment of priapism leads to damage to the tissue of the penis, which may result in irreversible impotence.

The safety and effectiveness of the combination of tadalafil with other PDE5 inhibitors and treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended.

Like other PDE-5 inhibitors, tadalafil has systemic vasodilatory properties, which may lead to a transient decrease in blood pressure. Before prescribing DYNAMICO LONG, the physician should carefully consider whether patients with cardiovascular disease would be adversely affected by these vasodilatory effects.

NAPION causes visual impairment, including complete loss of vision. There are rare post-marketing reports of cases of the development of NAPION, temporally associated with the use of PDE-5 inhibitors. Analysis of data from episodic use of PDE5 inhibitors for 1 to 4 days in men with erectile dysfunction suggests an increased risk of developing acute NAION. The doctor should advise patients in case of sudden vision loss to stop taking tadalafil and seek medical help. Physicians should also advise patients that the risk of recurrence of NAPI is greater in patients who have previously had NAPI.

Patients suspected of having BPH should undergo testing to rule out prostate cancer.

The effectiveness of DYNAMICO LONG in patients who have undergone pelvic surgery or radical prostatectomy without preservation of the neurovascular bundles is unknown.

Impact on the ability to drive vehicles and machinery

Despite the fact that the incidence of dizziness with placebo and tadalafil is the same, during the treatment period it is necessary to be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Tadalafil

Composition

1 tablet contains:

active substance:

tadalafil 5.00 mg;

excipients:

lactose monohydrate (spray dried) 88.25 mgg,

sodium lauryl sulfate 0.75 mg,

povidone-K12 12.50 m,

crospovidone 12.50 mg,

sodium stearyl fumarate 1.00 mg;

film cover:

Contraindications

Hypersensitivity to tadalafil or to any substance included in the drug.
Taking medications containing any organic nitrates.
Age up to 18 years.
The presence of contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days, unstable angina or the occurrence of an attack of angina during sexual intercourse, chronic heart failure class II or higher according to the NYHA classification within the last 6 months, uncontrolled arrhythmias, arterial hypotension (BP less than 90/50 mm Hg), uncontrolled arterial hypertension, ischemic stroke within the last 6 months.
Loss of vision due to the development of non-arteritic anterior ischemic optic neuropathy (NAPION) (regardless of the connection with previous use of PDE-5 inhibitors).
Simultaneous use: with doxazosin; with other PDE-5 inhibitors; with other treatment options for erectile dysfunction; with guanylate cyclase stimulators such as riociguat.
Use in patients with severe renal failure (creatinine clearance less than 30 ml/min).
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

Since there is insufficient data in patients with severe hepatic impairment (Child-Pugh class C), caution should be exercised when prescribing DYNAMICO LONG to this group of patients.

Caution should be exercised when prescribing the drug to patients taking alpha1-blockers, as concomitant use may lead to symptomatic hypotension in some patients. In two clinical pharmacology studies in healthy volunteers taking tadalafil, no symptomatic hypotension was observed when administered concomitantly with tamsulosin, a selective alpha1A blocker (see section “Interactions with Other Drugs”).

The drug should be used with caution in patients with a predisposition to priapism (sickle cell anemia, multiple myeloma or leukemia) or in patients with anatomical deformation of the penis (angular curvature, cavernous fibrosis or Peyronie’s disease). Caution should also be exercised when taken simultaneously with inhibitors of the CYP3A4 isoenzyme (ritonavir, saquinavir, ketoconazole, itraconazole, clarithromycin, erythromycin, grapefruit juice), antihypertensive drugs, 5-alpha reductase inhibitors.

Diagnosis of erectile dysfunction should include identifying the potential underlying cause, appropriate medical examination, and determining treatment options.

Side Effects

The most common adverse events in patients with erectile dysfunction and BPH are: headache, dyspepsia, as well as back pain and myalgia.

Below are the side effects that were reported during clinical trials and during post-registration use of the drug. Reported side effects were usually mild or moderate and transient. In accordance with the WHO classification, all reactions are distributed according to organ systems and frequency of development: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100): rare (≥1/10000, <1/1000): very rare (<1/10000); frequency unknown (cannot be determined from available data).

Immune system disorders: uncommon – hypersensitivity reactions; rarely – angioedema2.

Nervous system disorders: often – headache; infrequently – dizziness; rarely – stroke1 (including acute hemorrhagic cerebrovascular accident), fainting, transient ischemic attacks1, migraine2, epileptic seizures2, transient amnesia.

Violations of the organ of vision: infrequently – blurred visual perception, pain in the eyeball; rarely – impaired visual fields, swelling of the eyelids, conjunctival hyperemia, NAPION2, occlusion of retinal vessels2.

Hearing disorders and labyrinthine disorders: infrequently – tinnitus;

rarely – sudden hearing loss.

Cardiac disorders1: uncommon – tachycardia, palpitations; rarely – myocardial infarction, ventricular arrhythmias2, unstable angina2.

Vascular disorders: often – “flushes” of blood to the face; infrequently – decreased blood pressure3, increased blood pressure.

Disorders of the respiratory system, chest and mediastinal organs: often – nasal congestion; infrequently – shortness of breath, nosebleeds.

Gastrointestinal tract disorders: often – dyspepsia; uncommon – abdominal pain, gastroesophageal reflux, diarrhea in patients over 65 years of age, vomiting, nausea.

Disorders of the skin and subcutaneous tissues: infrequently – skin rash; rarely – urticaria, Stevens-Johnson syndrome2, exfoliative dermatitis2, hyperhidrosis (excessive sweating).

Musculoskeletal and connective tissue disorders: often – back pain, myalgia, pain in the extremities.

Renal and urinary tract disorders: uncommon – hematuria.

Disorders of the genital organs and mammary gland: infrequently – prolonged erection; rarely – priapism, hematospermia, bleeding from the penis.

General disorders: uncommon – chest pain1, peripheral edema, fatigue; rarely – facial edema2, sudden cardiac death1,2.

1 Observed in patients with pre-existing cardiovascular risk factors.

However, it is not possible to determine with certainty whether these events are directly related to these risk factors, to tadalafil, to sexual arousal, or to a combination of these or other factors.

2 Adverse reactions identified during post-marketing use that were not observed during clinical placebo-controlled studies.

3 More frequently observed when tadalafil is used in patients already taking antihypertensive agents.

Interaction

Effect of other drugs on tadalafil

Tadalafil is mainly metabolized with the participation of the CYP3A4 isoenzyme. A selective inhibitor of the CYP3A4 isoenzyme, ketoconazole (at a dose of 400 mg per day) increases the AUC of tadalafil by 312% and Cmax of tadalafil by 22%, and ketoconazole (at a dose of 200 mg per day) increases AUC of tadalafil by 107% and Cmax of tadalafil by 15%.

Ritonavir (at a dose of 200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19 and 2D6 isoenzymes, increases the AUC of tadalafil by 124% without changing Cmax. Although specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, such as saquinavir, as well as CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice, may increase tadalafil plasma concentrations.

The role of transporters (eg, P-glycoprotein) in the distribution of tadalafil is unknown. The potential for drug interactions mediated by transporter inhibition exists.

A selective inducer of the CYP3A4 isoenzyme, rifampicin (at a dose of 600 mg per day), reduces the AUC value of tadalafil by 88% and the Cmax of tadalafil by 46%. It can be assumed that the simultaneous use of other inducers of the CYP3A4 isoenzyme (such as phenobarbital, phenytoin or carbamazepine) may also reduce the concentration of tadalafil in the blood plasma.

Concomitant use of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing the AUC value of tadalafil.

An increase in gastric pH as a result of taking the H2-histamine receptor blocker nizatidine did not affect the pharmacokinetics of tadalafil.

The safety and effectiveness of combining tadalafil with other treatments for erectile dysfunction or other PDE5 inhibitors has not been studied and the use of such combinations is not recommended.

Effect of tadalafil on other drugs

Tadalafil is known to enhance the hypotensive effect of nitrates. This occurs as a result of the additive effect of nitrates and tadalafil on the metabolism of nitric oxide II (NO) and cGMP, therefore the use of tadalafil while taking nitrates is contraindicated.

Tadalafil does not have a clinically significant effect on the clearance of drugs whose metabolism occurs with the participation of isoenzymes of the cytochrome P450 system.

Studies have confirmed that tadalafil does not inhibit or induce the isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1.

Tadalafil does not have a clinically significant effect on the AUC of S-warfarin or R-warfarin. Tadalafil does not affect the effect of warfarin on prothrombin time.

Tadalafil does not potentiate the increase in the duration of bleeding caused by taking acetylsalicylic acid.

Tadalafil has systemic vasodilatory properties and may enhance the effect of antihypertensive drugs aimed at lowering blood pressure. Additionally, patients taking multiple antihypertensive agents and whose hypertension was poorly controlled experienced a slightly greater reduction in blood pressure. In most patients, the decrease in blood pressure was not accompanied by symptoms of hypotension. Patients treated with antihypertensive drugs and taking tadalafil should be given appropriate clinical advice.

According to the results of two clinical studies, there was no significant reduction in blood pressure when healthy volunteers co-administered tadalafil and the selective alpha1A-blocker tamsulosin.

Concomitant use of tadalafil with doxazosin is contraindicated. When tadalafil was administered to healthy volunteers taking the alpha1-blocker doxazosin (4-8 mg per day), an increase in the hypotensive effect of doxazosin was observed. Some patients experienced symptoms associated with low blood pressure, including fainting.

In clinical studies, riociguat was shown to enhance the hypotensive effect of PDE5 inhibitors. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated.

Drug interaction studies have not been conducted with tadalafil and 5-alpha reductase inhibitors; caution should be exercised when taking them simultaneously.

Tadalafil causes an increase in the bioavailability of ethinyl estradiol when taken orally. A similar increase in bioavailability can be expected with oral terbutaline, but the clinical consequences have not been established.

Tadalafil did not affect the concentration of ethanol, nor did ethanol affect the concentration of tadalafil. At high doses of ethanol (0.7 g/kg), taking tadalafil did not cause a statistically significant decrease in mean blood pressure. Postural dizziness and orthostatic hypotension have been observed in some patients. When taking tadalafil in combination with lower doses of ethanol (0.6 g/kg), no decrease in blood pressure was observed, and dizziness occurred with the same frequency as when taking ethanol alone.

Tadalafil does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.

Overdose

When a single dose of tadalafil was administered to healthy volunteers up to 500 mg and to patients with erectile dysfunction – repeatedly up to 100 mg/day, the undesirable effects were the same as when using lower doses. In case of overdose, standard symptomatic treatment should be carried out. During hemodialysis, tadalafil is practically not excreted.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

2 years.

Manufacturer

Teva Pharma, S.L.U., Spain