Tadalafil-SZ, 5 mg 28 pcs

Pharmacodynamics

Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (FDE-5) cyclic guanosine monophosphate (cGMP). When sexual arousal causes local release of nitric oxide, inhibition of FDE-5 by tadalafil leads to increased concentration of cGMP in the cavernous body of the penis. The consequence of this is relaxation of arterial smooth muscles and blood flow 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 inhibitor of FDE-5. FDE-5 is an enzyme found in the smooth muscles of the cavernous body, in vascular smooth muscles of internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum.

The action of tadalafil on FDE-5 is more active than on other phosphodiesterases. Tadalafil is 10,000 times more potent against FDE-5 than against FDE-1, FDE-2, FDE-4 and FDE-7, which are localized in the heart, brain, blood vessels, liver, white blood cells, skeletal muscles and other organs.

Tadalafil is 10,000 times more active in blocking FDE-5 than FDE-3, an enzyme found in the heart and blood vessels. This selectivity for FDE-5 over FDE-3 is important because FDE-3 is an enzyme involved in heart muscle contraction. In addition, tadalafil is about 700 times more active against FDE-5 than against FDE-6, which is found in the retina and is responsible for phototransmission.

Tadalafil is also 9,000 times more potent against FDE-5 compared to its effect on FDE-8, FDE-9 and FDE-10, and 14 times more potent against FDE-5 compared to FDE-11. Distribution in tissues and physiological effects of FDE-8 to FDE-11 inhibition have not yet been elucidated. Tadalafil improves erection and increases the possibility of a full sexual intercourse.

Tadalafil in healthy subjects causes no significant change 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 causes no significant change in heart rate. Tadalafil does not cause changes in color recognition (blue/green), which is due to its low affinity for FDE-6. In addition, there is no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.

To evaluate the effect of daily tadalafil administration on spermatogenesis, several studies have been conducted. No undesirable effect on sperm morphology and motility was observed in any of the studies.

One study found a decrease in average sperm concentration compared to placebo. The decrease in sperm concentration was associated with a higher frequency of ejaculation. In addition, there was no undesirable effect on the average concentration of sex hormones, testosterone, luteinizing hormone and follicle stimulating hormone when taking tadalafil compared to placebo.

An improvement in erections in patients with erectile dysfunction of all degrees of severity when tadalafil is taken once daily has been observed.
Mechanism of action in patients with benign prostatic hyperplasia (BPH)

Inhibition of FDE-5 by tadalafil, resulting in increase of cGMP concentration in cavernous body of penis, is also observed in smooth muscles of prostate, bladder and blood vessels which supply them.

The relaxation of vascular smooth muscles leads to increased blood perfusion in these organs and, as a consequence, to a reduction in the severity of BPH symptoms. Relaxation of the smooth muscles of the prostate and bladder may additionally enhance vascular effects.

Pharmacokinetics

Intake

After oral administration, tadalafil is rapidly absorbed. The average maximum concentration (Stah) in plasma is reached on average 2 hours after oral administration.

The speed and degree of absorption of tadalafil are not dependent on food intake, so Tadalafil-SZ can be used regardless of food intake. The time of intake (morning or evening) has no effect on the speed and degree of absorption.

The pharmacokinetics of tadalafil in healthy subjects are linear with respect to time and dose. In the dose range of 2.5 to 20 mg, the area under the concentration-time curve (AUC) increases in proportion to the dose. Equilibrium plasma concentrations are reached within 5 days if the drug is taken once daily.

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

Distribution

The average volume of distribution is about 63 liters, indicating that tadalafil is distributed in body tissues. In therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not altered in impaired renal function.

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

Metabolism

Tadalafil is mainly metabolized with participation of cytochrome P450 isoenzyme CYP3A4. The main circulating metabolite is methylcatecholglucuronide. This metabolite is at least 13,000 times less active against FDE-5 than tadalafil. Consequently, the concentration of this metabolite is not clinically significant.

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 mainly as inactive metabolites, mainly through the intestine (about 61% of the dose) and, to a lesser extent, by the kidneys (about 36% of the dose).

Particular Patient Groups
Age > 65 years

Healthy volunteers aged 65 years and older had lower clearance of tadalafil when ingested, as evidenced by a 25% increase in the area under the “concentration-time” curve compared to healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.

Renal Impairment

. In patients with mild renal failure (creatinine clearance of 51 to 80 ml/min) and moderate renal failure (creatinine clearance of 31 to 50 ml/min), as well as in patients with end-stage renal failure on hemodialysis, tadalafil exposure (AUC) approximately doubled.

The AUC was 41% higher in patients on hemodialysis compared to healthy volunteers. Excretion of tadalafil by hemodialysis is insignificant.

Hepatic impairment

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 are insufficient data in patients with severe hepatic impairment (Child-Pugh class C). When prescribing Tadalafil-SZ in patients with severe hepatic impairment, a prior risk-benefit assessment should be performed.

Patients with Diabetes Mellitus

Patients with diabetes mellitus on tadalafil had approximately 19% less area under the concentration-time curve compared to healthy volunteers. This difference does not require a dose adjustment.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

dosage 5 mg:

the active ingredient:

tadalafil – 5 mg

excipients (core):

Lactose monohydrate (milk sugar) – 53.8 mg; lactose monohydrate (lactopress) (milk sugar) – 64.0 mg; microcrystalline cellulose – 26.0 mg; croscarmellose sodium (primellose) – 12.5 mg; Crosspovidone (Collidon CL-M) – 4.0 mg; Crosspovidone (Collidon CL) – 3.0 mg; Extra Fine Hyprolose (Hydroxypropylcellulose) – 3.0 mg; Hyprolose (hydroxypropylcellulose) – 2.0 mg; sodium stearyl fumarate – 1.5 mg; sodium lauryl sulfate – 0.2 mg;

Auxiliary substances (coating):

Opadray II 85F22048 yellow, 5 mg (polyvinyl alcohol, partially hydrolyzed, 2.0 mg; titanium dioxide E 171, 1.0935 mg; macrogol (polyethylene glycol 3350), 1.01 mg; talc, 0.74 mg; quinoline yellow dye-based aluminum varnish, 0.1505 mg; sunset aluminum varnish yellow – 0.0035 mg; iron oxide (I) yellow E 172 – 0.0015 mg; indigo carmine aluminum varnish – 0.0010 mg);

How to take, the dosage

Interaction

The effect of other drugs on tadalafil

Tadalafil is mainly metabolized with participation of the CYP3A4 isoenzyme. The selective CYP3A4 isoenzyme inhibitor ketoconazole (400 mg per day) increases tadalafil single dose exposure (AUC) by 312% and Stah values by 22%, and ketoconazole (200 mg per day) increases tadalafil single dose exposure (AUC) by 107% and Stah values by 15% relative to AUC and Stah values for tadalafil alone.

Ritonavir (200 mg twice daily), an inhibitor of the CYP3A4, 2C9, 2C19, and 2D6 isoenzymes, increases single-dose tadalafil exposure (AUC) by 124% with no change in Stache.

While specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, such as saquinavir, as well as CYP3A4 isoenzyme inhibitors such as erythromycin, clarithromycin, and itraconazole and grapefruit juice, may increase tadalafil plasma concentrations. The role of transporters (e.g., P-glycoprotein) in the distribution of tadalafil is unknown.

There is a possibility of a drug interaction mediated by inhibition of transporters. The selective CYP3A4 isoenzyme inducer, rifampicin (at a dose of 600 mg daily), reduces single-dose tadalafil exposure (AUC) by 88% and Stach by 46%, relative to the AUC and Stach values for tadalafil alone.

The concomitant use of other CYP3A4 isoenzyme inducers (such as phenobarbital, phenytoin or carbamazepine) may also be expected to reduce plasma concentrations of tadalafil.

Concomitant administration of antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing the AUC for tadalafil.

The increase in gastric pH due to ingestion of the H2-histamine receptor blocker nizatidine had no effect on the pharmacokinetics of tadalafil.

The safety and efficacy of combining tadalafil with other erectile dysfunction treatments or other FDE-5 inhibitors have not been studied, so such combinations are not recommended.

The effect of tadalafil on other drugs

Tadalafil is known to increase the hypotensive effect of nitrates. This is due to the additive effect of nitrates and tadalafil on nitric oxide II (N0) and cGMP metabolism. Therefore, the use of tadalafil with nitrates is contraindicated.

Tadalafil has no clinically significant effect on the clearance of drugs whose metabolism involves cytochrome P450. Studies have confirmed that tadalafil neither inhibits nor induces CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1 isoenzymes. Tadalafil has no 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 an increase in the duration of bleeding caused by taking acetylsalicylic acid.

Tadalafil has systemic vasodilator properties and may increase the effect of hypotensive drugs to reduce blood pressure. Additionally, a slightly greater reduction in blood pressure was observed in patients taking multiple hypotensive drugs in whom blood pressure was poorly controlled.

In the vast majority of patients, this decrease was not associated with hypotensive symptoms. Patients treated with hypotensive medications and taking tadalafil should be given appropriate clinical advice. No significant reduction in blood pressure was observed with concomitant use of tadalafil and the selective alpha1A-adrenoblocker tamsulosin in healthy volunteers.

The concomitant use of tadalafil with doxazosin is contraindicated. When tadalafil was used by healthy volunteers who were taking doxazosin (4-8 mg per day), alpha]-adrenoblocker, an increase in the hypotensive effect of doxazosin was observed. Some patients experienced symptoms associated with decreased blood pressure, including fainting.

The concomitant use of riociguat with FDE-5 inhibitors, including tadalafil, is contraindicated because riociguat increases the hypotensive effect of FDE-5 inhibitors.
No studies of drug interaction between tadalafil and 5-alpha reductase inhibitors have been conducted, caution should be exercised when taking them concomitantly.

Tadalafil causes an increase in bioavailability of ethinylestradiol when taken orally.
A similar increase in bioavailability can be expected with terbutaline, but no clinical effects have been established.

Tadalafil had no effect on alcohol concentration, nor did alcohol affect tadalafil concentration. At high doses of alcohol (0.7 g/kg), tadalafil administration did not cause a statistically significant decrease in mean blood pressure. Postural dizziness and orthostatic hypotension were observed in some patients.

When tadalafil was taken in combination with lower doses of alcohol (0.6 g/kg), no decrease in blood pressure was observed, and dizziness occurred with the same frequency as when alcohol alone was taken.

Tadalafil has no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.

Special Instructions

Sexual activity has potential risks for patients with cardiovascular disease. Therefore, treatment of erectile dysfunction, including with Tadalafil-SZ, should not be performed in men with heart disease in which sexual activity is not recommended.

There have been reports of the occurrence of priapism when using FDE-5 inhibitors, including tadalafil. Patients should be informed to seek immediate medical attention if an erection lasts 4 hours or more. Failure to treat priapism in a timely manner leads to penile tissue damage, which may result in irreversible impotence.

The safety and efficacy of combination of Tadalafil-SZ with other FDE-5 inhibitors and treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. Like other FDE-5 inhibitors, tadalafil has systemic vasodilator properties, which may lead to a transient decrease in blood pressure.

Before prescribing tadalafil-SZ, physicians should carefully consider whether patients with cardiovascular disease would be adversely affected by such vasodilatory effects. Nonarterial anterior ischemic optical neuropathy (NAPION) causes visual impairment, including total vision loss.

There have been rare post-marketing reports of cases of NAPION development temporally associated with the intake of FDE-5 inhibitors. At

it is not currently possible to determine whether there is a direct link between the development of NAPION and the intake of FDE-5 inhibitors or other factors. Physicians should advise patients to discontinue tadalafil and seek medical attention in the event of sudden vision loss.

Doctors should also inform patients that people who have had NAPION have an increased risk of developing NAPION again. Patients with a suspected diagnosis of BPH should be screened to rule out prostate cancer.

The efficacy of Tadalafil-SZ in patients who have undergone pelvic surgery or radical neurosurgical prostatectomy is unknown.

When treating with Tadalafil-SZ, caution should be exercised when driving motor vehicle and engaging in other potentially dangerous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

Side effects

The most frequent adverse events in patients with erectile dysfunction and BPH are headache and dyspepsia, as well as back pain and myalgia.
According to the WHO classification, all reactions are categorized according to organ system and frequency of development: Very common (> 1/10); common (> 1/100, < 1/10); infrequent (> 1/1000, < 1/100); rare (> 1U0000, < 11000); very rare (< 1/10000), frequency unknown (the frequency of reactions cannot be determined from available data).

Disorders of the immune system:

Infrequent: hypersensitivity reactions. Rare: angioedema. Nervous system disorders:

Often: headache.
Infrequent: dizziness.
Rare: stroke’ (including hemorrhagic acute cerebral circulation disorder (ACAD)), syncope, transient ischemic attacks, migraine, epileptic seizures, transient amnesia.

Visual organ disorders:
Infrequent: blurred vision, pain in the eyeball.
Rarely: visual field disorders, eyelid swelling, conjunctival hyperemia, nonarterial anterior ischemic optical neuropathy, retinal vascular occlusion.

Hearing and labyrinth disorders:

Infrequent: tinnitus.
Rarely: sudden hearing loss.

Heart disorders:
Infrequent: palpitations, tachycardia.
Rare: myocardial infarction, ventricular rhythm disturbances, unstable angina pectoris.

Vascular disorders: Often: “flushes” of blood to the face.

Infrequent: decreased blood pressure, increased blood pressure.
Respiratory system disorders, thoracic and mediastinal organs:

Often: nasal congestion.
Infrequent: shortness of breath, nasal bleeding.
Gastrointestinal disorders:

Often: dyspepsia.
Infrequent: abdominal pain, gastroesophageal reflux, diarrhea in patients older than 65 years, vomiting, nausea.

Skin and subcutaneous tissue disorders:
Infrequent: rash.
Rare: urticaria, Stevens-Johnson syndrome, exfoliative dermatitis, hyperhidrosis (increased sweating).

Musculoskeletal and connective tissue disorders:

Often: back pain, myalgia, pain in the extremities. Renal and urinary tract disorders: Infrequent: hematuria.

Gender and mammary gland disorders: Infrequent: prolonged erection.
Rarely: priapism , hematospermia, bleeding from the penis.

General disorders:
Infrequent: chest pain, peripheral edema, fatigue. Rarely: facial edema, sudden cardiac death.

‘Observed in patients with previous cardiovascular risk factors. However, it is not possible to definitively determine whether these phenomena are directly related to these risk factors, to tadalafil, to sexual arousal, or to a combination of these or other factors.

The adverse reactions seen with post-marketing use not observed in clinical placebo-controlled studies.

Prevalently observed when tadalafil was used in patients already taking hypotensive medications.

Overdose

When tadalafil was administered to healthy volunteers in a single dose up to 500 mg and to patients with erectile dysfunction in multiple doses up to 100 mg/day, the adverse effects were the same as when lower doses were used.

Treatment: in case of overdose, standard symptomatic treatment should be administered. In hemodialysis tadalafil is practically not excreted.

Pregnancy use

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