ZYDENA Tablet Ref.[51199] Active ingredients: Udenafil

A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment. Physicians should consider the cardiovascular status of their patients, since there is a potential for cardiac risk associated with sexual activity. Treatments for erectile dysfunction, including ZYDENA, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

Physicians should advise patients to stop use of all PDE5 inhibitors, including ZYDENA, and seek immediate medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, which has been rarely reported in post-marketing surveillance (PMS) of PDE5 inhibitors, except ZYDENA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors (see Contraindications).

Physicians should advise patients to stop use of all PDE5 inhibitors, including ZYDENA, and seek medical attention in the event of a sudden hearing loss or deafness, which may be accompanied by tinnitus and dizziness, in one or both ears. ZYDENA has been shown to have systemic vasodilatory properties that result in transient decreases in blood pressure. This is of little or no consequence in most patients. However, prior to prescribing udenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.

Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukemia).

As ZYDENA is neither an aphrodisiac drug nor a sexual stimulant, it should be used only for the treatment of erectile dysfunction. ZYDENA has not been studied for the patients with spinal cord injury, adical prostatectomy, hyposexual desire, anticancer medication, and anticoagulant medication.

1) Effects of other drugs on the plasma concentration of ZYDENA:

• In vitro studies; Udenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4. Therefore, inhibitors of these enzymes are expected to increase the plasma concentration of udenafil. In human, ketoconazole, itraconazole, ritonavir, indinavir, cimetidine, erythromycin, and grapefruit juice are representative CYP450 3A4 inhibitors.
• In vivo studies; Ketoconazole (400 mg) induced 212% and 85% increase in AUC and C_max of udenafil, respectively, when coadministered with ZYDENA (100 mg) to healthy volunteers.
• Even though the interaction studies have not been studied, the coadministration with other CYP450 3A4 inhibitors such as itraconazole, cimetidine, erythromycin, and grapefruit juice are expected to increase plasma concentration of udenafil, therefore careful consideration is needed.
• The coadministration with HIV protease inhibitors ritonavir or indinavir, potent CYP450 3A4 inhibitors, results in a significant increase in plasma udenafil concentration. Therefore, the coadministration is not recommended.
• Moreover, CYP450 3A4 inducers such as dexamethasone, rafampin, and anticonvulsants (carbamazepine, phenytoin, and phenobarbital) can accelerate udenafil metabolism. Therefore the co-administration affects to decrease plasma concentration of udenafil.
• The coadministration of udenafil (200 mg) with alcohol (0.6 g/kg, mean maximum blood alcohol levels of 0.088%) did not potentiate the effect of alcohol on blood pressure and heart rate. The pharmacokinetics of udenafil was not affected by alcohol. However, physicians should inform patients of the possible symptoms, such as increased heart rate, decreased blood pressure, dizziness, myalgia, and orthostatic syndrome, as both udenafil and alcohol have mild vasodilatory properties.

2) When udenafil (30 mg/kg, p.o.) was coadministered with nitroglycerine (2.5 mg/kg, i.v.) to rats, the pharmacokinetics of udenafil was not affected. However, due to the blood-pressure-lowering effect of nitroglycerine, the concomitant use is not recommended.

3) When amlodipine besylate (5 mg/kg, 3 days, p.o.) was administered to rats, the blood pressure was significantly lowered. Therefore, the concomitant use with udenafil requires careful consideration.

4) When ZYDENA (200 mg) was given simultaneously with 0.4 mg of tamsulosin to healthy volunteers, the mean standing systolic blood pressure was decreased by 4 mmHg (maximum). Although 4 out of 28 subjects temporarily experienced a standing systolic blood pressure of lower than 85 mmHg, no subjects showed symptomatic hypotension. ZYDENA and alphablockers have not been evaluated to determine whether they can be safely administered together. However, as these two classes of drugs both act as vasodilators with blood-pressure-lowering effects, patients must be warned.

In some patients, concomitant use of alpha-blockers and PDE5 inhibitors including ZYDENA, may lead to symptomatic hypotension so, coadministration should be initiated at the lowest dose only when the patients are stable on either alphablockers or PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by variables including hypovolemia and other anti-hypertensive drugs.

5) When ZYDENA (30 mg/kg) was administered to rats after a week administration of omeprazole (30 mg/kg), C_max and AUC of udenafil were increased by approximately 30% and 37%, respectively.

6) Effects of ZYDENA on other drugs: Udenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC₅₀ >200 μM, except IC₅₀ = 67.7 for 2D6). Given udenafil peak plasma concentrations of approximately 2.2 μM after recommended doses, it is unlikely that ZYDENA will alter the clearance of substrates of these isozymes.

ZYDENA is not indicated for use in newborns, children, or women.

In the embryo fetal development study performed in rats and rabbits, only high doses of udenafil (300 mg/kg/day and 240 mg/kg/day) showed skeletal variations and ossific retardations in fetuses. In the study for the effects of udenafil on preand postnatal development, including maternal function, carried out in rats by oral administration, stillbirth or ateliosis of offsprings were noted at the dose of 300 mg/kg/day.

As adverse effects such as dizziness, blurred vision were reported in clinical trials, patients should be careful when driving and operating machinery.

ZYDENA was administered to 923 patients during Korean nationwide clinical trials. In general, most adverse events were temporal and its severity was mild to moderate. The most common adverse events were flushing and headache.

The following adverse events were reported in clinical trials:

In additional clinical studies, drug related adverse events unconfirmed before marketing are head discomfort, feeling cold, feeling dim, palpitation, postural dizziness, somnosis, ear daze, eye discomfort, rash, erythema, diarrhea, dyspnea, respiratory distress in exercise, cough, nasal hemorrhage, increase erection, and hypotension.

In clinical trials of single doses up to 200 mg per day, the types of adverse events and incidence rates were significantly increased from those seen at 100 mg dose level.

Not reported in the clinical studies, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely in post-marketing surveillance (PMS) studies of PDE5 inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

A sudden hearing loss or deafness in one or both ears, which might be in temporal association with the use of PDE5 inhibitors, has been rarely reported in post-marketing surveillance (PMS). Even though, it is reported that the disease status and other factors will be related to adverse events about hearing in a few cases, medical tracing data which can be aware of that relationship are not confirmed in major cases. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying deafness risk factors, to a combination of these factors, or to other factors.