BP Apollo 50,100 ml

Summary of product characteristics
1. NAME OF THE MEDICINAL PRODUCT

APOLLO 50 mg tablets
APOLLO 100 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
APOLLO 50 mg tablets
Each tablet contains sildenafil citrate, equivalent to 50 mg sildenafil. Excipient with known effect: Each tablet contains 61 mg of lactose (as monohydrate).

APOLLO 100 mg tablets
Each tablet contains sildenafil citrate, equivalent to 100 mg sildenafil. Excipient with known effect: Each tablet contains 122 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Tablets.
APOLLO 50 mg tablets
Blue square tablets with flat surface and rounded margins with a dividing line and “BP” inlay on one side. Marble is allowed on the surface of the tablets.
APOLLO 100 mg tablets
Round, biconvex blue tablets with “BP” in one side. Marble is allowed on the surface of the tablets.

4. CLINICAL DATA
4.1. Therapeutic indications
APOLLO is indicated for adult men with erectile dysfunction who are unable to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.
For APOLLO to be effective, sexual stimulation is required.

4.2. Posology and mode of administration
Dosage
Administration to adults
The recommended dose is 50 mg sildenafil administered approximately one hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg sildenafil, or may be lowered to 25 mg sildenafil. The maximum recommended dose is 100 mg sildenafil. The maximum recommended intake frequency is once a day. If APOLLO is taken during the meal, the effect is slower than when given as fast-food (see section 5.2).

Special patient groups
Elderly patients
No dose adjustment is required in elderly patients (≥ 65 years of age).
Patients with renal impairment
In patients with mild to moderate renal impairment (creatinine clearance = 30-80 ml / min), the same doses as those listed in the section “Adult Administration” are recommended.
Since clearance of sildenafil is low in patients with severe renal impairment (creatinine clearance <30 ml / min), a 25 mg dose should be considered. Depending on efficacy and tolerability, the dose may be increased gradually to 50 mg or 100 mg, if necessary.
Patients with hepatic impairment
Because sildenafil clearance is low in patients with hepatic impairment (for example cirrhosis), an initial dose of 25 mg sildenafil should be considered. Depending on efficacy and tolerability, the dose may be increased gradually to 50 mg sildenafil and up to 100 mg sildenafil, if necessary.

Children and adolescents
APOLLO is not indicated in people under the age of 18 years.
Administration to patients treated with other medicines
With the exception of ritonavir, in which concomitant use of sildenafil is not recommended (see section 4.4), an initial dose of 25 mg sildenafil should be considered in patients using concomitant CYP3A4 inhibitors (see section 4.5).
To minimize the possibility of postural hypotension in patients treated with alpha-blockers, patients should be hemodinamically stabilized under alpha-blocker therapy before starting sildenafil treatment. In addition, initiation of treatment with sildenafil at a dose of 25 mg should be considered (see sections 4.4 and 4.5).
Administration method
For oral use

4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Consistent with the known effects of sildenafil on nitric oxide / cyclic guanosine monophosphate (GMPc) (see section 5.1), it has been shown to potentiate the hypotensive effects of nitrates and therefore concomitant administration of sildenafil with nitric oxide donors ( such as amyl nitrite) or any form of nitrate.
Medicines for the treatment of erectile dysfunction, including sildenafil, should not be administered to men in whom sexual activity is not indicated (for example patients with severe cardiovascular disorders such as unstable angina or severe heart failure).
APOLLO is contraindicated in patients with ocular blindness due to non-arterial ischemic anterior neuropathy (NOAIN), whether or not this episode correlated with previous exposure to PDE5 inhibitors (see section 4.4).
The safety of sildenafil has not been studied in the following subgroups of patients and therefore its use is contraindicated in these cases: severe hepatic impairment, hypotension (blood pressure <90/50 mmHg), recent history of stroke or myocardial infarction, known retinal degenerative hereditary diseases such as pigmentary retinas (a small proportion of these patients present genetic disorders of retinal phosphodiesterases).

4.4 Special warnings and precautions for use
Before recommending a pharmacological treatment for erectile dysfunction, personal history and physical examination should be assessed to diagnose erectile dysfunction and establish potential preexisting etiologies.
Cardiovascular risk factors
Before initiating any treatment for erectile dysfunction, physicians should assess the cardiovascular status of patients as there is a degree of cardiac risk associated with sexual activity. Sildenafil has vasodilating properties, resulting in a mild and transient decrease in blood pressure (see section 5.1). Before prescribing sildenafil, physicians should carefully investigate how patients with certain pre-existing conditions may be affected by these vasodilatory effects, especially in association with sexual activity. In the category of patients with increased susceptibility to vasodilatory medicinal products, patients with left ventricular ejection pathway obstruction (for example aortic stenosis, obstructive hypertrophic cardiomyopathy) or those with rare systemic multiple atrophy manifested by severe impairment of autonomic tension control pressure.
APOLLO potentiates the hypotensive effect of nitrates (see section 4.3).
Serious cardiovascular events, including myocardial infarction, unstable angina, sudden death of cardiac etiology, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischemic stroke, hypertension, post-marketing experience with sildenafil have been reported in temporal association with sildenafil and hypotension.

Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events have been reported to occur during or shortly after sexual intercourse, some of which have been reported to occur shortly after sildenafil administration and without sexual intercourse. It is impossible to determine whether these events are directly related to these factors or whether they are determined by other factors.
Priapism
Medicines indicated for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical penile deformities (such as angulation, cavernosal fibrosis or Peyronie’s disease) or those with pruritus predisposing conditions (such as sickle cell disease, multiple myeloma or leukemia).
In the post-marketing experience of sildenafil, prolonged erections and priapism have been reported. If an erection persists for more than 4 hours, the patient should seek urgent medical attention. If priapism is not treated immediately, there is a risk of penile tissue damage and permanent impotence.
Concomitant use with other PDE5 inhibitors, or other treatments for erectile dysfunction.
The safety and efficacy of association of sildenafil with other PDE5 inhibitors, with other treatments for pulmonary arterial hypertension (PAH) including sildenafil (REVATIO), or with other treatments for erectile dysfunction, have not been studied. Therefore, the use of such associations is not recommended.
Effects on vision
Spontaneous cases of visual disturbances have been reported in association with the administration of sildenafil and other PDE5 inhibitors (see section 4.8). Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition associated with the use of sildenafil and other PDE5 inhibitors (see section 4.8), have been reported both spontaneously and in an observational study. Patients should be advised that in case of sudden appearance of a visual disturbance, they should stop taking APOLLO and contact the doctor immediately (see section 4.3).
Co-administration with ritonavir
Co-administration of sildenafil with ritonavir is not recommended (see section 4.5).
Concomitant use with alpha-blockers
Caution is advised when administering sildenafil to patients treated with alpha-adrenergic blockers, because in some patients susceptible to concomitant administration, symptomatic hypotension may occur (see section 4.5). This is most likely to occur within the first 4 hours after the sildenafil dose. To minimize the possibility of postural hypotension, patients should be hemodinamically stabilized under alpha-blocker therapy before initiating sildenafil treatment. Consideration should be given to initiating treatment with sildenafil at a dose of 25 mg (see section 4.2). In addition, physicians should advise patients on the symptoms of postural hypotension.
Effects on bleeding
Studies in human platelets have shown that in vitro sildenafil potentiates the anti-aggregating effect of sodium nitroprusside. There is no information on the safety of sildenafil in patients with bleeding disorder or active gastro-duodenal ulcer. Therefore, sildenafil should only be administered to these patients after careful consideration of the therapeutic benefit / potential risk ratio.
APOLLO contains lactose monohydrate. APOLLO should not be used in men with rare hereditary problems of galactose intolerance, Lapp lactase deficiency (Lapp), or glucose-galactose malabsorption syndrome.
Ladies
APOLLO is not indicated for use in women.

4.5 Interaction with other medicinal products and other forms of interaction
The effects of other medicines on sildenafil:
In vitro studies:
Metabolism of sildenafil is mainly mediated by cytochrome P450 (CYP) via the 3A4 (main pathway) and 2C9 (secondary pathway) isoenzymes. Therefore, inhibitors of these isoenzymes may reduce clearance of sildenafil, and their inducers may increase clearance of sildenafil.
In vivo studies:
Population pharmacokinetic data from clinical trials have shown a reduction in clearance of sildenafil when administered concomitantly with CYP3A4 isozyme inhibitors (such as ketoconazole, erythromycin, cimetidine). Although there has been no increase in the incidence of adverse events in these patients, concomitant administration of CYP3A4 isoenzyme inhibitors should take into account the use of an initial dose of sildenafil 25 mg.
At steady state, concomitant administration of ritonavir (500 mg twice daily), an HIV protease inhibitor, which is also a potent cytochrome P450 inhibitor, with sildenafil (single dose of 100 mg), increased the Cmax of sildenafil by 300% (4-fold) and the 1000-fold (11-fold) increase in sildenafil AUC (area under the time-concentration curve). At 24 hours, sildenafil plasma concentration was still approximately 200 ng / ml compared to the 5 ng / ml observed if sildenafil was given as monotherapy. This finding is in line with the marked effects of ritonavir on a wide spectrum of cytochrome P450 substrates. Sildenafil did not influence the pharmacokinetics of ritonavir. Based on these pharmacokinetic data, concomitant administration of sildenafil and ritonavir is not recommended (see section 4.4) and that in no case should the maximum dose of sildenafil exceed 25 mg within 48 hours.
At steady state, concomitant administration of saquinavir (1200 mg three times daily), another HIV protease inhibitor and CYP3A4 isoenzyme, with sildenafil (single dose of 100 mg) resulted in a 140% increase Cmax of sildenafil and 210% of sildenafil AUC. Sildenafil did not influence the pharmacokinetics of saquinavir (see section 4.2). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole may be more important.
At steady state, when sildenafil was given at the single dose of 100 mg concomitantly with erythromycin (500 mg twice daily for 5 days), a moderate CYP3A4 inhibitor, there was an increase of 182 % of systemic exposure to sildenafil (AUC). In healthy male volunteers, there was no effect of azithromycin (at the 500 mg daily dose for 3 days) on AUC, Cmax, Tmax, the elimination rate constant, or the consecutive half-life of sildenafil or the major metabolites circulating. In healthy volunteers, cimetidine (800 mg), a cytochrome P450 inhibitor and a non-specific CYP3A4 inhibitor when co-administered with sildenafil (50 mg) resulted in a 56% increase in sildenafil plasma concentration.
Grapefruit juice is a weak inhibitor of CYP3A4 involved in intestinal wall metabolism and may lead to a low increase in plasma sildenafil concentration.
Single doses of antacids (magnesium hydroxide / aluminum hydroxide) did not influence the bioavailability of sildenafil.
Although specific drug interaction studies have not been conducted, population pharmacokinetic studies have demonstrated that the pharmacokinetics of sildenafil have not been influenced by concomitant administration of CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as inhibitors selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and related diuretics, diuretics or potassium-sparing diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, beta-adrenergic receptor antagonists or CYP450 metaboliser induction are rifampicin, barbiturates).
In a study in healthy male volunteers, concomitant administration of sildenafil with endothelin antagonist, bosentan (CYP3A4 [moderate], CYP2C9 and possibly CYP2C19 inducer) after steady state dosing for bosentan (125 mg twice per day) and for sildenafil (80 mg 3 times daily) resulted in a decrease of 62.6% and 55.4% of AUC and C max, respectively, of sildenafil. Concomitant administration of potent CYP3A4 inducers, such as rifampicin, is expected to result in higher decreases in sildenafil plasma concentrations.
Nicorandil is a hybrid between a potassium channel and nitrate channel activator. Due to the presence of nitrate in the composition, strong interaction with sildenafil is possible.
The effects of sildenafil on other medicines
In vitro studies:
Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50> 150 μM). Taking into account maximum sildenafil plasma concentrations of approximately 1 μM achieved after the recommended dose, APOLLO is unlikely to alter the clearance of the substrates of these isoenzymes.
There are no data on drug interactions between sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.
In vivo studies:
Consistent with the known effects of sildenafil on nitric oxide / cyclic guanosine monophosphate (GMPc) (see section 5.1), it has been shown to potentiate the hypotensive effects of nitrates and therefore concomitant administration of sildenafil with nitric oxide donors or with any form of nitrate (see section 4.3).
Concomitant administration of sildenafil to patients treated with alpha-adrenergic blocking agents may cause symptomatic hypotension in some patients. This is more likely occur within the first 4 hours after the sildenafil dose (see sections 4.2 and 4.4). In 3 specific drug interaction studies, alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg or 100 mg) were co-administered to benign prostatic hyperplasia (HBP) patients undergoing hemodynamic therapy doxazosin.
In these groups of patients included in the study, additional mean blood pressure reductions of 7/7 mmHg, 9/5 mmHg and 8/4 mmHg, respectively, as well as mean additional reductions in blood pressure in 6/6 orthostatism mmHg, 11/4 mmHg and 4/5 mmHg, respectively. Concomitant administration of sildenafil and doxazosin to haemodynamically stabilized patients through doxazosin treatment has occasionally been reported with symptomatic hypotension. These reports included dizziness and confusion, but not syncope.
No significant interaction was observed when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both being metabolised via CYP2C9. Sildenafil (50 mg) did not potentiate the action of acetylsalicylic acid (150 mg) to increase bleeding time.
Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with a maximum alcoholic strength of 80 mg / dl.
It has been shown that there is no difference in the profile of adverse reactions when administering sildenafil to patients treated with an antihypertensive drug of one of the following classes – diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive agents with vasodilating action peripheral or central, calcium channel blockers and alpha-adrenergic receptors, compared to patients which administrates placebo. In a specific interaction study involving hypertensive amlodipine-treated patients co-administered with sildenafil (100 mg), an additional reduction in systolic blood pressure at 8 mmHg was observed. The additional decrease in diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were similar to those observed with sildenafil alone in healthy volunteers (see section 5.1).
At steady state, sildenafil (100 mg) did not influence the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, both active substances being substrates of CYP3A4. In healthy male volunteers at steady state (80 mg three times a day), sildenafil administration resulted in a 49.8% increase in bosentan AUC and a 42% increase in bosentan Cmax (125 mg twice a day).
4.6 Fertility, pregnancy and lactation
APOLLO is not indicated for use in women. No adequate and well-controlled studies have been performed in pregnant or lactating women. In reproductive toxicity studies in rats and rabbits, no significant adverse reactions were seen following oral administration of sildenafil. Administration of a single oral dose of 100 mg sildenafil to healthy volunteers had no effect on sperm motility or morphology (see section 5.1).
4.7 Effects on ability to drive or use machines
No studies have been conducted on the effects of sildenafil on the ability to drive or use machines.
Because dizziness and visual disturbances have been reported in clinical trials with sildenafil, patients should be alert to the reactions that may occur following administration of APOLLO before driving or operating machinery.

4.8 Side effects
Summary of the safety profile
The safety profile of sildenafil is established based on data from 9570 patients in 74 double-blind, placebo-controlled studies. The most commonly reported adverse reactions in sildenafil-experienced clinical trials were headache, facial hyperemia, dyspepsia, nasal congestion, dizziness, nausea, hot flashes, visual disturbances, cyanopsia, and vision in the fog.
Adverse reactions from post-marketing experience were obtained over a period of> 10 years. Because not all of the side effects are reported, the frequency of these reactions can’t be accurately determined.

Tabular list of adverse reactions In the table below
All major adverse reactions that occurred in clinical trials with a higher incidence than placebo are presented by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 and <1/10), uncommon (≥ 1/1000 and <1/100), rare (≥ 1/10000 and <1/1000), not known (can’t be estimated from baseline). In addition, the frequency of adverse reactions of medical significance reported in post-marketing experience is included as unknown.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse drug-related adverse reactions reported in clinical trials with a higher incidence than placebo and adverse medical effects reported in post-marketing experience:

* Reported only during post-marketing surveillance;
** Disturbances of color perception: Chlorophobia, Chromatopsia, Cyanopsia, Erythropsy, Xantopsia;
*** Disorders of the tear: Dry eye, Lacrimation disorders, Hypercription.

Report suspected adverse reactions
Reporting of suspected adverse drug reactions after authorization of the drug is important. This allows further monitoring of the benefit / risk ratio of the drug. Health professionals are asked to report any suspected adverse reactions.

4.9 Overdose
In studies in healthy volunteers with single doses up to 800 mg sildenafil, adverse reactions were similar to those seen at lower doses but their incidence and severity were increased. Administration of 200 mg sildenafil did not increase efficacy, but the incidence of side effects (headache, facial hyperaemia, dizziness, dyspepsia, nasal congestion, visual disturbances) was increased.
In the event of overdose, standard measures to support vital functions should be adopted, as appropriate. Since sildenafil is highly protein bound and not eliminated in urine, renal dialysis is not expected to increase clearance of sildenafil.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for the treatment of erectile dysfunction.
Mechanism of action
Sildenafil is an orally administered drug for the treatment of erectile dysfunction. Under natural conditions, that is, in the presence of sexual stimulation, sildenafil restores affected erectile function by increasing blood flow to the penis.
The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) in the cavernous body during sexual stimulation. Nitric oxide activates the guanylate-cyclase enzyme, which increases the levels of cyclic guanosine monophosphate (GMPc), producing relaxation of the smooth muscles of the cavernous body and thus favoring blood flow.
Sildenafil is a potent and selective PDE5-specific GMPc phosphodiesterase (PDE5), which is responsible for the degradation of GMPc in the cavernous body. Sildenafil influences erection through its peripheral action. Sildenafil does not have a direct relaxing effect on the isolated human tissue from the cavernous body but strongly increases the NO’s relaxing effect on this tissue. When activating the NO / GMPc pathway by sexual stimulation, inhibition of PDE5 by sildenafil induces increased GMPc concentrations in the cavernous body. Therefore, sexual stimulation is required for sildenafil to produce its desired pharmacological effect.

Pharmacodynamic effects
In vitro studies have shown that sildenafil has selectivity for PDE5, which is involved in the erection process. Its effect is stronger on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity for PDE5 than for PDE6 involved in retinal phototransduction. At the maximum recommended doses, selectivity is greater than 80 times the selectivity for PDE1 and over 700 times the selectivity for PDE2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has a selectivity of 4000 fold greater for PDE5 than for PDE3, which is the isoform of phosphodiesterase specific for AMPc involved in regulating cardiac contractility.

Clinical efficacy and safety
Two clinical trials have been specifically designed to evaluate the time interval between sildenafil dosing and the occurrence of erection in response to sexual stimulation. In the study in which sildenafil was given under fasting conditions, penile plethysmography (RigiScan) showed that the average time to achieve an erection with 60% stiffness (sufficient for sexual intercourse) was 25 minutes (with an interval of 12 – 37 minutes). In a separate study using RigiScan, it was observed that an erection was obtained 4-5 hours after sildenafil administration in response to sexual stimulation. Sildenafil produces mild and transient decreases in blood pressure, which in most cases do not produce clinical effects. After an oral 100 mg dose of sildenafil, the mean maximum reduction in systolic blood pressure at baseline was 8.4 mmHg. The corresponding reduction in diastolic blood pressure was 5.5 mmHg. These blood pressure reductions are consistent with the vasodilator effects of sildenafil, probably due to increased concentrations of GMPc in the vascular smooth muscle.
In healthy volunteers, single oral doses of sildenafil up to 100 mg did not cause any significant effect on the ECG.
In a study of the hemodynamic effects of oral administration of a single 100 mg sildenafil dose in 14 patients with severe coronary disease (stenosis> 70% on at least one artery coronary artery disease), mean values of systolic and diastolic blood pressure at baseline decreased by 7% and 6% relative to baseline. Systolic mean pulmonary blood pressure decreased by 9%. It has been shown that sildenafil does not influence cardiac output or blood flow in stenotic coronary arteries.
In a double-blind, placebo-controlled trial of exercise tolerance, 144 patients with erectile dysfunction and stable chronic angina, treated with anti-anginal drugs (without nitrates), were evaluated. The results did not indicate any clinically significant difference between the sildenafil and placebo group in terms of time to the occurrence of limbic angina attacks.
In some subjects examined on the Farnsworth-Munsell test on 100 shades of color, 1 hour after administration of a 100 mg dose of sildenafil, slight and transient differences in blue / green color perception were observed, and after No obvious effect was observed 2 hours after dosing. The postulated mechanism for this change in color perception mode is correlated with PDE6 inhibition involved in the retinal phototransduction cascade. Sildenafil has no effect on visual acuity or on visual contrast sensitivity.
In a placebo-controlled clinical trial in a small number of patients diagnosed with age-related macular degeneration (n = 9), sildenafil (single dose of 100 mg) did not cause significant visual impairment (visual acuity , Amsler grid, traffic light simulation for differential color perception, Humphrey perimeter and photostresis).
In healthy volunteers, no changes in sperm motility or morphology were observed after oral administration of a single dose of sildenafil 100 mg (see section 4.6).

Additional information from clinical trials
In clinical trials, sildenafil was administered to over 8000 patients aged 19-87 years, in the following categories: the elderly (19.9%), patients with hypertension (30.9%), diabetic patients (20.3%), ischemic heart disease (5.8%), hyperlipidemias (19.8%), spinal cord injuries (0.6%), depression (5.2%), transurethral prostate resection (3, 7%), radical prostatectomy (3.3%). The following categories of patients have not been well studied or excluded from clinical trials: patients with pelvic surgery, radiotherapy, patients with severe renal impairment or severe hepatic impairment, and patients with certain cardiovascular disorders (see section 4.3).
In fixed dose studies, the percentages of patients who reported improved erection due to treatment were 62% at the 25 mg dose, 74% at the 50 mg dose and 82% at the 100 mg dose versus 25% in the in case of placebo. In controlled clinical trials, the frequency of withdrawal from sildenafil due to adverse reactions was small and comparable to that seen with placebo. In all clinical trials, the percentage of patients who reported improvement from sildenafil treatment was 84% (in patients with psychotic erectile dysfunction), 77% (in mixed erectile dysfunction), 68% (in patients with erectile dysfunction), 67% (in the elderly), 59% (in diabetic patients), 69% (in patients with myocardial ischaemia), 68% (in patients with hypertension), 61% (in patients with resection prostate transurethral), 43% (in patients with radical prostatectomy), 83% (in patients with spinal cord injuries), 75% (in patients with depression). Long-term studies have shown to maintain the safety and efficacy of sildenafil treatment.

Children and adolescents
The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicine containing sildenafil in all subgroups of pediatric patients for the treatment of erectile dysfunction. See section 4.2 for information on use in children and adolescents.

5.2 Pharmacokinetic properties
Absorption:
Sildenafil is rapidly absorbed. After oral dosing, in fasting conditions, peak plasma concentrations are reached in 30 – 120 minutes (with an average of 60 minutes). The mean oral bioavailability is 41% (between 25-63%). Following oral administration, sildenafil AUC and Cmax, increase in dose proportionality within the recommended dose range (25-100 mg).
If sildenafil is administered with food, the rate of absorption decreases with an average delay of 60 minutes of Tmax, and an average reduction of 29% of Cmax.
Distribution:
The mean steady-state volume distribution (Vd) for sildenafil is 105 l, indicating the distribution in the tissues. Following oral single dose of 100 mg, the mean maximum sildenafil peak plasma concentration is approximately 440 ng / ml (40% VC). Since sildenafil (and its main circulating metabolite, N-desmethyl) binds to 96% of plasma proteins, an average mean peak plasma sildenafil concentration of 18 ng / ml (38 nM) results. Plasma protein binding is independent of the total plasma concentration of the drug.
In healthy volunteers using sildenafil (100 mg single dose), less than 0.0002% (mean 188 ng) of the administered dose is present in the ejaculate after 90 minutes of dosing.

Metabolism:
Sildenafil is primarily metabolised by the CYP3A4 (main pathway) and CYP2C9 (secondary pathway) microsomal enzymes. N-demethylation of sildenafil results in the main circulating metabolite. This metabolite has a selectivity profile for PDE similar to sildenafil and a PDE5 inhibitory potency in vitro of about 50% of that of the non-metabolised drug. Plasma concentrations of this metabolite are approximately 40% of those of sildenafil. The N-demethyl metabolite is further metabolised with an elimination half-life of approximately 4 hours.

Elimination:
The total body clearance of sildenafil is 41 l / h, resulting in a half-life of elimination half-life of 3-5 hours. After oral or intravenous administration, sildenafil is excreted as metabolites, predominantly by feces (approximately 80% of the oral dose) and less urine (approximately 13% of the oral dose).

Pharmacokinetics in special patient groups
Elderly
Healthy elderly volunteers (65 years of age or older) experienced a decreased clearance of sildenafil, with approximately 90% increases in plasma levels of sildenafil and the active N-demethyl metabolite compared to those observed in young healthy volunteers (18-45 years). Due to the different proportions of age-related plasma protein binding, the increase in free sildenafil plasma concentrations was approximately 40%.

Kidney failure
Following oral administration of a single dose of 50 mg of sildenafil to volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml / min), the pharmacokinetics of sildenafil have not been altered. The mean AUC and Cmax of the N-demethyl metabolite increased by 126% and 73%, respectively, compared to those obtained in volunteers of the same age without any renal dysfunction. However, taking into account the large variability among subjects, these differences did not show statistical significance. In volunteers with severe renal impairment (creatinine clearance <30 ml / min), sildenafil clearance was low, with a mean AUC increase of 100% and Cmax by 88% compared to those of the same age group without impairment. In addition, the AUC and Cmax of the N-desmethyl metabolite were significantly increased by 79% and 200%, respectively.

Hepatic impairment
In patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) clearance of sildenafil was low, resulting in increases in AUC (84%) and Cmax (47%) compared with volunteers of the same age and without hepatic impairment. In patients with severe hepatic impairment, the pharmacokinetics of sildenafil have not been studied.

5.3 Preclinical safety data
Animal studies have not demonstrated the existence of a specific human hazard based on conventional studies of safety pharmacology, repeated dose administration, genotoxicity, carcinogenicity, reproductive toxicity and developmental toxicity.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Kollidon 25 (polyvinylpyrrolodone)
Magnesium stearate
Color FDC Blue N.1.

6.2 Incompatibilities
It’s not necessary.

6.3 Shelf life
36 months.

6.4 Special precautions for storage
Keep protected from light and temperatures below 25 ° C.
Keep out of the reach and sight of children.

6.5 Nature and contents of container
APOLLO 50 mg tablets
The tablets are packaged in PVC/Al blisters. The secondary pack is a carton box with 1 blister of 2, 5 or 20 tablets.
APOLLO 100 mg tablets
The tablets are packaged in PVC/Al blisters. The secondary pack is a cardboard box with 1 blister of 2, 4 or 10 tablets.

6.6 Special precautions for disposal and other handling
No special requirements.

7. CERTIFICATE OF REGISTRATION
SC Balkan Pharmaceuticals SRL N. Grădescu str., 4, MD-2002, or. Chisinau, Republic of Moldova.
The manufacturer
SC Balkan Pharmaceuticals SRL Industrial Street, 7 / A, MD-2091, or. Singera, Republic of Moldova.

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