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Emposil

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Emposil
Sildenafil

Description
Emposil 50 mg:
Each tablet contains sildenafil citrate corresponding to sildenafil base 50 mg
Emposil 100 mg:
Each tablet contains sildenafil citrate corresponding to sildenafil base 100 mg

Actions
Sildenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Pharmacology
Mechanism of Action: The physiologic mechanism of erection of the penis Involves release of nitric.
The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil, at recommended doses, has no effect in the absence of sexual stimulation.

Pharmacokinetics
Sildenafil and it's major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein-binding is independent of total drug concentrations. Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes.

Indications
Treatment of erectile dysfunction

Dosage and Administration
For most patients, the recommended dose is 50 mg taken as needed, approximately 1 hr before sexual activity. However, Emposil may be taken anywhere from 4 hrs to 0.5 hr before sexual activity.
Based on the effectiveness and tolerance, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg.The maximum dosing frequency is once per day. The following factors are associated with increased plasma levels of sildenafil: Age › 65 (increase in AUC, 40%), hepatic impairment (eg, cirrhosis, 80%), severe renal impairment (creatinine clearance ‹ 30 mL/min, 100%), and concomitant use of potent cytochrome P-450 3A4 inhibitors [ketoconazole, itraconazole, erythromycin (182%), saquinavir (210%)]. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients. Ritonavir greatly increased the systemic level of sildenafil in a study of healthy, non-HIV-infected volunteers (11-fold increase in AUC, see Interactions). Based on these pharmacokinetic data, it is recommended not to exceed a minimum single dose of 25 mg of Emposil in a 48-hr period.

Overdosage
In studies with healthy volunteers, of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated in the urine.

Contra Indications
Patients with a known hypersensitivity to any component of Emposil. Consistent with its known effects on the nitric oxide/cGMP pathway (see Actions), Emposil was shown to potentiate the hypotensive effects of nitrates, and its administration in patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated. After patients have taken Emposil, it is unknown when nitrates, if necessary can be safely administered. Based on the pharmacokinetic profile of a single 100-mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hrs post-dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL) (see Pharmacokinetics under actions). In the following patients, age › 65 years, hepatic impairment (eg, cirrhosis), severe renal impairment (eg, creatinine clearance ‹ 30 mL/min), and concomitant use of potent cytochrome P-450 3A4 inhibitors (erythromycin), plasma levels of sildenafil at 24 hrs post-dose have been found to be 3-8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hrs post-dose are much lower than at peak concentrations, it is unknown whether nitrates can be safely co-administered at this time point. Emposil is not indicated for use in newborns, children or women.

Warnings
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including Emposil should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage and transient ischemic attack have been reported post-marketing in temporal association with the use of sildenafil for erectile dysfunction. Most, but not all, of these patients had pre existing cardiovascular risk factors.
Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without the sexual activity Others were reported to have occured hours to days after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient is underlying cardiovascular disease, to a combination of these factors, or to other factors.
Emposil has systemic vasodilatory properties that resulted in transient decreases in supine blood  pressure in healthy volunteers (mean maximum decrease of 8.3/5.5 mm Hg) (see Pharmacodynamics under Actions). While this normally would be expected to be of little consequence in most patients, prior to prescribing Emposil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity/There Is no controlled clinical data on the safety or efficacy of Emposil in the following groups; if prescribed, this should be done with caution: Patients who have suffered a myocardial Infarction, stroke or life-threatening arrhythmia within the last 6 months; patients with resting hypotension (BP ‹ 90/50) or hypertension (BP › 170/110); patients with cardiac failure or coronary artery disease causing unstable angina; patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).
Prolonged erection › 4 hrs and priapism (painful erections › 6 hrs in duration) have been reported infrequently since market approval of Emposil. In the event of an erection that persists › 4 hrs, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. The concomitant administration of the protease inhibitor, ritonavir, substantially increases serum concentrations of sildenafil (11 -fold increase in AUC). If Emposil is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildsnafil are limited. Visual disturbances occurred more commonly at higher levels of sildenafil exposure. Decreased blood pressure syncope and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200-800 mgl.To decrease the chance of adverse events in patients taking ritonavir, a decrease in sildenafil dosage is recommended (see Interactions, Adverse Reactions and Dosage & Administration).
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision or loss of vision, has been reported rarely post-marketing with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as low cup to disc ratio (icrowded disk), age over 50, diabetes, hypertension, coronary artery disease, hypcrlipidemia and smoking. No casual relationship has been made between us of PDE5 inhibitors and NAION. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION. The patients should be advised that in case of sudden visual loss, to stop taking sildenafil and consult a physician Immediately Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators Including Sildenafil - those with left ventricular outflow obstruction (e.g.aortic stenosis, idiopathic hyperthropic subaortic stenosis) and those with severity impaired autonomic control of blood pressure.

Precautions
The evaluation of erectile dysfunction should Include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.
Simultaneous administration of Emposil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in some patients. Therefore, Emposil doses above 25 mg should not be taken within 4 hours of taking an alpha-blocker.

Before prescribing Emposil, it is important to note the following:
Patients on multiple antihypertensive medications were included in the pivotal clinical trials for Emposil. In a separate drug interaction study, when arnlodipine 5 or 10 mg, and Emposil 100 mg were orally administered concomitantly to hypertensive patients, mean additional blood pressure reduction of 8 mm Hg systolic and 7 mm Hg diastolic were noted (see Interactions). Controlled studies of drug interactions between Emposil and other antihypertensive medications have not been performed. The safety of Emposil is unknown in patients with bleeding disorders and patients with active peptic ulceration.
Emposil should be used with caution in patients with anatomical deformation of the penis (eg, angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (eg, sickle cell anemia, multiple myeloma or leukemia).The safety and efficacy of combinations of Emposil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
In humans, Emposil has no effect on bleeding time when taken alone or with acetylsalicylic acid. In vitro studies with human platelets Indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (as nitric oxide donor). The combination of heparin and Emposil had an additive effect on bleeding time in the anesthetized rabbit.but this interaction has not been studied in humans.
Information for Patients: Physicians should discuss with patients the contraindication of Emposil with regular and/or intermittent use of organic nitrates.
Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (eg, angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician.
Physicians should warn patients that prolonged erections › 4 hrs and priapism (pain erections › 6 hrs in duration) have been reported infrequently since market approval of Emposil. In the event of an erection that persists › 4 hrs, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. The use of Emposil offers no protection against sexually transmitted diseases. Counseling the patients about the protective measures necessary to guard against sexually transmitted diseases, including the human immunodeficiency virus (HIV), may be considered.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29 and 42 times, for male and female rats, respectively, the exposures observed in human males given the maximum recommended human dose (MRHD) of 100 mg.
Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the maximum tolerated dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis.
Sildenafil was negative In in-vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes. and in vivo mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in rats given sildenafil up to 60
mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of › 25 times the human male AUC.
There was no effect on sperm motitity or morphology after single 100-mg oral doses of Emposil in healthy volunteers,
Use in pregnancy: Pregnancy Category B: No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the MRHD on a mg/m2 basis in a 50-kg subject. In the rat pre-and postnatal development study, the no-observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat, the AUC at this dose was about 20 times the human AUC. There are
no adequate and well-controlled studies of sildenafil in pregnant
women.
Use in the elderly; Healthy elderly volunteers (a 65 years) had a reduced clearance of sildenafil (see Pharmacokinetics in Special Populations under Actions). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered (see Dosage & Administration).

Adverse Reaction
In fixed-dose studies, the incidence of some adverse events increased with dose. The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage regimen, was similar to that for fixed-dose studies.
Other adverse reactions occurred at a rate of › 2%, but equally common on placebo: Respiratory tract infection, back pain, flu syndrome and arthralgia.
In fixed-dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 100 mg than at lower doses. At doses above the recommended dose range, adverse events were similar to those detailed previously but generally were reported more frequently.
The following events occurred in ‹ 2% of patients in controlled clinical trials; a causal relationship to Emposil is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful. Body as a Whole: Face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury. Cardiovascular: Angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy. Digestive: Vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, abnormal liver function tests, rectal hemorrhage, gingivitis. Hem ic and Lymphatic: Anemia and leukopenia. Metabolic and Nutritional: Thirst, edema, gout, unstable diabetes, hyperglycemla, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia. Musculoskeletal: Arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis. Nervous: Ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, decreased reflexes, hypesthesia. Respiratory: Asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum, increased cough. Skin and Appendages: Urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis. Special Senses: Mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, deafness, ear pain, eye hemorrhage, cataract, dry eyes. Urogenital: Cystitis, nocturia, urinary frequency, breast enlargement, urinary Incontinence, abnormal ejaculation, genital edema and anorgasmia.

Interactions
Effects of Other Drugs on Emposil:
In Vitro Studies: Sildenafil metabolism is principally mediated by the cytochrome P-450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these Isoenzymes may reduce sildenafil clearance. In Vivo Studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with Emposil (50 mg) to healthy volunteers. When a single 100-mg dose of Emposil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, co-administration with the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor at steady state (1200 mg 3 times a day) with Emposil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and 210% increase in sildenafil AUC. Emposil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors eg, ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (eg, ketoconazole, erythromycin or cimetidine). (See Dosage & Administration). In another study in healthy male voiunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P-450 inhibitor, at steady state (500 mg twice daily) with Emposil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hrs, the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P-450 substrates. Emposil had no effect on ritonavir pharmacokinetics (see Dosage & administration). Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. It can be expected that concomitant administration of CYP3A4 inducers eg, rifampin, will decrease plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of Emposil. Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics ofCYP2C9 inhibitors (eg, tolbutamide, warfarin), CYP2D6 inhibitors (eg, selective serotonin re-uptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium-channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific.-blockers. These effects on the metabolite are not expected to be of clinical consequence, Effects of Emposil on Other Drugs: In Vitro Studies: Sildenafil is a weak inhibitor of the cytochrome P-450 isoforms 1A2, 2C9, 2C19.2D6, 2E1 and 3A4 (IC50 › 150 micromolar). Given sildenafil peak plasma concentrations of approximately 1 micromolar after recommended doses, it is unlikely that Emposil will alter the clearance of substrates of these isoenzymes.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by
CYP2C9.
Emposil (50 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (150 mg).
Emposil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrate.
Emposil was shown to potentiate the hypotensive effects of nitrates and its administration in patients who also use nitric oxide donors or nitrates in any form is therefore contraindicated.

Storage
Store below 30°C and keep in dry place.
Keep out the reach of children

PRESENTATION
Emposil 50 mg film - coated tablet:
Available in boxes containing 1 blister @ 4 film coated tablets.
Reg.No:DKI1027700417A1
Emposil 100 mg film - coated tablet:
Available in boxes containing 1 blister @ 4 film coated tablets.
Reg.No: DKI1027700417B1

HARUS DENGAN RESEP DOKTER
Manufactured by
Actavis Ltd, Malta
Imported and packed by
PT Actavis Indonesia, Jakarta
(Actavis Group, Iceland)

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