Sildenafil 100mg - 1 Box x 8 Tabs (Erecfil 100)

FORMULATION:

Each film-coated tablet contains:

Sildenafil Citrate 100 mg

DRUG CATEGORY:

Vasodilator Agent, Phosphodiestrase Inhibitor.

PRODUCT DESCRIPTION:

Blue colored diamond shaped biconvex breakline on one side plain on other side film-coated tablet.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction.

Mechanism of action

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavemosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavemosum and allowing inflow of blood.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavemosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavemosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway isactivated, as occurs with sexual stimulation, inhibition of PDE5 by Sildenafil results in increased corpus cavemosum levels of cGMP. Therefore, sexual stimulation is required in order for Sildenafil to produce its intended beneficial pharmacological effects. — . _

Pharmacodynamic Effects

Studies in vitro have shown that Sildenafil is selective for PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximum recommended doses, there is an 80-fold selectivity over PDE1, and over700-fold over PDE 2,3,4,7,8,9,10, and 11. In particular, Sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.

Clinical efficacy and safety

Two clinical studies were specifically designed to assess the time window after dosing during which Sildenafil could produce an erection in response to sexual stimulation. In a penile plethysmography (RigiScan) study of fasted patients, the median time to onset for those who obtained erections of 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes) on Sildenafil. In a separate RigiScan study, Sildenafil was still able to produce an erection in response to sexual stimulation 4-5 hours post-dose.

Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 100 mg oral dosing of Siidenafii was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in biood pressure are consistent with the vasodilatory effects of Sildenafil, probably due to increased cGMP levels in vascular smooth muscle. Single oral doses of Sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

tn a studyofthe tremodynamic effects of asingieorat 100 rngxiose-ofSildenaftHnTApatients with sevefeeoronafyartefy-diseaseTCA&/(>70% stenosis-of at feast one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

Adouble-blind, placebo-controlled exercise stress trial evaluated 144 patients with erectile dysfunction and chronic stable angina who regularly received anti-anginal medicinal products (except nitrates). The results demonstrated no clinically relevant differences between Sildenafil and placebo in time to limiting angina.

Mild and transient differences in color discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Siidenafii has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9), Sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, color discrimination simulated traffic light, Humphrey perimeter, and photostress).

There was no effect on sperm motility or morphology after single 100 mg oral doses of Sildenafil in healthy volunteers.

Further information on clinical trials

In clinical trials Sildenafil was administered to more than 8000 patients aged 19-87. The following patient groups were represented: elderly (19.9%), patients with hypertension (30.9%), diabetes mellitus (20.3%), ischaemic heart disease (5.8%), hyperlipidaemia (19.8%), spinal cord injury (0.6%), depression (5.2%), transurethral resection of the prostate (3.7%), radical prostatectomy (3.3%). The following groups were not well represented or excluded from clinical trials: patients with pelvic surgery, patients post-radiotherapy, patients with severe renal or hepatic impairment and patients with certain cardiovascuiarconditions.

In fixed dose studies, the proportions of patients reporting that treatment improved their erections were 62% (25 mg), 74% (50 mg) and 82% (100 mgj compared to 25% on placebo. In controlled clinical trials, the discontinuation rate due to Sildenafil was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on Sildenafil were as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly (67%), diabetes mellitus (59%), ischaemic heart disease (69%), hypertension (68%), TURP (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75%). The safety and efficacy of Sildenafil was maintained in long term studies.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Sildenafil in all subsets of the paediatric population for the treatment of erectile dysfunction.

PHARMACOKINETIC PROPERTIES

Absorption

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41 % (range 25-63%). After oral dosing of Siidenafii, AUC and C_max increase in proportion with dose over the recommended dose range (25-100 mg).

When Sildenafil is taken with food, the rate of absorption is reduced with a mean delay in T^ of 60 minutes and a mean reduction in of 29%.

Distribution

The mean steady state volume of distribution (Vd) for Sildenafil is 105L, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of Sildenafil is approximately 440 ng/mL (CV 40%). Since Sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for Sildenafil of 18 ng/mL (38 nM). Protein binding is independent of total drug concentrations. . . .

In healthy volunteers receiving Sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.

Biotransformation

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of Sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to Sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for Sildenafil. The N-desmethyl metabolite is further metabolized, with a terminal half life of approximately 4 h.

Elimination

The total body clearance of Sildenafil is 41 L/h with a resultant terminal phase half life of 3-5 h. After either oral or intravenous administration, Sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).

INDICATION:

Forthe treatment of erectile dysfunction.

DOSAGE AND ADMINISTRATION:

For treatment of erectile dysfunction:

Adults up to 65 years of age - 50 mg as a single dose not more than once a day, 1 hour before sexual intercourse.

Adults 65 years of age and older - 25 mg as a single dose not more than once a day, 1 hour before sexual intercourse.

Administration in Hepatic Impairment:

In the management of erectile dysfunction, an initial dose of 25 mg of Sildenafil is recommended by licensed drug information in patients with hepatic impairment.

Administration in Hepatic Impairment:

In the management of erectile dysfunction, an initial dose of 25 mg of Sildenafil is recommended by licensed drug information in patients with severe renal impairment (creatinine clearance less than 30 ml/minute). If you are taking protease inhibitors, such as for the treatment of HIV, your doctor may recommend a 25 mg dose and may limit you to a maximum single dose of 25 mg in 48-hour period.

Fortreatment of pulmonary arterial hypertension:

Adults - 20 mg three times per day.

Children -use and dose must be determined by your doctor. Oras prescribed by the physician.

CONTRAINDICATIONS:

Consistent with its known effects on the nitric oxide cGMP pathway, Sildenafil citrate was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates either regularly and/or intermittently in any form is therefore contraindicated.

Sildenafil citrate is contraindicated in patients with a known hypersensitivity to any component of the tablet.

WARNINGS AND PRECAUTIONS:

Sildenafil has not been studied with other medicines used for treatment of erectile dysfunction. Presently, using them together is not recommended. If too much is used, the chance of side effects is increased. If you experience a prolonged or painful erection for 4 hours or more, contact your doctor immediately. This condition may require prompt medical treatment to prevent tissue damage of the penis and possible permanent impotence. This medicine does not protect you against sexually transmitted diseases. If you experience sudden loss of vision in one or both eyes, stop using Sildenafil and contact your doctor immediately.

Pregnancy:

Sildenafil is not indicated for use in women. Sildenafil has not been studied in pregnant women. However, Sildenafil has not been shown to cause birth defects or other problems in animal studies.

Breastfeeding:

It is not known whether Sildenafil passes into breast milk. Sildenafil is not indicated for use in women for erectile dysfunction. Mothers who are taking this medicine for pulmonary arterial hypertension and who wish to breastfeed should discuss this with their doctor.

Older adults:

Elderly people are especially sensitive to the effects of Sildenafil, which may increase their chance of having side effects. Patients 65 years of age and older who are taking this medicine forerectile dysfunction are started on a low dose, 25 mg, of Sildenafil.

ADVERSE DRUG REACTIONS:

Abnormal vision, including blurred vision, seeing shades of colors differently than before, or sensitivity to light; bladder pain; burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings; burning feeling in chest or stomach; cloudy or bloody urine; dizziness; increased frequency of urination; ingestion; indigestion; pain on urination; upset stomach; tenderness in stomach area.

DRUG INTERACTIONS:

Sildenafil or other phosphodiesterase type-5 inhibitors may potentiate the hypotensive effects of organic nitrates, and are therefore contraindicated in patients receiving such drugs. Sildenafil may also enhance the hypotensive effect of Nicorandil and use of the two drugs together should be avoided. Symptomatic hypotension may also occur when phosphodiesterase type-5 inhibitors are given with alpha blockers. Generally the patient should be established on alpha blocker therapy before the phosphodiesterase type-5 inhibitor is started at a low dose and adjusted according to response; minimum dosage intervals have also been recommended in some cases. Drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, such as Cimetidine, Delavirdine, Erythromycin, Itraconazole, Ketoconazole, and HIV-protease inhibitors, may reduce the clearance of phosphodiesterase type-5 inhibitors, necessitating a reduction in dosage. Furthermore, plasma concentrations of phosphodiesterase type-5 inhibitors are significantly increased by Ritonavir, requiring even greater dosage reduction, and such combinations should not be given unless absolutely essential. Grapefruit juice should be avoided with Sildenafil or other phospodiesterase type-5 inhibitors as it may increase their plasma concentrations.

Inducers of CYP3A4, such as Rifampicin, are likely to decrease plasma concentrations of phosphodiesterase type-5 inhibitors. Specific dosage recommendations have been made forthe use of phosphodiesterase Type-5 inhibitors with many ofthese drugs.

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of Sildenafil citrate. Sildenafil citrate (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil citrate (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, Saquinavir and Ritonavir, both of which are CYP3A4 substrates.

Alpha-blockers (medicine for high blood pressure - Sildenafil when taken together with an alpha-blocker medicine may cause very low blood pressure. Cimetidine, Erythromycin, Itraconazole, Ketoconazole and Mibefradil - These medicines may increase the unwanted effects of Sildenafil, unless lower starting doses of Sildenafil are used.

Erectile dysfunction medicines - These medicines should not be used at the same time as Sildenafil because the safety or using these medicines in combination has not been proven. Nitrates, such as Nitroglycerin - Sildenafil increases the lowering of blood pressure by nitrates too much and their use together is not recommended.

OVERDOSE AND TREATMENT:  

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 and severities 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 it is not eliminated in the urine.

CAUTION:

Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without prescription.

For suspected adverse drug reaction, report to the FDA: www.fda.gov.ph.

Seek medical attention immediately at the first sign of any adverse drug reaction.

STORAGE CONDITION;

Store at temperatures not exceeding 30°C.

KEEP ALL MEDICINES OUT OF REACH OF CHILDREN.

AVAILABILITY:

Alu//Clear PVC Blister Packx 4’s (Box of 4’s & 8's)