Endothik Es

Uses

Ethinylestradiol is an estradiol used as a contraceptive.

Ethinylestradiol is combined with other drugs for use as a contraceptive, premenstrual dysphoric disorder, moderate acne, moderate to severe vasomotor symptoms of menopause, prevention of postmenopausal osteoporosis.

Sildenafil Citrate is used for the treatment of Erectile Dysfunction.

Endothik Es is also used to associated treatment for these conditions: Menopausal Osteoporosis, Mild to Moderate Acne, Premenstrual Dysphoric Disorder ( PMDD), Moderate Acne vulgaris, Moderate, severe, Vasomotor Symptoms caused by Menopause, Contraception, Folate supplementation therapyErectile Dysfunction, NYHA Functional Class II-III Pulmonary arterial hypertension, Premature Ejaculation, Symptomatic pulmonary arterial hypertension (PAH)

How Endothik Es works

Ethinylestradiol is a synthetic estrogenic compound. Use of estrogens have a number of effects on the body including reduced bone density. Combined oral contraceptives suppress ovulation by suppressing gonadotrophic hormone, thickening cervical mucus to prevent the travel of sperm, and preventing changes in the endometrium required for implantation of a fertilized egg. Ethinylestradiol decreases luteinizing hormone, decreasing vascularity in the endometrium. It also increases sex hormone binding globulin.

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 the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum 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 cavernosum and allowing inflow of blood .

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, 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 cavernosum but potently enhances the relaxant effect of NO on this tissue . When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP . Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects .

Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature . Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation . In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation .

Dosage

Endothik Es dosage

The usual starting dose of Sildenafilis 50 mg once daily. lt should be taken before 30-40 minutes of intercourse. Depending on 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.

Some factors are associated with increased plasma levels of sildenafil: age>65, hepatic impairment, severe renal impairment and concomitant use of ketoconazole, itraconazole, erythromycin. 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.

Sildenafil may takes longer time to work if you take it with a heavy meal.

Side Effects

Like all medicines, Sildenafil can cause side effects although not everybody gets them.The side effects reported in association with the use of Sildenafil are usually mild to moderate and of a short duration. All medicines including Sildenafil can cause allergic reactions.

Contact with doctors immediately if experiences any of the following symptoms after taking Sildenafil: sudden wheeziness, difficulty in breathing or dizziness, swelling of the eyelids, face, lips or throat. Common side effect includes headache, facial flushing, indigestion, effects on vision, light sensitivity, blurred vision or reduced, stuffy nose and dizziness. Uncommon side effect includes vomiting, skin rash, bleeding at the back of the eye, red eyes, eye pain, double vision, abnormal sensation in the eye, irregular or rapid heartbeat, muscle pain, feeling sleepy, reduced sense of touch, vertigo, ringing in the ears, nausea, dry mouth, chest pain & feeling tired.

Toxicity

Female patients experiencing and overdose may present with withdrawal bleeding, nausea, vomiting, breast tenderness, abdominal pain, drowsiness, and fatigue. Overdose should be treated with symptomatic and supportive care including monitoring for potassium concentrations, sodium concentrations, and signs of metabolic acidosis.

In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased . Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased .

Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures .

The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied . Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk .

The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available .

Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients while others have documented that clinical efficacy as measured by 6-minute walk distance could be less in elderly patients . In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy .

Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed . This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years) . Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40% .

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 more than 25 times the human male AUC .

Precaution

Warnings: In patients with preexisting cardiovascular disease, there is a potential risk in sexual activity. Sildenafil should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Sildenafil has systemic vasodilatory properties (mean maximum decrease of 8.4/5.5 mmHg). Patients with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood can be particularly sensitive to the actions of vasodilators including Sildenafil.There is no controlled clinical data on the safety or efficacy of Sildenafil in Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months. Caution should be taken in patients with resting hypotension (BP <90/50) or hypertension (BP >170/110), cardiac failure or coronary artery disease causing unstable angina, retinitis pigmentosa. Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Sildenafil. In this situation, patient should seek immediate medical assistance.

Precautions: Please tell your doctor or pharmacist if you are taking or have recently taken other medicines, including medicines obtained without prescription. Sildenafil tablets may interfere with some medicines, especially those used to treat chest pain. In the event of a medical emergency, you should tell the healthcare professional treating your condition that you have taken Sildenafil and if you did, do not take Sildenafil with other medicines unless your doctor tells you can.You should not take Sildenafil if you are taking medicines called nitrates as the combination of these products may cause a potentially dangerous decrease in your blood pressure. Always tell your doctor or pharmacist if you are taking any of these medicines that are often used for the relief of angina pectoris (or chest painJ.You should not take Sildenafil if you are using any of the drugs known as nitric oxide donors such as amyl nitrite as the combination may also lead to potentially dangerous decrease in your blood pressure. If you are taking medicines known as protease inhibitors, such as for the treatment of HIV, your doctor may start you on the lowest dose (25 mg) of Sildenafil. Some patients who take alpha-blocker therapy for the treatment of high blood pressure or prostate enlargement may experience dizziness or light-headedness, which may be caused by low blood pressure upon sitting or standing up quickly. Certain patients have experienced these symptoms when taking Sildenafil with alpha-blocker. This is most likely to occur within 4 hours after taking Sildenafil. In order to reduce the likelihood of these symptoms occur,you should be on a regular daily dose of your alpha-blocker before you start Sildenafil. Your doctor may start you on a lower dose (2S mg) of Sildenafil if you have hypotension (avoid if systolic blood pressure below 90 mmHg), recent stroke, unstable angina & myocardial infarction. Drinking alcohol can temporally impair your ability to get an erection, to get the maximum benefit from your medicine; you are advised not to drink excessive amounts of alcohol before taking Sildenafil.

Interaction

Inhibitors of CYP3A4 such as cimetidine and erythromycin are likely to reduce sildenafil clearance. CYP3A4 inducers such as rifampicin may decrease the plasma concentrations of sildenafil. Symptomatic hypotension when used with α-blockers. Plasma concentrations are increased by ritonavir.

Volume of Distribution

A 30µg oral dose has an apparent volume of distribution of 625.3±228.7L and a 1.2mg topical dose has an apparent volume of distribution of 11745.3±15934.8L.

The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues .

Elimination Route

A 30µg oral dose of ethinylestradiol reaches a C_max of 74.1±35.6pg/mL, with a T_max of 1.5±0.5h, and an AUC of 487.4±166.6pg*h/mL. A 1.2mg dose delivered via a patch reaches a C_max of 28.8±10.3pg/mL, with a T_max of 86±31h, and an AUC of3895±1423pg*h/mL.

Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient . Moreover, the mean absolute bioavailability observed for sildenafil is about 41% (from a range of 25-63%) . In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg .

When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses .

Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29% . Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 % .

Half Life

A 30µg oral dose has a half life of 8.4±4.8h and a 1.2mg topical dose has a half life of 27.7±34.2h.

The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours .

Clearance

Ethinylestradiol has an intravenous clearance of 16.47L/h, and an estimated renal clearance of approximately 2.1L/h. A 30µg oral dose has a clearance of 58.0±19.8L/h and a 1.2mg topical dose has a clearance of 303.5±100.5L/h.

The total body clearance documented for sildenafil is 41 L/h .

Elimination Route

Ethinylestradiol is 59.2% eliminated in the urine and bile, while 2-3% is eliminated in the feces. Over 90% of ethinylestradiol is eliminated as the unchanged parent drug.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose) .

Pregnancy & Breastfeeding use

Sildenafil is not indicated for use in newborns, children & women.

Contraindication

Sildenafil 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.

Acute Overdose

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.

Storage Condition

Store below 30° C. Protect from light and moisture. Keep out of reach of children.

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