Penetal

Uses

Indicated for the treatment of premature ejaculation (PE) in men 18 to 64 years of age, who have all of the following:

• Persistent or recurrent ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the patient wishes.
• Marked personal distress or interpersonal difficulty as a consequence of PE and poor control over ejaculation.

Sildenafil Citrate is used for the treatment of Erectile Dysfunction.

Penetal is also used to associated treatment for these conditions: Premature EjaculationErectile Dysfunction, NYHA Functional Class II-III Pulmonary arterial hypertension, Premature Ejaculation, Symptomatic pulmonary arterial hypertension (PAH)

How Penetal works

The drug's mechanism of action is thought to be related to inhibition of neuronal reuptake of serotonin and subsequent potentiation of serotonin activity. The central ejaculatory neural circuit comprises spinal and cerebral areas that form a highly interconnected network. The sympathetic, parasympathetic, and somatic spinal centers, under the influence of sensory genital and cerebral stimuli integrated and processed at the spinal cord level, act in synergy to command physiologic events occurring during ejaculation. Experimental evidence indicates that serotonin (5-HT), throughout brain descending pathways, exerts an inhibitory role on ejaculation. To date, three 5-HT receptor subtypes (5-HT(1A), 5-HT(1B), and 5-HT(2C)) have been postulated to mediate 5-HT's modulating activity on ejaculation.

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

Penetal dosage

Adult (18 to 64 years of age): The recommended starting dose for all patients is 30 mg, taken as needed approximately 1 to 3 hours prior to sexual activity. If the effect of 30 mg is insufficient and the side effects are acceptable, the dose may be increased to the maximum recommended dose of 60 mg. The maximum recommended dosing frequency is one dose every 24 hours.

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

Dizziness, Headache, Somnolence, Tremor, Blurred vision, Tinnitus, Sinus congestion, Nausea, Diarrhea, Abdominal pain, Dry mouth, Fatigue, Insomnia, Hypertension.

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

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

Patient with bleeding disorders, epilepsy, susceptibility to angle-closure glaucoma or raised intraocular pressure. Not intended for use in women. Known CYP2D6 poor metabolisers.

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

CNS active medicinal products: The use of Dapoxetine in combination with CNS active medicinal products has not been systematically evaluated in patients with premature ejaculation. Consequently, caution is advised if the concomitant administration of Dapoxetine and such medicinal products is required.

PDE5 inhibitors: Tadalafil did not affect the pharmacokinetics of Dapoxetine. Sildenafil caused slight changes in Dapoxetine pharmacokinetics, which are not expected to be clinically significant. However, Dapoxetine should be prescribed with caution in patients who use PDE5 inhibitors due to possible reduced orthostatic tolerance.

Tamsulosin: Concomitant administration of single or multiple doses of 30 mg or 60 mg Dapoxetine to patients receiving daily doses of Tamsulosin did not result in changes in the pharmacokinetics of Tamsulosin. However, Dapoxetine should be prescribed with caution in patients who use alpha adrenergic receptor antagonists due to possible reduced orthostatic tolerance.

Warfarin: There are no data evaluating the effect of chronic use of Warfarin with Dapoxetine; therefore, caution is advised when Dapoxetine is used in patients taking Warfarin chronically.

Ethanol: Concomitant use of alcohol and Dapoxetine could increase the chance or severity of adverse reactions such as dizziness, drowsiness, slow reflexes, or altered judgment. Combining alcohol with Dapoxetine may increase these alcohol-related effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking Dapoxetine.

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

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

Rapidly absorbed.

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

Initial half-life of 1-2 hours.

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

Clearance

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

Elimination Route

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

Dapoxetine is not indicated for use by women. It is not known either dapoxetine or its metabolites are excreted through human breast milk.

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

Contraindication

• Patients with known hypersensitivity to Dapoxetine Hydrochloride.
• Patients with significant pathological cardiac conditions such as heart failure (NYHA class II-IV), conduction abnormalities (second or third degree AV block or sick sinus syndrome) not treated with a permanent pacemaker, significant ischemic heart disease of significant valvular disease.
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs), thioridazine. Similarly, MAOIs or thioridazine should not be administered within 7 days after Dapoxetine has been discontinued.
• Concomitant treatment with serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) or other medicinal/herbal products with serotonergic effects or within 14 days of discontinuing treatment with these medicinal/herbal products.

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

There were no unexpected adverse events in a clinical pharmacology study of Dapoxetine with daily doses up to 240 mg. In general, symptoms of overdose with SSRIs include serotonin-mediated adverse reactions such as somnolence, gastrointestinal disturbances such as nausea and vomiting, tachycardia, tremor, agitation and dizziness. In cases of overdose, standard supportive measures should be adopted as required.

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

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

Innovators Monograph

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