Description
Generics: Sildenafil Citrate
Dosage Form: Tablet.
Indications:
Sildenafil is suitable for the treatment of erectile dysfunction.
Pharmacology:
Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) and is used to treat erectile dysfunction. Danafil (sildenafil) enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for the degradation of cGMP in the cavernous body, leading to smooth muscle relaxation and blood flow to the sponge Body.
Mechanism of Action: 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 nitric oxide (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 and Metabolism: Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, Sildenafil. Both Sildenafil and the metabolite have terminal half lives of about 4 hours.
Absorption and Distribution: 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. When Sildenafil is taken with a high fat meal, the rate of absorption is reduced.
Metabolism and Excretion: Sildenafil is cleared by hepatic microsomal isoenzymes. 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 the administered oral dose).
Pharmacokinetics in Special Populations: Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of Sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of Sildenafil compared to those seen in healthy younger volunteers.
Dosage guideline:
once a day.
The recommended dose of Sildenafil is 50 mg collected approximately one hour before sexual activity. However, Sildenafil can be taken from 30 hours to 4 hours of sexual activity. On the basis of effectiveness and tolerance, the dose can increase up to 100 mg or decrease at 25 mg. The frequency of maximum recommended administration is once a day.
Erectile dysfunction: For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, Sildenafil may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day.
The following factors are associated with increased plasma levels of Sildenafil: age >65, hepatic impairment, severe renal impairment, and concomitant use of potent cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, saquinavir). 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 was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated. When Sildenafil is co-administered with an alpha-blocker, patients should be stable on alphablocker therapy prior to initiating Sildenafil treatment and Sildenafil should be initiated at the lowest dose.
Pulmonary arterial hypertension: The recommended dose of sildenafil citrate is 20 mg three times a day and should be taken approximately 4-6 hours apart, with or without food.
Route of administration: Orally.
Interaction:
Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes 15 may reduce Sildenafil clearance and inducers of these isoenzymes may increase Sildenafil clearance. Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma Sildenafil concentrations when coadministered with Sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of Sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid 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 of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Sildenafil (100 mg single dose) resulted in a 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as 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 coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine). In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Sildenafil (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 hours 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 P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. Although the interaction between other protease inhibitors and Sildenafil has not been studied, their concomitant use is expected to increase Sildenafil levels. In a study of healthy male volunteers, co-administration of Sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of Sildenafil AUC and a 55% decrease in Sildenafil Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of Sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of Sildenafil. Pharmacokinetic data from patients in clinical trials showed no effect on Sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake 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 16 nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.
Contraindications:
Sildenafil is contraindicated in patient with hypersensitivity to any component of this medication. Sildenafil potentiates the hypotensive effects of nitrates, so it is contraindicated in patients who are using organic nitrates, either regularly or intermittently.
Side Effects:
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, liver function tests abnormal, rectal hemorrhage, gingivitis.
Hemic and Lymphatic: anemia and leukopenia.
Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, 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, reflexes decreased, hyperesthesia.
Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.
Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.
Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes.
Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.
Cardiovascular and cerebrovascular: Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of Sildenafil. Most, but not all, of these patients had preexisting 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 sexual activity. Others were reported to have occurred 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’s underlying 23 cardiovascular disease, to a combination of these factors, or to other factors.
Nervous: seizure, seizure recurrence, anxiety, and transient global amnesia.
Urogenital: prolonged erection, priapism and hematuria.
Special Senses: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment/traction, paramacular edema and epistaxis.
Pregnancy & Lactation:
Grade B pregnancy. There are no adequate and well-controlled studies on the use of sildenafil in pregnant women. Sildenafil is not suitable for women. In animal studies, sildenafil has been shown to have no evidence of teratogenicity or embryotoxicity.
Precautions & Warnings:
Patients should proceed with caution if they are allergic to any other drugs or any other substances (such as food, preservatives or dyes), heart or blood vessel problems, or sudden blindness in one or both eyes. If the patient has any of the following diseases, such as diabetes, kidney or liver problems, leukemia, multiple myeloma, any disease or malformation of the penis, any bleeding disorder such as hemophilia, gastric ulcer, sickle cell anemia, you should be cautious Acting, color perception. Hearing problems, reduced or sudden loss or any other treatment for impotence.
Therapeutic Class:
Drugs for Erectile Dysfunction.
Storage Conditions:
Keep in a dry place, away from light and heat. Keep out of the reach of children.
Manufactured by: Eskayef Pharmaceuticals Ltd.
