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Description
Erectra is the oral drug for the treatment of erectile dysfunction. The description is as follows:
Active ingredient - Sildenafil citrate
Chemical name -
1-[{3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl}sulfonyl]-4-methylpiperazine citrate.
Physical Properties - Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water.
Molecular weight - 666.7
Mechanism Of Action
Physiology and Biochemistry with special reference to Erectra The physiological mechanism of normal erection begins with the sexual stimulation in the brain, from where impulses travel via the spinal cord, and the pelvic nerve to the penile corpus cavernosum.
In the corpus cavernosum the gaseous neurotransmitter, nitric oxide (NO) acts as a physiological mediator of penile erection. NO activates the enzyme guanylate cyclase, which converts GTP to cGMP in the carvernosal smooth muscle cells. cGMP then induces calcium to leave the cavernosal smooth muscle cells, the cells relax and penile erection results. cGMP is then metabolised by phosphodiesterase enzyme type V isoenzyme (PDE V) present in the penile tissue and erection subsides.
In conditions of erectile dysfunction the amount of NO released is significantly less. This results in less activation of guanylate cylase resulting in the slow conversion of GTP to cGMP. So there is less cGMP as PDE is capable of metabolizing it as rapidly as cGMP is produced. This results in an inability to either obtain or maintain an erection - a condition known medically as erectile dysfunction. Erectra selectively inhibits phosphodiesterase type V (PDE V), which metabolizes cGMP. As a result the duration of action of cGMP is prolonged. This facilitates and prolongs penile erection. Thus Erectra promotes erection only in response to sexual stimulation. The selectivity of Erectra for cGMP phosphodiesterase type Vis important. Erectra does not inhibit other forms of phophodiesterase. This means that it will not cause adverse effects due to inhibition of other PDE types.
Sildenafil is a potent, highly selective and a competitive inhibitor of PDE V, with modest affinity for PDE VI and is less potent against PDE types I-IV. Sildenafil is 10-fold as potent for PDE V compared to PDE VI, an enzyme found in the retina; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels. The approximately 4,000-fold selectivity for PDE V versus PDE III is important because PDE is involved in control of cardiac contractility.
Pharmacokinetics
The pharmocokinetics is dose proportional. Erectra is rapidly absorbed after oral administration. Peak plasma concentrations are reached about an hour later. The bioavailability of the drug is about 40%. Erectra is metabolized chiefly by cytochrome P450 3A4 (major route) and 2C9 (minor route) hepatic microsomal enzymes. It is converted to an active metabolite N-desmethyl sildenafil. This is similar but less potent in activity with properties similar to the parent, sildenafil. It accounts for about 20% of the biological effects of the administered dose. Both sildenafil and the metabolite have terminal half-lives of about 4 hours.
Absorption and Distribution
The rate of absorption of Erectra is reduced, when it is taken with a high fat meal. Sildenafil and its metabolite N-desmethyl are approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Less than 0.001% of the administered dose may appear in the semen of patients.
Metabolism and Excretion
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feaces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose.
Pharmacodynamics
Effect of Erectra on Erectile Response
On sexual stimulation, Erectra improved erections in men with both psychogenic and organic dysfunction as assessed by an objective measurement of hardness and duration of erections. The time course of effect was examined in one study, showing an effect for up to four hours but the response was diminished compared to 2 hours.
Effect of Erectra on Blood Pressure
Erectra reduced the blood pressure irrespective of the doses 25 mg, 50 mg and 100 mg. (mean maximum decrease of 8.4/5.5 mmHg). The decrease was noted after 1-2 hours of administration. The decrease in blood pressure was prominent in patients receiving concomitant nitrates.
Effect of Erectra on Cardiac Parameters
Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. However in a pilot study of patients with ischemic heart disease, the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in patients with ischemic heart disease. There is no data in patients with coronary artery disease, myocardial infarction, resting hypotension. Physicians are urged to consider whether their patients with underlying cardiovascular disease could be affected by the vasodilatory effects of sildenafil. It is not possible to determine whether the cardiovascular events are related to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors or to other factors.
Effect of Erectra on Vision
3% of patients taking a low dose (-25 mg) experience bluish vision, 10 to 11% of patients taking 50 to 100 mg reported bluish vision. About 50% of people taking more than 100 mg of sildenafil and who take overdoses themselves experience the phenomenon. This finding is consistent with the inhibition of PDE VI, which is involved in phototransduction in the retina.
Indication
Erectra is indicated for the treatment of erectile dysfunction.
Contraindications
Erectra is contraindicated in patients on concurrent organic nitrates. This is because it potentiates the hypothesize effects of such drugs through its effect on NO/cGMP mechanisms.
Erectra is contraindicated in patients with a known hypersensitivity to any component of the tablet.
Warnings
Physicians should be cautious in prescribing sildenafil for men at high risk of potential cardiovascular effects. There is a potential for cardiac risk on sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for erectile dysfunction, including Erectra should not be generally used in men for whom sexual activity is inadvisable, because of their underlying cardiovascular status.
Erectra 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 hypo tension (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).
Infrequently prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) occur. In this case, 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 Erectra is prescribed to patients taking ritonavir, caution should be used. Visual disturbances, decreased blood pressure, syncope, and prolonged erection were reported in healthy volunteers exposed to high doses of sildenafil (200-800 mg). To decrease the chance of adverse events in patients taking ritonavir, a decrease in sildenafil dosage is recommended
General precautions
Medical history and physical examination must precede the prescription of Erectra. Care must be taken to determine potential underlying cause and then decide on the appropriate treatment.
A complete medical assessment of medical and patient history is a must before prescribing Erectra.
The following precautions are to be taken:
· Lower doses should be considered in patients aged 65 year or those with hepatic impairment, moderate to severe renal impairment (creatinine clearance <30 mL/min) and also in patients receiving ritonavir, saquinavir, erythromycin, ketoconazole, itracanozole.
· Erectra should be used with caution in persons with anatomical deformation of the penis (e.g angulation, cavernosal fibrosis or Peyronie's disease), and in patients at risk of priapism (e.g. sickle cell anemia, multiple myeloma, or leukemia).
· Erectra should be administered with caution in patients on multiple antihypertensive medications.
· Erectra does not influence the bleeding time when taken alone or with aspirin, however in vitro studies indicate that it potentiates the antiaggregation effect of sodium nitroprusside, a nitric oxide donor. So safety measures has to be taken in patients with bleeding disorders and active peptic ulceration
· The safety and efficacy of combinations of Erectra with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Drug Interactions
Effects of other drugs on Erectra
In vitro studies:
Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance.
In vivo studies:
Drugs such as erythromycin, cimetidine, ketoconazole and itracanozole prolong the half-life of Erectra through inhibition of cytochrome P450 3A4. Therefore there is a reduction in the Sildenafil clearance.
The HIV protease inhibitor ritonavir, which is a potent P450 inhibitor, when co administered with Erectra (100 mg) resulted in 11-fold increase in sildenafil plasma AUC. Erectra 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.
Drugs such as rifampicin induce CYP3A4 isoenzyme and decrease plasma levels of sildenafil.
Sildenafil citrate pharmacokinetics is unaffected by thiazide and related diuretics, ACE inhibitors, CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin uptake inhibitors, tricyclic antidepressants), calcium channel blockers and antacids like magnesium hydroxide /aluminum hydroxide. Level of the active metabolite, N-desmethyl sildenafil, is increased to 62% by loop and potassium-sparing diuretics and to 102% by nonspecific beta-blockers. These effects on the metabolite are unlikely to be clinically significant.
Effect of Erectra on other drugs
In vitro studies:
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Since the drug is administered intermittently and the levels after therapeutic doses are low (1microM) as it is rapidly eliminated, it is unlikely that it will significantly alter the metabolism of other drugs. That is Erectra is unlikely to alter the clearance of substrates of these isoenzymes.
In vivo studies:
When Erectra 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Erectra (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Erectra produces a mild decrease in blood pressure, but it does not potentiate the hypotensive effect of alcohol or hypertensive drugs.
Erectra (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.
Almlodipine- 5 mg or 10 mg, and Erectra 100 mg were orally administered concomitantly to hypertensive patients. This resulted in a decrease in blood pressure of 8 mm Hg systolic and 7 mmHg diastolic. Controlled studies of drug interactions between Erectra and other antihypertensive medications have not been performed.
Paediatric use and use in women
Erectra is not indicated for use in newborns, children, or women.
Geriatric use
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered.
Carcinogenesis, mutagenesis, impairment of fertility:
In the studies carried out sildenafil citrate was not carcinogenic in rats. sildenafil citrate was negative for mutagenicity in invitro bacterial and Chinese hamster ovary cell assays. There was no impairment of fertility in rats. There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.
Adverse reactions
Adverse effects with sildenafil citrate are dose dependent. Headache, flushing, dyspepsia, rhinitis, nasal congestion, urinary tract infection, abnormal vision, diarrhoea, dizziness, rash are some of the adverse effects.
The following events occurred in less than 2% of patients in controlled clinical trials; a causal relationship to sildenafil 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 and 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.
The use of sildenafil is associated with serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and hypertension. 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 or to the patient.
Digestive:
Vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.
Haemic and Lymphatic:
Anemia and leukopenia.
Metabolic and Nutritional:
Thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.
Arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.
Nervous:
Ataxia, hypertonia, neuralgia, neuropathy, parasthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypersthesia.
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:
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, prolonged erection, priapism and hematuria.
Overdosage
With 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 it is not eliminated in the urine.
Dosage and administration
The recommended dose of Erectra is 50 mg taken as needed, approximately 1 hour before sexual activity. However, Erectra may be taken from 4 hours to 1/2 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 dosage frequency is once per day.
The factors associated with increased plasma levels of sildenafil are:
· Age>65 (40% increase in AUC)
· Hepatic impairment (e.g. cirrhosis, 80%)
· Severe renal impairment (creatinine clearance <30 mL/min, 100%)
· Concomitant use of potent cytochrome P450 3A4 inhibitors like 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 increased the systemic level of sildenafil 11-fold in AUC. Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg of Erectra in a 48-hour period in these patients. Erectra potentiates the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated. |
