FORMULATION:

Each 5g sachet contains:
Sildenafil (as citrate)…50mg
Sildenafil (as citrate)…100mg

DESCRIPTION

50 mg & 100 mg: Orange colored, homogenized jelly with sweet taste and pleasant odor.

PHARMACODYNAMICS

Sildenafil oral jelly is a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterases type 5 (PDE5). 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 enzymes gyanylate 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 phosphodiesterases 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 increase level 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.

In vitro studies have shown that Sildenafil is selective for PDE5, its effect is more potent on PDE5 than on other phosphodiesterases (> 80 – fold for PDE 1, >1000- fold for PDE2, PDE3 and PDE4). The approximately 4,000-fold selectively for PDE5 versus PDE3 is important because that PDE is involved in control of cardiac contractility. Sildenafil is only about 10- fold potent for PDE5 compared to PDE6, an enzyme found in the retina; this lower selectively is thought to be the basis for abnormalities related to colour vision observed with higher doses or plasma levels.

PHARMACOKINETICS

Sildenafil is rapidly absorbed following administration by mouth, with a bioavailability of approximately 40%. Peak plasma concentrations are attained within 30 to 120 minutes; the rate of absorption is reduced when Sildenafil is administered with food.

Sildenafil is widely distributed into tissues and is approximately 96% bound to plasma proteins. It is metabolized in the liver primarily by cytochrome P450 is isoenzymes CYP3A4 (the major route) and CYP2C9. The major metabolite, N-desmethyl-sildenafil, also has some activity. The terminal half-lives of Sildenafil and the N-desmethyl metabolite are about 4 hours.

Sildenafil is excreted, predominantly as metabolites, in the feces, and to a lesser extent the urine. Clearance may be reduced in the elderly and in patients with hepatic or severe renal impairment.

INDICATIONS

Sildenafil is used in the management of erectile dysfunction or impotence in men. Erectile dysfunction signifies inability of a male to achieve satisfactory erection of the penis during sexual intercourse.

CONTRAINDICATIONS

Use of Sildenafil oral jelly is contraindicated in patients with a known hypersensitivity to any component of the jelly. Consistent with its known effects on the nitric oxide/ cyclic guanosine monophosphate (cGMP) pathway, Sildenafil oral jelly was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are concurrently using organic nitrates in any form is therefore contraindicated.

DOSAGE AND ADMINISTRATION

The usual dose for most patients is 50mg, as needed, approximately about one hour before sexual intercourse. The dose may be increased or decreased depending on response. The maximum recommended dose is 100mg, and Sildenafil should not be taken more often than once in 24 hours.

Directions for Use: Open sachet and consume entire contents. One sachet for one-time-use only. Use strictly under Medical supervision

WARNINGS AND PRECAUTIONS

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. Prior to prescribing Sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.

The cardiovascular risks of sexual activity should be considered before beginning therapy with Sildenafil; in some patients, sexual activity may be inadvisable. Caution is required in patients with hepatic or severe renal impairment, and dosage reduction may be necessary. Care is also needed in patients with anatomical and hematological disorders which may predispose them to priapism. Patients who experience dizziness or visual disturbances should not drive or operate hazardous machinery. The safety of Sildenafil is uncertain in patients with severe hepatic impairment, bleeding disorders, active peptic ulceration, hypotension, a recent history of stroke, myocardial infarction, or life-threatening arrhythmia, unstable angina, heart failure or retinal disorders such as retinitis pigmentosa (a minority of whom have genetic disorders of retinal phosphodiesterases). The manufacturers advise that it should not be used in these groups.

Caution is advised when Sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post Sildenafil dosing. In order to minimize the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating Sildenafil treatment. Initiation of Sildenafil at a dose of 25mg should be considered. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.

Studies with human platelets indicate that Sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in-vitro. There is no safety information on the administration of Sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore Sildenafil should be administered to these patients only after careful benefit-risk assessment.

DRUG INTERACTIONS

Sildenafil may potentiate the hypotensive effects of organic nitrates, and is therefore contraindicated in patients receiving such drugs. Concomitant administration of Sildenafil with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, such as cimetidine, erythromycin, itraconazole, ketoconazole, and HIV-protease inhibitors may reduce Sildenafil clearance necessitating a reduction in dosage. However, plasma concentrations of Sildenafil are significantly increased by ritonavir, requiring even greater dosage reduction, and it is therefore strongly recommended that these two drugs are not given together.

Antivirals: Rises in Sildenafil concentrations following concomitant administration of saquinavir or ritonavir were consistent with inhibition of metabolism mediated by the cytochrome P450 isoenzyme CYP3A4. The larger increases seen with ritonavir may be due to its additional inhibition of the isoenzyme CYP2C9. Death following myocardial infarction has been reported in a 47-year-old patient who took Sildenafil 25mg concomitantly with ritonavir and saquinavir.

Nitrates: Administration of Sildenafil 50mg to patients receiving isosorbide mononitrate, or sublingual administration of glyceryl trinitrate 1 hour after Sildenafil, resulted in substantially greater decreases in blood pressure than when the nitrate was administered alone in 2 crossover studies in patients with angina. Treatment-related adverse effects were reported in 8 of 16 patients who took Sildenafil with isosorbide mononitrate and 3 of 15 who received Sildenafil with glyceryl trinitrate. The authors confirmed that Sildenafil should not be taken concomitantly with nitrates.

Effects of Sildenafil on other medicinal products: In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50>150µM). Given Sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that Sildenafil will alter the clearance of substrates of these isoenzymes.

In vitro studies: No significant interactions were shown with Tolbutamide (250mg) or warfarin (40mg), both of which are metabolized by CYP2C9.

Sildenafil (50mg) did not potentiate the increase in bleeding time caused by aspirin (150mg).

Sildenafil (50mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

No interaction was seen when Sildenafil (100mg) was co-administered with amlodipine in hypertensive patients. The mean additional reduction on supine blood pressure (systolic-8mmHg, diastolic-7mmHg) was of a similar magnitude to that seen when Sildenafil was administered alone to healthy volunteers.

Analysis of the safety database has shown no difference in the side effect profile in patients taking Sildenafil with and without anti-hypertensive medication.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINE

No studies on the effects on the ability to drive and use machines have been performed. As dizziness and altered vision were reported in clinical trials with Sildenafil, patients should be aware of how they react to Sildenafil, before driving or operating machinery.

Women: Sildenafil is not indicated in pregnant women.

Pediatrics: Sildenafil is not indicated in children.

Pregnancy: There are no adequate and well controlled studies of Sildenafil in pregnant women. Sildenafil is not indicated in pregnant women.

Lactation: Sildenafil is not indicated in nursing mothers.

ADVERSE EFFECTS

Sildenafil citrate was administered to over 3700 patients (aged 19-87 years) during clinical trials worldwide; over 550 patients were treated for a period longer than one year. In placebo controlled clinical studies the discontinuation rate due to adverse events for Sildenafil citrate (2.5%) was not significantly different from placebo (2.3%). The adverse events were generally transient and mild to moderate in nature. In case of oral jelly preparation patient is expected to report similar adverse effects like those occurring with the other oral dosage forms.

Adverse effects most commonly reported from Sildenafil are headache, flushing, and dyspepsia. There may be visual disturbances, dizziness, and nasal congestion. Other adverse effects reported included diarrhea, muscle pain, skin rashes, and urinary- or respiratory-tract infection. Priapism has also occurred. There have also been reports of serious cardiovascular events, including sudden cardiac death, associated with the use of Sildenafil.

Effects on the cardiovascular system:

There has been considerable uncertainty about the potential cardiovascular risk associated with Sildenafil treatment. Minor effects associated with vasodilation, such as headache and flushing are relatively common, but in patients without pre-existing cardiovascular risk factors the risk of serious cardiovascular events associated with the drug appears to be low. However, there has been a report of myocardial infarction in a patient without apparent risk factors that patients with erectile dysfunction are mostly over 65 years of age and are more likely to have risk factors predisposing them to cardiovascular disease.

Effects on eyes: A bluish tinge or haze to vision and some increased light sensitivity has been reported by a significant percentage of patients taking Sildenafil, with the percentage of reports increasing with increasing dose. The visual symptoms usually peak after 1 to 2 hours following ingestion and resolve about 3 to 4 hours later.

The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to Sildenafil in 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 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

Digestive: Vomitting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver functions test abnormal, rectal hemorrhage, gingivitis

Hemic and Lymphatic: Anemia and leucopenia

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, refluxes decreased, hypesthesia

Respiratory: Asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, and cough increased

Skin and appendages: Urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact 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

OVERDOSAGE

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

STORE AT TEMPERATURES NOT EXCEEDING 30°C.

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.

AVAILABILITY

Sildenafil citrate (KAMAGRA®) 50mg in Aluminum/ Polyester/ Polyethylene Sachet pack x 5g (box of 30’s) Sildenafil citrate (KAMAGRA®) 100mg in Aluminum/ Polyester/ Polyethylene Sachet pack x 5g (box of 30’s)