EXTRA
( SILDENAFIL CITRATE )

DESCRIPTION
EXTRA an oral therapy for erectile dysfunction, is the citrate salt of SILDENAFIL.
SILDENAFIL citrate is designated chemically as 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 and has the following structural formula:

CLINICAL PHARMACOLOGY
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 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 (erection). SILDENAFIL at recommended doses has no effect in the absence of sexual stimulation.
Pharmacodynamics:
SILDENAFIL administration in patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections. The erectile response which is approximately 60 minutes post dose generally increased with increasing SILDENAFIL dose and plasma concentration. The time course of effect is up to 4 hours but the response was diminished compared to 2 hours.
Transient effect on blood pressure were recorded among patients receiving concomitant nitrates, and also mild transient dose– related impairment of color discrimination (blue/green) was detected.
Absorption:
SILDENAFIL is rapidly absorbed after oral administration with absolute bioavailability of
about 40 %. Maximum absorbed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state.
SILDENAFIL and its major metabolite (N-desmethyl) are both 96 % bound to plasma proteins.

Elimination & Metabolism:
SILDENAFIL is eliminated predominantly by hepatic metabolism and excreted in the feces and urine. Both SILDENAFIL and the metabolite have terminal half lives of about 4 hours.
Pharmacokinetics in Special Populations:
Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of SILDENAFIL, with free plasma concentration approximately 40% greater than those seen in healthy younger volunteers (18-45 years).
Renal Insufficiency:
In volunteers with mild (CLcr=50-80 ml/min) and moderate (CLcr=30-49 ml/min) renal impairment the pharmacokinetics of a single oral dose of SILDENAFIL (50 mg) were not altered in volunteers with severe (CLcr = <30 ml/min) renal impairment, SILDENAFIL clearance was reduced. Resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.
Hepatic Insufficiency:
In volunteers with hepatic cirrhosis (Child-Pugh A and B), SILDENAFIL clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to matched volunteers with no hepatic impairment.

N.B.: SILDENAFIL should be used with caution and in low doses in elderly patients , hepatic impairment, renal impairment and in combination with other specific medication (see DOSAGE & ADMINISTRATION).

Clinical Studies:
At the end of the long-term study, 88 % of patients reported that SILDENAFIL improved their erection, sexual function, satisfaction and enjoyment of intercourse, and overall relationship satisfaction.
 

Clinical Pharmacology:
SILDENAFIL effectiveness is regardless of ED severity, etiology race and age. SILDENAFIL was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, trans-urethral resection of the prostate (TURP) and spinal cord injury, and in patients taking anti-depressants/ anti-psychotics and anti-hypertensives / diuretics.
 

INDICATIONS
SILDENAFIL is indicated for the treatment of erectile dysfunction.
 

CONTRAINDICATIONS
Use of SILDENAFIL is contraindicated in patients with a known hypersensitivity to any component of the tablet.

N.B: 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.

PRECAUTIONS
In general there is a degree of cardiac risk associated with sexual activity, therefore, physicians may whish to consider the cardiovascular status of their patients. Treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
SILDENAFIL combination with other treatments for erectile dysfunction have not been studied, therefore it is not recommended.
There is no safety information on the administration of SILDENAFIL to patients with bleeding disorders or active peptic ulceration. Therefore, SILDENAFIL should be administered with caution to these patients.
In patients with retinitis pigmentosa SILDENAFIL should be administered with caution.
 

Information for Patients:
Physicians should discuss with patients the contraindication of SILDENAFIL with concurrent organic nitrates.
The use of SILDENAFIL offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures. Necessary to guard against sexually transmitted diseases.
 

DRUG INTERACTION
In vitro studies:
Effects of other drugs on SILDENAFIL
Drugs which inhibits the isoenzymes P450 (CYP) reduces SILDENAFIL clearance.

In Vivo Studies:
Ketoconazole, erythromycin or cimetidine may reduce SILDENAFIL clearance.
Rifampin, will decrease plasma levels of SILDENAFIL.
Single dose of antacid ( magnesium hydroxide / aluminum hydroxide ) did not affect the bioavailability of SILDENAFIL.
No effect on SILDENAFIL by products such as: tolbutamide, warfarin, selective serotonin reuptake inhibitors, tricyclic antidepressants, thiazide and related diuretics, ACE inhibitors, and calcium channel blockers were reported.
SILDENAFIL (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg.).
SILDENAFIL (50 mg) did not potentiate the hypotensive effect of alcohol.
No interaction was seen when SILDENAFIL (100 mg) was co-administered with amlodipine in hypertensive patients.
No difference in the side effect profile in patients taking SILDENAFIL with and without anti-hypertensive medication.
 

Carcinogenesis:
SILDENAFIL was not carcinogenic when administered to rats for 24 months.
Impairment of Fertility:
There was no effect on sperm motility or morphology after single 100 mg. oral dose of SILDENAFIL in healthy volunteers.
Pregnancy, Nursing Mothers & Pediatric Use:
SILDENAFIL is not indicated for use in children or women.
 

SIDE EFFECTS
In placebo-controlled clinical studies, the discontinuation rate due to adverse events for SILDENAFIL (2.5 %) was not significantly different from placebo (2.3 %).
The adverse events were generally transient and mild to moderate in nature. Headache 16 %, Flushing 10 %, Dyspepsia 7 %, Nasal congestion 4 %, Urinary tract infection 3 %, Abnormal vision 3 %, Dizziness 2 %, Rash 2 %, Diarrhea 3 %.
The following events occurred in < 2 % of patients in controlled clinical trials, a causal relationship to SILDENAFIL in uncertain:
- 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.
- Nervous: Ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.
- Respiratory: Asthma, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.
- Skin and appendages: Urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.
 

OVERDOSAGE
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 accelerated clearance as SILDENAFIL is highly bound to plasma proteins and it is not eliminated in the urine.
 

DOSAGE & ADMINISTRATION
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 hours before sexual activity. Based on effectiveness and toleration, the dose may be increased to 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 (40 % increase in AUC).
- Hepatic impairment (e. g. cirrhosis 80 %)
- Severe renal impairment 100 %.
- Concomitant use of (erythromycin, Ketoconazole, itraconazole, 200 %).
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.

N.B. 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.

PACKAGES & COMPOSITION
EXTRA 50: 1 x 4 F.C. tablets, each tablet contains:
SILDENAFIL Citrate 70.20 mg. Corresponding to SILDENAFIL Base 50 mg.
EXTRA 100: 1 x 4 F.C. tablets, each tablet contains:
SILDENAFIL Citrate 140.40 mg. Corresponding to SILDENAFIL Base 100 mg.
 

STORAGE
Store below 30 oC.
Keep out of the reach of children.