Overnight delivery cialis

In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose.

Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

VIAGRA has systemic vasodilatory properties and may further lower blood pressure in patients taking anti-hypertensive medications. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted [ see Drug Interactions (7.3) and Clinical Pharmacology (12.2) ]. 5.6 Adverse Reactions with the Concomitant Use of Ritonavir.

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC).

If VIAGRA is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to

high

To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [ see Dosage and Administration (2.4), Drug Interactions (7.4), and Clinical Pharmacology (12.3) ]. 5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies. The safety and efficacy of combinations of VIAGRA with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied.

Such combinations may further lower blood pressure. Therefore, the use of such combinations is not recommended. There have been postmarketing reports of bleeding events in patients who have taken VIAGRA.

A causal relationship between VIAGRA and these events has not been established.

In humans, VIAGRA has no effect on bleeding time when taken alone or with aspirin. However, in vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).

In addition, the combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

The safety of VIAGRA is unknown in patients with bleeding disorders and patients with active peptic ulceration.

5.9 Counseling Patients About Sexually Transmitted Diseases.

The use of VIAGRA offers no protection against sexually transmitted diseases.

Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

The following are discussed in more detail in other sections of the labeling: Cardiovascular [ see Warnings and Precautions (5.1) ] Prolonged Erection and Priapism [ see Warnings and Precautions (5.2) ] Effects on the Eye [ see Warnings and Precautions (5.3) ] Hearing Loss [ see Warnings and Precautions (5.4) ] Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [ see Warnings and Precautions (5.5) ] Adverse Reactions with the Concomitant Use of Ritonavir [

see

VIAGRA was administered to over 3700 patients (aged 19–87 years) during pre-marketing clinical trials worldwide.

Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for VIAGRA (2.5%) was not significantly different from placebo (2.3%).

In fixed-dose studies, the incidence of some adverse reactions increased with dose.

The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently.

Table 1: Adverse Reactions Reported by ?2% of Patients Treated with VIAGRA and More Frequent than Placebo in Fixed-Dose Phase II/III Studies Adverse Reaction 25 mg (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) * Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision.

Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision* 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1%

Dizziness

Adverse Reactions Reported by ?2% of Patients Treated with VIAGRA and More Frequent than Placebo in Flexible-Dose Phase II/III Studies Adverse Reaction VIAGRA PLACEBO N=734 N=725 * Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision. Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision* 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% The following events occurred in 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. 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, hypesthesia.

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, overnight delivery cialis dry eyes. Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.

Analysis of the safety database from controlled clinical trials showed no apparent difference in adverse reactions in patients taking VIAGRA with and without anti-hypertensive medication.

This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions. The following adverse reactions have been identified during post approval use of VIAGRA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. 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 VIAGRA. 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 VIAGRA without sexual activity.

Others were reported to have occurred hours to days after the use of VIAGRA and sexual activity.

It is not possible to determine whether these events are related directly to VIAGRA, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors [ see Warnings and Precautions (5.1) and Patient Counseling Information (17) ].

Hemic and Lymphatic: vaso-occlusive crisis: In a small, prematurely terminated study of REVATIO (sildenafil) in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo. The clinical

relevance

In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events.

In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of overnight delivery cialis VIAGRA, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [ see Warnings and Precautions (5.4) and Patient Counseling Information (17) ]. Ocular : diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, and vitreous traction/detachment.

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50,

diabetes

Urogenital: prolonged erection, priapism [ see Warnings and Precautions (5.2) and Patient Counseling Information (17) ], and hematuria. Administration of VIAGRA with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown to potentiate the hypotensive effects of nitrates [ see Dosage and Administration (2.3), Contraindications (4.1), Clinical Pharmacology (12.2) ] . Use caution when co-administering alpha-blockers with VIAGRA because of potential additive blood pressure-lowering effects. When VIAGRA is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [ see Dosage and Administration (2.3),Warnings and Precautions (5.5), Clinical Pharmacology (12.2) ] .

When VIAGRA 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [ see Warnings and Precautions (5.5), Clinical Pharmacology (12.2) ].

Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC).

It is therefore recommended not to exceed a maximum single dose of 25 mg of VIAGRA in a 48 hour period [ see Dosage and Administration (2.4), Warnings and Precautions (5.6), Clinical Pharmacology (12.3) ].

Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil C max and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil C max and AUC, respectively.

Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with

saquinavir

A starting dose of 25 mg of VIAGRA should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [ see Dosage and Administration (2.4), Clinical Pharmacology (12.3) ] .

In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [ see Clinical Pharmacology (12.2) ].

There are no data with the use of VIAGRA in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show overnight delivery cialis adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2 basis ( see Data ).

No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m 2 basis in a 50 kg subject.

In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2 basis in a 50 kg subject.

Limited data indicate that sildenafil and its active metabolite are present in human milk. There is no information on the effects on the breastfed child, or the effects on milk production.

VIAGRA is not indicated for use in pediatric patients.

Safety and effectiveness have not been established in pediatric patients. 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 and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18–45 years) [ see Clinical Pharmacology (12.3) ]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Clinical Pharmacology (12.3) ].

Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older.

No overall differences in safety or efficacy were observed between older (? 65 years of age) and younger ( see Dosage and Administration (2.5) ]. No dose adjustment is required for mild (CLcr=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr max and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [ see Dosage and

Administration

In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied.

A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] .

In studies with healthy volunteers of single doses up to 800 mg, adverse reactions 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.

VIAGRA (sildenafil citrate), an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo[4,3- d ]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate

and

NO then activates the enzyme guanylate cyclase, which results in increased levels of

cyclic

Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human 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.

Studies in vitro have shown that sildenafil is selective for PDE5.

Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina.

This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2) ].

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle.

The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro , an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo . Effects of VIAGRA on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ® ), after VIAGRA administration compared with placebo.

Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ® , generally

increased

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of VIAGRA on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting overnight delivery cialis blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1–2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4.1) ]. Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers.

Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL).

In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance see Contraindications (4.1) ].

Effects of VIAGRA on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent. In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH).

Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg.