Solvetra

Solvetra^® é indicado para o tratamento da disfunção erétil.

Informações gerais sobre doses

Para a maioria dos pacientes, a dose inicial recomendada de Solvetra é de 10 mg, tomada por via oral, conforme necessário, aproximadamente 60 minutos antes da atividade sexual. A dose pode ser aumentada para uma dose máxima recomendada de 20 mg ou diminuída para 5 mg com base na eficácia e nos efeitos colaterais. A frequência máxima de dosagem recomendada é uma vez por dia. A estimulação sexual é necessária para uma resposta ao tratamento.

Use com comida

Solvetra pode ser tomado com ou sem alimentos.

Use em populações específicas

Geriatria

Uma dose inicial de 5 mg de Solvetra deve ser considerada em pacientes com idade ≥ 65 anos.

Compromisso hepático

Para doentes com compromisso hepático moderado (Child-Pugh B), recomenda-se uma dose inicial de 5 mg de Solvetra. A dose máxima em pacientes com insuficiência hepática moderada não deve exceder 10 mg.

Não utilize Solvetra em doentes com compromisso hepático grave (Child-Pugh C).

Compromisso renal

Não use Solvetra em pacientes em diálise renal.

Medicamentos concomitantes

Nitratos

O uso concomitante com doadores de nitratos e óxido nítrico, sob qualquer forma, é contra-indicado.

Estimuladores de Guanylate Cyclase (GC), como riociguat: O uso concomitante é contra-indicado.

Inibidores do CYP3A4

A dose de Solvetra pode exigir ajustes em pacientes que recebem inibidores potentes do CYP3A4, como cetoconazol, itraconazol, ritonavir, indinavir, saquinavir, atazanavir e claritromicina, bem como em outros pacientes que recebem inibidores moderados do CYP3A4, como a eritromicina. Para o ritonavir, uma dose única de 2,5 mg de Solvetra não deve ser excedida em um período de 72 horas. Para indinavir, saquinavir, atazanavir, cetoconazol 400 mg por dia, itraconazol 400 mg por dia e claritromicina, uma dose única de 2,5 mg de Solvetra não deve ser excedida em um período de 24 horas. Para o cetoconazol 200 mg por dia, itraconazol 200 mg por dia e eritromicina, uma dose única de 5 mg de Solvetra não deve ser excedida em um período de 24 horas.

Bloqueadores alfa

Nos pacientes que são estáveis em terapia com bloqueadores alfa, os inibidores da fosfodiesterase tipo 5 (PDE5) devem ser iniciados na dose inicial mais baixa recomendada. O tratamento concomitante deve ser iniciado apenas se o paciente estiver estável em sua terapia com bloqueadores alfa. O aumento gradual da dose de bloqueador alfa pode estar associado a uma redução adicional da pressão arterial em pacientes que tomam um inibidor da fosfodiesterase (PDE5), incluindo o vardenafil. Nos doentes estáveis em terapêutica com bloqueadores alfa, Solvetra deve ser iniciado na dose de 5 mg (2,5 mg quando utilizado concomitantemente com certos inibidores do CYP3A4).

Um intervalo de tempo entre a dosagem deve ser considerado quando Solvetra é prescrito concomitantemente com terapia com bloqueadores alfa.

Nitratos

A administração de Solvetra com doadores de nitratos (regular e / ou intermitentemente) e óxido nítrico é contra-indicada. Consistentes com os efeitos da inibição da PDE5 na via monofosfato de óxido nítrico / guanosina cíclica, os inibidores da PDE5, incluindo Solvetra, podem potencializar os efeitos hipotensores dos nitratos. Não foi determinado um intervalo de tempo adequado após a administração de Solvetra para a administração segura de nitratos ou doadores de óxido nítrico.

Estimuladores de Guanilato Ciclase (GC)

Não use Solvetra em pacientes que estão usando um estimulador de GC, como o riociguat. Inibidores da PDE5, incluindo Solvetra, podem potencializar os efeitos hipotensores dos estimuladores da GC.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment.

Before prescribing Solvetra, it is important to note the following:

Cardiovascular Effects

General

Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatment for erectile dysfunction, including Solvetra, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status.

There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of <90 mmHg); uncontrolled hypertension (>170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.

Left Ventricular Outflow Obstruction

Patients with left ventricular outflow obstruction, (for example, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.

Blood Pressure Effects

Solvetra has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic). While this normally would be expected to be of little consequence in most patients, prior to prescribing Solvetra, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

Potential For Drug Interactions With Potent Or Moderate CYP3A4 Inhibitors

Concomitant administration with potent CYP3A4 inhibitors (such as ritonavir, indinavir, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil. Dosage adjustment is necessary when Solvetra is administered with certain CYP3A4 inhibitors.

Long-term safety information is not available on the concomitant administration of vardenafil with HIV protease inhibitors.

Risk Of Priapism

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including vardenafil. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Solvetra should be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

Effects On The Eye

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Solvetra, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of nonarteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥50.

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION.

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including Solvetra, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Solvetra, for this uncommon condition.

Solvetra has not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.

Sudden Hearing Loss

Physicians should advise patients to stop taking all PDE5 inhibitors, including Solvetra, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.

Alpha-Blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Solvetra, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Consideration should be given to the following:

• Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose.
• In those patients already taking an optimized dose of 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 in patients 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.

Congenital Or Acquired QT Prolongation

In a study of the effect of Solvetra on QT interval in 59 healthy males , therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QT_c interval. A postmarketing study evaluating the effect of combining Solvetra with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone. These observations should be considered in clinical decisions when prescribing Solvetra to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

Patients taking Class 1A (for example. quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using Solvetra.

Hepatic Impairment

Dosage adjustment is necessary in patients with moderate hepatic impairment (Child-Pugh B). Do not use Solvetra in patients with severe (Child-Pugh C) hepatic impairment.

Renal Impairment

Do not use Solvetra in patients on renal dialysis, as vardenafil has not been evaluated in this population.

Combination With Other Erectile Dysfunction Therapies

The safety and efficacy of Solvetra used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Effects On Bleeding

In humans, vardenafil alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin. Solvetra has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore Solvetra should be administered to these patients after careful benefit-risk assessment.

Sexually Transmitted Disease

The use of Solvetra offers no protection against sexually transmitted diseases. Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

Patient Counseling Information

“See FDA-approved patient labeling (PATIENT INFORMATION)”

Nitrates

Inform patients that Solvetra is contraindicated with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of Solvetra with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.

Guanylate Cyclase (GC) Stimulators

Inform patients that Solvetra is contraindicated in patients who use guanylate cyclase stimulators, such as riociguat.

Cardiovascular

Discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.

Concomitant Use With Drugs Which Lower Blood Pressure

Inform patients that in some patients concomitant use of PDE5 inhibitors, including Solvetra, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting).

Patients prescribed Solvetra who are taking alpha-blockers should be started on the lowest recommended starting dose of Solvetra. Patients should be advised of the possible occurrence of symptoms related to postural hypotension and appropriate countermeasures. Patients should be advised to contact the prescribing physician if other anti-hypertensive drugs or new medications that may interact with Solvetra are prescribed by another healthcare provider.

Recommended Administration

Discuss with patients the appropriate use of Solvetra and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking Solvetra. Solvetra should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of Solvetra especially regarding the maximum daily dose. Patients should be advised to contact their healthcare provider for dose modification if they are not satisfied with the quality of their sexual performance with Solvetra or in the case of an unwanted effect.

Priapism

Inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for Solvetra and this class of compounds. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Drug Interactions

Advise patients to contact the prescribing physician if new medications that may interact with Solvetra are prescribed by another healthcare provider.

Sudden Loss Of Vision

Inform patients to stop use of all PDE5 inhibitors, including Solvetra, and seek medical attention in the event of sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including Solvetra, for this uncommon condition.

Sudden Hearing Loss

Advise patients to stop taking PDE5 inhibitors, including Solvetra, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Solvetra. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.

Sexually Transmitted Disease

Inform patients that Solvetra offers no protection against sexually transmitted diseases. Counsel patients that protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

Dose Adjustment

Inform patients that the recommended starting dose of Solvetra is 10 mg. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and tolerability. The maximum recommended dosing frequency is one tablet per day.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were approximately 400-and 170-fold for male and female rats, respectively, and 21-and 37-fold for male and female mice, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg.

Mutagenesis

Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V₇₉ cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test.

Impairment Of Fertility

Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28 days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.

Use In Specific Populations

Pregnancy

Pregnancy Category B Solvetra is not indicated for use in women. There are no studies of Solvetra use in pregnant women.

No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the maximum recommended human dose (MRHD) of 20 mg.

In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day. Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk. The number of living pups born to rats exposed pre-and postnatally was reduced at 60 mg/kg/day. Based on the results of the pre-and postnatal study, the developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.

Nursing Mothers

Solvetra is not indicated for use in women. It is not known if vardenafil is excreted in human breast milk.

Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.

Pediatric Use

Solvetra is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population.

Geriatric Use

Elderly males 65 years of age and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean Cmax and AUC were 34% and 52% higher, respectively. Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of Solvetra 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg Solvetra should be considered in patients ≥65 years of age.

Hepatic Impairment

Dosage adjustment is necessary in patients with moderate hepatic impairment.

Do not use Solvetra in patients with severe hepatic impairment (Child-Pugh C). Vardenafil has not been evaluated in this patient population.

A starting dose of 5 mg is recommended in patients with moderate hepatic impairment (Child-Pugh B) and the maximum dose should not exceed 10 mg. In volunteers with moderate hepatic impairment, the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects.

In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. No dosage adjustment is necessary in patients with mild hepatic impairment.

Renal Impairment

Do not use Solvetra in patients on renal dialysis as vardenafil has not been evaluated in such patients.

No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. In male volunteers with CLcr = 50-80 ml/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30-50 mL/min or CLcr<30 mL/min, the AUC of vardenafil was 20.30% higher compared to that observed in a control group with CLcr>80 mL/min.

The following serious adverse reactions with the use of Solvetra (vardenafil) are discussed elsewhere in the labeling:

• Cardiovascular Effects
• Priapism
• Effects on Eye
• Sudden Hearing Loss
• QT Prolongation

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Solvetra was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year.

In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for Solvetra compared to 1.1% for placebo.

When Solvetra was taken as recommended in placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1).

Table 1: Adverse Reactions Reported By ≥2% of Patients Treated with Solvetra and More Frequent on Drug than Placebo in Fixed and Flexible^a Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil

Back pain was reported in 2.0% of patients treated with Solvetra and 1.7% of patients on placebo

Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of Solvetra.

All Vardenafil Studies

Solvetra film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18.89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.

In the placebo-controlled clinical trials for Solvetra film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo.

The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of Solvetra film-coated tablets and vardenafil orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:

Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain

Auditory: tinnitus, vertigo

Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension

Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases

Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia

Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure

Respiratory: dyspnea, sinus congestion

Skin and appendages: erythema, rash

Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis

Urogenital: increase in erection, priapism

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Solvetra. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Ophthalmologic

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking.

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil.

Neurologic

Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil.

Otologic

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some 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 vardenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.

A dose máxima de Solvetra para a qual existem dados humanos está disponível é uma dose única de 120 mg administrada a voluntários saudáveis do sexo masculino. A maioria desses indivíduos experimentou dor nas costas reversível / mialgia e / ou “visão anormal.”Doses únicas de até 80 mg de vardenafil e doses múltiplas de até 40 mg de vardenafil administradas uma vez ao dia durante 4 semanas foram toleradas sem produzir efeitos colaterais adversos graves.

Quando 40 mg de vardenafil foram administrados duas vezes ao dia, foram observados casos de dor nas costas intensa. Nenhuma toxicidade muscular ou neurológica foi identificada.

Em casos de sobredosagem, medidas de suporte padrão devem ser tomadas conforme necessário. Não se espera que a diálise renal acelere a depuração, pois o vardenafil está altamente ligado às proteínas plasmáticas e não é significativamente eliminado na urina.

Effects On Blood Pressure

In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents.

Effects On Blood Pressure And Heart Rate When Solvetra Is Combined With Nitrates

A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with Solvetra 20 mg at various times before NTG administration. Solvetra 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when Solvetra 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when Solvetra 20 mg was dosed 24 hours before NTG. (See Figure 1.)

Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, and 1 hour before 0.4 mg NTG sublingually

Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated.

Blood Pressure Effects In Patients On Stable Alpha-Blocker Treatment

Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment, consisting of alfuzosin, tamsulosin or terazosin.

Study 1

This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21). The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha-blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. For blood pressure (BP) results see Table 2. One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg. A decrease in standing SBP of >30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.

Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)

Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours are shown in Figure 2. Blood pressure effects (standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours, are shown in Figure 3.

Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1)

Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1)

Study 2

This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23) on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks. The design was a randomized, double blind, two-period cross-over study. Vardenafil or placebo was given simultaneously with tamsulosin. Blood pressure and pulse were evaluated over the 6hour interval after vardenafil dosing. For BP results see Table 3. One patient experienced a decrease from baseline in standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood pressure values (standing SBP <85 mmHg or decrease from baseline in standing SBP of >30 mmHg). Three patients reported dizziness following vardenafil 20 mg. There were no cases of syncope.

Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)

Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4.

Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg (Stage 1), vardenafil 20 mg (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 2)

Study 3

This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a randomized, double blind, 3period cross-over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo. For BP results see Table 4.

Table 4: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 and 10 mg in BPH patients on stable alpha-blocker therapy with alfuzosin 10 mg daily (Study 3)

One patient experienced decreases from baseline in standing systolic blood pressure >30 mm Hg after administration of vardenafil 5 mg film-coated tablet and vardenafil 10 mg film-coated tablet. No instances of standing systolic blood pressure <85 mm Hg were observed during this study. Four patients, one dosed with placebo, two dosed with vardenafil 5 mg film-coated tablets and one dosed with vardenafil 10 mg film-coated tablets, reported dizziness. Blood pressure effects (standing SBP) in normotensive men on a stable dose of alfuzosin 10 mg following administration of vardenafil 5 mg, vardenafil 10 mg, or placebo separated by 4 hours, are shown in Figure 5.

Figure 5: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following 4 hr separation administration of vardenafil 5 mg (stage 1), vardenafil 10 mg (stage 2) or placebo with stable dose

Blood Pressure Effects In Normotensive Men After Forced Titration With Alpha-Blockers

Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy normotensive volunteers (age range, 45-74 years) were performed after forced titration of the alpha-blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects receiving tamsulosin. Instances of outlier blood pressure values (defined as standing SBP <85 mmHg and/or a decrease from baseline of standing SBP >30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP <85 mmHg given vardenafil and terazosin to achieve simultaneous Tmax led to early termination of that arm of the study. In most (7/8) of these subjects, instances of standing SBP <85 mmHg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil and terazosin were given to achieve simultaneous Tmax than when dosing was administered to separate Tmax by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and vardenafil. Seven subjects experienced dizziness mainly occurring with simultaneous Tmax administration of tamsulosin. There were no cases of syncope.

Table 5: Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy

Figure 6: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 10 mg, vardenafil 20 mg or placebo with terazosin (10 mg) in healthy volunteers

Figure 7: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 10 mg, vardenafil 20 mg or placebo with tamsulosin

Effects On Cardiac Electrophysiology

The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind, randomized, placebo-and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males (81% White, 12% Black, 7% Hispanic) aged 45-60 years. The QT interval was measured at one hour post dose because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of Solvetra (four times the highest recommended dose) was chosen because this dose yields plasma concentrations covering those observed upon co-administration of a low-dose of Solvetra (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with vardenafil. Table 6 summarizes the effect on mean uncorrected QT and mean corrected QT interval (QT_c) with different methods of correction (Fridericia and a linear individual correction method) at one hour post-dose. No single correction method is known to be more valid than the other. In this study, the mean increase in heart rate associated with a 10 mg dose of Solvetra compared to placebo was 5 beats/minute and with an 80 mg dose of Solvetra the mean increase was 6 beats/minute.

Table 6. Mean QT and QT_c changes in msec (90% CI) from baseline relative to placebo at 1 hour post-dose with different methodologies to correct for the effect of heart rate.

Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced similar increases in QT_c interval. This study, however, was not designed to make direct statistical comparisons between the drug or the dose levels. The clinical impact of these QT_c changes is unknown.

In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg Solvetra resulted in a placebo- subtracted mean change from baseline of QT_cF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When Solvetra 10mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11). The clinical impact of these QT changes is unknown.

Effects On Exercise Treadmill Test In Patients With Coronary Artery Disease (CAD)

In two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively, vardenafil did not alter the total treadmill exercise time compared to placebo. The patient population included men aged 40-80 years with stable exercise-induced angina documented by at least one of the following: 1) prior history of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear perfusion study.

Results of these studies showed that Solvetra did not alter the total treadmill exercise time compared to placebo (10 mg Solvetra vs. placebo: 433±109 and 426±105 seconds, respectively; 20 mg Solvetra vs. placebo: 414±114 and 411±124 seconds, respectively). The total time to angina was not altered by Solvetra when compared to placebo (10 mg Solvetra vs. placebo: 291±123 and 292±110 seconds; 20 mg Solvetra vs. placebo: 354±137 and 347±143 seconds, respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both the 10 mg and the 20 mg Solvetra groups (10 mg Solvetra vs. placebo: 380±108 and 334±108 seconds; 20 mg Solvetra vs. placebo: 364±101 and 366±105 seconds, respectively).

Effects On Eye

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration. In a single dose study in 25 normal males, Solvetra 40 mg, twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings.

In another double-blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo to 52 males. Thirty-two (32) males (62%) of the patients completed the trial. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. The trial was designed to detect changes in retinal function that might occur in more than 10% of patients. Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia (objects appear blue).

Effects On Sperm Motility/Morphology

There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in healthy volunteers.

A farmacocinética do vardenafil é aproximadamente proporcional à dose no intervalo de doses recomendado..

Absorção

As concentrações plasmáticas médias de vardenafil medidas após a administração de uma dose oral única de 20 mg a voluntários saudáveis do sexo masculino são representadas na Figura 8.

Figura 8: Curva de concentração plasmática de vardenafil (média ± DP) para uma dose única de 20 mg de Solvetra

O vardenafil é rapidamente absorvido com biodisponibilidade absoluta de aproximadamente 15%. As concentrações plasmáticas máximas observadas após uma dose única de 20 mg em voluntários saudáveis são geralmente atingidas entre 30 minutos e 2 horas (mediana 60 minutos) após a administração oral em jejum. Foram realizados dois estudos de efeito alimentar que mostraram que refeições com alto teor de gordura causaram uma redução na Cmax em 18% a 50%.

Distribuição

O volume médio de distribuição no estado estacionário (Vss) do vardenafil é de 208 L, indicando extensa distribuição tecidual. O vardenafil e seu principal metabólito circulante, M1, estão altamente ligados às proteínas plasmáticas (cerca de 95% para o medicamento original e M1). Essa ligação às proteínas é reversível e independente das concentrações totais de medicamentos.

Após uma dose oral única de 20 mg de vardenafil em voluntários saudáveis, uma média de 0,00018% da dose administrada foi obtida no sêmen 1,5 horas após a administração.

Metabolismo

O vardenafil é metabolizado predominantemente pela enzima hepática CYP3A4, com contribuição das isoformas CYP3A5 e CYP2C. O principal metabolito circulante, M1, resulta da desetilação na fração piperazina do vardenafil. M1 está sujeito a metabolismo adicional. A concentração plasmática de M1 é aproximadamente 26% da do composto original. Este metabolito mostra um perfil de seletividade da fosfodiesterase semelhante ao do vardenafil e um in vitro potência inibitória para PDE5 28% da do vardenafil. Portanto, M1 representa aproximadamente 7% da atividade farmacológica total.

Excreção

A depuração corporal total do vardenafil é de 56 L / h, e a meia-vida terminal do vardenafil e seu metabolito primário (M1) é de aproximadamente 4-5 horas. Após administração oral, o vardenafil é excretado como metabolitos predominantemente nas fezes (aproximadamente 91-95% da dose oral administrada) e, em menor grau, na urina (aproximadamente 2-6% da dose oral administrada).