Treatment of erectile dysfunction in adult men. In order for Vantra to be effective, sexual stimulation is required.

Posology

Use in adult men The recommended dose is 100 mg taken as needed approximately 15 to 30 minutes before sexual activity (See Section 5.1). Based on individual efficacy and tolerability, the dose may be increased to a maximum dose of 200 mg or decreased to 50 mg. The maximum recommended dosing frequency is once per day. Sexual stimulation is required for a response to treatment.

Special populations

Older men (≥ 65 years old) Dose adjustments are not required in older patients. Limited data are available in older patients aged 70 years or above.

Renal impairment Dose adjustments are not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min). Vantra is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.3 and 5.2). Patients with mild or moderate renal impairment (creatinine clearance ≥30 mL/min but <80 mL/min) who were enrolled in phase 3 studies showed decreased efficacy compared to those with normal renal function

Hepatic impairment Vantra is contraindicated in patients with severe hepatic impairment (Child Pugh class C) (see sections 4.3 and 5.2). Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) should initiate treatment with the minimum efficacious dose and adjust posology based on tolerance

Use in men with diabetes Dose adjustments are not required in diabetic patients.

Pediatric population There is no relevant use of Vantra in the pediatric population in the indication of erectile dysfunction.

Use in patients using other medicinal products

Concomitant use of CYP3A4 inhibitors Co-administration of Vantra with potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin) is contraindicated (see sections 4.3, 4.4 and 4.5). In patients receiving concomitant treatment with moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of Vantra should not exceed 100 mg, with an interval of at least 48 hours between doses (see section 4.5).

Method of administration

For oral use. If Vantra is taken with food, the onset of activity may be delayed compared to the fasted state (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients who are using any form of organic nitrate or nitric oxide donors (such as amyl nitrite) (see section 4.5). The co-administration of type 5 phosphodiesterase (PDE5) inhibitors, including Vantra, with guanylatecyclase stimulators, such as riociguat is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5). Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease before prescribing Vantra. The use of Vantra is contraindicated in: - Patients who have suffered from a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; - Patients with resting hypotension (blood pressure < 90/50 mmHg) or hypertension (blood pressure > 170/100 mmHg); - Patients with unstable angina, angina with sexual intercourse, or congestive heart failure categorized as New York Heart Association Class 2 or greater. Patients with severe hepatic impairment (Child-Pugh C). Patients with severe renal impairment (creatinine clearance < 30 mL/min). Patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4). Patients with known hereditary degenerative retinal disorders. Patients who are using potent CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin) (see sections 4.2, 4.4 and 4.5).

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

Cardiovascular status

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 (see section 4.3). Vantra has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 4.5), and as such potentiates the hypotensive effect of nitrates (see section 4.3). Patients with left ventricular outflow obstruction, e.g. aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators, including PDE5 inhibitors.

Priapism

Patients who experience erections lasting 4 hours or more (priapism) should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result. Vantra 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 anaemia, multiple myeloma or leukaemia).

Visual problems

Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported in connection with the intake of other PDE5 inhibitors. The patient should be advised that in case of sudden visual effects, he should stop taking Vantra and consult a physician immediately (see section 4.3)

Effect on bleeding

In vitro studies with human platelets indicate that PDE5 inhibitors do not have an effect on platelet aggregation on their own, but at supratherapeutic doses they potentiate the antiaggregatory effect of the nitric oxide donor sodium nitroprusside. In humans, PDE5 inhibitors do not appear to affect bleeding time alone or in combination with acetylsalicylic acid. There is no safety information on the administration of Vantra to patients with bleeding disorders or active peptic ulceration. Therefore, Vantra should be administered to such patients only after careful benefit-risk assessment.

Decreased or sudden loss of hearing

Patients should be advised to stop taking PDE5 inhibitors, including Vantra, 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors.

Concomitant use of alpha-blockers

The concomitant use of alpha-blockers and Vantra may lead to symptomatic hypotension in some patients due to additive vasodilatory effects (see section 4.5). Consideration should be given to the following: • Patients should be stable on alpha-blocker therapy prior to initiating Vantra. Patients who demonstrate haemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of Vantra. • In those patients who are stable on alpha-blocker therapy, Vantra should be initiated at the lowest dose of 50 mg. • In those patients already taking an optimised dose of Vantra, 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 Vantra. • The safety of combined use of Vantra and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive medicinal products.

Concomitant use of CYP3A4 inhibitors

 

Co-administration of Vantra with potent inhibitors of CYP3A4, such as ketoconazole or ritonavir is contraindicated (see sections 4.2, 4.3 and 4.5).

Concomitant use of other treatments for erectile dysfunction

The safety and efficacy of combinations of Vantra and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take Vantra in such combinations

Concomitant use of alcohol

Consumption of alcohol in combination with Vantra can increase the potential for symptomatic hypotension (see section 4.5). Patients should be advised that concurrent use of Vantra and alcohol may increase the likelihood of hypotension, dizziness, or syncope. Physicians should also advise patients on what to do in the event of postural hypotensive symptoms.

Populations not studied

Vantra has not been evaluated in patients with erectile dysfunction due to spinal cord injury or other neurological disorders and in subjects with severe renal or hepatic impairment.

Potential for pharmacodynamic interactions with Vantra

Nitrates

Vantra was shown to augment the hypotensive effects of nitrates compared to placebo in healthy subjects. This is thought to result from the combined effects of nitrates and Vantra on the nitric oxide/cGMP pathway. Therefore, administration of Vantra to patients who are using any form of organic nitrate or nitric oxide donor (such as amyl nitrite) is contraindicated. In a patient who has taken Vantra within 12 hours, where nitrate administration is deemed medically necessary in a life-threatening situation, the likelihood of a significant and potentially dangerous drop in blood pressure is increased. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate haemodynamic monitoring (see section 4.3). Medicinal products reducing systemic blood pressure As a vasodilator, Vantra may reduce systemic blood pressure. If Vantra is used in combination with another medicinal product which reduces systemic blood pressure, the additive effects may result in symptomatic hypotension (e.g. dizziness, light-headedness, syncope or nearsyncope). In phase III clinical trials no events of “hypotension” but occasional episodes of “dizziness” were observed (see section 4.8). One episode of “syncope” was observed in placebo and one episode on 100 mg of Vantra in phase III clinical trials. Patients with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators including Vantra.

Alpha-blockers

Haemodynamic interactions with doxazosin and tamsulosin were studied in healthy subjects in a two-period crossover-design trial. In patients receiving stable doxazosin treatment, the placebo-subtracted mean maximum decreases in standing and supine systolic blood pressure following Vantra dosing were 2.5 mmHg and 6.0 mmHg, respectively. In total, 7/24 subjects experienced values or decreases from baseline that were of potential clinical significance following Vantra dosing (see section 4.4). In patients receiving stable tamsulosin treatment, the placebo-subtracted mean maximum decreases in standing and supine systolic blood pressure following Vantra dosing were 3.6 mmHg and 3.1 mmHg, respectively and 5/24 subjects experienced blood pressure values or decreases from baseline that were of potential clinical significance following Vantra dosing (see section 4.4). There were no reports of syncope or other severe adverse events associated with lowering of blood pressure on either cohort of subjects.

Antihypertensives other than alpha-blockers

A clinical study was conducted to assess the effect of Vantra on the potentiation of the blood pressure-lowering effects of selected antihypertensive medicinal products (amlodipine and enalapril). Results showed a mean maximum decrease in supine blood pressure of 2/3 mmHg compared to placebo with enalapril and 1/-1 mmHg with amlodipine when Vantra was coadministered. There was a statistically significant difference in maximum decrease from baseline in supine diastolic blood pressure with enalapril and Vantra only, which returned to baseline 4 hours after the dose of Vantra. In both cohorts, one subject experienced a decrease in blood pressure without symptoms of hypotension, which resolved within 1 hour of onset. Vantra had no effect on the pharmacokinetics of amlodipine, but amlodipine increased the maximum and total exposure of Vantra by 28% and 60%, respectively

Alcohol

Consumption of alcohol in combination with Vantra can increase the potential for symptomatic hypotension. In a single-dose three-way crossover design study evaluating healthy subjects, the mean maximum reduction in diastolic blood pressure was significantly greater following Vantra administered in combination with alcohol than following Vantra alone (3.2 mmHg) or alcohol alone (5.0 mmHg) (see section 4.4). Other treatments for erectile dysfunction The safety and efficacy of combinations of Vantra and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied (see section 4.4)

Effects of other substances on Vantra

Vantra is a substrate of and predominantly metabolised by CYP3A4. Studies have shown that medicinal products that inhibit CYP3A4 can increase Vantra exposure (see section 4.2).

CYP3A4 Inhibitors

Ketoconazole (400 mg daily), a selective and highly potent inhibitor of CYP3A4, increased Vantra 50 mg single-dose Cmaxand exposure (AUC) equal to 3-fold and 14-fold respectively and prolonged the half-life of Vantra to approximately 9 hours. Ritonavir (600 mg twice daily), a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9, increased Vantra 50 mg single-dose Cmax and AUC equal to approximately 2-fold and 13-fold, and prolonged the halflife of Vantra to approximately 9 hours. Other strong inhibitors of CYP3A4 (e.g. itraconazole, voriconazole, clarithromycin, nefazodone, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) would be expected to have similar effects. Consequently, co-administration of Vantra with potent CYP3A4 inhibitors is contraindicated (see sections 4.2, 4.3 and 4.4). Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, increased Vantra 200 mg single-dose Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of Vantra to approximately 8 hours. Other moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects. Consequently, the maximum recommended dose of Vantra is 100 mg, not to exceed once every 48 hours for patients taking concomitant moderate CYP3A4 inhibitors (see section 4.2). Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase Vantra exposure. Patients should be advised to avoid grapefruit juice within 24 hours prior to taking Vantra.

CYP3A4 substrate

Amlodipine (5 mg daily) increased Vantra 200 mg single-dose Cmax and AUC by approximately 28% and 60%, respectively. These exposure changes are not considered clinically significant. There was no effect of a single dose of Vantra on amlodipine plasma levels. Although specific interactions of Vantra with rivaroxaban and apixaban (both CYP3A4 substrates) have not been studied, an interaction is not expected. Cytochrome P450 Inducers The potential effect of CYP inducers, especially inducers of CYP3A4 (e.g. bosentan, carbamazepine, efavirenz, phenobarbital and rifampicin) on the pharmacokinetics and efficacy of Vantra has not been evaluated. The concomitant use of Vantra and a CYP inducer is not recommended as it may decrease the efficacy of Vantra.

Effects of Vantra on other medicinal products

Cytochrome P450 Inhibition

In in vitro studies in human liver microsomes, Vantra showed a negligible potential for drugdrug interactions with CYP1A1/2, 2A6, 2B6 and 2E1. Further, the metabolites of Vantra (M4, M16 and M27), also demonstrated a minimal inhibition of CYPs 1A1/2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Based on these data Vantra is not anticipated to have a significant effect on other medicinal products metabolised by these enzymes. Since the in vitro data identified potential Vantra interactions with CYPs 2C19, 2C8/9, 2D6 and 3A4, further clinical studies using omeprazole, rosiglitazone and desipramine did not reveal clinically relevant interactions with CYPs 2C19, 2C8/9 and 2D6.

Cytochrome P450 Induction

The potential induction of CYP1A2, CYP2B6 and CYP3A4 by Vantra evaluated in primary human hepatocytes in vitro did not reveal any potential interaction at clinically relevant concentrations. Transporters In vitro results showed for Vantra a modest potential for acting as P-gp substrate and P-gp inhibitor with digoxin as a substrate at concentrations lower than the calculated intestinal concentration. The potential of Vantra to interfere with the transport of other medicinal products mediated by P-gp is not known. Based on in vitro data, at clinically relevant concentrations Vantra could be an inhibitor of BCRP. At clinically relevant concentrations Vantra is not an inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3 and BSEP. The impact of Vantra on other transporters is unknown. Riociguat Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including Vantra, is contraindicated (see section 4.3)

Pregnancy

Vantra is not indicated for use in women. There are no data from the use of Vantra in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or postnatal development (see section 5.3).

Breast-feeding

There are no data on the use of Vantra during breast-feeding.

Fertility

There was no effect on sperm motility or morphology after single 200 mg oral doses of Vantra in healthy volunteers. Currently, no data on spermatogenesis on healthy adult males and adult males with mild ED are available.

Vantra has minor influence on the ability to drive and use machines. As dizziness and altered vision were reported in clinical trials with Vantra, patients should be aware of how they react to Vantra before driving or using machines.

Summary of the safety profile

The safety profile of Vantra is based on 2436 subjects exposed to Vantra during the clinical development program. The most common adverse reactions reported in clinical studies were headache, flushing, nasal and sinus congestion and back pain. Overall adverse events and adverse reactions for Vantra-treated subjects were more frequent in subjects with a Body Mass Index (BMI) <25 (normal BMI subjects). In the long term clinical study, the percentage of patients who experienced adverse reactions decreased with increasing length of exposure.

Tabulated list of adverse reactions

The table below lists the adverse reactions observed in placebo-controlled clinical trials according to the MedDRA frequency convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Adverse reaction (MedDRA Preferred Term)
System Organ Class	Common	Uncommon	Rare
Infections and infestations			Influenza  Nasopharyngitis
Immune system disorders			Seasonal allergy
Metabolism and nutrition disorders			Gout
Psychiatric disorders			Insomnia  Premature ejaculation  Inappropriate affect
Nervous system disorders	Headache	Dizziness  Somnolence  Sinus headache	Psychomotor hyperactivity
Eye disorders		Vision blurred
Cardiac disorders		Palpitations	Angina pectoris  Tachycardia
Vascular disorders	Flushing	Hot flush	Hypertension
Respiratory, thoracic and mediastinal disorders	Nasal congestion	Sinus congestion  Dyspnoeaexertional	Rhinorrhoea  Upper respiratory tract congestion
Gastrointestinal disorders		Dyspepsia  Nausea  Vomiting  Stomach discomfort	Dry mouth  Gastritis  Abdominal pain lower  Diarrhoea
Skin and subcutaneous tissue disorders			Rash
Musculoskeletal and connective tissue disorders		Back pain  Muscle tightness	Flank pain  Myalgia  Muscle spasms
Renal and urinary disorders			Pollakiuria
Reproductive system and breast disorders			Penis disorder  Spontaneous penile erection  Pruritus genital
General disorders and administration site conditions		Fatigue	Asthenia  Chest pain  Influenza like illness  Oedema peripheral
Investigations		Hepatic enzyme increased  Electrocardiogram abnormal  Heart rate increased	Blood pressure increased  Blood urine present  Cardiac murmur  Prostate specific antigen increased  Weight increased  Blood bilirubin increased  Blood creatinine increased  Body temperature increased

Description of selected adverse reactions observed with other PDE5 inhibitors

Non-arteritic anterior ischaemic optic neuropathy (NAION) and sudden loss of hearing have been reported in a small number of postmarketing and clinical trial cases with other PDE5 inhibitors. No cases were reported during clinical trials of Vantra (see section 4.4). Priapism has been reported in a small number of post-marketing and clinical trial cases with other PDE5 inhibitors. No cases were reported during clinical trials of Vantra. Haematuria, haematospermia and penile haemorrhage has been reported in a small number of post-marketing and clinical trial cases with other PDE5 inhibitors. Hypotension has been reported post marketing with other PDE5 inhibitors, and dizziness, a symptom commonly caused by lowered blood pressure, has been reported in clinical trials with Vantra (see section 4.5).

Reporting of suspected adverse reactions

To report any side effect(s):  The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

Single dose of up to 800 mg of Vantra have been given to healthy subjects and multiple daily doses up to 300 mg have been given to patients. 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 Vantra is highly bound to plasma proteins and it is not eliminated in the urine.

Pharmacotherapeutic group: Drugs used in erectile dysfunction. ATC code: G04BE10.

Mechanism of action

Vantra is a highly selective and potent, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5. When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by Vantra produces increased levels of cGMP in the corpus cavernosum of the penis. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Vantra has no effect in the absence of sexual stimulation.

Pharmacodynamic effects

Studies in vitro have shown that Vantra is highly selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (> 100-fold for PDE6; > 1,000-fold for PDE4, PDE8 and PDE10; > 5,000-fold for PDE2 and PDE7; > 10,000-fold for PDE1, PDE3, PDE9, and PDE11). Vantra is > 100-fold more potent for PDE5 than PDE6, which is found in the retina and is responsible for phototransduction. The approximately 20,000-fold selectivity for PDE5 versus PDE3, and enzyme found in heart and blood vessels, is important because PDE3 is involved in control of cardiac contractility. In a penile plethysmography (RigiScan) study, Vantra 200 mg produced erections considered sufficient for penetration (60% rigidity by RigiScan) in some men as early as 20 minutes after dosing and overall response of these subjects to Vantra was statistically significant, compared to placebo, in the 20-40 minute time interval

Clinical efficacy and safety

In clinical trials, Vantra was assessed for its effect on the ability of men with erectile dysfunction (ED) to achieve and maintain an erection sufficient for satisfactory sexual activity. Vantra was evaluated in 4 randomized, double-blind, placebo-controlled, parallel group trials of up to 3 months in duration in the general population with ED, in patients with Type 1 or Type 2 diabetes and ED, and in patients with ED following bilateral nerve-sparing radical prostatectomy. The fourth study investigated the onset of action of Vantra at two doses (100 and 200 mg) in terms of per-subject proportion of sexual attempts resulting in satisfactory completion of sexual intercourse. A total of 1774 patients received Vantra, which was taken as needed at doses of 50 mg (one study), 100 mg and 200 mg (four studies), respectively. Patients were instructed to take 1 dose of study medication approximately 30 minutes prior to initiation of sexual activity. In the fourth study patients were encouraged to attempt sexual intercourse approximately 15 minutes post-dosing, to assess the onset of the erectogenic effect of Vantra, taken on an as needed basis, at 100 and 200 mg dose. In addition, a subset of patients was enrolled into an open-label extension trial with 493 patients receiving Vantra for at least 6 months and 153 patients for at least 12 months. Patients were initially assigned to Vantra 100 mg and at any point during the trial, they could request to have their dose of Vantra increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In all trials, statistically significant improvement in all primary efficacy measures were observed for all three doses of Vantra compared to placebo. These differences were maintained with long term treatment (as per studies in the general ED population, in diabetics with ED and in men with ED following bilateral nerve-sparing radical prostatectomy and in the open-label extension trial). In the general population with ED, the mean percentage of attempts resulting in successful intercourse was approximately 47%, 58%, and 59% for the 50 mg, 100 mg, and 200 mg Vantra groups, respectively, as compared with approximately 28% for placebo. In men with either Type 1 or Type 2 diabetes mellitus, the mean percentage of attempts resulting in successful intercourse was approximately 34% and 40% for the 100 mg and 200 mg Vantra groups, respectively, compared to approximately 21% for the placebo group. In men with ED following bilateral nerve-sparing radical prostatectomy, the mean percentage of attempts resulting in successful intercourse was approximately 23% and 26% for the 100 mg and 200 mg Vantra groups, respectively, compared to approximately 9% for placebo. In the Time to onset study, Vantra demonstrated statistically significant improvement in the primary efficacy variable (average per subject proportion of successful responses by time after dose administration, to the Sexual Encounter Profile 3 - SEP3) as compared with placebo, resulting in successful intercourse in 24.71% of the attempts for the 100 mg dose and 28.18% for the 200 mg dose at approximately 15 minutes after dosing compared to 13.78% for placebo. Across all of the pivotal trials of Vantra, the percentage of successful intercourse attempts was significantly higher for all doses of Vantra compared to placebo for attempts at all post-dosing time intervals examined

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Vantra in all subsets of the paediatric population in erectile dysfunction (see section 4.2 for information on paediatric use)

Vantra is rapidly absorbed after oral administration, with a median Tmax of 30 to 45 minutes. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4). The concomitant use of potent CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) is associated with increased plasma exposure of Vantra (see section 4.5). Vantra has a terminal half-life of approximately 6-17 hours.

Absorption

Vantra is rapidly absorbed. Maximum observed plasma concentrations are reached within 0.5 to 0.75 hours of oral dosing in the fasted state. When Vantra is taken with a high fat meal, the rate of absorption is reduced with a mean delay in Tmaxof 1.25 hours and a mean reduction in Cmax of 39% (200 mg). There was no effect on the extent of exposure (AUC). The small changes in VantraCmax are considered to be of minimal clinical significance.

Distribution

Vantra is approximately 99% bound to plasma proteins. Protein binding is independent of total active substance concentrations, age, renal and hepatic function. Vantra was not found to accumulate in plasma when dosed 200 mg twice daily over 7 days. Based upon measurements of Vantra in semen of healthy volunteers 45-90 minutes after dosing, less than 0.0002% of the administered dose may appear in the semen of patients.

Biotransformation

Vantra is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The plasma concentrations of the major circulating metabolites, M4 and M16, are approximately 23% and 29% that of the parent compound, respectively. The M4 metabolite shows a phosphodiesterase selectivity profile similar to that of Vantra and an in vitro inhibitory potency for PDE5 18% of that of Vantra. Therefore, M4 accounts for approximately 4% of total pharmacologic activity. The M16 metabolite was inactive against PDE5.

Elimination

Vantra is extensively metabolised in humans. After oral administration, Vantra is excreted as metabolites predominantly in the faeces (approximately 63% of administered oral dose) and to a lesser extent in the urine (approximately 21% of the administered oral dose).

Other special populations

Older men Older patients (65 years or over) had comparable exposure to that seen in younger patients (18- 45 years). However, data on subjects older than 70 years are limited. Renal impairment In subjects with mild (creatinine clearance ≥ 50 - < 80 mL/min) and moderate (creatinine clearance ≥ 30 - < 50 mL/min) renal impairment, the pharmacokinetics of a single 200 mg dose of Vantra were not altered. There are no data available for subjects with severe renal insufficiency or end-stage renal disease on haemodialysis. Hepatic impairment Subjects with mild hepatic impairment (Child-Pugh A) had comparable exposure to subjects with normal hepatic function when a single dose of 200 mg Vantra was administered. The exposure 4 hours post-dose was lower in subjects with moderate hepatic impairment (Child-Pugh B) compared to subject with normal hepatic function after 200 mg of Vantra. The maximum concentration and exposure was similar to that observed after subjects with normal hepatic function received an efficacious Vantra 100 mg dose.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

In a rat fertility and early embryonic development trial, a decrease in fertility and sperm motility, altered estrous cycles, and an increased percentage of abnormal sperm occurred at 1000 mg/kg/day, a dose which also caused parental toxicity in the treated males and females. No effects on fertility or sperm parameters were noted at doses up to 300 mg/kg/day (in male rats 9 times human exposure based on unbound AUC at a dose of 200 mg). There were no treatment-related testicular findings in mice or rats treated with doses up to 600 or 1000 mg/kg/day for 2 years, and no testicular findings in dogs treated with Vantra for 9 months at exposures 110 times human exposure at the Maximum Recommended Human Dose (MRHD). In pregnant rats, no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed at doses up to 300 mg/kg/day (approximately 15 times the MRHD on a mg/m2 basis in a 60 kg subject). At a maternally toxic dose of 1000 mg/kg/day (approximately 49 times the MRHD on a mg/m2 basis), decreased fetal body weight occurred with no signs of teratogenicity. In pregnant rabbits, no teratogenicity, embryotoxicity or fetotoxicity was observed at doses up to 240 mg/kg/day (approximately 23 times the MRHD on a mg/m2 basis. In the rabbit study, maternal toxicity was observed at 240 mg/kg/day. In a rat pre- and post-natal development study, pups exhibited persistent decreases in body weight at 300 mg/kg/day and higher (approximately 15 times the MRHD on a mg/m2 basis) and delayed sexual development at 600 mg/kg/day (approximately 29 times the MRHD on a mg/m2 basis).

The other ingredients are Mannitol B.P, Fumaric Acid NF, Klucel EXF Pharm (Hydroxypropyl Cellulose ), Iron Oxide Yellow, Hydroxypropyl Methylcellulose Low-S., Calcium Carbonate Precipitated, and Magnesium Stearate

Not applicable.

24Months/2 Years

Store below 30°C

Clear PVC/PE/PVDC 250/25/120 95mm Each pack of Vantra 50 mg tablets contains 4, 12, and 30 tablets. Each pack of Vantra 100 mg tablets contains 4, and 12 tablets. Each pack of Vantra 200 mg tablets contains 4, and 12 tablets. Not all pack sizes may be marketed.

No special requirements.