2.1 General

STAXYN is available in 10 mg orally disintegrating tablets. STAXYN is not interchangeable with vardenafil 10 mg film-coated tablets (LEVITRA). STAXYN provides higher systemic exposure compared to vardenafil 10 mg film-coated tablets (LEVITRA). [See Clinical Pharmacology (12.3).]

STAXYN should be taken orally, as needed, approximately 60 minutes before sexual activity. The maximum dosing frequency is one STAXYN tablet per day. Sexual stimulation is required for a response to treatment.

STAXYN should be placed on the tongue where it will disintegrate. The tablet should be taken without liquid. It should be taken immediately upon removal from the blister.

Those patients who require a lower or higher dose of vardenafil need to be prescribed vardenafil film-coated tablets [see Patient Counseling Information (17.11)].

2.2 Use with Food

STAXYN can be taken with or without food.

2.3 Use in Special Populations

Hepatic Impairment:  Do not use STAXYN in  patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].

Renal Impairment: Do not use STAXYN in patients on renal dialysis [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)].

2.4 Concomitant Medications

Nitrates: Concomitant use with nitrates in any form is contraindicated [see Contraindications (4.1)].

CYP3A4 Inhibitors: Do not use STAXYN with potent or moderate CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, clarithromycin and erythromycin [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. 

Alpha-Blockers: In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose. In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN. Lower doses of vardenafil film-coated tablets should be used as initial therapy in these patients. [see Dosage and Administration (2.4)]. Patients taking alpha-blockers who have previously used vardenafil film-coated tablets may change to STAXYN at the advice of their healthcare provider. [See Warnings and Precautions (5.6) and Drug Interactions (7.1).]

4.1 Nitrates

Administration of STAXYN with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated [see Clinical Pharmacology (12.2)]. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including STAXYN, may potentiate the hypotensive effects of nitrates. A suitable time interval following STAXYN dosing for the safe administration of nitrates or nitric oxide donors has not been determined.

5.1 Cardiovascular effects

5.2 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. Do not use STAXYN in patients taking potent or moderate CYP3A4 inhibitors. [See Dosage and Administration (2.4), Drug Interactions (7.2) and Patient Counseling Information (17.11).]

5.3 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.

STAXYN 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).

5.4 Effects on the Eye

Physicians should advise patients to stop use of all PDE5 inhibitors, including STAXYN, 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 postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Adverse Reactions (6.2)].

STAXYN 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.

5.5 Sudden Hearing Loss

Physicians should advise patients to stop taking all PDE5 inhibitors, including STAXYN, 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 [see Adverse Reactions (6.2)].

5.6 Alpha-Blockers

In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN. Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be changed to STAXYN at the advice of their healthcare provider. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including STAXYN, 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)] 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 patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN. Lower doses of vardenafil film-coated tablets should be used as initial therapy in these patients [see Dosage and Administration (2.4)].
• In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases 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.

5.7 Congenital or Acquired QT Prolongation

In a study of the effect of vardenafil on QT interval in 59 healthy males [see Clinical Pharmacology (12.2)], therapeutic (10 mg film-coated tablets) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QTc interval. A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone [see Clinical Pharmacology (12.2)]. These observations should be considered in clinical decisions when prescribing vardenafil 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 STAXYN .

5.8 Hepatic Impairment

Do not use STAXYN in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Dosage and Administration (2.3) Clinical Pharmacology (12.3)] and Use in Specific Populations (8.6)].

5.9 Renal Impairment

Do not use STAXYN in patients on renal dialysis, as vardenafil has not been evaluated in this population [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].

5.10 Combination with Other Erectile Dysfunction Therapies

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

5.11 Effects on Bleeding

In humans, vardenafil film-coated tablet 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. STAXYN has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore STAXYN should be administered to these patients after careful benefit-risk assessment.

5.12 Phenylketonurics

STAXYN contains aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.

Phenylketonurics: Each STAXYN tablet contains 1.01 mg phenylalanine per tablet.

5.13 Fructose Intolerance

STAXYN contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take STAXYN.

5.14 Sexually Transmitted Disease

The use of STAXYN 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.

6.1 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.

STAXYN: Safety of STAXYN was evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials. In both pivotal studies, enrollment was stratified so that approximately 50% of patients were ≥65 years old. Approximately 8% (n=29) were ≥75 years old. An integrated analysis of both studies included a total of 355 subjects that received STAXYN compared to 340 subjects that received placebo (mean age was 61.7, range 21.0 to 88.0; 68% White, 5% Black, 6% Asian, 11% Hispanic and 11% Other). The discontinuation rates due to adverse reactions were 1.4% for STAXYN compared to 0.6% for placebo. Table 1 below details the most frequently reported adverse reactions.

Adverse drug reactions reported in the STAXYN placebo controlled trials were comparable to the adverse drug reactions reported in earlier vardenafil film-coated tablets placebo controlled trials.

All Vardenafil Studies: Vardenafil film-coated tablets and STAXYN has 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 vardenafil film-coated tablets and STAXYN, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo.

Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (for example, dizziness, headache, flushing, dyspepsia, nausea, nasal congestion) over the 5 mg, 10 mg, and 20 mg doses of vardenafil film-coated tablets.

The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of vardenafil film-coated tablets and STAXYN. 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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of vardenafil in the film-coated tablet formulation. 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions (5.4) and Patient Counseling Information (17.8)].

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 [see Patient Counseling Information (17.9)].

7.1 Potential for Pharmacodynamic Interactions with STAXYN

Nitrates: Concomitant use of STAXYN and nitrates is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of vardenafil in healthy middle-aged subjects. These effects were not observed when vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of STAXYN and nitrates is contraindicated [see Contraindications (4.1) and Clinical Pharmacology (12.2)].

Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with STAXYN.  Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be switched to STAXYN at the advice of their healthcare provider. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including STAXYN 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. Clinical pharmacology studies have been conducted with co-administration of vardenafil with terazosin or tamsulosin. [See Dosage and Administration (2.4), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2).]

Antihypertensives: STAXYN may add to the blood pressure lowering effect of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg vardenafil 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.

Alcohol: Vardenafil 20 mg did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

7.2 Effect of Other Drugs on Vardenafil

7.3 Effects of Vardenafil on Other Drugs

8.1 Pregnancy

Pregnancy Category B: STAXYN is not indicated for use in women. There are no studies of STAXYN 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. There are no adequate and well-controlled trials of vardenafil in pregnant women.

8.3 Nursing Mothers

STAXYN 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.

8.4 Pediatric Use

STAXYN is not indicated for use in pediatric patients. Safety and efficacy in children has not been established.

8.5 Geriatric Use

Vardenafil AUC and Cmax in elderly patients (65 years or older) taking STAXYN were increased by 39% and 21%, respectively, in comparison to patients aged 45 years and below. No overall differences in safety or effectiveness were observed between patients ≥65 years old and those < 65 years old in placebo-controlled clinical trials [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Do not use STAXYN in patients with moderate or severe hepatic impairment.

In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil (film-coated tablets) dose were increased by 22% and 17%, respectively, compared to healthy control subjects. STAXYN can be used in patients with mild hepatic impairment. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil (film-coated tablets) dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment. Do not use STAXYN in patients with moderate to severe hepatic impairment. [See Warnings and Precautions (5.8) and Dosage and Administration (2).]

8.7 Renal Impairment

Do not use STAXYN in patients on renal dialysis.

In volunteers with mild renal impairment (CLcr = 50–80 mL/min), the pharmacokinetics of vardenafil 20 mg film-coated tablets were similar to those observed in a control group with normal renal function. In the moderate (CLcr = 30–50 mL/min) or severe (CLcr <30 mL/min) renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with normal renal function (CLcr >80 mL/min). STAXYN can be used in patients with mild, moderate or severe renal impairment. Do not use STAXYN in patients on renal dialysis as vardenafil has not been evaluated in such patients [see Dosage and Administration (2.3) and Warnings and Precautions (5.9)].

12.1 Mechanism of Action

Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific PDE5; therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.

In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

12.2 Pharmacodynamics

The pharmacodynamic studies described below were conducted using vardenafil film-coated tablets.

Effects on Blood Pressure and Heart Rate when Vardenafil 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 vardenafil 20 mg film-coated tablets at various times before NTG administration. Vardenafil 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 vardenafil 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 vardenafil 20 mg film-coated tablet 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 [see Contraindications (4.1)].

Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment

Two clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment for at least four weeks.

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil film-coated tablets 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; two and one patient (vardenafil and placebo, respectively) had a decrease in standing SBP of >30 mmHg. 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% CI) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (study 1)

Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP	-6 (-9.9, -2.1)	-4 (-8.3, -0.5)
	Supine SBP	-4 (-7, -0.8)	-5 (-7.9, -1.7)

Blood pressure effects (standing SBP) in normotensive men on stable dose 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 (film-coated tablets) (stage 1) and 20 mg vardenafil (film-coated tablets) (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 6-hour 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% CI) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg (film-coated tablets) in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (study 2)

	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 20 mg or placebo, or following administration of vardenafil 20 mg or placebo separated by 6 hours 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 film-coated tablet (stage 1), vardenafil 20 mg film-coated tablet (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (study 2)

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 simultaneously the amount of time at the maximum concentration in serum (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 4: Mean (95% CI) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg (film-coated tablets) in healthy volunteers on daily alpha-blocker therapy

		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16)*	-14 (-33, 11)*
	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)*	-7 (-31, 22)*
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

* Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.

Figure 5: 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 and 20 mg (film-coated tablets) or placebo with terazosin (10 mg) in healthy volunteers

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 and 20 mg (film-coated tablets) or placebo with tamsulosin (0.4 mg) in healthy volunteers

12.3 Pharmacokinetics

The pharmacokinetics of vardenafil and its M1 metabolite from STAXYN have been evaluated in healthy male volunteers (18–50 years) and in young (18–45 years) and elderly (≥ 65 years) erectile dysfunction patients. Studies have shown that STAXYN provides higher systemic exposure of vardenafil compared to vardenafil 10 mg film-coated tablets. 

Absorption

Figure 7: Vardenafil Plasma Concentration (Mean ± SD) Profile for STAXYN in men age 18-45 years with erectile dysfunction

The median time to reach Cmax (Tmax) in patients receiving STAXYN in the fasted state was 1.5 h [range: 0.75 – 2.5 h]. After administration of STAXYN to elderly (≥ 65 years) and young (18–45 years) patients with erectile dysfunction, mean vardenafil AUC was increased by 21 to 29%, respectively while mean Cmax was lower by 19% and 8%, respectively, in comparison to 10 mg vardenafil (film-coated tablets). In a study of healthy male volunteers (18–50 years), the mean Cmax and AUC of vardenafil from STAXYN were higher by 15% and 44%, respectively compared to 10 mg vardenafil film-coated tablets.

Vardenafil was not found to accumulate in plasma when STAXYN was dosed daily over ten days.

Effect of food: A high fat meal had no effect on vardenafil AUC and Tmax from STAXYN in healthy volunteers and reduced Cmax by 35%. Clinical trials for STAXYN were conducted without regard to meals. STAXYN can be taken with or without food.

Effect of water: When STAXYN was swallowed with water, the AUC of vardenafil was reduced by 29% and median Tmax was shortened by 60 minutes while Cmax was not affected. In clinical trials, dosing was done without water. STAXYN should be taken without liquid.

13.1 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 males, 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.

14.1 Other Vardenafil Clinical Trials Using Film-Coated Tablets

16.1 How Supplied

STAXYN (vardenafil HCl) are white, round orally disintegrating tablets with no debossing. STAXYN orally disintegrating tablets are packaged into foil blisterpacks and supplied as a 4 tablet unit or as a 40 tablet bulk pack.

In addition to the active ingredient, vardenafil, each tablet contains aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).

16.2 Recommended Storage

Store STAXYN at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

STAXYN is dispensed in blisterpacks. The patient should be advised to examine the blisterpack before use and not use if blisters are torn, broken, or missing.

17.1 Use with Other Formulations of Vardenafil

Physicians should inform patients that STAXYN is not interchangeable with vardenafil film-coated tablets (LEVITRA) as it provides higher systemic exposure. They should also discuss that the maximum dosage is one STAXYN tablet per 24 hours.

17.2 Nitrates

Physicians should discuss with patients the contraindication of STAXYN with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of vardenafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.

17.3 Cardiovascular

Physicians should discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.

17.4 Concomitant Use with Drugs which Lower Blood Pressure

Physicians should inform their patients that in some patients concomitant use of PDE5 inhibitors, including STAXYN, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting). Patients who are taking alpha-blockers should only use STAXYN when previous treatment with vardenafil film-coated tablets has been well tolerated [see Dosage and Administration (2) and Drug Interactions (7)]. 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 STAXYN are prescribed by another healthcare provider.

17.5 Recommended Administration

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

17.6 Priapism

Physicians should 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 vardenafil 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.

17.7 Drug Interactions

Patients should be advised to contact the prescribing physician if new medications that may interact with STAXYN are prescribed by another healthcare provider.

17.8 Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including STAXYN, 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 postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Adverse Reactions (6.1)].

17.9 Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including STAXYN, 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 STAXYN. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6)].

17.10 Sexually Transmitted Disease

The use of STAXYN 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.

17.11 Dose Adjustment

STAXYN is available only in a single strength. Patients who require a different dosage should be prescribed vardenafil film-coated tablets (LEVITRA).

Additional barcode labeling by:
Physicians Total Care, Inc.
Tulsa, Oklahoma       74146