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)].

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)].

Guanylate Cyclase (GC) Stimulators, such as riociguat: Concomitant use is contraindicated [see Contraindications (4.2)].

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. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a phosphodiesterase (PDE5) inhibitor including vardenafil. 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).]

A time interval between dosing should be considered when STAXYN is prescribed concomitantly with alpha-blocker therapy [see Clinical Pharmacology (12.2)].

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.

4.2 Guanylate Cyclase (GC) Stimulators

Do not use STAXYN in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including STAXYN may potentiate the hypotensive effects of GC stimulators.

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).]

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 phosphodiesterase type 5 (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 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 study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, 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)].

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 [see Adverse Reactions (6.2)].

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 Staxyn, 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 STAXYN, for this uncommon condition.

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 [see Warnings and Precautions (5.4) and Patient Counseling Information (17)].

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 alfuzosin, 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

8.2 Lactation

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 Cmaxin elderly males 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 Cmaxand 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.

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.

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.

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.