vardenafil 10 MG (vardenafil hydrochloride 11.85 MG) Disintegrating Oral Tablet
DRUG INTERACTIONS
7 The drug interaction studies described below were conducted using vardenafil film-coated tablets.
• STAXYN can potentiate the hypotensive effects of nitrates, alpha-blockers, and antihypertensives.
( 7.1 ) • Do not use STAXYN with moderate or potent CYP3A4 inhibitors as co-administration will result in significant increases in plasma vardenafil concentrations.
( 7.2 ) 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 In vitro studies Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9.
Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)] .
In vivo studies Do not use STAXYN with moderate and potent CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions ( 5 ) and Dosage and Administration ( 2.4 )] .
Potent CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil 5 mg in healthy volunteers.
[See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max and a 2-fold increase in vardenafil half-life.
[See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C max .
The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9.
[See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 ).] Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil C max when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5 )].
Other Drug Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine.
In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.
Cimetidine (400 mg b.i.d.) had no effect on AUC and C max of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.
7.3 Effects of Vardenafil on Other Drugs In vitro studies Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar).
Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing.
The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 C max values after an 80 mg vardenafil dose.
In vivo studies Nifedipine: Vardenafil 20 mg (film-coated tablets), when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or C max of nifedipine, a drug that is metabolized via CYP3A4.
Nifedipine did not alter the plasma levels of vardenafil when taken in combination.
STAXYN, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily in patients whose hypertension was controlled with nifedipine, produced mean additional supine systolic/diastolic blood pressure reductions of 3/4 mmHg (age group 65 to 69 years) and 5/5 mmHg (age group 70 to 80 years) compared to placebo.
Ritonavir and Indinavir: Upon concomitant administration of 5 mg vardenafil with 600 mg b.i.d.
ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%.
Upon administration of 10 mg of vardenafil (film-coated tablets) with 800 mg t.i.d.
indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively.
Aspirin: Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other Interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
OVERDOSAGE
10 The maximum dose of vardenafil for which human data are available is a single 120 mg dose of the film–coated tablets administered to healthy male volunteers.
The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.” Single doses up to 80 mg vardenafil and multiple doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing serious adverse side effects.
When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed.
No muscle or neurological toxicity was identified.
In cases of overdose, standard supportive measures should be taken as required.
Renal dialysis is not expected to accelerate clearance because vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.
DESCRIPTION
11 STAXYN (vardenafil hydrochloride) is an oral therapy for the treatment of erectile dysfunction.
This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5.
Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula: Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.
STAXYN is formulated as white round orally disintegrating tablets with no debossing.
Each tablet contains 11.85 mg vardenafil hydrochloride, which corresponds to 10 mg vardenafil, and the following inactive ingredients: aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).
Structural Formula
CLINICAL STUDIES
14 The efficacy and safety of STAXYN were evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials (studies 1 and 2).
STAXYN was dosed without regard to meals on an as-needed basis in men with erectile dysfunction (ED), many of whom had multiple other medical conditions.
In both pivotal studies, randomization was stratified so that approximately 50% of patients were ≥65 years old.
Primary efficacy assessment was by means of the Erectile Function (EF) Domain score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3).
The primary endpoints were assessed at 3 months.
Study 1 evaluated 355 mainly European (Belgium, France, Germany, Spain, South Africa, and Netherlands) patients (mean age 61.9; 67% White, 4% Black, 3% Asian, 26% Unknown).
The mean baseline EF domain scores were 13 for both placebo and STAXYN groups.
Study 2 evaluated 331 mainly North American (USA, Canada, Mexico, and Australia) patients (mean age 61.7; 69% White, 5% Black, 4% Asian, 22% Hispanic).
The mean baseline EF domain scores were 12 for STAXYN and 13 for placebo.
In both studies STAXYN demonstrated clinically meaningful and statistically significant improvements over placebo in all 3 primary efficacy variables (see Table 7).
Table 7: Change from Baseline for the Primary Efficacy Variables in Studies 1 and 2 Study 1 Study 2 Placebo STAXYN p-value Placebo STAXYN p-value EF Domain Score (N=172) (N=181) (N=160) (N=167) Endpoint 14 21 14 21 Change from baseline 1.6 8.7 <.0001 1.5 8.5 <.0001 Insertion of Penis (SEP2) (N=169) (N=179) (N=161) (N=168) Endpoint 45% 74% 43% 69% Change from baseline 6.9% 35.9% <.0001 4.8% 30.8% <.0001 Maintenance of Erection (SEP3) (N=164) (N=178) (N=160) (N=168) Endpoint 26% 65% 27% 60% Change from baseline 11.6% 51.6% <.0001 12.4% 45.9% <.0001 14.1 Other Vardenafil Clinical Trials Using Film-Coated Tablets Patients with ED and Diabetes Mellitus Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose [10 and 20 mg vardenafil film-coated tablets], double-blind, placebo-controlled trial of patients with diabetes mellitus (n=439; mean age 57 years, range 33–81; 80% White, 9% Black, 8% Hispanic, and 3% Other).
Significant improvements in the EF Domain were shown in this study (EF Domain scores of 17 on 10 mg vardenafil and 19 on 20 mg vardenafil compared to 13 on placebo; p <0.0001).
Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (61% on 10 mg and 64% on 20 mg vardenafil compared to 36% on placebo; p <0.0001).
Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (49% on 10 mg, 54% on 20 mg vardenafil compared to 23% on placebo; p <0.0001).
Patients with ED after Radical Prostatectomy Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose 10 and 20 mg vardenafil film-coated tablets, double-blind, placebo-controlled trial in post-prostatectomy patients (n=427, mean age 60, range 44–77 years; 93% White, 5% Black, 2% Other).
Significant improvements in the EF Domain were shown in this study (EF Domain scores of 15 on 10 mg vardenafil and 15 on 20 mg vardenafil compared to 9 on placebo; p <0.0001).
Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (47% on 10 mg and 48% on 20 mg vardenafil compared to 22% on placebo; p <0.0001).
Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (37% on 10 mg, 34% on 20 mg vardenafil compared to 10% on placebo; p <0.0001).
HOW SUPPLIED
16 /STORAGE AND HANDLING 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.
Package Strength NDC Code 1 blister card containing 4 tablets 10 mg 0173-0822-04 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.
RECENT MAJOR CHANGES
Warnings and Precautions, Effects on the Eye ( 5.4 ) 8/2017
GERIATRIC USE
8.5 Geriatric Use Vardenafil AUC and C max in 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 )].
DOSAGE FORMS AND STRENGTHS
3 STAXYN is available in 10 mg white, round, orally disintegrating tablets (not scored), no debossing.
• STAXYN 10 mg: White, round, orally disintegrating tablets (not scored) ( 3 )
MECHANISM OF ACTION
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).
INDICATIONS AND USAGE
1 STAXYN ® is indicated for the treatment of erectile dysfunction.
• STAXYN is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use STAXYN is not indicated for use in pediatric patients.
Safety and efficacy in children has not been established.
PREGNANCY
8.1 Pregnancy Risk Summary STAXYN is not indicated for use in females.
There are no data with the use of STAXYN in pregnant women to inform any drug-associated risks.
In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of vardenafil during organogenesis at exposures for unbound vardenafil and its major metabolite at approximately 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg based on AUC (see Data) .
Data Animal Data 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 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment.
Before prescribing STAXYN, it is important to note the following: • Cardiovascular Effects: Patients should not use STAXYN if sex is inadvisable due to cardiovascular status.
( 5.1 ) • Potent and Moderate CYP3A4 Inhibitors: Do not use STAXYN in patients taking potent or moderate CYP3A4 inhibitors.
( 5.2 , 7.2 ) • Risk of Priapism: In the event that an erection lasts more than 4 hours, the patient should seek immediate medical assistance.
( 5.3 ) • Effects on the Eye: Patients should stop use of STAXYN, and seek medical attention in the event of sudden loss of vision in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION).
STAXYN should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION.
Patients with a “crowded” optic disc may also be at an increased risk of NAION.
( 5.5 , 6.2 ) • Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.
In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting).
In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN.
( 2.4 , 5.6 ) • QT Prolongation: Patients with congenital QT syndrome or taking class IA or III antiarrhythmics should avoid using STAXYN.
( 5.7 , 12.2 ) • Phenylketonurics: Each STAXYN tablet contains 1.01 mg phenylalanine per tablet, which could be harmful for patients with phenylketonuria.
( 5.12 ) 5.1 Cardiovascular Effects General Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity.
Therefore, treatment for erectile dysfunction, including STAXYN, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status.
There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of 170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.
Left Ventricular Outflow Obstruction Patients with left ventricular outflow obstruction (for example, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.
Blood Pressure Effects Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic) [see Clinical Pharmacology ( 12.2 )] .
While this normally would be expected to be of little consequence in most patients, prior to prescribing STAXYN, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Use with Other Formulations of Vardenafil 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.
Nitrates Discuss with patients that STAXYN is contraindicated 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.
Guanylate Cyclase (GC) Stimulators Inform patients that Staxyn is contraindicated in patients who use guanylate cyclase stimulators, such as riociguat.
Cardiovascular Discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.
Concomitant Use with Drugs which Lower Blood Pressure Inform patients that in some patients concomitant use of PDE5 inhibitors, including 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.
Recommended Administration 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.
Priapism Inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for 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.
Drug Interactions Advise patients to contact the prescribing physician if new medications that may interact with STAXYN are prescribed by another healthcare provider.
Sudden Loss of Vision Inform 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.
Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye.
Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including Staxyn, for this uncommon condition [see Warnings and Precautions ( 5.4 ) and [see Adverse Reactions ( 6.1 )].
Sudden Hearing Loss 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 )].
Sexually Transmitted Disease Inform patients that STAXYN offers no protection against sexually transmitted diseases.
Counsel patients that protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.
Dose Adjustment STAXYN is available only in a single strength.
Patients who require a different dosage should be prescribed vardenafil film-coated tablets (LEVITRA).
DOSAGE AND ADMINISTRATION
2 • 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).
( 2.1 ) • STAXYN is taken as needed, orally, approximately 60 minutes before sexual activity.
( 2.1 ) • The maximum recommended dosing frequency is one tablet per day.
( 2.1 ) • STAXYN should be placed on the tongue where it will disintegrate.
It should be taken without liquid.
( 2.1 ) • STAXYN may be taken with or without food.
( 2.2 ) 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 )].