Staxyn

• Levitra^®
• Staxyn^®

• GlaxoSmithKline LLC

Do not take Staxyn if you:

• take any medicines called “nitrates”. Nitrates are commonly used to treat angina. Angina is a symptom of heart disease and can cause pain in your chest, jaw, or down your arm.
  Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide mononitrate. Some recreational drugs called “poppers” also contain nitrates, such as amyl nitrate and butyl nitrate. Do not use Staxyn if you are using these drugs. Ask your doctor or pharmacist if you are not sure if any of your medicines are nitrates.
• you have been told by your healthcare provider to not have sexual activity because of health problems. Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease.
• are allergic to Staxyn or any of its ingredients. 

Staxyn may uncommonly cause:

• an erection that won’t go away (priapism). If you get an erection that lasts more than 4 hours, get medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to your penis including the inability to have erections.
• color vision changes, such as seeing a blue tinge to objects or having difficulty telling the difference between the colors blue and green.

In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including Staxyn, reported a sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including Staxyn, and call a doctor right away.

Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including Staxyn. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking Staxyn and contact a doctor right away.

Each Staxyn tablet contains 1.01 mg phenylalanine per tablet, which could be harmful for patients with phenylketonuria.

Patients with congenital QT syndrome or taking class IA or III antiarrhythmics should avoid using Staxyn as this medication may increase your risk of QT prolongation. 

These are not all the side effects of Staxyn. For more information, ask your doctor or pharmacist.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category B. Staxyn is only for use in men. Additionally, there are no studies of Staxyn use in pregnant women. No evidence of potential for harm to unborn babies in animal studies have been observed.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• There is more than 1 brand of Staxyn. One brand cannot safely be used for the other. The doctor will tell you about any needed change.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Do not take Staxyn with other drugs used to treat a change in sex ability.
• Talk with your doctor before you drink alcohol.
• Avoid grapefruit and grapefruit juice.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• A very bad eye problem has rarely happened with this medicine. This may lead to a change in eyesight and sometimes loss of eyesight, which may not come back. Talk with the doctor.
• If you are 65 or older, use Staxyn with care. You could have more side effects.
• This medicine is not approved for use in children. Talk with the doctor.
• This medicine is not approved for use in women. If you are a woman using this medicine, talk with your doctor if you are pregnant, plan on getting pregnant, or are breast-feeding.
• If you have phenylketonuria (PKU), talk with your doctor. Some products have phenylalanine.
• This medicine has sorbitol in it and may lead to upset stomach and diarrhea in people who have fructose intolerance. Talk with the doctor.

Staxyn® is indicated for the treatment of erectile dysfunction.

Staxyn is available in 10 mg white, round, orally disintegrating tablets (not scored), no debossing.

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).

Pharmacodynamics

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

Effects on Blood Pressure

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

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

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

Study 1: This study was designed to evaluate the effect of 5 mg vardenafil 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. A decrease in standing SBP of >30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.

Table 2: Mean (95% 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 of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4.

 

Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg 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)

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

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

	Vardenafil 5 mg Placebo-subtracted	Vardenafil 10 mg Placebo-subtracted
Standing SBP	-2 (-5.8, 1.2)	-5 (-8.8, -1.6)
Supine SBP	-1 (-4.1, 2.1)	-6 (-9.4, -2.8)

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

Figure 5: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following 4 hr separation administration of vardenafil 5 mg (stage 1), vardenafil 10 mg (stage 2) or placebo with stable dose alfuzosin 10 mg in BPH patients (Study 3)

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 5: 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 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 terazosin (10 mg) in healthy volunteers

Figure 7: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 10 mg and 20 mg (film-coated tablets) or placebo with tamsulosin (0.4 mg) in healthy volunteers

Effects on Cardiac Electrophysiology

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

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

* Active control (drug known to prolong QT)
Drug/Dose	QT Uncorrected (msec)	Fridericia QT Correction (msec)	Individual QT Correction (msec)
Vardenafil 10 mg	-2 (-4, 0)	8 (6, 9)	4 (3, 6)
Vardenafil 80 mg	-2 (-4, 0)	10 (8, 11)	6 (4, 7)
Moxifloxacin* 400 mg	3 (1, 5)	8 (6, 9)	7 (5, 8)

Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced similar increases in QTc interval. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. The clinical impact of these QTc changes is unknown [see Warnings and Precautions (5)].

In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg vardenafil (film-coated tablet) resulted in a placebo-subtracted mean change from baseline of QTcF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400 mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When vardenafil 10mg (film-coated tablets) and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11). The clinical impact of these QT changes is unknown [see Warnings and Precautions (5.7)].

Effects on Exercise Treadmill Test in Patients with Coronary Artery Disease (CAD)

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

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

Effects on Eye

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

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

Effects on Sperm Motility Morphology

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

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

Mean vardenafil plasma concentrations measured after the administration of a single oral dose Staxyn to patients with erectile dysfunction (18- 45 years) are depicted in Figure 8.

Figure 8: 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 Cmaxand 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.

Distribution

The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.

Following a single oral dose of 20 mg vardenafil film-coated tablet in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.

Metabolism

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.

Excretion

The mean terminal half-life of vardenafil in patients receiving Staxyn tablets varied between about 4–6 hours. The elimination half-life of the metabolite M1 is between 3 to 5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91–95% of administered oral dose) and to a lesser extent in the urine (approximately 2–6% of administered oral dose). Vardenafil is a high clearance drug with a plasma clearance of 56.4 L/h following intravenous administration.

Pharmacokinetics in Specific Populations

Pediatrics

Staxyn is not indicated for use in pediatric patients. Vardenafil trials were not conducted in the pediatric population.

Geriatrics

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 [see Use in Specific Populations (8.5)].

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. 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. [See Dosage and Administration (2.3), Warnings and Precautions (5.8), and Use in Specific Populations (8.6).]

Renal Impairment

In volunteers with mild renal impairment (CLcr = 50–80 mL/min), the pharmacokinetics of vardenafil 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). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis [see Dosage and Administration (2.3), Warnings and Precautions (5.9), and Use in Specific Populations (8.7)].

Taking Staxyn orally disintegrating tablets with certain other medicines can cause a sudden and serious decrease in blood pressure. Do not take vardenafil if you also take riociguat (Adempas) or a nitrate drug such as nitroglycerin.

Stop using this medicine and get emergency medical help if you have sudden vision loss.

Contact your doctor or seek emergency medical attention if your erection is painful or lasts longer than 4 hours. A prolonged erection (priapism) can damage the penis.

During sexual activity, if you become dizzy or nauseated, or have pain, numbness, or tingling in your chest, arms, neck, or jaw, stop and call your doctor right away. You could be having a serious side effect.

Usual Adult Dose for Erectile Dysfunction:

-Initial dose: 10 mg orally once a day, as needed, approximately 60 minutes before sexual activity. Increase to 20 mg or decrease to 5 mg based on efficacy and tolerability.
-Maximum dose: 20 mg once a day

Patients on stable alpha blocker therapy:
-Initial dose: 5 mg orally once a day

Comments:
-Sexual stimulation is required for a response to treatment.
-A time interval between dosing should be considered when administering this drug concomitantly with alpha-blockers.
-Patients taking alpha-blockers should not initiate therapy with the Staxyn orally disintegrating tablet.

Use: Erectile dysfunction

Usual Geriatric Dose for Erectile Dysfunction:

65 years or older:
-Initial dose: 5 mg orally once a day, as needed, approximately 60 minutes before sexual activity

Comments: Sexual stimulation is required for a response to treatment.

Use: Erectile dysfunction