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Levitra
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There are no controlled clinical data on the safety or efficacy of LEVITRA in the following patients; and therefore its use is not recommended until further information is available.
Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase Type 5 (PDE5) inhibitors, including LEVITRA, 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 , ) leading to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:
Hepatic Insufficiency:
In volunteers with moderate impairment (Child-Pugh B), the C and AUC following a 10 mg vardenafil dose were increased 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepatic impairment and the maximum dose should not exceed 10 mg (see , and ). Vardenafil has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).
Congenital or Acquired QT Prolongation:
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Renal Insufficiency:
In patients with moderate (CL = 30-50 ml/min) to severe (CL<30 ml/min) renal impairment, the AUC of vardenafil was 20 – 30% higher compared to that observed in a control group with normal renal function (CL>80 ml/min) (see , ). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis.
General:
Treatment for erectile dysfunction should generally 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).
The safety and efficacy of LEVITRA used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Information for Patients
Physicians should discuss with patients the contraindication of LEVITRA with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of LEVITRA with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Physicians should inform their patients that in some patients concomitant use of PDE5 inhibitors, including LEVITRA, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (e.g., fainting). Patients prescribed LEVITRA who are taking alpha-blockers should be started on the lowest recommended starting dose of LEVITRA (see and ). 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 LEVITRA are prescribed by another healthcare provider.
Physicians should discuss with patients the appropriate use of LEVITRA and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking LEVITRA. LEVITRA should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of LEVITRA. Patients should be advised to contact their healthcare provider for dose modification if they are not satisfied with the quality of their sexual performance with LEVITRA or in the case of an unwanted effect. Patients should be advised to contact the prescribing physician if new medications that may interact with LEVITRA are prescribed by another healthcare provider.
Physicians should advise patients to stop use of all PDE5 inhibitors, including LEVITRA, 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 post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors (see , ).
Physicians should advise patients to stop taking PDE5 inhibitors, including LEVITRA, 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 LEVITRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ).
Physicians should discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.
The use of LEVITRA 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.
Physicians should inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for LEVITRA 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
Effect of other drugs on LEVITRA
In vitro studies:
In vivo studies: Cytochrome P450 Inhibitors
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C) of vardenafil when co-administered with 20 mg LEVITRA in healthy volunteers.
Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C when co-administered with LEVITRA 5 mg in healthy volunteers (see ). It is recommended not to exceed a single 5 mg dose of LEVITRA in a 24-hour period when used in combination with erythromycin.
Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in C when co-administered with LEVITRA (5 mg) in healthy volunteers. A 5-mg LEVITRA dose should not be exceeded when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in C and AUC, a single 2.5 mg dose of LEVITRA should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily (see and ).
HIV Protease Inhibitors:
Indinavir (800 mg t.i.d.) co-administered with LEVITRA 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg LEVITRA dose in a 24-hour period when used in combination with indinavir (see and ).
Ritonavir (600 mg b.i.d.) co-administered with LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg LEVITRA dose in a 72-hour period when used in combination with ritonavir (see and ).
Other CYP3A4 inhibitors
Other Drug Interactions:
Effects of LEVITRA on other drugs
In vitro studies:
Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 µM). 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 µM toward CYP3A4, which is about 20 times higher than the M1 C values after an 80 mg LEVITRA dose.
In vivo studies:
Nitrates: 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 were potentiated by a 20 mg dose of LEVITRA in healthy middle-aged subjects. These effects were not observed when LEVITRA 20 mg was taken 24 hours before the NTG. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of LEVITRA and nitrates is contraindicated (see ;).
Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative bioavailability (AUC) or maximum concentration (C) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA when taken in combination. In these patients whose hypertension was controlled with nifedipine, LEVITRA 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.
Alpha-blockers:
Blood pressure effects in patients on stable alpha-blocker treatment:
Two clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment for at least four weeks.
Study 1: This study was designed to evaluate the effect of 5 mg vardenafil 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 BP results see . One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg; two and one patient (vardenafil and placebo, respectively) had a decrease in standing SBP of >30 mmHg. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.
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 3. 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 4.
Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (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 . 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.
Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 20 mg or placebo, or following administration of vardenafil 20 mg or placebo separated by 6 hours are shown in Figure 5.
Concomitant treatment with vardenafil and alpha-blockers should be initiated only if the patient is stable on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose (see ).
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 simultaneous T 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 T than when dosing was administered to separate T 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 T administration of tamsulosin. There were no cases of syncope.
Ritonavir and indinavir: Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the C and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the C and AUC of indinavir were reduced by 40% and 30%, respectively.
Alcohol: Alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person) and vardenafil plasma levels were not altered when dosed simultaneously. LEVITRA (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).
Aspirin: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
Carcinogenesis, Mutagenesis, Impairment of Fertility
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. Vardenafil was not mutagenic as assessed in either the bacterial Ames assay or the forward mutation assay in Chinese hamster V cells. Vardenafil was not clastogenic as assessed in either the chromosomal aberration test or the mouse micronucleus test. 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 male, 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.
There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in healthy volunteers.
Pregnancy, Nursing Mothers and Pediatric Use
LEVITRA is not indicated for use in women, newborns, or children. Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours. It is not known if vardenafil is excreted in human breast milk.
Pregnancy Category B:
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. There are no adequate and well-controlled trials of vardenafil in pregnant women.
Geriatric Use
Elderly males age 65 years and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean C and AUC were 34% and 52% higher, respectively (see , and ). Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of LEVITRA 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg LEVITRA should be considered in patients ≥65 years of age.
Overview
What is Levitra?
LEVITRA 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 phosphodiesterase type 5 (PDE5).
Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-][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. LEVITRA is formulated as orange, round, film-coated tablets with “BAYER” cross debossed on one side and “2.5”, “5”, “10”, and “20” on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
What does Levitra look like?
What are the available doses of Levitra?
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What should I talk to my health care provider before I take Levitra?
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How should I use Levitra?
LEVITRA is indicated for the treatment of erectile dysfunction.
For most patients, the recommended starting dose of LEVITRA is 10 mg, taken orally approximately 60 minutes before sexual activity. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and side effects. The maximum recommended dosing frequency is once per day. LEVITRA can be taken with or without food. Sexual stimulation is required for a response to treatment.
Geriatrics:
Hepatic Impairment:
CLINICAL PHARMACOLOGY
Renal Impairment:
CLINICAL PHARMACOLOGY
Concomitant Medications:
PRECAUTIONS,
PRECAUTIONS
What interacts with Levitra?
Nitrates:
CLINICAL PHARMACOLOGY
Pharmacodynamics
Hypersensitivity:
What are the warnings of Levitra?
Cardiovascular effects
General:
Left Ventricular Outflow Obstruction:
Blood Pressure Effects:
CLINICAL PHARMACOLOGY
Effect of Co-administration of Potent CYP3A4 Inhibitors
Long-term safety information is not available on the concomitant administration of vardenafil with HIV protease inhibitors. Concomitant administration with ritonavir or indinavir substantially increases plasma concentrations of vardenafil. Because ritonavir prolongs LEVITRA elimination half-life (5 to 6-fold), no more than a single 2.5 mg dose of LEVITRA should be taken in a 72-hour period by patients also taking ritonavir. Patients taking indinavir, saquinavir, atazanavir or other potent CYP3A4 inhibitors such as clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily should not exceed a dose of LEVITRA 2.5 mg once daily. For patients taking ketoconazole 200 mg daily or itraconazole 200 mg daily, a single dose of 5 mg LEVITRA should not be exceeded in a 24-hour period (see , and ).
Other Effects
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.
Patient Subgroups Not Studied in Clinical Trials
There are no controlled clinical data on the safety or efficacy of LEVITRA in the following patients; and therefore its use is not recommended until further information is available.
What are the precautions of Levitra?
The evaluation of erectile dysfunction should include a determination of potential underlying causes, a medical assessment, and the identification of appropriate treatment.
Before prescribing LEVITRA, it is important to note the following:
Alpha-blockers:
Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase Type 5 (PDE5) inhibitors, including LEVITRA, 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 , ) leading to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:
Hepatic Insufficiency:
In volunteers with moderate impairment (Child-Pugh B), the C and AUC following a 10 mg vardenafil dose were increased 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepatic impairment and the maximum dose should not exceed 10 mg (see , and ). Vardenafil has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).
Congenital or Acquired QT Prolongation:
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Renal Insufficiency:
In patients with moderate (CL = 30-50 ml/min) to severe (CL<30 ml/min) renal impairment, the AUC of vardenafil was 20 – 30% higher compared to that observed in a control group with normal renal function (CL>80 ml/min) (see , ). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis.
General:
Treatment for erectile dysfunction should generally 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).
The safety and efficacy of LEVITRA used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Information for Patients
Physicians should discuss with patients the contraindication of LEVITRA with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of LEVITRA with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Physicians should inform their patients that in some patients concomitant use of PDE5 inhibitors, including LEVITRA, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (e.g., fainting). Patients prescribed LEVITRA who are taking alpha-blockers should be started on the lowest recommended starting dose of LEVITRA (see and ). 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 LEVITRA are prescribed by another healthcare provider.
Physicians should discuss with patients the appropriate use of LEVITRA and its anticipated benefits. It should be explained that sexual stimulation is required for an erection to occur after taking LEVITRA. LEVITRA should be taken approximately 60 minutes before sexual activity. Patients should be counseled regarding the dosing of LEVITRA. Patients should be advised to contact their healthcare provider for dose modification if they are not satisfied with the quality of their sexual performance with LEVITRA or in the case of an unwanted effect. Patients should be advised to contact the prescribing physician if new medications that may interact with LEVITRA are prescribed by another healthcare provider.
Physicians should advise patients to stop use of all PDE5 inhibitors, including LEVITRA, 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 post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events were related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors (see , ).
Physicians should advise patients to stop taking PDE5 inhibitors, including LEVITRA, 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 LEVITRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ).
Physicians should discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.
The use of LEVITRA 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.
Physicians should inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for LEVITRA 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
Effect of other drugs on LEVITRA
In vitro studies:
In vivo studies: Cytochrome P450 Inhibitors
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C) of vardenafil when co-administered with 20 mg LEVITRA in healthy volunteers.
Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C when co-administered with LEVITRA 5 mg in healthy volunteers (see ). It is recommended not to exceed a single 5 mg dose of LEVITRA in a 24-hour period when used in combination with erythromycin.
Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in C when co-administered with LEVITRA (5 mg) in healthy volunteers. A 5-mg LEVITRA dose should not be exceeded when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in C and AUC, a single 2.5 mg dose of LEVITRA should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily (see and ).
HIV Protease Inhibitors:
Indinavir (800 mg t.i.d.) co-administered with LEVITRA 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg LEVITRA dose in a 24-hour period when used in combination with indinavir (see and ).
Ritonavir (600 mg b.i.d.) co-administered with LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg LEVITRA dose in a 72-hour period when used in combination with ritonavir (see and ).
Other CYP3A4 inhibitors
Other Drug Interactions:
Effects of LEVITRA on other drugs
In vitro studies:
Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 µM). 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 µM toward CYP3A4, which is about 20 times higher than the M1 C values after an 80 mg LEVITRA dose.
In vivo studies:
Nitrates: 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 were potentiated by a 20 mg dose of LEVITRA in healthy middle-aged subjects. These effects were not observed when LEVITRA 20 mg was taken 24 hours before the NTG. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of LEVITRA and nitrates is contraindicated (see ;).
Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative bioavailability (AUC) or maximum concentration (C) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA when taken in combination. In these patients whose hypertension was controlled with nifedipine, LEVITRA 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.
Alpha-blockers:
Blood pressure effects in patients on stable alpha-blocker treatment:
Two clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment for at least four weeks.
Study 1: This study was designed to evaluate the effect of 5 mg vardenafil 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 BP results see . One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg; two and one patient (vardenafil and placebo, respectively) had a decrease in standing SBP of >30 mmHg. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.
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 3. 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 4.
Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (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 . 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.
Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 20 mg or placebo, or following administration of vardenafil 20 mg or placebo separated by 6 hours are shown in Figure 5.
Concomitant treatment with vardenafil and alpha-blockers should be initiated only if the patient is stable on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose (see ).
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 simultaneous T 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 T than when dosing was administered to separate T 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 T administration of tamsulosin. There were no cases of syncope.
Ritonavir and indinavir: Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the C and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the C and AUC of indinavir were reduced by 40% and 30%, respectively.
Alcohol: Alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person) and vardenafil plasma levels were not altered when dosed simultaneously. LEVITRA (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).
Aspirin: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mgand Alpha-Blocker,Placebo-Subtracted | Dosing of Vardenafil 5 mgand Alpha-BlockerSeparated by 6 Hours,Placebo-Subtracted | |||
| Terazosin5 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) | |||
| Tamsulosin0.4 mg daily | Standing SBPSupine SBP | -6 (-9.9, -2.1)-4 (-7.0, -0.8) | -4 (-8.3, -0.5)-5 (-7.9, -1.7) | Vardenafil 10 mgPlacebo-subtracted | Vardenafil 20 mgPlacebo-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) | |||
| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours | Simultaneous dosing of Vardenafil and Alpha-Blocker | ||||
| Alpha-Blocker | Vardenafil10 mgPlacebo-Subtracted | Vardenafil20 mgPlacebo-Subtracted | Vardenafil10 mgPlacebo-Subtracted | Vardenafil20 mgPlacebo-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) |
Carcinogenesis, Mutagenesis, Impairment of Fertility
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. Vardenafil was not mutagenic as assessed in either the bacterial Ames assay or the forward mutation assay in Chinese hamster V cells. Vardenafil was not clastogenic as assessed in either the chromosomal aberration test or the mouse micronucleus test. 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 male, 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.
There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in healthy volunteers.
Pregnancy, Nursing Mothers and Pediatric Use
LEVITRA is not indicated for use in women, newborns, or children. Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours. It is not known if vardenafil is excreted in human breast milk.
Pregnancy Category B:
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. There are no adequate and well-controlled trials of vardenafil in pregnant women.
Geriatric Use
Elderly males age 65 years and older have higher vardenafil plasma concentrations than younger males (18 – 45 years), mean C and AUC were 34% and 52% higher, respectively (see , and ). Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of LEVITRA 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg LEVITRA should be considered in patients ≥65 years of age.
What are the side effects of Levitra?
LEVITRA was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer, and 880 patients were treated for at least 1 year.
In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for LEVITRA compared to 1.1% for placebo.
When LEVITRA was taken as recommended in placebo-controlled clinical trials, the following adverse events were reported (see ).
Back pain was reported in 2.0% of patients treated with LEVITRA and 1.7% of patients on placebo.
Placebo-controlled trials suggested a dose effect in the incidence of some adverse events (headache, flushing, dyspepsia, nausea, rhinitis) over the 5 mg, 10 mg, and 20 mg doses of LEVITRA. The following section identifies additional, less frequent events (<2%) reported during the clinical development of LEVITRA. Excluded from this list are those events 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: anaphylactic reaction (including laryngeal edema), asthenia, face edema, pain
AUDITORY: sudden decrease or loss of hearing, tinnitus
CARDIOVASCULAR: angina pectoris, chest pain, hypertension, hypotension, myocardial ischemia, myocardial infarction, palpitation, postural hypotension, syncope, tachycardia
DIGESTIVE: abdominal pain, abnormal liver function tests, diarrhea, dry mouth, dysphagia, esophagitis, gastritis, gastroesophageal reflux, GGTP increased, vomiting
MUSCULOSKELETAL: arthralgia, back pain, myalgia, neck pain
NERVOUS: hypertonia, hypesthesia, insomnia, paresthesia, somnolence, vertigo
RESPIRATORY: dyspnea, epistaxis, pharyngitis
SKIN AND APPENDAGES: photosensitivity reaction, pruritus, rash, sweating
OPHTHALMOLOGIC: abnormal vision, blurred vision, chromatopsia, changes in color vision, conjunctivitis (increased redness of the eye), dim vision, eye pain, glaucoma, photophobia, watery eyes
UROGENITAL: abnormal ejaculation, priapism (including prolonged or painful erections)
| Adverse Event | Percentage of Patients Reporting Event | |
| PlaceboN = 1199 | LEVITRAN = 2203 | |
| Headache | 4% | 15% |
| Flushing | 1% | 11% |
| Rhinitis | 3% | 9% |
| Dyspepsia | 1% | 4% |
| Accidental Injury | 2% | 3% |
| Sinusitis | 1% | 3% |
| Flu Syndrome | 2% | 3% |
| Dizziness | 1% | 2% |
| Increased Creatine Kinase | 1% | 2% |
| Nausea | 1% | 2% |
What should I look out for while using Levitra?
Nitrates:
CLINICAL PHARMACOLOGY
Pharmacodynamics
Hypersensitivity:
What might happen if I take too much Levitra?
The maximum dose of LEVITRA for which human data are available is a single 120 mg dose administered to eight healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.”
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.
How should I store and handle Levitra?
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].LEVITRA (vardenafil HCl) is formulated as orange, film-coated round tablets with debossed “BAYER” cross on one side and “2.5”, “5”, “10”, and “20” on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. LEVITRA (vardenafil HCl) is formulated as orange, film-coated round tablets with debossed “BAYER” cross on one side and “2.5”, “5”, “10”, and “20” on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively.
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CLINICAL PHARMACOLOGY
Pharmacodynamics
Hypersensitivity:
Effect of other drugs on LEVITRA
In vivo studies: Cytochrome P450 Inhibitors
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C) of vardenafil when co-administered with 20 mg LEVITRA in healthy volunteers.
Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C when co-administered with LEVITRA 5 mg in healthy volunteers (see ). It is recommended not to exceed a single 5 mg dose of LEVITRA in a 24-hour period when used in combination with erythromycin.
Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in C when co-administered with LEVITRA (5 mg) in healthy volunteers. A 5-mg LEVITRA dose should not be exceeded when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in C and AUC, a single 2.5 mg dose of LEVITRA should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily (see and ).
HIV Protease Inhibitors:
Indinavir (800 mg t.i.d.) co-administered with LEVITRA 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg LEVITRA dose in a 24-hour period when used in combination with indinavir (see and ).
Ritonavir (600 mg b.i.d.) co-administered with LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg LEVITRA dose in a 72-hour period when used in combination with ritonavir (see and ).
Other CYP3A4 inhibitors
Other Drug Interactions:
Effects of LEVITRA on other drugs
In vitro studies:
Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 µM). 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 µM toward CYP3A4, which is about 20 times higher than the M1 C values after an 80 mg LEVITRA dose.
In vivo studies:
Nitrates: 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 were potentiated by a 20 mg dose of LEVITRA in healthy middle-aged subjects. These effects were not observed when LEVITRA 20 mg was taken 24 hours before the NTG. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of LEVITRA and nitrates is contraindicated (see ;).
Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative bioavailability (AUC) or maximum concentration (C) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA when taken in combination. In these patients whose hypertension was controlled with nifedipine, LEVITRA 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.
Alpha-blockers:
Blood pressure effects in patients on stable alpha-blocker treatment:
Two clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment for at least four weeks.
Study 1: This study was designed to evaluate the effect of 5 mg vardenafil 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 BP results see . One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg; two and one patient (vardenafil and placebo, respectively) had a decrease in standing SBP of >30 mmHg. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.
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 3. 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 4.
Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (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 . 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.
Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 20 mg or placebo, or following administration of vardenafil 20 mg or placebo separated by 6 hours are shown in Figure 5.
Concomitant treatment with vardenafil and alpha-blockers should be initiated only if the patient is stable on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose (see ).
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 simultaneous T 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 T than when dosing was administered to separate T 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 T administration of tamsulosin. There were no cases of syncope.
Ritonavir and indinavir: Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the C and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the C and AUC of indinavir were reduced by 40% and 30%, respectively.
Alcohol: Alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person) and vardenafil plasma levels were not altered when dosed simultaneously. LEVITRA (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).
Aspirin: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
The evaluation of erectile dysfunction should include a determination of potential underlying causes, a medical assessment, and the identification of appropriate treatment.
Before prescribing LEVITRA, it is important to note the following:
LEVITRA was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer, and 880 patients were treated for at least 1 year.
In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for LEVITRA compared to 1.1% for placebo.
When LEVITRA was taken as recommended in placebo-controlled clinical trials, the following adverse events were reported (see ).
Back pain was reported in 2.0% of patients treated with LEVITRA and 1.7% of patients on placebo.
Placebo-controlled trials suggested a dose effect in the incidence of some adverse events (headache, flushing, dyspepsia, nausea, rhinitis) over the 5 mg, 10 mg, and 20 mg doses of LEVITRA. The following section identifies additional, less frequent events (<2%) reported during the clinical development of LEVITRA. Excluded from this list are those events 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: anaphylactic reaction (including laryngeal edema), asthenia, face edema, pain
AUDITORY: sudden decrease or loss of hearing, tinnitus
CARDIOVASCULAR: angina pectoris, chest pain, hypertension, hypotension, myocardial ischemia, myocardial infarction, palpitation, postural hypotension, syncope, tachycardia
DIGESTIVE: abdominal pain, abnormal liver function tests, diarrhea, dry mouth, dysphagia, esophagitis, gastritis, gastroesophageal reflux, GGTP increased, vomiting
MUSCULOSKELETAL: arthralgia, back pain, myalgia, neck pain
NERVOUS: hypertonia, hypesthesia, insomnia, paresthesia, somnolence, vertigo
RESPIRATORY: dyspnea, epistaxis, pharyngitis
SKIN AND APPENDAGES: photosensitivity reaction, pruritus, rash, sweating
OPHTHALMOLOGIC: abnormal vision, blurred vision, chromatopsia, changes in color vision, conjunctivitis (increased redness of the eye), dim vision, eye pain, glaucoma, photophobia, watery eyes
UROGENITAL: abnormal ejaculation, priapism (including prolonged or painful erections)
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 phosphodiesterase type 5 (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
Non-Clinical Toxicology
Nitrates:CLINICAL PHARMACOLOGY
Pharmacodynamics
Hypersensitivity:
Effect of other drugs on LEVITRA
In vivo studies: Cytochrome P450 Inhibitors
Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C) of vardenafil when co-administered with 20 mg LEVITRA in healthy volunteers.
Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C when co-administered with LEVITRA 5 mg in healthy volunteers (see ). It is recommended not to exceed a single 5 mg dose of LEVITRA in a 24-hour period when used in combination with erythromycin.
Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in C when co-administered with LEVITRA (5 mg) in healthy volunteers. A 5-mg LEVITRA dose should not be exceeded when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in C and AUC, a single 2.5 mg dose of LEVITRA should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily (see and ).
HIV Protease Inhibitors:
Indinavir (800 mg t.i.d.) co-administered with LEVITRA 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg LEVITRA dose in a 24-hour period when used in combination with indinavir (see and ).
Ritonavir (600 mg b.i.d.) co-administered with LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg LEVITRA dose in a 72-hour period when used in combination with ritonavir (see and ).
Other CYP3A4 inhibitors
Other Drug Interactions:
Effects of LEVITRA on other drugs
In vitro studies:
Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 µM). 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 µM toward CYP3A4, which is about 20 times higher than the M1 C values after an 80 mg LEVITRA dose.
In vivo studies:
Nitrates: 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 were potentiated by a 20 mg dose of LEVITRA in healthy middle-aged subjects. These effects were not observed when LEVITRA 20 mg was taken 24 hours before the NTG. Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of LEVITRA and nitrates is contraindicated (see ;).
Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative bioavailability (AUC) or maximum concentration (C) of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA when taken in combination. In these patients whose hypertension was controlled with nifedipine, LEVITRA 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.
Alpha-blockers:
Blood pressure effects in patients on stable alpha-blocker treatment:
Two clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment for at least four weeks.
Study 1: This study was designed to evaluate the effect of 5 mg vardenafil 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 BP results see . One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg; two and one patient (vardenafil and placebo, respectively) had a decrease in standing SBP of >30 mmHg. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. There were no cases of syncope.
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 3. 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 4.
Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (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 . 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.
Blood pressure effects (standing SBP) in normotensive men on stable dose tamsulosin 0.4 mg following simultaneous administration of vardenafil 20 mg or placebo, or following administration of vardenafil 20 mg or placebo separated by 6 hours are shown in Figure 5.
Concomitant treatment with vardenafil and alpha-blockers should be initiated only if the patient is stable on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose (see ).
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 simultaneous T 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 T than when dosing was administered to separate T 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 T administration of tamsulosin. There were no cases of syncope.
Ritonavir and indinavir: Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the C and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the C and AUC of indinavir were reduced by 40% and 30%, respectively.
Alcohol: Alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person) and vardenafil plasma levels were not altered when dosed simultaneously. LEVITRA (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).
Aspirin: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).
The evaluation of erectile dysfunction should include a determination of potential underlying causes, a medical assessment, and the identification of appropriate treatment.
Before prescribing LEVITRA, it is important to note the following:
LEVITRA was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer, and 880 patients were treated for at least 1 year.
In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for LEVITRA compared to 1.1% for placebo.
When LEVITRA was taken as recommended in placebo-controlled clinical trials, the following adverse events were reported (see ).
Back pain was reported in 2.0% of patients treated with LEVITRA and 1.7% of patients on placebo.
Placebo-controlled trials suggested a dose effect in the incidence of some adverse events (headache, flushing, dyspepsia, nausea, rhinitis) over the 5 mg, 10 mg, and 20 mg doses of LEVITRA. The following section identifies additional, less frequent events (<2%) reported during the clinical development of LEVITRA. Excluded from this list are those events 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: anaphylactic reaction (including laryngeal edema), asthenia, face edema, pain
AUDITORY: sudden decrease or loss of hearing, tinnitus
CARDIOVASCULAR: angina pectoris, chest pain, hypertension, hypotension, myocardial ischemia, myocardial infarction, palpitation, postural hypotension, syncope, tachycardia
DIGESTIVE: abdominal pain, abnormal liver function tests, diarrhea, dry mouth, dysphagia, esophagitis, gastritis, gastroesophageal reflux, GGTP increased, vomiting
MUSCULOSKELETAL: arthralgia, back pain, myalgia, neck pain
NERVOUS: hypertonia, hypesthesia, insomnia, paresthesia, somnolence, vertigo
RESPIRATORY: dyspnea, epistaxis, pharyngitis
SKIN AND APPENDAGES: photosensitivity reaction, pruritus, rash, sweating
OPHTHALMOLOGIC: abnormal vision, blurred vision, chromatopsia, changes in color vision, conjunctivitis (increased redness of the eye), dim vision, eye pain, glaucoma, photophobia, watery eyes
UROGENITAL: abnormal ejaculation, priapism (including prolonged or painful erections)
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Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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