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VARDENAFIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Specific Substances

    1) 1-{[3-(3,4-Dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl}-4-ethylpiperazine
    2) Vardenafil hydrochloride
    3) Vardenafil dihydrochloride
    4) Bay-38-9456
    5) CAS 224785-90-4
    1.2.1) MOLECULAR FORMULA
    1) C23-H32-N6-O4-S

Available Forms Sources

    A) FORMS
    1) Vardenafil is available as 2.5 mg, 5 mg, 10 mg, and 20 mg film-coated tablets and 10 mg oral disintegrating tablets (Prod Info STAXYN(R) oral disintegrating tablets, 2014; Prod Info LEVITRA(R) oral tablets, 2014).
    B) USES
    1) Vardenafil is indicated for the treatment of erectile dysfunction (Prod Info STAXYN(R) oral disintegrating tablets, 2014; Prod Info LEVITRA(R) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Vardenafil, a phosphodiesterase (PDE) 5 inhibitor, is used in the treatment of erectile dysfunction.
    B) PHARMACOLOGY: During sexual stimulation, nitric oxide is released from the nerve endings and endothelial cells in the corpus cavernosum, which activates the enzyme guanylate cyclase producing an increase synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterase type 5 (PDEs). The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.
    C) EPIDEMIOLOGY: Inadvertent ingestion in children occurs but rarely causes serious effects. PDE5s have the potential for abuse and misuse, and may be deliberately ingested with other drugs (eg amphetamines, hallucinogenic amphetamines, GHB, ketamine, amyl nitrate) to enhance sexual experiences.
    D) TOXICOLOGY: Vardenafil has systemic vasodilatory effects that can produce transient decreases in blood pressure, flushing, or headache. Based on the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibition may potentiate the hypotensive effects of nitrates.
    E) WITH THERAPEUTIC USE
    1) Headache, flushing, and rhinitis may frequently occur with vardenafil therapy and appears to be dose-related. Other adverse effects that may occur include dizziness, dyspepsia, nausea, vision abnormalities, chest pain, and priapism. In postmarketing experience, seizures, seizure recurrence and transient global amnesia have developed in temporal association with vardenafil.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Adverse events are anticipated to be similar to events observed with therapeutic use. During clinical trials in healthy volunteers, ingestion of a single 120-mg dose of vardenafil was associated with the development of reversible back pain, myalgias, and vision abnormalities.
    2) SEVERE TOXICITY: Information is limited. Hemodynamic compromise (eg, tachycardia, hypotension) may develop when combined with nitrates. In postmarketing experience, seizures and global amnesia have a temporal association with vardenafil.
    3) ABUSE/MISUSE: There have been reports of misuse/abuse with other PDE5 inhibitors and may occur with vardenafil. These agents have been used by younger individuals and combined with club drugs.
    0.2.20) REPRODUCTIVE
    A) Vardenafil is classified as FDA pregnancy category B

Laboratory Monitoring

    A) Monitor vital signs, especially blood pressure, and ECG after significant overdose.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise clinically indicated.
    C) Vardenafil serum concentrations are not widely available or clinically useful.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor vital signs. HYPOTENSION: Monitor blood pressure, administer isotonic fluids at 10 to 20 mL/kg. CHEST PAIN: Nitrates are CONTRAINDICATED in patients with a recent vardenafil ingestion due to the possibility of a severe hypotensive reaction. Nitrates should be avoided for 24 hours longer if on P450 inhibitors or if hepatic or renal dysfunction are present), given the risk of hypotension and exacerbation of ischemia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. HYPOTENSION: Patients with persistent hypotension despite intravenous fluids require vasopressors, theoretically alpha agonists norepinephrine and phenylephrine may be more effective. PRIAPISM is an emergency requiring immediate consult with a urologist.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be considered in a recent, large ingestion and the patient is alert and can protect the airway.
    2) HOSPITAL: Activated charcoal may be considered, in a recent significant ingestion or coingestants are suspected and the patient is alert and can protect the airway.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor exposure; airway management may be necessary in patients that develop hemodynamic or cardiovascular instability.
    E) ANTIDOTE
    1) None.
    F) PRIAPISM
    1) An immediate urological consult is necessary. Clinical history should include the use of other agents (ie, antihypertensives, antidepressants, illegal agents) that may also be contributing to priapism. In a patient with ischemic priapism the corpora cavernosa are often completely rigid and the patient complains of pain, while nonischemic priapism the corpora are typically tumescent, but not completely rigid and pain is not typical. Aspirate blood from the corpus cavernosum with a fine needle. Blood gas testing of the aspirated blood may be used to distinguish ischemic (typically PO2 less than 30 mmHg, PCO2 greater than 60 mmHg, and pH less than 7.25) and nonischemic priapism. Color duplex ultrasonography may also be useful. If priapism persists after aspiration, inject a sympathomimetic. PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and give 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism. Distal shunting (NOT first-line therapy) should only be considered after a trial of intracavernous injection of sympathomimetics.
    G) ENHANCED ELIMINATION
    1) Hemodialysis or hemoperfusion are unlikely to be of benefit due to the high protein binding and large volume of distribution of vardenafil.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor inadvertent dose (a single dose) in an asymptomatic child can likely be monitored at home with adult supervision. An inadvertent extra dose(s) (up to 20 mg) in an asymptomatic adult can be managed at home.
    2) OBSERVATION CRITERIA: A patient with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with suspected or known coingestants (eg, nitrates, club drugs) should be monitored and evaluated.
    3) ADMISSION CRITERIA: Patients with persistent hemodynamic or cardiovascular instability should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for cases severe toxicity or in whom the diagnosis is unclear. Consult a urologist in cases of priapism. Consult a cardiologist for assistance in managing patients with persistent chest pain or evidence of myocardial ischemia.
    I) PHARMACOKINETICS
    1) Vardenafil is rapidly absorbed with an absolute bioavailability of 15%. Vardenafil and its major metabolite (M1) are highly protein bound (95%). It is primarily metabolized in the liver by CYP3A4 and to a lesser extent, CYP3A5 and CYP2C9 isozymes. It is primarily excreted as metabolites in the feces (91% to 95%) with the remainder excreted in the urine (2% to 6%). The elimination half-life of vardenafil and M1 is approximately 4 to 5 hours.
    J) PITFALLS
    1) Obtain a complete history of drug use, hypotensive emergencies may result from the combination of vardenafil and nitrates (ie, nitroglycerin, isosorbide dinitrate, nitroprusside, amyl nitrite (also a recreational drug), and nitric oxide). Intentional misuse and abuse has been reported among younger individuals.
    K) DIFFERENTIAL DIAGNOSIS
    1) Vasodilator or nitrate overdose. Underlying cardiovascular disease may result in an increased risk to develop significant hypotension or cardiac instability. Events may be due the use of other agents (ie, nitrates).

Range Of Toxicity

    A) TOXICITY: Limited data. In postmarketing experience, tonic-clonic seizures occurred in one patient, 3 hours after ingesting a 40 mg dose with another seizure reported 2 months later after a 30 mg dose. During clinical trials in healthy volunteers, a single 120-mg dose of vardenafil resulted in minor adverse effects, including reversible back pain, myalgias, and vision abnormalities.
    B) THERAPEUTIC DOSE: Initial recommended dose for most patients is 10 mg once daily, taken approximately 60 minutes prior to sexual activity. The dose may be decreased to 5 mg once daily in patients older than 65 with a suggested maximum dose of 20 mg once daily. Vardenafil is NOT indicated for use in women, newborns or children.

Clinical Effects

Summary Of Exposure

    A) USES: Vardenafil, a phosphodiesterase (PDE) 5 inhibitor, is used in the treatment of erectile dysfunction.
    B) PHARMACOLOGY: During sexual stimulation, nitric oxide is released from the nerve endings and endothelial cells in the corpus cavernosum, which activates the enzyme guanylate cyclase producing an increase synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterase type 5 (PDEs). The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.
    C) EPIDEMIOLOGY: Inadvertent ingestion in children occurs but rarely causes serious effects. PDE5s have the potential for abuse and misuse, and may be deliberately ingested with other drugs (eg amphetamines, hallucinogenic amphetamines, GHB, ketamine, amyl nitrate) to enhance sexual experiences.
    D) TOXICOLOGY: Vardenafil has systemic vasodilatory effects that can produce transient decreases in blood pressure, flushing, or headache. Based on the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibition may potentiate the hypotensive effects of nitrates.
    E) WITH THERAPEUTIC USE
    1) Headache, flushing, and rhinitis may frequently occur with vardenafil therapy and appears to be dose-related. Other adverse effects that may occur include dizziness, dyspepsia, nausea, vision abnormalities, chest pain, and priapism. In postmarketing experience, seizures, seizure recurrence and transient global amnesia have developed in temporal association with vardenafil.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Adverse events are anticipated to be similar to events observed with therapeutic use. During clinical trials in healthy volunteers, ingestion of a single 120-mg dose of vardenafil was associated with the development of reversible back pain, myalgias, and vision abnormalities.
    2) SEVERE TOXICITY: Information is limited. Hemodynamic compromise (eg, tachycardia, hypotension) may develop when combined with nitrates. In postmarketing experience, seizures and global amnesia have a temporal association with vardenafil.
    3) ABUSE/MISUSE: There have been reports of misuse/abuse with other PDE5 inhibitors and may occur with vardenafil. These agents have been used by younger individuals and combined with club drugs.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) In one placebo-controlled study, no cases of altered color-vision perception were observed with doses of 5, 10, or 20 mg (average, 30 doses over 12 weeks). However, increased sensitivity to bright light and haziness was described by some patients (Porst et al, 2001).
    2) Light sensitivity and blurred or abnormal vision were reported in 4 patients and 3 patients (n=295), respectively, following vardenafil administration during a randomized placebo-controlled trial (Brock et al, 2003).
    3) In a review of 8 cases (6 men and 2 females treated for pulmonary artery hypertension) of PDE5 inhibitor use that resulted in significant visual impairment (ie, anterior and posterior nonarteritic ischemic optic neuropathy, central retinal vein occlusion, cilio-retinal artery occlusion, acute angle closure glaucoma and optic atrophy), there was no increased risk of developing serious vision-threatening complications compared to the general population. In each case, sildenafil was administered. No conclusive evidence was available to suggest that PDE5 inhibitors produce an increase in visual adverse events (Azzouni & Abu samra , 2011).
    4) POSTMARKETING EXPERIENCE: Visual disturbances including vision loss (temporary or permanent) including visual field defect, retinal vein occlusion, and reduced visual acuity, have been rarely reported. It is not clear if these events are directly related to vardenafil use (Prod Info LEVITRA(R) oral film coated tablets, 2011).
    B) WITH POISONING/EXPOSURE
    1) Healthy volunteers reported the occurrence of vision abnormalities following ingestion of a single 120-mg dose of vardenafil which was reversible (Prod Info LEVITRA(R) oral film coated tablets, 2011).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) RHINITIS: Rhinitis occurred in 9% of patients receiving doses of 5 to 20 mg compared to 3% in the placebo group (Prod Info LEVITRA(R) oral film coated tablets, 2011). Ten and 20-mg doses are more likely to cause this effect. After 16 weeks of therapy, rates of rhinitis with the 5-mg dose are similar to placebo (Hellstrom et al, 2003).
    2) SINUSITIS: Sinusitis was reported in 3% to 7% of patients receiving vardenafil in doses of 5 to 20 mg (Prod Info LEVITRA(R) oral film coated tablets, 2011; Brock et al, 2003).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Mild reductions in recumbent blood pressure were reported in a small study after doses of 10 or 20 mg; standing blood pressure was not taken (Klotz et al, 2001).
    b) Administration of single 20-mg doses of vardenafil resulted in a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic during a vardenafil clinical trial involving patients with erectile dysfunction. The maximum decrease in blood pressure occurred between 1 and 4 hours after vardenafil administration (Prod Info Levitra (R), 2004).
    B) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Chest pain and tachycardia were reported in 6 patients who received vardenafil (n=295) during a randomized clinical trial as compared to 2 patients who received placebo (n=145) (Brock et al, 2003).
    C) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ECG abnormalities, including sinus bradycardia, first degree AV block, ST and T wave abnormalities, and QT interval prolongation, have been infrequently reported with vardenafil therapy (Prod Info Levitra (R), 2004; Goldstein et al, 2003).
    b) Small QTc interval increases of 7 and 9 ms have occurred following administration of therapeutic (10 mg) and supratherapeutic (80 mg) doses, respectively, as compared with placebo (Kloner, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: In postmarketing experience, seizure and seizure recurrence have been reported in temporal association with vardenafil therapy (Prod Info LEVITRA(R) oral film coated tablets, 2011).
    b) CASE REPORT: A 78-year-old man developed a partial seizure after ingesting, for a second time, a 10 mg dose of vardenafil (Striano et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS: A 60-year-old healthy man developed a tonic-clonic seizure 3 hours after ingesting 40 mg of vardenafil because the prescribed 10 mg dose was ineffective. Another episode occurred 2 months later after 30 mg was taken (Striano et al, 2006).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache is a relatively common (15%) and dose-related adverse effect of oral vardenafil (Prod Info LEVITRA(R) oral film coated tablets, 2011; Brock et al, 2003; Klotz et al, 2001; Porst et al, 2001).
    b) In one large study, headache occurred at some point during treatment in 7%, 9%, and 15% of patients receiving a daily dose of 5, 10, and 20 mg, respectively, as compared to 4% of the patients in the placebo group. Headache required discontinuation in some patients (Porst et al, 2001).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in 2% of patients receiving vardenafil compared to 1% in the placebo group (Prod Info LEVITRA(R) oral film coated tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia appears to be dose-related but is infrequent, occurring in less than 4% of patients receiving 5 to 20 mg as a once daily maximum dose in clinical studies (Prod Info LEVITRA(R) oral film coated tablets, 2011).
    b) During a vardenafil randomized clinical trial, the occurrence of dyspepsia appeared to be greater (5%) during the first 4 weeks of treatment with 20 mg vardenafil, and subsequently decreased to 2% during the third month of vardenafil therapy (Porst et al, 2003).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea is an infrequent occurrence with vardenafil therapy (Prod Info LEVITRA(R) oral film coated tablets, 2011; Brock et al, 2003).
    b) Nausea caused 2 of 188 patients, who were taking vardenafil 20 mg, to discontinue therapy (Hellstrom et al, 2002).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transient elevations of liver enzyme levels were reported with vardenafil therapy (Crowe & Streetman, 2004).
    b) Abnormal liver function tests caused 3 of 199 patients, who were taking vardenafil 10 mg, to discontinue therapy (Hellstrom et al, 2002).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SEXUAL DISORDER
    1) WITH THERAPEUTIC USE
    a) A diminished sensitivity to stimulation caused 2 of 199 patients, who were taking vardenafil 10 mg, to discontinue therapy (Hellstrom et al, 2002).
    B) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) Rare cases of prolonged erections (greater than 4 hours) and priapism have been reported with vardenafil (Prod Info LEVITRA(R) oral film coated tablets, 2011).
    C) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) Renal calculi caused 2 of 188 patients, who were taking vardenafil 20 mg, to discontinue therapy (Hellstrom et al, 2002).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Cutaneous flushing has occurred in 9% to 11% of patients receiving doses of 5 to 20 mg compared to less than 1% treated with placebo (Prod Info LEVITRA(R) oral film coated tablets, 2011; Goldstein et al, 2003; Porst et al, 2001).
    b) In a 26-week study of vardenafil, the incidence of flushing was greater at 10 mg (20/199, 10%) and 20 mg (24/188, 13%) than at 5 mg (9/193, 5%) (Hellstrom et al, 2003; Hellstrom et al, 2002).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH POISONING/EXPOSURE
    a) Healthy volunteers reported the occurrence of reversible back pain and myalgias following ingestion of a single 120-mg dose of vardenafil (Prod Info LEVITRA(R) oral film coated tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Vardenafil is classified as FDA pregnancy category B
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT - There was no evidence of the occurrence or potential for teratogenicity, embryotoxicity, or fetotoxicity in rats and rabbits who received vardenafil at up to 18 mg/kg/day during organogenesis (Prod Info Levitra (R), 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Vardenafil is classified, by the manufacturer, as FDA pregnancy category B, although it is not indicated for use in women and there are no adequate and well-controlled studies involving women (Prod Info Levitra (R), 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown if vardenafil is excreted in human breast milk (Prod Info Levitra (R), 2004).
    B) ANIMAL STUDIES
    1) RATS - Vardenafil was secreted into the milk of lactating rats at concentrations that were approximately 10-fold greater than that of plasma. After administration of 3 mg/kg of vardenafil as a single oral dose, 3.3% was excreted into the milk within 24 hours (Prod Info Levitra (R), 2004).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS224785-90-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS224789-15-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Vardenafil was not carcinogenic in rats and mice following daily administration for 24 months (Prod Info Levitra(R), , 2003.).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, especially blood pressure, and ECG after significant overdose.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise clinically indicated.
    C) Vardenafil serum concentrations are not widely available or clinically useful.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent hemodynamic or cardiovascular instability should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor inadvertent dose (a single dose) in an asymptomatic child can likely be monitored at home with adult supervision. An inadvertent extra dose(s) (up to 20 mg) in an asymptomatic adult can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for cases severe toxicity or in whom the diagnosis is unclear. Consult a urologist in cases of priapism. Consult a cardiologist for assistance in managing patients with persistent chest pain or evidence of myocardial ischemia.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) A patient with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with suspected or known coingestants (eg, nitrates, club drugs) should be monitored and evaluated.

Monitoring

    A) Monitor vital signs, especially blood pressure, and ECG after significant overdose.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed unless otherwise clinically indicated.
    C) Vardenafil serum concentrations are not widely available or clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) CHARCOAL ADMINISTRATION
    1) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    B) CHARCOAL DOSE
    1) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    a) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    2) ADVERSE EFFECTS/CONTRAINDICATIONS
    a) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    2) Nitrates should be avoided for 24 hours (longer if on P450 inhibitors or if hepatic or renal dysfunction are present), given the risk of hypotension and exacerbation of ischemia.
    3) Males should be observed for signs of priapism, which is an emergency requiring immediate consult with a urologist.
    B) MONITORING OF PATIENT
    1) All overdose cases should be monitored for signs of hypotension, especially when organic nitrates have been concomitantly taken.
    2) Obtain a baseline ECG and institute continuous cardiac monitoring after significant overdose. Routine laboratory studies are not routinely necessary, unless otherwise indicated.
    3) Vardenafil plasma concentrations are not clinically useful or widely available.
    4) Males should be observed for signs of priapism.
    C) CONTRAINDICATED TREATMENT
    1) Hypotensive emergencies may result from the combination of vardenafil and nitrates, which include but are not limited to: nitroglycerin, isosorbide dinitrate, nitroprusside, amyl nitrite (also a recreational drug), and nitric oxide. These drugs are CONTRAINDICATED in patients who have recently ingested vardenafil, and clinicians are cautioned to obtain medical histories on all patients presenting to an emergency department with conditions normally treated with nitrates.
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. Patients with persistent hypotension despite intravenous fluids require vasopressors, theoretically alpha agonists norepinephrine and phenylephrine may be more effective. Consider central venous pressure monitoring to guide further fluid therapy.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    3) PHENYLEPHRINE
    a) MILD OR MODERATE HYPOTENSION
    1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    b) CONTINUOUS INFUSION
    1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    c) ADVERSE EFFECTS
    1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    E) PRIAPISM
    1) PRIAPISM is an emergency requiring immediate consult with a urologist.
    2) CASE REPORT: In a case of sildenafil-induced priapism, the penis was aspirated and irrigated with 4 doses of 400 mcg of phenylephrine in 10 mL of normal saline for 1 hour (total 1600 mcg) with resolution of the priapism (Sur & Kane, 2000).
    3) GUIDELINES ON THE MANAGEMENT OF PRIAPISM
    a) The following American Urological Association Guideline has been developed to evaluate and treat priapism (Montague et al, 2003):
    1) Ischemic priapism is characterized by little or no cavernous blood flow and abnormal cavernous blood gases (hypoxic, hypercarbic and acidotic).
    a) CLINICAL HISTORY: A clear history can determine the most effective treatment and should include the following:
    1) Duration of erection.
    2) Degree of pain (ischemic priapism is painful; nonischemic is not painful).
    3) Use of drug(s) associated with priapism (eg, antihypertensives, anticoagulants, antidepressants, illegal agents).
    4) Underlying disease (eg, sickle cell) or trauma.
    b) LABORATORY ANALYSIS: CBC, reticulocyte count, hemoglobin electrophoresis to rule out acute infection or underlying disease, psychoactive medication screening, and urine toxicology.
    c) PHYSICAL EXAMINATION: In a patient with ischemic priapism the corpora cavernosa are often completely rigid and painful while nonischemic priapism the corpora are typically tumescent, but not completely rigid, and is usually not painful.
    d) DIAGNOSTIC STUDIES: Blood gas testing and color duplex ultrasonography are the most reliable methods to distinguish between ischemic and nonischemic priapism.
    1) Ischemic finding: Blood aspirated from the corpus cavernosum is hypoxic and appears dark, and on blood gas testing typically has a PO2 of less than 30 mmHg and a PCO2 of greater than 60 mmHg and a pH of less than 7.25.
    2) Nonischemic finding: Blood is generally well oxygenated and appears bright red. Cavernosal blood gases are similar to normal arterial blood gas findings.
    3) Color Duplex Ultrasonography: Ischemic patient: Little or no blood flow in the cavernosal arteries.
    4) Penile Arteriography: An adjunctive study that has been mostly replaced by ultrasonography; it is often used only as part of an embolization procedure.
    e) TREATMENT: Ischemic priapism: Initial treatment usually includes therapeutic aspiration (with or without irrigation) followed by intracavernous injection of sympathomimetics (agents frequently used: epinephrine, norepinephrine, phenylephrine, ephedrine and metaraminol) as needed. Of these agents, resolution of ischemic effects occurred in 81% treated with epinephrine, 70% with metaraminol, 43% with norepinephrine and 65% with phenylephrine. To minimize adverse events, phenylephrine is an alpha1-selective adrenergic agonist is often selected because it produces no indirect neurotransmitter releasing action. Repeat sympathomimetic injection prior to considering surgical intervention.
    1) PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism.
    2) DISTAL SHUNTING (NOT first-line therapy): Inserting a surgical shunt should ONLY be considered after a trial of intracavernous injection of sympathomimetics. A caveroglanular (corporoglanular) shunt is the preferred method to avoid complications.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis or hemoperfusion are unlikely to be of benefit due to the high protein binding and large volume of distribution of vardenafil.

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. In postmarketing experience, tonic-clonic seizures occurred in one patient, 3 hours after ingesting a 40 mg dose with another seizure reported 2 months later after a 30 mg dose. During clinical trials in healthy volunteers, a single 120-mg dose of vardenafil resulted in minor adverse effects, including reversible back pain, myalgias, and vision abnormalities.
    B) THERAPEUTIC DOSE: Initial recommended dose for most patients is 10 mg once daily, taken approximately 60 minutes prior to sexual activity. The dose may be decreased to 5 mg once daily in patients older than 65 with a suggested maximum dose of 20 mg once daily. Vardenafil is NOT indicated for use in women, newborns or children.

Therapeutic Dose

    7.2.1) ADULT
    A) ERECTILE DYSFUNCTION
    1) NOTE: 10-mg film-coated tablets and 10-mg disintegrating tablets are not interchangeable. Disintegrating tablets provide a higher systemic exposure compared with film-coated tablets (Prod Info STAXYN(R) oral disintegrating tablets, 2014).
    2) DISINTEGRATING TABLET: 10 mg once daily approximately 60 minutes prior to sexual activity. MAX: 10 mg once daily (Prod Info STAXYN(R) oral disintegrating tablets, 2014).
    3) FILM-COATED TABLET: 10 mg once daily approximately 60 minutes prior to sexual activity. MAX: 20 mg once daily (Prod Info LEVITRA(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Vardenafil is not indicated for use in pediatric or adolescent patients (Prod Info STAXYN(R) oral disintegrating tablets, 2014; Prod Info LEVITRA(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) SUMMARY
    1) In postmarketing experience, a 60-year-old man developed tonic-clonic seizures, 3 hours after ingesting 40 mg of vardenafil because the prescribed dose of 10 mg was reportedly ineffective. Another tonic-clonic seizure developed 2 months later after the patient took a 30 mg dose of vardenafil. Following clinical evaluation, no other cause could be identified. A partial epileptic seizure was also reported in a 78-year-old man after taking a 10 mg dose for the second time (Striano et al, 2006).
    2) Reversible back pain, myalgias, and vision abnormalities were reported in healthy volunteers following ingestion of a single 120-mg dose of vardenafil. Seizures and global amnesia have also been reported in postmarketing experience (Prod Info LEVITRA(R) oral film coated tablets, 2011).

Workplace Standards

    A) ACGIH TLV Values for CAS224785-90-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS224789-15-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS224785-90-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS224789-15-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS224785-90-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS224789-15-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS224785-90-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS224789-15-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Vardenafil is a phosphodiesterase type5 (PDE5) inhibitor indicated for treatment of erectile dysfunction (Prod Info Levitra (R), 2004; Klotz et al, 2001). Inhibition of PDE5 reduces or blocks catabolism of cyclic guanosine monophosphate (cGMP) resulting in its accumulation; cGMP is a mediator of smooth muscle-cell relaxation of the corpus cavernosum and is involved in initiating and maintaining penile erection (Klotz et al, 2001).
    B) Vardenafil was highly selective for PDE5 relative to other PDE isoenzymes (i.e. 1, 2, 3, 4, and 6) (Klotz et al, 2001), and is reportedly more selective than sildenafil for PDE5 versus PDE1 or PDE6 (Anon, 2001); this selectivity is claimed to offer a reduced propensity for cardiovascular and visual problems compared to sildenafil (Anon, 2001).

Physicochemical

Physical Characteristics

    A) Vardenafil is a colorless, solid substance with a solubility of 0.11 mg/mL in water (Prod Info Levitra(R), , 2003.).

Molecular Weight

    A) 488.6 g/mol(Sweetman, 2004)

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