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AVANAFIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Avanafil is a phosphodiesterase 5 (PDE5) inhibitor that enhances the effect of nitrous oxide (NO) in the corpus cavernosum. Sexual stimulation is required to initiate local release of NO in the corpus cavernosum. The effects of NO activate the enzyme guanylate cyclase and increase levels of cGMP. The increased levels of cGMP produce smooth muscle relaxation and blood inflow in the corpus cavernosum, facilitating erection of the penis. In the absence of sexual stimulation, inhibition of PDE5 has no effect.

Specific Substances

    1) Avanafilo
    2) Avanafilum
    3) TA-1790
    4) CAS 330784-47-9
    5) C23H26ClN7O3
    1.2.1) MOLECULAR FORMULA
    1) C23H26ClN7O3 (Prod Info STENDRA(TM) oral tablets, 2012)

Available Forms Sources

    A) FORMS
    1) Avanafil is available in 50 mg, 100 mg, and 200 mg tablets (Prod Info STENDRA(TM) oral tablets, 2012).
    B) USES
    1) Avanafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (Prod Info STENDRA(TM) oral tablets, 2012).

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: Avanafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.
    B) PHARMACOLOGY: Avanafil inhibits phosphodiesterase 5 (PDE5), which is responsible for the degradation of cGMP in the corpus cavernosum. Sexual stimulation is required to initiate local release of nitrous oxide (NO) in the corpus cavernosum. Avanafil enhances the local effect of NO, which activates the enzyme guanylate cyclase and increases levels of cGMP. The increased levels of cGMP help produce smooth muscle relaxation and blood inflow in corpus cavernosum, facilitating erection of the penis. In the absence of sexual stimulation, inhibition of PDE5 has no effect.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include: back pain, flushing, headache, nasal congestion, and nasopharyngitis. LESS FREQUENT: Other adverse effects occurring less frequently include: URI, bronchitis, influenza, sinusitis, sinus congestion, mild hypotension, hypertension, dyspepsia, nausea, constipation, dizziness, and rash. Adverse effects reported with the use of other PDE5 inhibitors include: sudden hearing loss, change in color vision (rarely), and loss of vision (rarely).
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Avanafil is classified as FDA pregnancy category C, although it is not indicated for use in women. Decreased fetal body weight and reduced growth and maturation of offspring occurred in rats administered avanafil at various doses. Evidence showed low maternal body weight, increased postimplantation loss, and increased late resorptions in pregnant rabbits exposed to high doses. Further evidence showed decreased fertility and altered estrous cycles in female rats as well as reduced sperm motility and abnormal sperm production in male rats. Abnormal sperm production was shown to be reversible after a drug-free period of 9 weeks.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of avanafil.

Laboratory Monitoring

    A) Monitor blood pressure.
    B) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    C) Toxic levels of avanafil have not been established; routine drug plasma levels are not likely to be available.

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 avanafil 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: Monitor blood pressure, administer isotonic fluids at 10 to 20 mL/kg. Administer norepinephrine or dopamine if hypotension persists. PRIAPISM is an emergency requiring immediate consult with a urologist.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    2) HOSPITAL: Consider activated charcoal for a large overdose if the ingestion is recent and the patient is not vomiting and the airway can be maintained.
    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) HYPOTENSIVE EPISODE
    1) Monitor blood pressure, administer isotonic fluids at 10 to 20 mL/kg for severe hypotension.
    G) PRIAPISM
    1) Priapism is an emergency requiring immediate consult with a urologist. At the time of this review, priapism has not been reported with avanafil but it has been reported with other PDE5 inhibitors.
    2) 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.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be observed with frequent monitoring of blood pressure.
    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 of 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.
    J) PITFALLS
    1) Obtain a complete history of drug use, hypotensive emergencies may result from the combination of avanafil and nitrates (ie, nitroglycerin, isosorbide dinitrate, nitroprusside, amyl nitrite (also a recreational drug), and nitric oxide). Underlying cardiovascular disease may result in an increased risk for developing significant hypotension or cardiac instability. Events may be due the use of other agents (ie, nitrates).
    K) PHARMACOKINETICS
    1) Following the administration of an oral dose, avanafil is rapidly absorbed and approximately 99% protein bound. Metabolism of avanafil is primarily hepatic, being metabolized by CYP3A4 isoenzyme and to a minor extent by CYP2C isoforms. Circulating metabolites include M4 and M16. Approximately 62% of an oral dose is excreted in feces as metabolites and approximately 21% is excreted in urine as metabolites. The estimated half-life is 5 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Vasodilator or nitrate overdose. Overdose with another phosphodiesterase inhibitor.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. In clinical trials, patients tolerated single doses of 800 mg and multiple doses up to 300 mg.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 50 to 200 mg orally 30 minutes prior to sexual activity once daily. PEDIATRIC: Avanafil is not indicated for pediatric patients. Safety and efficacy have not been established in patients less than 18 years of age.

Clinical Effects

Summary Of Exposure

    A) USES: Avanafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.
    B) PHARMACOLOGY: Avanafil inhibits phosphodiesterase 5 (PDE5), which is responsible for the degradation of cGMP in the corpus cavernosum. Sexual stimulation is required to initiate local release of nitrous oxide (NO) in the corpus cavernosum. Avanafil enhances the local effect of NO, which activates the enzyme guanylate cyclase and increases levels of cGMP. The increased levels of cGMP help produce smooth muscle relaxation and blood inflow in corpus cavernosum, facilitating erection of the penis. In the absence of sexual stimulation, inhibition of PDE5 has no effect.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include: back pain, flushing, headache, nasal congestion, and nasopharyngitis. LESS FREQUENT: Other adverse effects occurring less frequently include: URI, bronchitis, influenza, sinusitis, sinus congestion, mild hypotension, hypertension, dyspepsia, nausea, constipation, dizziness, and rash. Adverse effects reported with the use of other PDE5 inhibitors include: sudden hearing loss, change in color vision (rarely), and loss of vision (rarely).
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) COLOR VISION CHANGES: Changes in color vision were reported in 1 patient receiving any dose of avanafil across all clinical trials (Prod Info STENDRA(TM) oral tablets, 2012).
    2) LOSS OF VISION: Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely with all phosphodiesterase 5 inhibitors, resulting in loss of vision in one or both eyes (Prod Info STENDRA(TM) oral tablets, 2012).
    3) CHORIORETINOPATHY: Rare cases of central serous chorioretinopathy (CSC) have been associated with other phosphodiesterase 5 inhibitors (sildenafil, tadalafil, and vardenafil) when used for erectile dysfunction (Aliferis et al, 2012).
    a) CASE SERIES: A retrospective, observational case series identified 11 male patients 33 to 70 years of age (mean, 51 years) who developed CSC after taking sildenafil in doses ranging from 50 mg to 100 mg/day 1 to 6 times/week for a duration of 1 day to 2 years. Four of the 10 patients whose ages were reported were older than 60 years. Of the 8 patients where dechallenge was documented, vision improved after sildenafil discontinuation in 6 cases while 2 patients had no improvement. Positive rechallenge was reported in 3 cases (Fraunfelder & Fraunfelder, 2008).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) SUDDEN HEARING LOSS: Sudden hearing loss, with or without tinnitus and dizziness, has been reported in patients taking other phosphodiesterase 5 inhibitors. A direct causal relationship to the drug has not been established (Prod Info STENDRA(TM) oral tablets, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Transient decreases in sitting blood pressure were reported in healthy volunteers receiving avanafil 200 mg. A reduction of 8 mmHg systolic and 3.3 mmHg diastolic was observed with a maximum decrease occurring 1 hour after the dose (Prod Info STENDRA(TM) oral tablets, 2012).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in 1% to less than 2% of men in any dose group receiving avanafil on an as needed basis in 3 randomized, placebo controlled trials (n=1267) for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).
    C) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Electrocardiogram abnormalities were reported in 1% and 3% of subjects taking avanafil doses of 100 mg and 200 mg, respectively in a trial of 298 men who had undergone bilateral nerve-sparing radical prostatectomy (Prod Info STENDRA(TM) oral tablets, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) NASAL CONGESTION
    1) WITH THERAPEUTIC USE
    a) Nasal congestion was reported in 1.8%, 2.9%, and 2% of men receiving avanafil doses of 50 mg (n=217), 100 mg (n=349), and 200 mg (n=352), respectively on an as needed basis, compared to 1.1% of patients taking placebo in 3 randomized, placebo controlled trials involving 1267 men for a duration of up to 3 months. In a long-term extension study for a duration of up to 52 weeks (n=711), nasal congestion was reported in 2.1% of men receiving avanafil on an as needed basis in varying doses (Prod Info STENDRA(TM) oral tablets, 2012).
    B) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Nasopharyngitis was reported in 0.9%, 2.6%, and 3.4% of men receiving avanafil doses of 50 mg (n=217), 100 mg (n=349), and 200 mg (n=352), respectively on an as needed basis, compared to 2.9% of patients taking placebho, in 3 randomized, placebo controlled trials involving 1267 men for a duration of up to 3 months. In a long-term extension study for a duration of up to 52 weeks (n=711), nasopharyngitis was reported in 3.4% of men receiving avanafil on an as needed basis in varying doses (Prod Info STENDRA(TM) oral tablets, 2012).
    C) RESPIRATORY TRACT INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory infections, bronchitis, sinusitis, and sinus congestion were reported in 1% to less than 2% of men in any dose group receiving avanafil on an as needed basis in 3 randomized, placebo controlled trials (n=1267) for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).
    D) INFLUENZA
    1) WITH THERAPEUTIC USE
    a) Influenza was reported in 1% to less than 2% of men in any dose group receiving avanafil on an as needed basis in 3 randomized, placebo controlled trials (n=1267) for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 5.1%, 6.9%, and 10.5% of men receiving avanafil doses of 50 mg (n=217), 100 mg (n=349), and 200 mg (n=352), respectively on an as needed basis, compared to 1.7% of patients taking placebo, in 3 randomized, placebo controlled trials involving 1267 men for a duration of up to 3 months. In a long-term extension study for a duration of up to 52 weeks (n=711), headache was reported in 5.6% of men receiving avanafil on an as needed basis in varying doses (Prod Info STENDRA(TM) oral tablets, 2012).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 1% to less than 2% of men receiving avanafil in a long-term extension study for a duration of up to 52 weeks (n=711). However, vertigo was reported in less than 1% of patients receiving avanafil in other controlled trials (n=1267). A direct causal relationship to the drug has not been established (Prod Info STENDRA(TM) oral tablets, 2012).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was reported in 1% to less than 2% of men in any dose group receiving avanafil on an as needed basis in 3 randomized, placebo controlled trials (n=1267) for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was reported in 1% to less than 2% of subjects receiving avanafil in clinical trials (n=1267) (Prod Info STENDRA(TM) oral tablets, 2012).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 1% to less than 2% of subjects receiving avanafil in clinical trials (n=1267) (Prod Info STENDRA(TM) oral tablets, 2012).
    D) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia was reported in 1% to less than 2% of subjects receiving avanafil in clinical trials (n=1267) (Prod Info STENDRA(TM) oral tablets, 2012).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) Prolonged (greater than 4 hours) and/or painful erections (over 6 hours duration) have been reported with other phosphodiesterase 5 inhibitors (Prod Info STENDRA(TM) oral tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing was reported in 3.2%, 4.3%, and 4% of men receiving avanafil doses of 50 mg (n=217), 100 mg (n=349), and 200 mg (n=352), respectively on an as needed basis, and in 0% of patients receiving placebo, in 3 randomized, placebo controlled trials involving 1267 men for a duration of up to 3 months. In a long-term extension study for a duration of up to 52 weeks (n=711), flushing was reported in 3.5% of men receiving avanafil on an as needed basis in varying doses (Prod Info STENDRA(TM) oral tablets, 2012).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash was reported in 1% to less than 2% of men in any dose group receiving avanafil on an as needed basis in 3 randomized, placebo controlled trials (n=1267) for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain was reported in 3.2%, 2%, and 1.1% of men receiving avanafil doses of 50 mg (n=217), 100 mg (n=349), and 200 mg (n=352), respectively, on an as needed basis, compared with 1.1% of patients taking placebo, in 3 randomized, placebo controlled trials involving 1267 men for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia was reported in 1% to less than 2% of men in any dose group receiving avanafil on an as needed basis in 3 randomized, placebo controlled trials (n=1267) for a duration of up to 3 months (Prod Info STENDRA(TM) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Avanafil is classified as FDA pregnancy category C, although it is not indicated for use in women. Decreased fetal body weight and reduced growth and maturation of offspring occurred in rats administered avanafil at various doses. Evidence showed low maternal body weight, increased postimplantation loss, and increased late resorptions in pregnant rabbits exposed to high doses. Further evidence showed decreased fertility and altered estrous cycles in female rats as well as reduced sperm motility and abnormal sperm production in male rats. Abnormal sperm production was shown to be reversible after a drug-free period of 9 weeks.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RABBITS: No evidence of teratogenicity was observed in rabbits administered doses up to approximately 6 times the maximum recommended human dose, based on AUC, from gestation days 6 to 18 (Prod Info STENDRA(R) oral tablets, 2014).
    2) RATS: No evidence of teratogenicity was observed in rats administered doses up to approximately 30 times the maximum recommended human dose (MRHD) of 1,000 mg/kg/day, based on AUC, from gestation days 6 to 17. The no observed adverse effect levels (NOAEL) for developmental toxicity was calculated as 100 mg/kg/day, approximately 2-fold greater than the systemic exposure at the MRHD (Prod Info STENDRA(R) oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified avanafil as FDA pregnancy category C, although it is not indicated for use in women (Prod Info STENDRA(R) oral tablets, 2014; Prod Info ERIVEDGE(TM) oral capsules, 2012).
    B) ANIMAL STUDIES
    1) RABBITS: Increased postimplantation loss, with increased late resorptions, was observed in rabbits administered doses up to approximately 6 times the maximum recommended human dose, based on AUC, from gestation days 6 to 18 (Prod Info STENDRA(R) oral tablets, 2014).
    2) RATS: No evidence of embryotoxicity or fetotoxicity was observed in rats administered doses up to approximately 8 times the maximum recommended human dose (MRHD) of 200 mg, based on AUC, from gestation days 6 to 17; however, decreased fetal body weight was observed at exposures approximately 30 times the MRHD, based on AUC. In a separate study, fetal growth and maturation were reduced in rats administered doses of 300 mg/kg/day (approximately 17 times the human exposure) or higher, from gestation day 6 through lactation day 20 (Prod Info STENDRA(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FEMALE RATS: No effect on reproductive performance was observed in female rats (or their offspring) when administered doses up to 600 mg/kg/day, from gestation day 6 through lactation day 20 (Prod Info STENDRA(R) oral tablets, 2014). There was evidence of decreased fertility and altered estrous cycles in female rats administered avanafil 100, 300, or 1000 mg/kg/day for 14 days prior to pairing through gestation day 7 (Prod Info ERIVEDGE(TM) oral capsules, 2012).
    2) MALE RATS: There was evidence of absent or reduced sperm motility in male rats administered avanafil 100, 300, or 1000 mg/kg/day for 28 days prior to pairing through euthanasia. An increased percentage of abnormal sperm, including broken sperm with detached heads, occurred in male rats administered 200 mg doses (approximately 11 times the human exposure). However, after a 9-week drug-free period, the broken sperm effects were reversible (Prod Info ERIVEDGE(TM) oral capsules, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of avanafil.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) MICE AND RATS: There were no carcinogenic effects observed at the highest dose tested when CD-1 mice were given oral avanafil at doses of 100, 200, or 600 mg/kg/day (approximately 11 times the maximum recommended human dose (MRHD) on an AUC basis) for 98 weeks or longer. Likewise, no effects were observed at the highest dose in Sprague Dawley rats given oral doses of 100, 300, or 1000 mg/kg/day (approximately 8 times above the MRHD on an AUC basis for males and 34 times for females) for 100 weeks or longer (Prod Info STENDRA(TM) oral tablets, 2012).

Genotoxicity

    A) There was no evidence of mutagenicity in Ames assays. There was no evidence of clastogenicity in the following tests: chromosome aberration assays with Chinese hamster ovary and lung cells, or in vivo in the mouse micronucleus assay. There was no evidence of genotoxicity in a series of tests. DNA repair was not affected in the rat unscheduled DNA synthesis assay (Prod Info STENDRA(TM) oral tablets, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure.
    B) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    C) Toxic levels of avanafil have not been established; routine drug plasma levels are not likely to be available.
    4.1.2) SERUM/BLOOD
    A) Serum levels of avanafil may not be useful because therapeutic and toxic levels have not been established and are generally not available in a timely fashion.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Due to the potential for hypotension, particularly when concomitant organic nitrates are ingested, it is recommended that blood pressure be monitored in all overdose cases. There is insufficient data to determine the duration of monitoring required.

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 patient with an inadvertent, small exposure that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for cases of 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) Patients with a deliberate overdose, and those who are symptomatic, need to be observed with frequent monitoring of blood pressure.

Monitoring

    A) Monitor blood pressure.
    B) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    C) Toxic levels of avanafil have not been established; routine drug plasma levels are not likely to be available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    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.
    B) MONITORING OF PATIENT
    1) Monitor blood pressure.
    2) No specific lab work (CBC, electrolytes, urinalysis) is needed, unless otherwise clinically indicated.
    3) Toxic levels of avanafil have not been established; routine drug plasma levels are not likely to be available or clinically useful.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) 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).
    D) CONTRAINDICATED TREATMENT
    1) Hypotensive emergencies may result from the combination of avanafil 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 (Prod Info STENDRA(TM) oral tablets, 2012).
    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) LACK OF EFFECT
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (Prod Info STENDRA(TM) oral tablets, 2012).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. In clinical trials, patients tolerated single doses of 800 mg and multiple doses up to 300 mg.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 50 to 200 mg orally 30 minutes prior to sexual activity once daily. PEDIATRIC: Avanafil is not indicated for pediatric patients. Safety and efficacy have not been established in patients less than 18 years of age.

Therapeutic Dose

    7.2.1) ADULT
    A) INITIAL DOSE: 100 mg orally once daily as needed. May be taken as early as 15 minutes prior to sexual activity (Prod Info STENDRA(R) oral tablets, 2014).
    B) DOSE ADJUSTMENT: Based on efficacy and tolerability, the dose may be decreased to 50 mg as early as 30 minutes prior to sexual activity or increased to a maximum 200 mg as early as 15 minutes prior to sexual activity. Use lowest effective dose to provide benefit (Prod Info STENDRA(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Avanafil is not indicated for pediatric administration. Safety and efficacy have not been established in patients less than 18 years of age (Prod Info STENDRA(R) oral tablets, 2014).

Minimum Lethal Exposure

    A) There have been no reports of avanafil toxicity at the time of this review (Prod Info STENDRA(TM) oral tablets, 2012).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established and there have been no reports of avanafil overdose at the time of this review. In clinical trials, patients have tolerated single doses of 800 mg and multiple doses up to 300 mg (Prod Info STENDRA(TM) oral tablets, 2012).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) PEAK CONCENTRATION
    a) Following a single oral dose of avanafil 50 mg in healthy Korean male volunteers (n=8), the mean (SD) Cmax value was 1206 ng/mL (Jung et al, 2010).
    b) Following a single oral dose of avanafil 100 mg in healthy Korean male volunteers (n=8), the mean (SD) Cmax value was 2630 ng/mL (Jung et al, 2010).
    c) Following a single oral dose of avanafil 200 mg in healthy Korean male volunteers (n=8), the mean (SD) Cmax value was 5161.25 ng/mL (Jung et al, 2010).
    2) TIME TO PEAK CONCENTRATION
    a) The median Tmax is 30 to 45 minutes without food (Prod Info STENDRA(TM) oral tablets, 2012).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Avanafil inhibits phosphodiesterase 5 (PDE5), which is responsible for the degradation of cGMP in the corpus cavernosum. Sexual stimulation is required to initiate local release of nitrous oxide (NO) in the corpus cavernosum. Avanafil enhances the local effect of NO, which activates the enzyme guanylate cyclase and increases levels of cGMP. The increased levels of cGMP help produce smooth muscle relaxation and blood inflow in corpus cavernosum, facilitating erection of the penis. In the absence of sexual stimulation, inhibition of PDE5 has no effect (Prod Info STENDRA(TM) oral tablets, 2012).

Physicochemical

Physical Characteristics

    A) Avanafil is a white crystalline powder that is soluble in 0.1 mol/L hydrochloric acid, slightly soluble in ethanol, and practically insoluble in water (Prod Info STENDRA(TM) oral tablets, 2012).

Molecular Weight

    A) 483.95

References

General Bibliography

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