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SILDENAFIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sildenafil acts peripherally, as a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5).

Specific Substances

    1) Sildenafilo
    2) Sildenafilum
    3) UK 92480
    4) Molecular Formula: C22-H30-N6-O4-S
    5) CAS 139755-83-2
    6) CAS 171599-83-0

Available Forms Sources

    A) FORMS
    1) Sildenafil is available as 20 mg, 25 mg, 50 mg, 100 mg tablets, 10 mg/mL oral powder for suspension, and 10 mg/12.5 mL intravenous solution (Prod Info REVATIO oral tablets, suspension, intravenous injection, 2015; Prod Info VIAGRA(R) oral tablets, 2015).
    2) ADULTERATED PRODUCTS
    a) In April 2012, the FDA confirmed that "African Black Ant", a product sold on the internet for sexual enhancement, contained sildenafil and tadalafil. This agent is sold as a "natural sexual enhancer" with no known side effects. The FDA advised consumers to stop taking the product (U.S. Food and Drug Administration, 2012).
    b) CASE REPORT: A man developed persistent priapism after taking African Black Ant for erectile dysfunction and methamphetamine; symptoms resolved following treatment on 2 separate days. Laboratory analysis of the product detected sildenafil (96 mg/capsule; the maximum recommended dose is 100 mg/day according to the manufacturer) (Coralic et al, 2013).
    B) USES
    1) Sildenafil is used in the treatment of erectile dysfunction in male adults (Prod Info VIAGRA(R) oral tablets, 2015). It is also used for the treatment of pulmonary arterial hypertension (Prod Info REVATIO oral tablets, suspension, intravenous injection, 2015).
    2) Sildenafil has been used as a recreational drug by both men and women for enhancing libido. Often it is used in combination with other illicit drugs, including amyl nitrite. Serious adverse drug interactions are a potential hazard (Aldridge & Measham, 1999).

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: Smooth muscle relaxant used for erectile dysfunction and pulmonary hypertension. Sildenafil is also abused, often in conjunction with other drugs to enhance sexual performance.
    B) PHARMACOLOGY: Inhibition of cGMP specific phosphodiesterase type-5 (PDE5) in smooth muscle in the pulmonary vascular bed in the lungs and the corpus cavernosum of the penis.
    C) TOXICOLOGY: Overdose causes excessive vasodilatation resulting in hypotension, tachycardia, headache, priapism, facial flushing, dizziness, and general weakness.
    D) EPIDEMIOLOGY: Poisoning is uncommon and rarely severe.
    E) WITH THERAPEUTIC USE
    1) Facial flushing, rash, diarrhea, dyspepsia, dizziness/vertigo, headache, abnormal vision, nasal congestion, hypotension, tachycardia, myocardial infarction, non-arteritic ischemic optic neuropathy, priapism (rare), and musculoskeletal pain have been reported.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Headache, facial flushing, dizziness, general weakness, priapism and vertigo.
    2) SEVERE TOXICITY: Severe effects may include significant hypotension, tachycardia, and generalized weakness. Theoretically, CNS depression, cerebral ischemia, and other end organ ischemia are possible after severe overdose, but have not been reported. A young adult developed recurrent tonic-clonic seizures after misusing sildenafil (100 mg).
    0.2.20) REPRODUCTIVE
    A) Sildenafil is classified as FDA pregnancy category B. Studies in rats and rabbits have not shown evidence of teratogenicity, embryotoxicity, or fetotoxicity with the administration of sildenafil at doses up to 40 times the maximum recommended human dose. In humans, limited experience with sildenafil use during pregnancy for the treatment of pulmonary hypertension has reported minimal fetal and maternal risks.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential with sildenafil (Prod Info VIAGRA(R) oral tablets, 2010; Prod Info REVATIO(R) oral tablets, IV injection, 2009). However, a prospective cohort study found that use of sildenafil was associated with an increased risk of melanoma, although no increased risk of squamous cell or basal cell carcinoma was observed for sildenafil users.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Sildenafil plasma levels are not clinically useful or readily available. In addition, sildenafil is not detected on a urine drug screen.
    C) No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension, ataxia, coma, and diarrhea).
    D) Monitor renal function, troponin and liver enzymes in patients with prolonged hypotension, seizures or coma to screen for end-organ damage. Ensure good neurological exam as patients are at elevated risk for stroke.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The vast majority of sildenafil overdoses requires only supportive care; activated charcoal is indicated if patients present shortly after ingestion. Treat headache, facial flushing, dizziness and general weakness with IV fluids. Hypotension and tachycardia are generally mild and well tolerated and usually respond to IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients who experience respiratory compromise or significant CNS depression require early endotracheal intubation for airway protection. While activated charcoal is indicated in these cases, is should be performed only in patients who can protect their airway or who are intubated. Patients with persistent hypotension despite intravenous fluids require vasopressors, theoretically alpha agonists norepinephrine and phenylephrine may be more effective.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal should be given to those who are able to reliably protect their airway and IV fluids should be given for hypotension or tachycardia.
    2) HOSPITAL: Activated charcoal should be given to those who are able to reliably protect their airway. Fatalities are extremely rare and gastric lavage is generally not indicated.
    D) AIRWAY MANAGEMENT
    1) It is unlikely that a patient with an isolated sildenafil overdose will require airway management. Perform early in patients with severe intoxication (ie, seizures, dysrhythmias, severe delirium, CNS or respiratory depression).
    E) ANTIDOTE
    1) No specific antidote for sildenafil exists. IV fluids and peripheral vasopressors are the primary treatment of choice.
    F) TACHYCARDIA
    1) Reflex tachycardia is usually seen from hypotension.
    G) SEIZURES
    1) Unlikely, but can be due to cerebral ischemia. Correct hypotension and treat with benzodiazepines.
    H) 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.
    I) ENHANCED ELIMINATION
    1) Because sildenafil is highly protein bound and is not eliminated in the urine, hemodialysis and hemoperfusion are not expected to be of benefit in overdose.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children (other than mild drowsiness) with small ingestions and asymptomatic adults who have inadvertently ingested an extra dose may be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions or children with significant ingestions should be referred to a health care facility for observation for 6 to 8 hours. All symptomatic patients should be sent to a health care facility for observation for 6 to 8 hours.
    3) ADMISSION CRITERIA: Patients with significant persistent CNS depression (ie, weakness, ataxia, vertigo, coma) or those with persistent abnormal vital signs such as tachycardia and hypotension should be admitted. Patients with coma, seizures, dysrhythmias, or end organ damage should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, dysrhythmias, severe hypotension, coma) or in whom the diagnosis is not clear.
    K) PITFALLS
    1) Not identifying a possible septic patient or ingestion of another agent like a calcium channel blocker. Failing to recognize a stroke or myocardial infarction. Overhydrating patients which might precipitate pulmonary edema after the medication has been metabolized. Overdose of sildenafil typically responds well to aggressive intensive, supportive care. Failure to ask about coingestion of nitrates.
    L) DRUG INTERACTIONS
    1) Concomitant use with nitrates may cause profound hypotension. Drugs that inhibit P450 3A4 (cimetidine, erythromycin, ketoconazole) can increase sildenafil plasma concentrations and may increase toxicity. Coadministration with HIV protease inhibitor therapy has been associated with myocardial ischemia.
    M) PHARMACOKINETICS
    1) Sildenafil undergoes extensive first-pass metabolism. It is 96% protein bound and is extensively metabolized and conjugated in the liver. Approximately 80% is excreted in the feces, 13% in the urine, both mainly as metabolites. Half-life is 4 hours.
    N) TOXICOKINETICS
    1) Onset of symptoms generally occur within 30 minutes to one hour, toxicity may persist for more than 6 hours, and may last longer in the elderly and patients with liver disease.
    2) CASE REPORT: An adult intentionally ingested 65 tablets of 100 mg (6500 mg) of sildenafil citrate and developed only minor toxicity following a large overdose. Half-life was estimated to be 4.2 hours (similar to pharmacokinetics).
    O) DIFFERENTIAL DIAGNOSIS
    1) Overdose of any vasodilator (eg, nitrates), theophylline overdose, beta-blocker or calcium channel blockers (although should see both bradycardia and hypotension with these agents), CNS infection, sepsis, or ethanol intoxication.

Range Of Toxicity

    A) TOXICITY: ADULT: Adults who ingest less than 800 mg typically have symptoms consistent with therapeutic dosing. A 56-year-old man reportedly intentionally ingested 6500 mg of sildenafil and initially developed severe vomiting and complaints of blurred vision. Upon admission 24 hours later, his serum level was 22.2 mcg/mL (higher than previously reported in fatal and non fatal cases). Symptoms were managed with supportive care and he recovered completely. However, one adult developed rhabdomyolysis after ingesting 250 mg of sildenafil and improved without permanent sequelae following supportive care. In another case, a young adult developed recurrent tonic-clonic seizures after misusing sildenafil 100 mg; no intervention was needed. Doses in excess of 2000 mg have caused hypotension and tachycardia. Fatalities are exceedingly rare. PEDIATRIC: A 2-year-old developed persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. THERAPEUTIC: ADULT: ERECTILE DYSFUNCTION: Usual dose is 50 mg taken approximately 1 hour prior to sexual activity (range, 0.5 to 4 hours before sexual activity); dose range: 25 to 100 taken once per day. PULMONARY HYPERTENSION: ADULT: 20 mg 3 times daily (given every 4 to 6 hours). PEDIATRIC: Safety and efficacy of sildenafil for pediatric pulmonary hypertension has not been established.
    B) THERAPEUTIC: ADULT: ERECTILE DYSFUNCTION: Usual dose is 50 mg taken approximately 1 hour prior to sexual activity (range, 0.5 to 4 hours before sexual activity); dose range: 25 to 100 taken once per day. PULMONARY HYPERTENSION: ADULT: 20 mg 3 times daily (given every 4 to 6 hours). PEDIATRIC: Safety and efficacy of sildenafil for pediatric pulmonary hypertension has not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Smooth muscle relaxant used for erectile dysfunction and pulmonary hypertension. Sildenafil is also abused, often in conjunction with other drugs to enhance sexual performance.
    B) PHARMACOLOGY: Inhibition of cGMP specific phosphodiesterase type-5 (PDE5) in smooth muscle in the pulmonary vascular bed in the lungs and the corpus cavernosum of the penis.
    C) TOXICOLOGY: Overdose causes excessive vasodilatation resulting in hypotension, tachycardia, headache, priapism, facial flushing, dizziness, and general weakness.
    D) EPIDEMIOLOGY: Poisoning is uncommon and rarely severe.
    E) WITH THERAPEUTIC USE
    1) Facial flushing, rash, diarrhea, dyspepsia, dizziness/vertigo, headache, abnormal vision, nasal congestion, hypotension, tachycardia, myocardial infarction, non-arteritic ischemic optic neuropathy, priapism (rare), and musculoskeletal pain have been reported.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Headache, facial flushing, dizziness, general weakness, priapism and vertigo.
    2) SEVERE TOXICITY: Severe effects may include significant hypotension, tachycardia, and generalized weakness. Theoretically, CNS depression, cerebral ischemia, and other end organ ischemia are possible after severe overdose, but have not been reported. A young adult developed recurrent tonic-clonic seizures after misusing sildenafil (100 mg).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Abnormalities related to color vision may be observed at higher doses or higher plasma concentrations due to sildenafil's effect on a PDE isoenzyme found in the retina (Prod Info Viagra(TM), sildenafil citrate, 1998; Vobig et al, 1999).
    a) Dose-related (greater than 100 mg) impairment of blue/green color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects close to the time of peak plasma levels. This effect is consistent with inhibition of PDE6, which is involved in phototransduction in the retina (Krenzelok, 2000; Prod Info Viagra(TM), sildenafil citrate, 1998).
    2) Vobig et al (1999) studied the retinal effects of a single 100 mg dose in 5 healthy volunteers. No changes is visual acuity, visual field, color vision, intraocular pressure, or visual evoked potentials occurred. However, a single dose induced an a-wave and b-wave reduction in the saturated response of the ERG, with complete recovery after 6 hours. Effects in the elderly or in patients with preexisting retinal disease are unknown.
    3) Anterior ischemic optic neuropathy has been reported following a 50 mg dose of sildenafil in a 52-year-old man with no known vasculopathic risk factors. Symptoms began one hour after the sildenafil dose. Nine months later ophthalmic examination revealed pallor superiorly in the left eye (Egan & Pomeranz, 2000).
    B) WITH POISONING/EXPOSURE
    1) CASE REPORT: A 54-year-old man presented with a sudden vision loss in his left eye several hours after ingesting 200 mg of sildenafil. He had been taking sildenafil therapeutically at a dose of 100 mg 2 to 3 times per week over a period of a few months. An ocular examination revealed a left relative afferent papillary defect and a combined cilioretinal artery occlusion and anterior ischemic optic neuropathy of the left fundus. He was hypotensive (98/60 mmHg) and the intraocular pressure was 24 mmHg in both eyes. The patient was given aspirin 75 mg/day in order to reduce the risk of occurrence in his right eye; however, he subsequently developed left optic atrophy and sildenafil therapy was permanently discontinued. The authors believed that the patient's vision loss was due to increased intraocular pressure superimposed on a state of systemic hypotension, leading to ocular hypoperfusion (Akash et al, 2005).
    2) CASE REPORT: A 45-year-old healthy man was admitted approximately 10 hours after taking 250 mg of sildenafil (obtained illegally) after failing to achieve the desired sexual response with complaints of myalgia, in particular, in the lower extremities, darkish urine, and changes in visual perception. Serum laboratory studies were consistent with rhabdomyolysis. Several ocular examinations were completed including vision blindness, color test, fundus photoscopy and fluorescent angiography to evaluate the patient's complaint of darkness. All studies were within normal limits. Following IV hydration and urine alkalization to prevent kidney injury, laboratory levels gradually returned to normal. Symptoms of myalgia and visual changes slowly resolved over several days. The patient was discharged on day 5 with no permanent sequelae (Oh, 2014).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) SILDENAFIL: Transient nasal congestion is a common adverse reaction following therapeutic sildenafil ingestion. Rhinitis, related to PDE5 inhibition, is a common adverse effect (Moreira et al, 2000).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Healthy male volunteers given single oral doses of 100 mg experienced an average decrease of approximately 10 mmHg from baseline blood pressure levels (Prod Info Viagra(TM), sildenafil citrate, 1998).
    b) No clinically significant effects on pulse rate or blood pressure were seen in healthy volunteers following single oral doses up to 200 mg (Boolell et al, 1996).
    c) In the AAPCC TESS database for 1998, hypotension occurred in 3.9% of the exposures to sildenafil alone (Krenzelok, 2000).
    d) The FDA has issued a warning cautioning clinicians against prescribing sildenafil for patients with preexisting heart disease which could be affected by transient decreases in blood pressure (Anon, 1998).
    2) WITH POISONING/EXPOSURE
    a) Hypotension may occur following overdoses, especially when concomitant nitrates, whose effects are potentiated by sildenafil, are also taken. These effects are possibly related to PDE5 in vascular smooth muscle and effects on the nitric oxide/cGMP pathway (Prod Info Viagra(TM), sildenafil citrate, 1998).
    B) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) In a series of 129 exposures to sildenafil-alone in the 1998 AAPCC TESS database, tachycardia accounted for 7.8% of the total reported adverse effects (Krenzelok, 2000).
    b) A case of atrial fibrillation in a previously healthy 35-year-old man with no known risk factors occurred following a single 100 mg sildenafil dose. It was suggested that sildenafil caused profound hypotension leading to syncope and reflex tachycardia via catecholamine excess. Sildenafil was identified as causally related to the dysrhythmia (Hahn & Hoffman, 2000).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia may accompany hypotension in severe overdoses due to its mechanism of action as a phosphodiesterase inhibitor or as a reflex response to hypotension.
    b) CASE REPORT: About 2 hours following the intentional ingestion of 20 sildenafil tablets (2000 mg) a 42-year-old woman presented to the ED with palpitations and tachycardia (101 bpm), non-specific ST-T changes on ECG, facial flushing and fine tremors of the extremities. Full recovery was reported after gastric decontamination and supportive management (Hung & Yang, 2001).
    c) CASE REPORT (PEDIATRIC): A 19-month-old healthy toddler ingested up to 6 (50 mg) sildenafil tablets and developed mild facial flushing, tachycardia (bpm 140), and priapism with normal blood flow. He appeared to be in no distress or pain. Following observation, all symptoms completely resolved within 24 hours; gastric decontamination was not performed (Wills et al, 2007) .
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction has been rarely reported following therapeutic use of sildenafil in patients with no history of cardiovascular disease and no concomitant drugs that would increase the risk of hypotension or other cardiovascular problems (Muniz & Holstege, 2000; Feenstra et al, 1998).
    b) In a hemodynamic study of 14 men with preexisting severe coronary artery disease, dosing with a single 100 mg dose of sildenafil produced no adverse cardiovascular effects (Herrmann et al, 2000). However, in this study no controls were used, diphenhydramine and diazepam were given with the sildenafil, no adjustment for other concomitant medications was made, and the sample size was small (Malozowski & Sahlroot, 2000).
    c) Myocardial infarction has been reported following therapeutic use of sildenafil in patients with known coronary artery disease but no history of nitrate use. It has been suggested that sildenafil-induced emotional arousal followed by physical exertion may trigger plaque rupture leading to acute myocardial infarction (Porter et al, 1999).
    d) CASE REPORT: A 65-year-old man developed acute anterior myocardial infarction following one tablet of sildenafil (50 mg), first time use. Within 30 minutes of ingestion, the patient experienced nausea, vomiting and severe left-sided chest pain. There was no history of coronary artery disease, no risk factors for cardiovascular disease and no other medications were taken. Sildenafil was causally related to the acute myocardial infarction (Feenstra et al, 1998).
    D) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Patients with preexisting hypertrophic cardiomyopathy may experience a decreased preload and afterload due to sildenafil, which may culminate in an unstable hemodynamic state in these patients and possibly sudden death (Stauffer et al, 1999).
    E) DISORDER OF CORONARY ARTERY
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, placebo-controlled cross-over trial of 105 men with erectile dysfunction and known or highly suspected coronary artery disease (CAD), cardiovascular effects of sildenafil, given 1 hour prior, were analyzed during maximal, symptom-limited bicycle exercise testing. In men with stable CAD, sildenafil use was reported to have no effect on symptoms, exercise duration, or presence or extent of exercise-induced ischemia, as evaluated by exercise electrocardiography or echocardiography (Arruda-Olson et al, 2002).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Anesthetized cats administered various IV doses of sildenafil experienced marked, but transient drops in mean blood pressure (ca. 40%), LV systolic pressure (ca. 25%), and LV dP/dT (20%) which were statistically significant but not dose-related (FDA, NDA, 1998).
    2) TACHYCARDIA
    a) Anesthetized cats administered various IV sildenafil doses experienced an 18% increase in heart rate at the highest dose (FDA, NDA, 1998).
    3) VASODILATATION
    a) At IV doses of 3 to 300 mcg/Kg, dogs displayed dose-related arteriovenous dilator properties with a profile similar to that of isosorbide dinitrate (equipotent on both arterial and venous sides) (FDA, NDA, 1998).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT (PEDIATRIC): A 2-year-old man experienced persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. He recovered completely with no permanent sequelae (Cantrell, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Headache and facial flushing were the most commonly reported adverse effects following single doses of sildenafil (90 mg or greater) during clinical studies. These effects were transient, resolving in a few hours (Moreira et al, 2000; Boolell et al, 1996; Boolell et al, 1996a). Dizziness has also been reported as an adverse event. In a series of 129 exposures to sildenafil-alone in the 1998 AAPCC TESS database, headache and dizziness/vertigo accounted for 7.8% of the total reported adverse effects (Krenzelok, 2000).
    b) INCIDENCE: In a retrospective subanalysis of data from double-blind controlled efficacy studies (9 studies) and safety studies (11 studies), 25% of patients without ischemic heart disease experienced headache and 21% of ischemic heart disease patients experienced headache after therapeutic doses (Conti et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur following overdose with sildenafil (Hung & Yang, 2001).
    b) CASE REPORT: Following an overdose of 20 sildenafil tablets (2000 mg), a 42-year-old woman presented to the ED with headache, dizziness, general weakness, palpitations, and facial flushing. She recovered and was discharged 12 hours later after gastric decontamination and supportive management (Hung & Yang, 2001).
    B) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Fine tremors or the upper extremities and tachycardia have been reported following a sildenafil overdose (2000 mg) in a 42-year-old woman (Hung & Yang, 2001).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-year-old developed recurrent tonic-clonic seizures approximately one hour after intentionally ingesting 100 mg of sildenafil (obtained without a prescription) to enhance his sexual performance. The seizures were witnessed by his girlfriend. Upon admission, his neurologic examination and head CT were essentially normal. He reported marijuana use about once per week. A urine drug screen was positive for tetrahydrocannabinol (THC) only. An EEG obtained the following day was normal and he was discharged without being prescribed any medications. About a month later, the patient tried sildenafil again and developed another episode of tonic-clonic seizure and was going to seek help from a therapist for his situational ED (Calabro et al, 2015).
    D) CRANIAL NERVE DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Complete unilateral pupil-sparing third nerve palsy occurred 36 hours after ingesting 50 mg of sildenafil in a 56-year-old man. Concomitant medication included amitriptyline as well as tobacco use. A history of preexisting vascular disease was reported. It was suggested that a drop in systemic blood pressure may have caused transient hypoperfusion of the right third nerve (Donahue & Taylor, 1998).
    E) CEREBRAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 35-year-old man with no prior medical history developed a severe headache approximately 2 hours after taking sildenafil 50 mg. He had been taking sildenafil 2 to 3 times daily for about a month without medical supervision. Upon admission, his vitals signs, neurologic examination and laboratory studies were within normal limits. A cranial CT scan showed a hemorrhage in the right nucleus caudatus, which opened in the lateral and third ventricles. Diagnostic studies revealed no vascular pathology. A cardiology exam was also normal. The patient was monitored for several days and discharged to home on day 5 with normal neurologic function (Ayberk et al, 2014).
    F) CEREBRAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) VERTEBRAL ARTERY DISSECTION
    1) CASE REPORT/CHRONIC MISUSE: A 49-year old man, with a history of sildenafil misuse for sexual enhancement for 2 years, took 300 mg of sildenafil (usual dose, 50 mg daily per the manufacturer) on the morning of admission and developed hemiparesthesia of the right side, neck pain and ataxia of the right arm. He had no family history of stroke or cerebral vascular events, but he smoked half a pack of cigarettes daily. Duplex sonography demonstrated a dissection of the right vertebral artery. A cerebral MRI showed similar findings, as well as an infarct of the right posterior inferior cerebellar artery territory. The patient was treated with intravenous heparin for 6 days that was followed by clopidogrel (75 mg daily) orally. Upon follow-up, a Doppler ultrasound study showed resolution of the dissection (Dersch et al, 2013).
    G) TRANSIENT CEREBRAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A transient ischemic attack occurred in a 50-year-old man after he took 50 mg of sildenafil; the patient experienced a stroke 6 days later when he took 100 mg of the drug (on neither occasion did he attain an erection). His only other medication at the time was insulin. His risk factors included type 2 diabetes mellitus, 30 pack-years of smoking, hypertension, hyperlipidemia, and family history of stroke. Symptoms included right facial weakness, slurred speech, difficulty swallowing, right hemiparesis, and right altered hemibody sensation. On examination, he exhibited hypertension, dysarthria, right lower facial weakness, right palatal weakness, tongue deviation, and decreased strength and sensation in his right extremities. Magnetic resonant imaging and angiography of the brain revealed cranial hyperintensity consistent with an acute or subacute infarct in the territory of the anterior choroidal artery. He abstained from sildenafil use. Six months later, he had improved but continued to have residual mild right hemiparesis and right arm spasticity (Morgan et al, 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Mild and transient dyspepsia has been reported in clinical studies following therapeutic doses of sildenafil (Moreira et al, 2000; Boolell et al, 1996a). In a series of 129 exposures to sildenafil-alone in the 1998 AAPCC TESS database, nausea accounted for 3.9% of the adverse effects reported (Krenzelok, 2000).
    b) INCIDENCE: In a retrospective subanalysis of data from double-blind controlled efficacy studies (9 studies) and safety studies (11 studies), 12% of patients without ischemic heart disease experienced dyspepsia and 10% of ischemic heart disease patients experienced dyspepsia after therapeutic doses (Conti et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) Dyspepsia and abdominal fullness have been reported following a sildenafil overdose (2000 mg) (Hung & Yang, 2001).
    b) CASE REPORT (PEDIATRIC): A 2-year-old toddler experienced persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. He recovered completely with no permanent sequelae (Cantrell, 2004).
    B) ULCER OF ESOPHAGUS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Oral sildenafil was strongly suspected of causing esophageal ulcers in a 61-year-old man. The patient presented with dysphagia, odynophagia, and low-grade fever. Two days earlier, he had swallowed a half tablet of sildenafil (Viagra(R) 100 mg) without water just before going to bed. He reported that he felt as if the pill had stuck in his chest. Within a few hours, he experienced progressive retrosternal burning pain and odynophagia. He had no history of esophageal disease or dyspepsia. Upper GI endoscopy showed multiple irregular erosions with white exudates in the upper part of the esophagus and multiple punched out ulcers with whitish bases in the middle to lower esophagus. Biopsy of specimens from the ulcers revealed severe inflammation and necrosis. He was treated with a histamine-2 antagonist; the lesions healed after 2 weeks. The authors dissolved a 50-mg tablet of sildenafil in 10 mL of distilled water. The resulting solution was acidic and had a pH of 4.4 (Higuchi et al, 2001).
    C) RECTAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hemorrhoidal bleeding was associated with sildenafil therapeutic use in a 36-year-old man with a previous diagnosis of internal hemorrhoids one year earlier. The patient took a dose of sildenafil on several separate occasions followed by rectal bleeding on each occasion. Since stopping sildenafil, no further rectal bleeding was reported. The authors suggested vasodilatation in the hemorrhoidal venous plexus resulted following sildenafil use which triggered bleeding (Sheikh et al, 2001).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IN-VITRO STUDIES
    a) Sildenafil has been shown to potentiate endogenous nitric oxide at higher concentrations in dog isolated lower esophageal sphincter muscle causing a significant relaxation. Higher concentrations also relaxed pre-contracted mouse and rat ileum with equivalent potency (FDA, NDA, 1998).
    2) LACK OF EFFECT
    a) No effect was seen on basal gastric acid secretion or gastrointestinal propulsive activity in the rat following oral doses up to 10 mg/kg (FDA, NDA, 1998).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) One case of priapism was reported in a patient after drug marketing. Erectile response has generally increased with increasing doses and plasma concentrations of sildenafil with a time course of effect up to 4 hours. Priapism greater than 6 hours in duration has been reported following therapeutic use (Prod Info Viagra(TM), sildenafil citrate, 1998). The FDA has issued a warning about the rare occurrence of painful, prolonged erections (greater than 4 hours) (Anon, 1998).
    b) Conditions which may predispose patients to priapism include sickle cell anemia, multiple myeloma, or leukemia (Prod Info Viagra(TM), sildenafil citrate, 1998).
    c) CASE REPORT: A case of sildenafil-associated low-flow priapism was reported in a 28-year-old man following a 100 mg dose 24 hours previously. The priapism resolved following aspiration and intracorporal injection of alpha-agonists (Sur & Kane, 2000).
    2) WITH POISONING/EXPOSURE
    a) Erectile response has generally increased with increasing doses and plasma concentrations of sildenafil with a time course of effect up to 4 hours (Prod Info Viagra(TM), sildenafil citrate, 1998); thus it may be possible in an overdose situation to see priapism.
    b) CASE REPORT (PEDIATRIC): A 19-month-old healthy toddler ingested up to 6 (50 mg) sildenafil tablets and developed mild facial flushing, tachycardia (140 beats/min), and priapism. The toddler appeared to be in no distress or pain. Following observation, all symptoms completely resolved within 24 hours; no urologic intervention was required (Wills et al, 2007).
    c) CASE REPORT (PEDIATRIC): A 2-year-old toddler experienced persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. He recovered completely with no permanent sequelae (Cantrell, 2004).
    d) ADULTERATED PRODUCT/CASE REPORT: A 49-year-old man developed persistent priapism after taking African Black Ant (herbal supplement) and illicit methamphetamine for erectile dysfunction. Symptoms lasted 5 days and required treatment on 2 separate hospital admissions that included cavernosal aspiration and a bilateral T-shunt with tunneling of the corpora cavernosa. Laboratory analysis using liquid chromatograph time-of-flight mass spectrometer detected sildenafil (96 mg/capsule; maximum recommended dose per manufacturer is 100 mg/day) in one of the Africa Black Ant capsules(Coralic et al, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) WITH POISONING/EXPOSURE
    a) In clinical trials, sildenafil had no effect on bleeding time when taken alone or in combination with aspirin. In vitro effects on human platelets indicate that sildenafil may potentiate the antiaggregatory effect of sodium nitroprusside (Prod Info Viagra(TM), sildenafil citrate, 1998).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) BLEEDING TIME INCREASED
    a) Rats given an IV dose of 0.3 mg/kg experienced a 60% increase in bleeding time, without appreciably affecting the clotting time (FDA, NDA, 1998). These effects are consistent with identified actions of sildenafil on platelets in the absence of an effect on clotting cascade.
    b) Rabbits given IV doses of sildenafil were reported to have potentiation of the antiaggregatory effect of SNP (a nitric oxide donor) with a duration of action consistent with its plasma half-life in this species (FDA, NDA, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Facial flushing and headache were the most commonly reported adverse effects in clinical studies after single doses of 90 mg or greater (Moreira et al, 2000; Boolell et al, 1996).
    b) INCIDENCE: In a retrospective subanalysis of data from double-blind controlled efficacy studies (9 studies) and safety studies (11 studies), 14% of patients without ischemic heart disease experienced flushing and 15% of ischemic heart disease patients experienced flushing after therapeutic doses (Conti et al, 1999). In a series of 129 exposures to sildenafil-alone in the 1998 AAPCC TESS database, erythema (flushing) accounted for 13.7% of the total reported adverse effects (Krenzelok, 2000).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Facial flushing and headache may occur following overdose of these agents, and has been reported following overdose of 2000 mg sildenafil in a 42-year-old woman (Hung & Yang, 2001).
    b) CASE REPORT (PEDIATRIC): A 2-year-old toddler experienced persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. He recovered completely with no permanent sequelae (Cantrell, 2004).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Mild and transient musculoskeletal pain has been reported in clinical studies following therapeutic doses of sildenafil (Boolell et al, 1996a).
    B) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 45-year-old healthy man was admitted approximately 10 hours after taking 250 mg (five 50 mg tablets) of sildenafil that was obtained illegally after failing to achieve the desired sexual response with complaints of myalgia, in particular, in the lower extremities, darkish urine, and changes in visual perception. He reported taking sildenafil on a routine basis. Physical examination was positive for muscle tenderness only. Laboratory studies revealed a CPK of 25,325 International Units/L and elevated transaminases. Urine microscopy showed 3 to 5 red blood cells. Several ocular studies were performed and found to be normal. Following IV hydration and urine alkalization to prevent kidney injury, laboratory levels gradually returned to normal. Symptoms of myalgia and visual changes slowly resolved over several days. The patient was discharged on day 5 with no permanent sequelae (Oh, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Sildenafil is classified as FDA pregnancy category B. Studies in rats and rabbits have not shown evidence of teratogenicity, embryotoxicity, or fetotoxicity with the administration of sildenafil at doses up to 40 times the maximum recommended human dose. In humans, limited experience with sildenafil use during pregnancy for the treatment of pulmonary hypertension has reported minimal fetal and maternal risks.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) The late antepartum use of sildenafil in 2 women with severe pulmonary arterial hypertension (PAH) had no adverse effect on the health of the delivered infants. The first case, a 30-year-old female with a history of systemic lupus erythematous and antiphospholipid syndrome, received sildenafil (titrated up to 50 mg 3 times daily) and epoprostenol (titrated up to 9 nanograms (ng)/kg/min over 7 days) for PAH. After approximately 4 weeks of treatment (36 weeks' gestation), she delivered a healthy 2410-g infant with an Apgar score of 5 and 9 at 1 minute and 5 minutes, respectively. In the second case, a 21-year-old female with a history of ventricular septal defect and Eisenmenger's syndrome was treated with sildenafil (up to 50 mg 3 times daily) and epoprostenol (up to 8 ng/kg/min) for progressively worsening PAH symptoms. After one week of treatment (37 weeks' gestation), she delivered a healthy baby via cesarean section (Goland et al, 2010).
    2) A 29-year-old woman with pulmonary arterial hypertension associated with systemic lupus erythematosus delivered a healthy infant following 32 weeks of treatment with low molecular weight heparin, sildenafil (50 mg 3 times/day), azathioprine, hydroxychloroquine, and prednisone. After being stable on this regimen, the patient developed elevated right ventricular pressure at week 35, which was subsequently treated with inhaled iloprost (titrated up to 100 mcg/day). At 37 weeks, the patient delivered a healthy female infant weighing 2760 g and with Apgar scores of 8, 9, and 10 at 1, 5, and 10 minutes, respectively (Streit et al, 2009).
    3) No adverse neonatal effects were reported following intermittent sildenafil therapy for severe pulmonary hypertension in a 22-year-old pregnant woman with a history of Eisenmenger syndrome. The patient received sildenafil 150 mg/day and diltiazem 60 mg/day during the first trimester of pregnancy and later was treated with sildenafil 150 mg/day and L-arginine 3 g/day for worsening cardiac status during the last weeks of pregnancy. At 36 weeks of gestation, the patient delivered a healthy male infant weighing 2290 g and with an Apgar score of 9 at 1 and 5 minutes (Lacassie et al, 2004).
    B) ANIMAL STUDIES
    1) No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in rats and rabbits administered up to 200 mg/kg/day during organogenesis. These doses represent, respectively, approximately 20 and 40 times the maximum recommended human dose (MRHD) on a mg/m(2) basis in a patient weighing 50 kg. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat, the AUC at this dose was about 20 times the human AUC (Prod Info VIAGRA(R) oral tablets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Sildenafil is classified as FDA pregnancy category B (Prod Info VIAGRA(R) oral tablets, 2010; Prod Info Revatio(TM), 2005).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether sildenafil is secreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown (Prod Info Revatio(TM), 2005).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) In human studies, single doses of 100 mg sildenafil given to healthy males did not impair sperm motility or morphology. In animal studies, sildenafil did not impair fertility in rats given sildenafil in doses of 60 mg/kg/day for 36 days in females and for 102 days in males, corresponding to an AUC that was greater than 25 times that produced in human males (Prod Info VIAGRA(R) oral tablets, 2010).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS139755-83-2 (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
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential with sildenafil (Prod Info VIAGRA(R) oral tablets, 2010; Prod Info REVATIO(R) oral tablets, IV injection, 2009). However, a prospective cohort study found that use of sildenafil was associated with an increased risk of melanoma, although no increased risk of squamous cell or basal cell carcinoma was observed for sildenafil users.
    3.21.3) HUMAN STUDIES
    A) SKIN CARCINOMA
    1) A prospective cohort study analyzing the data from 25,848 men, of whom 1378 (5.3%) took sildenafil recently for erectile dysfunction (ED) and 1618 (6.3%) ever used sildenafil, demonstrated that sildenafil use significantly increased risk of melanoma by nearly 100%; however, sildenafil use was not associated with an increased risk of squamous cell carcinoma (SCC) or basal cell carcinoma (BCC). A total of 142 cases of melanoma, 580 cases of SCC, and 3030 cases of BCC were identified. Using a multivariate-adjusted model of analysis, recent sildenafil use was associated with a significantly increased risk of melanoma (hazard ratio [HR], 1.84; 95% CI, 1.04 to 3.22), and ever use of sildenafil was also associated with a significantly increased risk of melanoma (HR, 1.92; 95% CI, 1.14 to 3.22). In contrast, an association was not observed between sildenafil use and an increased risk of SCC (HR, 0.84; 95% CI, 0.59 to 1.2) or BCC (HR, 1.08; 95% CI, 0.93 to 1.25) (Li et al, 2014).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenic potential when male and female rats were given sildenafil at doses up to 29- and 42-times, respectively, the maximum recommended human dose (for males) of 100 mg/day for 24 months. Carcinogenicity was also not found when mice were administered sildenafil doses of 10 mg/kg/day (approximately 0.6 times the MRHD on a mg/m(2) basis) for 18 to 21 months (Prod Info VIAGRA(R) oral tablets, 2010).

Genotoxicity

    A) There was no evidence of mutagenicity in in vitro bacterial and Chinese hamster ovary cell assays or clastogenicity in in vitro human lymphocytes and in vivo mouse micronucleus assays (Prod Info VIAGRA(R) oral tablets, 2010; Prod Info REVATIO(R) oral tablets, IV injection, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Sildenafil plasma levels are not clinically useful or readily available. In addition, sildenafil is not detected on a urine drug screen.
    C) No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension, ataxia, coma, and diarrhea).
    D) Monitor renal function, troponin and liver enzymes in patients with prolonged hypotension, seizures or coma to screen for end-organ damage. Ensure good neurological exam as patients are at elevated risk for stroke.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels of sildenafil may not be useful, since therapeutic and toxic levels have not been established, and are generally not readily available.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Due to the potential for hypotension, especially if 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.

Methods

    A) CHROMATOGRAPHY
    1) Boolell et al (1996) have reported using a sensitive and specific high performance liquid chromatography (HPLC) assay following solid phase extraction for plasma and urine quantitative measurements of sildenafil.
    2) For the identification and quantitation of sildenafil and its metabolites in urine and tissue samples in a postmortem case, solid-phase extract, LC/MS and MS/MS methods were developed (Weinmann et al, 2001).

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 significant persistent CNS depression (ie, weakness, ataxia, vertigo, coma) or those with persistent abnormal vital signs such as tachycardia and hypotension should be admitted. Patients with coma, seizures, dysrhythmias, or end-organ damage should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children (other than mild drowsiness) with small ingestions and asymptomatic adults who have inadvertently ingested an extra dose may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, dysrhythmias, severe hypotension, coma) or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, those with deliberate ingestions or children with significant ingestions should be referred to a health care facility for observation for 6 to 8 hours. All symptomatic patients should be sent to a health care facility for observation for 6 to 8 hours.

Monitoring

    A) Monitor vital signs and mental status.
    B) Sildenafil plasma levels are not clinically useful or readily available. In addition, sildenafil is not detected on a urine drug screen.
    C) No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension, ataxia, coma, and diarrhea).
    D) Monitor renal function, troponin and liver enzymes in patients with prolonged hypotension, seizures or coma to screen for end-organ damage. Ensure good neurological exam as patients are at elevated risk for stroke.

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) SUMMARY
    1) Due to the rapid absorption (within 60 minutes) of sildenafil, gastric decontamination, particularly gastric lavage, is unlikely to be of benefit. However, following a massive ingestion, particularly if delayed absorption is likely, gastric decontamination may be beneficial. Pediatric unintentional ingestions are unlikely to produce significant adverse effects, and; therefore, GI decontamination is probably unnecessary in most cases (Krenzelok, 2000).
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) 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.
    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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific treatment for sildenafil overdose other than supportive care. Nitrates should be avoided for 24 hours if myocardial ischemia is evident (longer if on P450 inhibitors or if hepatic or renal dysfunction are present), given the risk of hypotension and exacerbation of ischemia.
    B) MONITORING OF PATIENT
    1) All overdose cases should be monitored for signs of hypotension, especially when organic nitrates have been concomitantly taken. Males should be observed for signs of priapism.
    C) CONTRAINDICATED TREATMENT
    1) Hypotensive emergencies may result from the combination of sildenafil 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 sildenafil, and clinicians are cautioned to obtain medical histories on all patients presenting to an ED 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. If hypotension persists, administer norepinephrine or phenylephrine. 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) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE/INDICATIONS
    a) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    3) LIDOCAINE/DOSE
    a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    4) LIDOCAINE/MAJOR ADVERSE REACTIONS
    a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    5) LIDOCAINE/MONITORING PARAMETERS
    a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    6) ESMOLOL: Prepare a solution containing 10 mg esmolol per ml of a compatible intravenous solution. LOADING DOSE - Infuse 500 mcg/kg for 1 minute. MAINTENANCE DOSE: Follow loading dose with infusion of 50 mcg/kg/min for 4 min. If inadequate response, repeat loading dose followed by maintenance infusion of 100 mcg/kg/min for 4 minutes. Reevaluate effect. If inadequate response, repeat loading dose and increase maintenance dose by increments of 50 mcg/kg/min, administered as above.
    a) CAUTION: Esmolol is a short-acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol may be hazardous in patients with bronchospastic disease (asthmatics, COPD) (Prod Info Brevibloc(R), esmolol hydrochloride, 1996).
    F) PRIAPISM
    1) SUMMARY
    a) PRIAPISM is an emergency requiring immediate consult with a urologist.
    b) CASE REPORT: In one case of 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).
    2) GUIDELINE 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) DIURESIS
    1) There is no evidence that forced diuresis will enhance elimination.
    2) Sildenafil is highly protein bound and it is not eliminated in the urine, thus forced diuresis is not expected to enhance elimination (Prod Info Viagra (R), 2000).
    B) HEMODIALYSIS
    1) Because sildenafil is highly protein bound and is not eliminated in the urine, renal dialysis is not expected to be of benefit in overdoses (Prod Info Viagra (R), 2000).

Range Of Toxicity

Summary

    A) TOXICITY: ADULT: Adults who ingest less than 800 mg typically have symptoms consistent with therapeutic dosing. A 56-year-old man reportedly intentionally ingested 6500 mg of sildenafil and initially developed severe vomiting and complaints of blurred vision. Upon admission 24 hours later, his serum level was 22.2 mcg/mL (higher than previously reported in fatal and non fatal cases). Symptoms were managed with supportive care and he recovered completely. However, one adult developed rhabdomyolysis after ingesting 250 mg of sildenafil and improved without permanent sequelae following supportive care. In another case, a young adult developed recurrent tonic-clonic seizures after misusing sildenafil 100 mg; no intervention was needed. Doses in excess of 2000 mg have caused hypotension and tachycardia. Fatalities are exceedingly rare. PEDIATRIC: A 2-year-old developed persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. THERAPEUTIC: ADULT: ERECTILE DYSFUNCTION: Usual dose is 50 mg taken approximately 1 hour prior to sexual activity (range, 0.5 to 4 hours before sexual activity); dose range: 25 to 100 taken once per day. PULMONARY HYPERTENSION: ADULT: 20 mg 3 times daily (given every 4 to 6 hours). PEDIATRIC: Safety and efficacy of sildenafil for pediatric pulmonary hypertension has not been established.
    B) THERAPEUTIC: ADULT: ERECTILE DYSFUNCTION: Usual dose is 50 mg taken approximately 1 hour prior to sexual activity (range, 0.5 to 4 hours before sexual activity); dose range: 25 to 100 taken once per day. PULMONARY HYPERTENSION: ADULT: 20 mg 3 times daily (given every 4 to 6 hours). PEDIATRIC: Safety and efficacy of sildenafil for pediatric pulmonary hypertension has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ERECTILE DYSFUNCTION
    1) ORAL: 50 mg taken approximately 1 hour (range, 0.5 to 4 hours) prior to sexual activity; MAX: 100 mg once per day (Prod Info VIAGRA(R) oral tablets, 2014).
    B) PULMONARY ARTERIAL HYPERTENSION
    1) INTRAVENOUS: Recommended dose is 2.5 or 10 mg IV bolus 3 times a day (Prod Info REVATIO(R) oral tablets, oral suspension, intravenous injection, 2014).
    2) ORAL: Recommended dose is 5 or 20 mg 3 times a day, taken 4 to 6 hours apart. Higher doses are not recommended (Prod Info REVATIO(R) oral tablets, oral suspension, intravenous injection, 2014).
    7.2.2) PEDIATRIC
    A) ERECTILE DYSFUNCTION
    1) Safety and efficacy in the pediatric or adolescent population has not been established (Prod Info VIAGRA(R) oral tablets, 2014).
    B) PULMONARY ARTERIAL HYPERTENSION
    1) FDA WARNING
    a) As of August 30, 2012, the FDA notified healthcare professionals that sildenafil should not be prescribed to children (ages 1 through 17 for the treatment of pulmonary arterial hypertension (PAH). This is based on a recent long-term clinical pediatric trial showing that children taking a high dose of sildenafil had a higher risk of death than children taking a low dose (the low dose is ineffective in improving exercise ability). Treatment of PAH in children with sildenafil is an off-label use and a new warning, stating the use of sildenafil is not recommended in pediatric patients has been added to the Revatio(R) label (U.S. Food and Drug Administration (FDA), 2012).

Maximum Tolerated Exposure

    A) ADULT
    1) Acute exposures in healthy male adults of up to 800 mg produced adverse effects similar to those seen at lower doses, except with increased incidence rates (Prod Info Viagra(TM), sildenafil citrate, 1998).
    2) Healthy male volunteers given single oral doses of 100 mg experienced an average decrease of approximately 10 mmHg from baseline blood pressure levels (Prod Info Viagra(TM), sildenafil citrate, 1998).
    3) CASE REPORT: An acute overdose of 2000 mg in a 42-year-old woman resulted in general weakness, palpitation, headache, dizziness, flushing, fine tremor of the upper extremities, tachycardia (heart rate, 101 bpm), nonspecific ST-T changes on ECG, and mild leukocytosis. The patient was discharged 12 hours after decontamination and supportive therapy (Hung & Yang, 2001).
    4) CASE REPORT: A 54-year-old man developed vision loss in his left eye due to nonarteritic anterior ischemic optic neuropathy several hours after ingesting 200 mg of sildenafil. He had been taking sildenafil therapeutically at a dose of 100 mg 2 to 3 times per week over a period of a few months (Akash et al, 2005).
    5) CASE REPORT/ADULTERATED PRODUCT: A man developed persistent priapism after taking African Black Ant for erectile dysfunction and methamphetamine; symptoms resolved following treatment on 2 separate hospital admissions. Laboratory analysis of the product detected sildenafil (96 mg/capsule; the maximum recommended dose is 100 mg/day according to the manufacturer) (Coralic et al, 2013). In April 2012, the FDA confirmed that "African Black Ant", a product sold on the internet for sexual enhancement, contained sildenafil and tadalafil. This agent is sold as a "natural sexual enhancer" with no known side effects. The FDA advised consumers to stop taking the product (U.S. Food and Drug Administration, 2012).
    6) CASE REPORT/LACK OF SEVERE SYMPTOMS: A 56-year-old man intentionally ingested 65 sildenafil citrate tablets (100 mg each; total: 6500 mg) and initially developed severe vomiting and blurred vision, but no priapism. Upon admission 24 hours later, his laboratory studies were within normal limits with a minor decrease in kidney function (ie, glomerular filtration rate) and an increase in inflammatory parameters (ie, elevated C-reactive protein and leukocytosis). His serum sildenafil level was 22.2 mcg/mL (about 3 times higher than a previously reported fatal case with a serum concentration of 6.3 mcg/mL). It was estimated that his initial serum concentration was approximately 900 mcg/mL. His serum concentration gradually declined to 9.2 and 2.3 mcg/mL, respectively about 5 and 14 hours later. The estimated half-life was thought to be 4.2 hours. The patient remained stable without developing significant toxicity and recovered with supportive care (Matheeussen et al, 2015).
    7) CASE REPORT/MISUSE: An 18-year-old developed recurrent tonic-clonic seizures approximately one hour after intentionally ingesting 100 mg of sildenafil (obtained without a prescription) to enhance his sexual performance. The seizures were witnessed by his girlfriend. Upon admission, his neurologic examination and head CT were essentially normal. He reported marijuana use about once per week. A urine drug screen was positive for tetrahydrocannabinol (THC) only. An EEG obtained the following day was normal and he was discharged without being prescribed any medications. About a month later, the patient tried sildenafil again and developed another episode of tonic-clonic seizure and was going to seek help from a therapist for his situational ED (Calabro et al, 2015).
    8) CASE REPORT/CHRONIC MISUSE: A 49-year old man, with a history of sildenafil misuse for sexual enhancement for 2 years, took 300 mg of sildenafil (usual dose, 50 mg daily per the manufacturer) on the morning of admission and developed hemiparesthesia of the right side, neck pain and ataxia of the right arm. He had no family history of stroke or cerebral vascular events, but he smoked half a pack of cigarettes daily. Duplex sonography demonstrated a dissection of the right vertebral artery. A cerebral MRI showed similar findings, as well as an infarct of the right posterior inferior cerebellar artery territory. The patient was treated with intravenous heparin for 6 days that was followed by clopidogrel (75 mg daily) orally. Upon follow-up, a Doppler ultrasound study showed resolution of the dissection (Dersch et al, 2013).
    9) CASE REPORT/RHABDOMYOLYSIS: A 45-year-old healthy man was admitted approximately 10 hours after taking 250 mg (five 50 mg tablets) of sildenafil that was obtained illegally after failing to achieve the desired sexual response with complaints of myalgia, in particular, in the lower extremities, darkish urine, and changes in visual perception. He reported taking sildenafil on a routine basis. Physical examination was positive for muscle tenderness only. Laboratory studies revealed a CPK of 25,325 International Units/L and elevated transaminases. Urine microscopy showed 3 to 5 red blood cells. Several ocular studies were performed and found to be normal. Following IV hydration and urine alkalization to prevent kidney injury, laboratory levels gradually returned to normal. Symptoms of myalgia and visual changes slowly resolved over several days. The patient was discharged on day 5 with no permanent sequelae (Oh, 2014).
    10) CASE REPORT/INTRACEREBRAL HEMORRHAGE: A 35-year-old man with no prior medical history developed a severe headache approximately 2 hours after taking sildenafil 50 mg. He had been taking sildenafil 2 to 3 times daily for about a month without medical supervision. Upon admission, his vitals signs, neurologic examination and laboratory studies were within normal limits. A cranial CT scan showed a hemorrhage in the right nucleus caudatus, which opened in the lateral and third ventricles. Diagnostic studies revealed no vascular pathology. A cardiology exam was also normal. The patient was monitored for several days and discharged to home on day 5 with normal neurologic function (Ayberk et al, 2014).
    B) PEDIATRIC
    1) CASE REPORT (PEDIATRIC): A 19-month-old healthy toddler ingested up to 6 (50 mg) sildenafil tablets and developed mild facial flushing, tachycardia (140 beats/min), and priapism with no apparent pain. The patient was observed for 24 hours; decontamination was not performed. All symptoms completely resolved within 24 hours (Wills et al, 2007).
    2) CASE REPORT (PEDIATRIC): A 2-year-old toddler experienced persistent facial flushing, painful transient penile engorgement, bilateral rhonchi, and diarrhea after ingesting approximately 1.5 pills (75 mg) of sildenafil. He recovered completely with no permanent sequelae (Cantrell, 2004).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT (ADULT): A 56-year-old man intentionally ingested 65 sildenafil citrate tablets (100 mg each) and initially developed severe vomiting and blurred vision, but no priapism. Upon admission 24 hours later, his serum sildenafil level was 22.2 mcg/mL (about 3 times higher than a previously reported fatal case with a serum concentration of 6.3 mcg/mL). It was estimated that his initial serum concentration was approximately 900 mcg/mL. His serum concentration gradually declined to 9.2 and 2.3 mcg/mL, respectively about 5 and 14 hours later. The estimated half-life was thought to be 4.2 hours. The patient did not develop significant toxicity and recovered with supportive care (Matheeussen et al, 2015).
    2) CASE REPORT (PEDIATRIC): A 19-month-old healthy toddler ingested up to 6 (50 mg) sildenafil tablets and developed mild facial flushing, tachycardia (140 beats/min), and priapism (presumed to be a high flow state) with no apparent pain. Serum sildenafil concentration obtained approximately 7 hours after ingestion was 3900 ng/mL (reporting limit 24 ng/mL) and N-desmethylsildenafil concentration was 1700 ng/mL (limit 24 ng/mL). All symptoms resolved within 24 hours with no interventions required (Wills et al, 2007).

Workplace Standards

    A) ACGIH TLV Values for CAS139755-83-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS139755-83-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS139755-83-2 :
    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

    D) OSHA PEL Values for CAS139755-83-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Sildenafil is an orally active, reversible, selective competitive inhibitor of type-5 phosphodiesterase, the predominant isoenzyme causing inactivation of cyclic guanosine monophosphate (cGMP) in human corpus cavernosum. It completely inhibits cGMP hydrolytic activity of the PDE5 peak from human corpus cavernosum, with no significant effect of the PDE2 or PDE3 peaks (Prod Info Cialis(R), 2003; Porst, 2002; Prod Info Viagra(TM), sildenafil citrate, 1998; Boolell et al, 1996).
    1) This inhibition relaxes corpus cavernosal smooth muscle cells, which increases blood flow into the cavernosal spaces. This in turn leads to increased intracavernosal pressure, which is a major factor in producing erections.
    2) Sildenafil has been shown to have low activity against PDE2 and PDE3 from corpus cavernosum and PDE4 from skeletal muscle. Only moderate activity was demonstrated against PDE1 from human cardiac ventricle. Relative to isoenzymes from PDE families 1 through 4, sildenafil was at least 70-fold selective for PDE5.
    3) In vitro studies have shown that sildenafil's effect is more potent on PDE5 than other known phosphodiesterases (>80-fold for PDE1, >1000-fold for PDE2, PDE3, and PDE4). Sildenafil has been shown to have approximately a 4000-fold selectivity for PDE5 versus PDE3, the isoenzyme involved in cardiac contractility. It is only about 10-fold as potent for PDE5 compared to PDE6, an isoenzyme found in the retina, which may account for some abnormalities related to color vision observed with higher doses or plasma levels (Prod Info Viagra(TM), sildenafil citrate, 1998).
    4) Other tissue sites containing and responding to PDE5 include platelets and muscle (vascular, skeletal, gastrointestinal) (FDA, NDA, 1998).

Toxicologic Mechanism

    A) RETINAL EFFECTS: Rhodopsin, the visual pigment of the rod, stimulates retinal PDE6 via G-protein, transducin. When levels of cGMP decrease, cGMP- gated channels close and hyperpolarize photoreceptors and appear to affect blue/green color vision. This effect is consistent with inhibition of PDE6, which is involved in phototransduction in the retina (FDA, NDA, 1998).

Physicochemical

Physical Characteristics

    A) SILDENAFIL: White to off-white crystalline powder with a solubility of 3.5 mg/mL in water (Prod Info Viagra(TM), sildenafil citrate, 1998).

Ph

    A) SILDENAFIL: A 50 mg Viagra(TM) tablet dissolved in 10 mL of distilled water was found to be acidic (pH = 4.4) (Higuchi et al, 2001).

Molecular Weight

    A) 666.7 (sildenafil)

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