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TADALAFIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tadalafil is a selective inhibitor of phosphodiesterase type 5 (PDE5).

Specific Substances

    1) Cialis
    2) GF-196960
    3) GG-960
    4) IC-351
    5) ICI-351
    6) ICOS-351
    7) LY-450190
    8) Molecular Formula: C22-H19-N3-O4
    9) CAS 171596-29-5
    1.2.1) MOLECULAR FORMULA
    1) C22-H19-N3-O4

Available Forms Sources

    A) FORMS
    1) Tadalafil is available as 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration (Prod Info ADCIRCA(R) oral tablets, 2015; Prod Info CIALIS(R) oral tablets, 2014).
    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) USES
    1) Tadalafil is indicated for the treatment of erectile dysfunction and the signs and symptoms of benign prostatic hyperplasia (Prod Info CIALIS(R) oral tablets, 2011). It is also used to treat pulmonary arterial hypertension (WHO Group 1) to improve exercise ability (Prod Info ADCIRCA(R) oral tablets, 2015).

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: Tadalafil is used in the treatment of erectile dysfunction and for the signs and symptoms of benign prostatic hyperplasia.
    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: Similar to other phosphodiesterase 5 inhibitors, overdose is likely to cause 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) COMMON: The most common adverse effects are headache, back pain, dyspepsia, and myalgia. Other adverse effects that may occur include nasal congestion, flushing, and limb pain.
    2) RARE: The following have rarely been reported and a causal relationship of these events to tadalafil is uncertain: CARDIOVASCULAR: Angina pectoris, chest pain, hypotension, hypertension, myocardial infarction, postural hypotension, palpitations, syncope, and tachycardia can develop. GASTROINTESTINAL: Nausea, vomiting, diarrhea, dry mouth, dysphagia, esophagitis, gastroesophageal reflux, gastritis, epistaxis, pharyngitis, and upper abdominal pain have been observed. DERMATOLOGIC: Rash, pruritus, and increased sweating can occur. OTHER: Dyspnea, abnormal liver enzymes, changes in color vision, dizziness, hypesthesia, insomnia, paresthesia, somnolence, and vertigo can develop.
    3) DRUG INTERACTION: Severe hypotension may develop in patients taking tadalafil and nitrates.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Data limited. Following the administration of single doses up to 500 mg to healthy volunteers or multiple daily doses up to 100 mg to patients, adverse effects were similar to therapeutic doses.
    2) Intracerebral hemorrhage was associated with tadalafil (40 mg dose) misuse in an older adult; no permanent sequelae was reported.
    0.2.20) REPRODUCTIVE
    A) Tadalafil is classified as FDA Pregnancy Category B. It is not indicated for use in women.

Laboratory Monitoring

    A) Monitor vital signs and mental status in symptomatic patients.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed in most patients, unless otherwise clinically indicated.
    C) Tadalafil plasma levels are not clinically useful or readily available.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Limited data. Tadalafil overdoses are likely to require only supportive care; there is no specific treatment. Treat headache, facial flushing, dizziness and general weakness with IV fluids. Hypotension and tachycardia are anticipated to be generally mild and well tolerated and usually respond to IV fluids. Infuse IV NaCL 10 to 20 mL/kg as necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Reflex tachycardia is usually seen due to hypotension. 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 may be considered following a significant exposure, if the patient is able to protect their airway and IV fluids should be given for hypotension or reflex tachycardia.
    2) HOSPITAL: Activated charcoal may be considered following a significant exposure and the airway is protected. Significant toxicity is not anticipated following a minor exposure unless coingestants are involved.
    D) CONTRAINDICATED TREATMENT
    1) Hypotensive emergencies may result from the combination of tadalafil and nitrates, which include but are not limited to: nitroglycerin, isosorbide dinitrate, nitroprusside, amyl nitrite (also a recreational drug), and nitric oxide. Nitrates are CONTRAINDICATED in patients who ingested tadalafil within the past 24 hours due to the possibility of a severe hypotensive reaction. Nitrates should be also be avoided for 24 hours if myocardial ischemia is evident (longer if receiving P450 inhibitors or if hepatic or renal dysfunction are present), given the risk of hypotension and exacerbation of ischemia.
    E) AIRWAY MANAGEMENT
    1) It is unlikely that a patient with an isolated tadalafil overdose will require airway management. Perform airway management early in patients that develop significant intoxication.
    F) ANTIDOTE
    1) No specific antidote for tadalafil exists. IV fluids and peripheral vasopressors are the primary treatment of choice.
    G) 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.
    H) SEIZURES
    1) Unlikely, but can be due to cerebral ischemia. Correct hypotension and treat with benzodiazepines.
    I) ENHANCED ELIMINATION
    1) Tadalafil is highly protein bound and has a large volume of distribution; 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 a small ingestion (1 tablet) 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 healthcare facility for observation for a minimum of 6 to 8 hours.
    3) ADMISSION CRITERIA: Patients with significant persistent abnormal vital signs such as hypotension and tachycardia should be admitted. Patients with severe symptoms (ie, coma, dysrhythmias, or evidence of 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 tadalafil typically responds well to aggressive intensive, supportive care. Failure to ask about coingestion of nitrates.
    L) PHARMACOKINETICS
    1) Following a single oral dose, Cmax occurs between 30 minutes and 6 hours (median time 2 hours). The mean volume of distribution following oral administration is approximately 63 L. Tadalafil has a plasma protein binding of 94%. It has an mean oral clearance of 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy adults. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of a dose) and to a lesser extent in the urine (approximately 36% of a dose).
    M) 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: Limited data. A toxic dose has not been established. Single doses of 500 mg and daily doses of 100 mg were well tolerated in healthy volunteers. THERAPEUTIC: ADULT: Initial dose: 10 mg orally no more than once daily; may increase to 20 mg or decrease to 5 mg, based on efficacy and tolerability; maximum: 20 mg daily. PEDIATRIC: Tadalafil is not indicated for use in pediatric patients

Clinical Effects

Summary Of Exposure

    A) USES: Tadalafil is used in the treatment of erectile dysfunction and for the signs and symptoms of benign prostatic hyperplasia.
    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: Similar to other phosphodiesterase 5 inhibitors, overdose is likely to cause 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) COMMON: The most common adverse effects are headache, back pain, dyspepsia, and myalgia. Other adverse effects that may occur include nasal congestion, flushing, and limb pain.
    2) RARE: The following have rarely been reported and a causal relationship of these events to tadalafil is uncertain: CARDIOVASCULAR: Angina pectoris, chest pain, hypotension, hypertension, myocardial infarction, postural hypotension, palpitations, syncope, and tachycardia can develop. GASTROINTESTINAL: Nausea, vomiting, diarrhea, dry mouth, dysphagia, esophagitis, gastroesophageal reflux, gastritis, epistaxis, pharyngitis, and upper abdominal pain have been observed. DERMATOLOGIC: Rash, pruritus, and increased sweating can occur. OTHER: Dyspnea, abnormal liver enzymes, changes in color vision, dizziness, hypesthesia, insomnia, paresthesia, somnolence, and vertigo can develop.
    3) DRUG INTERACTION: Severe hypotension may develop in patients taking tadalafil and nitrates.
    F) WITH POISONING/EXPOSURE
    1) OVERDOSE: Data limited. Following the administration of single doses up to 500 mg to healthy volunteers or multiple daily doses up to 100 mg to patients, adverse effects were similar to therapeutic doses.
    2) Intracerebral hemorrhage was associated with tadalafil (40 mg dose) misuse in an older adult; no permanent sequelae was reported.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase, and swelling of eyelids have been reported infrequently in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014; Meuleman, 2003).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Nasal congestion has been reported in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014; Brock, 2003; Rotella, 2003).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Angina pectoris, chest pain, hypotension, hypertension, myocardial infarction, postural hypotension, palpitations, syncope, and tachycardia have been reported infrequently in patients taking tadalafil; however, a casual relationship of these events to tadalafil is uncertain (Prod Info CIALIS(R) oral tablets, 2014).
    B) PERIPHERAL ISCHEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 43-year-old man intentionally injected oral tadalafil gel into his left radial artery (attempting to inject the gel intravenously) and initially developed severe pain that reportedly subsided, which was followed by acute ischemia of his hand and digits approximately 24 hours later. The patient delayed medical care for 48 hours, by this time the hand was discolored with widespread mottling. Capillary refill was delayed (12 to 15 seconds) along with a large ischemic area on the dorsum of the hand. Injury was limited to the microvasculature of the skin and distal digits. Treatment included IV heparin and iloprost which seemed to subjectively improve circulation (ie, feels of warmth) and decrease pain; surgical intervention was not immediately required. However, 36 hours after exposure, the patient continued to have pain and the absence of digital perfusion. Prophylactic carpal tunnel decompression and a thenar eminence fasciotomy was performed. He continued to improve with outpatient dressing changes and physiotherapy, but the tip of the thumb and index finger auto-amputated. Although the gel could have produced tissue loss, histologic evidence did not suggest embolism by the gel (Vaughan et al, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Dyspnea, epistaxis and pharyngitis have been reported in a small number of patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported frequently in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014; Brock, 2003; Rotella, 2003; Porst, 2002; Sorbera et al, 2001; Padma-Nathan et al, 2001). During on-demand treatment, headache appeared dose-related up to 10 mg (Saenz de Tejada et al, 2001; Padma-Nathan et al, 2001; Porst, 2002).
    B) MIGRAINE
    1) WITH THERAPEUTIC USE
    a) Migraine has been associated with the use of tadalafil in post-marketing surveillance reports; however, a causal relationship of these events to tadalafil is uncertain and it is not possible to reliably estimate the frequency (Prod Info CIALIS(R) oral tablets, 2014).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizure and seizure recurrence have been associated with the use of tadalafil in post-marketing surveillance reports; however, a causal relationship of these events to tadalafil is uncertain and it is not possible to reliably estimate the frequency (Prod Info CIALIS(R) oral tablets, 2014).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Dizziness, hypesthesia, insomnia, paresthesia, somnolence, and vertigo have been reported in less than 2% of patients given tadalafil in controlled clinical trials; however, a causal relationship of these events to tadalafil is uncertain (Prod Info CIALIS(R) oral tablets, 2014).
    E) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) During post-marketing surveillance, serious adverse events including stroke has been reported in patients with and without preexisting cardiovascular risk factors. Mostly these events occurred during or shortly after sexual activity or shortly after the use of tadalafil without sexual activity. Occasionally events occurred hours to days following tadalafil use and sexual activity (Prod Info CIALIS(R) oral tablets, 2014).
    F) CEREBRAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) An acute headache was reported in a 70-year-old man approximately one hour after taking 40 mg (recommended dose 20 mg) of tadalafil. On presentation, the patient complained of headache, nausea and vomiting for several days; he was also anxious and confused. A head CT showed an intracerebral hemorrhage (2 x 4 cm in diameter) in the right temporal lobe. Angiography revealed no vascular anomalies or malformations. The patient was discharged to home on day 7 with normal neurologic function. A follow-up MRI/angiography one month later, showed a hypointense lesion with no signs of a vascular malformation (Gazzeri et al, 2008).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Dyspepsia has been reported in 4% to 10% of patients (n=1180) taking tadalafil (5 mg, 10 mg, or 20 mg) (Prod Info CIALIS(R) oral tablets, 2014; Brock, 2003; Rotella, 2003; Porst, 2002; Sorbera et al, 2001).
    b) Diarrhea, dry mouth, dysphagia, esophagitis, gastroesophageal reflux, gastritis, nausea, vomiting, and upper abdominal pain have been reported infrequently in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014; Padma-Nathan et al, 2001).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal liver enzymes have been reported infrequently in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing has been reported in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014; Brock, 2003; Porst, 2002).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash and pruritus have been rarely reported in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014).
    C) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Increased diaphoresis has been rarely reported in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Asthenia, arthralgia, neck and back pain have been reported in patients taking tadalafil (Prod Info CIALIS(R) oral tablets, 2014; Brock, 2003; Rotella, 2003; Padma-Nathan et al, 2001; Anon, 2001; Porst, 2002).

Reproductive

    3.20.1) SUMMARY
    A) Tadalafil is classified as FDA Pregnancy Category B. It is not indicated for use in women.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE, RATS: No teratogenic, embryotoxic, or fetotoxic effects were seen in the offspring of rats and mice exposed to approximately 11 times the maximum recommended human dose (MRHD) of tadalafil 20 mg/day during organogenesis (Prod Info CIALIS(R) oral tablets, 2014).
    2) MICE, RATS: Teratogenicity, embryotoxicity, and fetotoxicity were not observed in rats or mice that received up to 1000 mg/kg/day (Meuleman, 2003).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified tadalafil as FDA pregnancy category B. It is not indicated for use in women (Prod Info CIALIS(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: Developmental studies of rats administered tadalafil doses approximately 10 times the MRHD resulted in decreased postnatal pup survival. Maternal toxicity was observed in rats administered doses approximately 16 times the MRHD. Tadalafil doses of 60, 200, and 1000 mg/kg/day given during prenatal and postnatal development resulted in decreased pup survival (Prod Info CIALIS(R) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF EFFECT
    1) It is unknown if tadalafil is excreted in human breast milk (Prod Info CIALIS(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: In animal studies, tadalafil and/or its metabolites were excreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma (Prod Info CIALIS(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) Following the administration of tadalafil to men (10 and 20 mg daily) for 6 months, there appeared to be no effect on sperm count, motility or morphology. However, a study of tadalafil 10 mg/day for 6 months, revealed a decrease in mean sperm concentration relative to placebo (Meuleman, 2003).
    B) ANIMAL STUDIES
    1) DOGS, MICE, RATS: Male and female rats administered oral tadalafil up to 400 mg/kg/day (up to 26-fold the maximum recommended human dose of 20 mg/day) had no effect on fertility, reproductive performance, or reproductive organ morphology. Daily administration of tadalafil greater than or equal to 10 mg/kg/ day in beagle dogs for a duration of 3 to 12 months resulted in nonreversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20% to 100% of the dogs. Decreased spermatogenesis occurred in 40% to 75% of the dogs. Administration of tadalafil up to 400 mg/kg/day for up to 2 years in rats and mice resulted in no treatment-related testicular findings (Prod Info CIALIS(R) oral tablets, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS171596-29-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status in symptomatic patients.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed in most patients, unless otherwise clinically indicated.
    C) Tadalafil plasma levels are not clinically useful or readily available.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension).

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 abnormal vital signs such as hypotension and tachycardia should be admitted. Patients with severe symptoms (ie, coma, dysrhythmias, or evidence of 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 a small ingestion (1 tablet) 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 healthcare facility for observation for a minimum of 6 to 8 hours.

Monitoring

    A) Monitor vital signs and mental status in symptomatic patients.
    B) No specific lab work (CBC, electrolyte, urinalysis) is needed in most patients, unless otherwise clinically indicated.
    C) Tadalafil plasma levels are not clinically useful or readily available.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension).

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) Activated charcoal may be considered following a significant exposure and the airway is protected. Significant toxicity is not anticipated following a minor exposure unless coingestants are involved.
    B) 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.
    C) 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) MANAGEMENT OF MILD TO MODERATE TOXICITY: Limited data. Tadalafil overdoses are likely to require only supportive care; there is no specific treatment. Treat headache, facial flushing, dizziness and general weakness with IV fluids. Hypotension and tachycardia are anticipated to be generally mild and well tolerated and usually respond to IV fluids. Infuse IV NaCL 10 to 20 mL/kg, as necessary.
    2) MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Reflex tachycardia is usually seen from hypotension. Patients with persistent hypotension despite intravenous fluids require vasopressors, theoretically alpha agonists norepinephrine and phenylephrine may be more effective.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status in symptomatic patients. No specific lab work (CBC, electrolyte, urinalysis) is needed in most patients, unless otherwise clinically indicated. Tadalafil plasma levels are not clinically useful or readily available. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, tachycardia, hypotension).
    C) CONTRAINDICATED TREATMENT
    1) Hypotensive emergencies may result from the combination of tadalafil 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 tadalafil. Clinicians should obtain a history of tadalafil use prior to the administration of nitrates. Nitrates should be also be avoided for 24 hours if myocardial ischemia is evident (longer if receiving P450 inhibitors or if hepatic or renal dysfunction are present), given the risk of hypotension and exacerbation of ischemia.
    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) PRIAPISM
    1) SUMMARY
    a) PRIAPISM is an emergency requiring immediate consult with a urologist.
    b) In one case of priapism with sildenafil use, the penis was aspirated and irrigated with four doses of 400 micrograms of phenylephrine in 10 milliliters of normal saline for 1 hour (total 1600 micrograms) 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) SUMMARY
    1) Tadalafil is highly protein bound (94%) and has a large volume of distribution (63 L) (Prod Info CIALIS(R) oral tablets, 2014); therefore, hemodialysis and hemoperfusion are not expected to be of benefit in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. A toxic dose has not been established. Single doses of 500 mg and daily doses of 100 mg were well tolerated in healthy volunteers. THERAPEUTIC: ADULT: Initial dose: 10 mg orally no more than once daily; may increase to 20 mg or decrease to 5 mg, based on efficacy and tolerability; maximum: 20 mg daily. PEDIATRIC: Tadalafil is not indicated for use in pediatric patients

Therapeutic Dose

    7.2.1) ADULT
    A) ERECTILE DYSFUNCTION
    1) AS NEEDED DOSING:
    a) ORAL: The recommended dose for males is 10 mg prior to sexual activity as needed; may be increased to 20 mg or decreased to 5 mg; the maximum recommended dosing frequency is once per day (Prod Info CIALIS(R) oral tablets, 2014).
    2) DAILY DOSING:
    a) ORAL: Initial dose, 2.5 mg once daily taken at the same time every day without regard to time of sexual activity; maintenance dose up to 5 mg/day (Prod Info CIALIS(R) oral tablets, 2014).
    B) BENIGN PROSTATIC HYPERPLASIA
    1) ORAL: 5 mg once daily taken at the same time every day (Prod Info CIALIS(R) oral tablets, 2014).
    C) BENIGN PROSTATIC HYPERPLASIA AND ERECTILE DYSFUNCTION
    1) ORAL: 5 mg once daily taken at the same time every day without regard to time of sexual activity (Prod Info CIALIS(R) oral tablets, 2014).
    D) PULMONARY HYPERTENSION
    1) ORAL: The usual recommended dose is 40 mg once daily. Divided doses are not recommended (Prod Info ADCIRCA(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric population have not been established; tadalafil is not indicated in children (Prod Info CIALIS(R) oral tablets, 2014; Prod Info ADCIRCA(R) oral tablets, 2014).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) In studies with healthy volunteers, single doses of 500 milligrams or daily doses of 100 milligrams caused adverse effects similar to those observed at lower doses (Prod Info CIALIS(R) oral tablets, 2014).
    B) CASE REPORT: An intracerebral hemorrhage in the right temporal lobe was associated with tadalafil use in a 70-year-old man following a 40 mg (recommended: 20 mg daily) dose. An acute headache was reported one hour after ingestion with a persistent headache, anxiety and confusion persisting for several days. Following supportive care, the patient was discharged to home on day 7 with normal neurologic function (Gazzeri et al, 2008).

Workplace Standards

    A) ACGIH TLV Values for CAS171596-29-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS171596-29-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS171596-29-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS171596-29-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tadalafil is a reversible, selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (Porst, 2002; Sorbera et al, 2001; Eardley & Cartledge, 2002). Like other PDE5 inhibitors (eg; sildenafil), PDE5 inhibition enhances nitric oxide-mediated responses to sexual stimulation, increasing intracellular accumulation of cyclic guanosine monophosphate (cGMP) (cGMP is broken down by PDE5); as cGMP is a mediator of smooth muscle-cell relaxation of the corpus cavernosum, this facilitates initiation and maintenance of penile erection (Prod Info CIALIS(R) oral tablets, 2008; Meuleman, 2003; Porst, 2002; Padma-Nathan et al, 2001; Sorbera et al, 2001; Boolell et al, 1996).
    B) In preclinical studies, the 50% inhibitory concentration of tadalafil for human recombinant PDE5 was 2 nanomoles/liter (nmol/L) (Sorbera et al, 2001), suggesting lower potency than vardenafil (0.7 nmol/L). Tadalafil was shown to be highly selective for PDE5 relative to other PDE isoenzymes (eg; 1,2,3,4, and 6). It is more selective than both sildenafil and vardenafil for PDE5 versus PDE1, PDE3, PDE4, and PDE6 (Porst, 2002; Eardley & Cartledge, 2002; Brock, 2001); vardenafil is more selective than sildenafil for PDE5 versus PDE1 or PDE6. The greater selectivity of tadalafil and vardenafil is claimed to offer a reduced propensity for visual and other adverse effects relative to sildenafil (Brock, 2001).

Physicochemical

Physical Characteristics

    A) A crystalline solid that is practically insoluble in water and very slightly soluble in ethanol (Prod Info Cialis(R), 2003).

Molecular Weight

    A) 389.4 (Prod Info Cialis(R), 2003)

References

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