40 mg / 6 mg

• Tadalafil: A long-acting PDE5 inhibitor – improves penile blood flow
• Apomorphine HCl: A centrally acting dopamine agonist – stimulates sexual arousal via the hypothalamus

Troches (buccal/sublingual lozenges) allow for:

• Rapid mucosal absorption
• Avoidance of first-pass metabolism
• Faster onset of action
• Ye combination un patients ke liye useful hoti hai jinke ED mein central (neurogenic) aur peripheral (vascular) dono factors involved hote hain.

Tadalafil:

• Inhibits Phosphodiesterase type 5 (PDE5)

• Increases cGMP concentration in smooth muscle cells

• Promotes vasodilation in penile tissues

• Enhances erectile response to sexual stimulation

Apomorphine HCl:

• D1 and D2 dopamine receptor agonist

• Acts on paraventricular nucleus of hypothalamus

• Stimulates libido, sexual desire, and erectile reflex pathways

• Activates parasympathetic outflow → erection initiation

 Combination targets both:

• Central initiation (Apomorphine)

• Peripheral maintenance (Tadalafil)

Contraindications:

• Use of nitrates or guanylate cyclase stimulators (e.g., riociguat)

• Known hypersensitivity to tadalafil or apomorphine

• History of syncope, hypotension, or cardiac arrhythmias

• Severe hepatic or renal impairment

• Psychiatric disorders (e.g., psychosis or schizophrenia)

• Parkinson’s patients taking dopaminergic drugs (risk of dopaminergic overload)

Precautions:

• Risk of hypotension and fainting, especially in first doses

• Avoid in patients with unstable angina, recent MI or stroke

• Caution in elderly, especially those on antihypertensives

• Monitor for impulse control disorders (e.g., hypersexuality, gambling)

Tadalafil-related:

• Headache

• Flushing

• Nasal congestion

• Back/muscle pain

• Dyspepsia

• Rare: Vision/hearing loss, priapism

Apomorphine-related:

• Nausea, vomiting (especially at initiation)

• Dizziness, fainting

• Fatigue or drowsiness

• Increased libido or compulsive behaviors (rare)

• Mood changes, anxiety

• Syncope (especially with alcohol or rapid absorption)

Troche-specific:

• Bitter or metallic taste

• Oral numbness or mild irritation

• Faster onset of action may lead to sudden hypotensive episodes in sensitive individuals

Pregnancy:

• Tadalafil: Category B – animal studies show no fetal harm; human data limited

• Apomorphine: Insufficient data in pregnancy; theoretical risk due to CNS effects

• Not recommended in pregnancy

Breastfeeding:

• Unknown if either drug is excreted in human milk

• Potential CNS effects on infant (from apomorphine)

• Avoid during breastfeeding

Tadalafil

Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism (painful and prolonged erection); heart disease, angina, a history of heart attack, irregular heart beats; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to tadalafil. If you notice any changes in your vision while taking this drug, call your doctor or health care professional as soon as possible. Stop using this medicine and call your healthcare provider right away if you have a loss of sight in one or both eyes. Contact your healthcare provider right away if the erection lasts longer than 4 hours or if it becomes painful. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not drink alcohol when taking this medicine as alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections.

Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.54

The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.4

Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH (see Drug Interactions).4

Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered.

Use tadalafil cautiously in patients with renal impairment. Dosing recommendations vary depending upon the severity of renal impairment, indication, and the dosing regimen being used (see Dosage in renal impairment). Tadalafil is not recommended in patients receiving the drug on a once daily basis for erectile dysfunction, benign prostatic hyperplasia, or pulmonary arterial hypertension when the creatinine clearance is less than 30 ml/min or the patient has renal failure or is receiving dialysis.4

Use tadalafil with caution in patients with altered hepatic function secondary to hepatic disease and/or drug-induced inhibition. Dosage modifications are needed in patients with mild to moderate hepatic impairment (see Dosage). In patients with severe hepatic impairment, use of tadalafil is not recommended because of insufficient data. Additionally, tadalafil is metabolized by CYP3A4 in the liver. Dosage adjustments are necessary in patients taking potent CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole (see Dosage and Drug Interactions).

There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Tadalafil and other PDE5 inhibitors have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. The following groups of patients with cardiac disease were excluded from clinical safety and efficacy trials for tadalafil, and, therefore, the manufacturer does not recommend the use of tadalafil in these groups until more data are available: myocardial infarction within the last 90 days; coronary artery disease resulting in unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (< 90/50 mmHg); uncontrolled hypertension ( 170/100 mmHg); or a stroke within the last 6 months. Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that tadalafil be used with caution in the following: patients with active coronary ischemia (angina) who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status (hypovolemia); patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of tadalafil. Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Also, patients with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure can be sensitive to the action of vasodilators, including PDE5 inhibitors. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary veno-occlusive disease (PVOD) may experience significant worsening in cardiovascular status. Due to a lack of clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. The possibility of associated PVOD should be considered should signs of pulmonary edema occur when tadalafil is administered. Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil, and other agents for the treatment of erectile dysfunction, with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis, or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).47 Educate patients that tadalafil, when used for erectile dysfunction, offers no protection against sexually transmitted disease. Counsel patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, as appropriate to the individual circumstances. Use tadalafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Although visual disturbances have been reported rarely with tadalafil, there is no safety information on the administration of tadalafil to patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Therefore, it is recommended that tadalafil not be administered to these patients until further data are available. Geriatric patients ( = 65 years) made up approximately 25% of patients in the primary efficacy and safety studies of tadalafil for the treatment of erectile dysfunction and 28% of patients in the clinical study of tadalafil for pulmonary arterial hypertension. In clinical trials for benign prostatic hyperplasia, geriatric patients greater than 65 years of age accounted for 40% of study participants and those 75 years of age and older accounted for 10% of study participants. No overall differences in efficacy and safety were observed between older and younger patients for these indications. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.45 Prior to initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consideration should be given to other urological conditions that may cause similar symptoms. Prostate cancer and benign prostatic hyperplasia (BPH) cause many of the same symptoms and frequently they coexist. Prior to starting tadalafil therapy for BPH, patients should be evaluated to rule out the presence of prostate cancer.4 Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed;5 Tadalafil is not indicated for use in women.4 Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.8 Additionally, tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant active peptic ulcer disease (PUD) since the effects of the drug in this patient population have not been formally studied.4 It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breastfeeding women.5 Tadalafil is not indicated for use in women.4 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA. Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant hematological disease (e.g., bleeding disorders) since the effects of the drug in this patient population have not been formally studied.4 This list may not include all possible contraindications.

Apomorphine

Apomorphine is a morphine derivative and should not be used in patients with a hypersensitivity to apomorphine or any of the product ingredients, namely sodium metabisulfite (sulfite hypersensitivity). Angioedema and anaphylaxis may occur as well as mild to life-threatening asthmatic episodes in susceptible patients. Sulfite sensitivity is seen more frequently in patients with asthma than in nonasthmatic people. Use apomorphine with caution in those with a history of opiate agonist hypersensitivity. Because benzyl alcohol is an ingredient in some apomorphine subcutaneous injection products (e.g., pen injection cartridges), these products should not be used in patients with a benzyl alcohol hypersensitivity.23

Apomorphine possesses potent emetic effects; nausea/vomiting occurs in almost all patients, and it is recommended that antiemetic therapy (e.g., trimethobenzamide) be instituted 3 days prior to the first dose of apomorphine. Treatment with trimethobenzamide should only be continued as long as needed to control nausea and vomiting, and generally no longer than 2 months. Based on reports of profound low blood pressure and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of drugs of the 5HT3 antagonist class (e.g., serotonin antagonists such as ondansetron, granisetron, dolasetron, palonosetron) is contraindicated.23

Somnolence (drowsiness) is commonly associated with apomorphine. There are reports of patients receiving apomorphine who have experienced sudden sleep onset without prior warning of sleepiness while engaged in activities of daily living. Continually reassess patients receiving apomorphine for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Advise patients to use caution when driving or operating machinery until they are aware of the effects of the medication on their cognition. Ethanol ingestion should be avoided with apomorphine due to the additive effects on cognition and blood pressure. Before initiating treatment with apomorphine, advise patients of the risk of drowsiness and ask them about factors that could increase the risk of somnolence, such as coadministration with other CNS depressants and the presence of sleep disorders (e.g., narcolepsy, sleep apnea). If a patient develops significant daytime sleepiness or falls asleep during activities that require active participation (e.g., conversations, eating, etc.), apomorphine should generally be discontinued. If apomorphine is continued, such patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.23

Apomorphine should generally be avoided in patients with a major psychotic disorder such as those with a history of psychosis or schizophrenia due to the risk of exacerbating psychosis. In clinical studies, hallucinations were reported in clinical trials of both subcutaneous and sublingual apomorphine. Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing the dose of apomorphine. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more manifestations, including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium.23

Patients can experience impulse control symptoms, such as intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges and the inability to control these urges while taking dopaminergic medications used to treat Parkinson’s disease, including apomorphine. In some cases, these urges stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges. Apomorphine dose reduction or discontinuation should be considered in those who experience these effects.23

Patients with Parkinson’s disease (PD) are at risk of falling due to underlying postural instability, possible autonomic instability, and syncope caused by the blood pressure lowering effects of the drugs used to treat PD. Patients with PD may also have an impaired capacity to respond to an orthostatic challenge. Apomorphine might increase the risk of falling by simultaneously lowering blood pressure and altering mobility. Apomorphine causes dose-related decreases in systolic and diastolic blood pressure. Orthostatic hypotension and syncope have occurred. Carefully monitor apomorphine-treated patients for signs and symptoms of hypotension and orthostatic hypotension, particularly at times of dose escalation. The hypotensive effect of apomorphine is exacerbated by the concomitant use of alcohol or nitrate/nitrite therapy such as sublingual nitroglycerin (0.4 mg). Patients taking apomorphine should also lie down before and after taking sublingual nitroglycerin. Other vasodilators and antihypertensive agents may also increase the hypotensive effects of apomorphine. Monitor blood pressure regularly with concomitant use of antihypertensive medications or vasodilators with apomorphine.23

Apomorphine reduces resting systolic and diastolic blood pressure and may have the potential to exacerbate coronary (and cerebral) ischemia in patients with known cardiac disease and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, re-evaluate the continued use of apomorphine. In clinical studies, 4% of patients treated with subcutaneous apomorphine experienced angina, acute myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and MI occurred in close proximity to apomorphine dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. There is a dose-related QT prolongation after subcutaneous apomorphine exposure similar to that achieved with therapeutic doses of the drug. Although the extent of exposure of sublingual apomorphine is lower than subcutaneous apomorphine, QT prolongation with sublingual apomorphine cannot be excluded. Drugs that prolong the QTc interval have been associated with torsade de pointes (TdP) and sudden death. The relationship of QTc prolongation to TdP is most clear for larger increases (20 msec or more), but it is possible that smaller QTc prolongations may also increase risk or increase risk in susceptible individuals. Although TdP has not been observed with apomorphine at recommended doses, data are too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of TdP. The risks and benefits of apomorphine should be considered before initiating treatment in patients with risk factors for QT prolongation, including congenital long QT syndrome, history of cardiac arrhythmias, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, the elderly 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.239101112

Apomorphine should be used cautiously and with close monitoring in those with mild to moderate hepatic disease because of the increased systemic exposure of apomorphine in these patients. Because of the potential for increased exposure, sublingual apomorphine should be titrated under medical supervision in mild to moderate hepatic disease. Sublingual apomorphine should be avoided in patients with severe hepatic impairment. Although specific guidelines are not available for subcutaneous apomorphine, a dosage reduction may be warranted; the effects of subcutaneous apomorphine in severe hepatic impairment have not been evaluated.23

Because of the potential for increased exposure, sublingual apomorphine should be titrated under medical supervision in patients with mild to moderate renal impairment. Sublingual apomorphine should be avoided in severe renal impairment. The starting dose of subcutaneous apomorphine should be reduced in patients with mild to moderate renal impairment because the concentration and exposure are increased in these patients. Studies of subcutaneous apomorphine in severe renal impairment or renal failure have not been conducted.23

Dyskinesia or exacerbation of pre-existing dyskinesia was reported in 24% of patients during clinical trial evaluation of subcutaneous apomorphine. Inform patients that this may occur. Overall, 2% of patients treated with subcutaneous apomorphine discontinued the drug due to dyskinesias. Dyskinesia was not reported during clinical trial evaluation of sublingual apomorphine; however, the potential for dyskinesia with sublingual apomorphine cannot be excluded.23

Apomorphine may cause prolonged painful erections in some patients. Priapism is considered a medical emergency and severe priapism may require surgical intervention. Advise male patients that apomorphine may cause prolonged painful erections and that they should seek medical attention immediately if this occurs.23

Abrupt discontinuation of apomorphine is generally not advised unless medically necessary. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.23

In premarketing clinical experience, apomorphine did not reveal any tendency for drug-seeking behavior. However, there are rare postmarketing reports of substance abuse of products containing apomorphine. In general, these reports consist of patients taking increasing doses of medication in order to achieve a euphoric state.23

Debilitated or geriatric patients may show increased susceptibility to apomorphine; therefore, the drug should be used cautiously in these patient populations. In clinical trials of subcutaneous apomorphine, the elderly were more likely to experience confusion and hallucinations than younger adults. They were also more likely to develop other complications such as falls, respiratory or cardiac symptoms, and gastrointestinal complaints. Close monitoring for side effects is recommended if apomorphine is required.23 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antiparkinson medications may cause significant confusion, restlessness, delirium, dyskinesia, nausea, dizziness, hallucinations, and agitation. In addition, there is an increased risk of postural hypotension and falls, particularly during concurrent use of antihypertensive medications.13

There are no adequate data on the developmental risks associated with the use of apomorphine during human pregnancy. Apomorphine has been administered to a limited number of pregnant women prior to undergoing Caesarean section. Infant Apgar scores were similar between the 2 groups and depressant effects were not observed in the apomorphine infant group; however, the women did not receive apomorphine chronically and also received the drug close to obstetric delivery. In animal reproduction studies, apomorphine was associated with adverse developmental effects, an increased incidence of fetal malformations, and maternal toxicity when administered during pregnancy at clinically relevant doses.2143

There are no data on the presence of apomorphine in human milk, the effects of apomorphine on the breastfed infant, or the effects of apomorphine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for apomorphine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.23

Safety and efficacy of apomorphine administration in infants, children, and adolescents less than 18 years of age have not been established.3

Injectable apomorphine should not be given via intravenous administration due to complications such as IV crystallization with subsequent thrombus formation and pulmonary embolism. Apomorphine injection should only be administered subcutaneously.2

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, it is not known whether non-ergot derived dopamine agonists, such as apomorphine, can cause these reactions.23

Tadalafil

It is not known if tadalafil is excreted in breastmilk. Adcirca should be used with caution in breastfeeding women.5 Tadalafil is not indicated for use in women.4 Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated coAnchorndition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Apomorphine

There are no data on the presence of apomorphine in human milk, the effects of apomorphine on the breastfed infant, or the effects of apomorphine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for apomorphine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.23

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15. Padma-Nathan H, McMurray JG, Pullman WE, et al. On-demand IC351 (Tadalafil) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 2001;13:2-9.
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