Tadalafil / Apomorphine HCl Troche

Tadalafil

Tadalafil is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and vardenafil. It is administered orally for the treatment of male erectile dysfunction (ED), pulmonary arterial hypertension (PAH), benign prostatic hypertrophy (BPH), or the concurrent treatment of erectile dysfunction and BPH. Tadalafil does not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). Unlike sildenafil, visual disturbances have not been reported with tadalafil, which is more selective for PDE5 than for PDE6 present in the retina. The duration of action of tadalafil for the treatment of ED (up to 36 hours) appears to be longer than that of sildenafil and vardenafil. Because PDE inhibitors promote erection only in the presence of sexual stimulation, the longer duration of action of tadalafil allows for more spontaneity in sexual activity. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.1 Tadalafil was in phase II trials for the treatment of female sexual dysfunction, however, further investigation was discontinued. FDA approval was granted November 2003 for treatment of male erectile dysfunction (ED), and in January 2008, approval was granted for once daily use without regard to timing of sexual activity. Tadalafil (Adcirca) was FDA approved for the treatment of pulmonary arterial hypertension (PAH) in May 2009. In clinical studies of patients with pulmonary arterial hypertension (PAH), tadalafil-treated patients experienced improved exercise capacity and less clinical worsening compared to placebo. In October 2011, tadalafil received FDA approval for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) and for the concurrent treatment of erectile dysfunction and BPH.

Apomorphine

Apomorphine, a non-narcotic derivative of morphine, is approved as a sublingual film for the treatment of acute, intermittent ‘off’ episodes associated with Parkinson’s disease and as a subcutaneous injection for use in patients with advanced Parkinson’s disease. Apomorphine has also been used as a diagnostic test for dopaminergic responsiveness in parkinsonian syndromes to determine whether a patient will respond or is still responsive to levodopa therapy. Apomorphine has a quick onset of action, a significant effect on parkinsonian hypomobility (‘off’ episodes) unresponsive to oral medications, and a therapeutic effect comparable to levodopa. Due to a high incidence of nausea and vomiting, apomorphine is coadministered with the antiemetic drug trimethobenzamide. Based on reports of profound low blood pressure and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of 5-HT3 antagonists with apomorphine is contraindicated. Similar to other dopamine agonists, apomorphine has been associated with sudden sleep onset during activities of daily living and impulse control symptoms (e.g., intense urges to gamble or spend money, increased sexual urges). During treatment with apomorphine, practitioners should monitor for hypotension, orthostasis, new or worsening impulse control symptoms, and patient reports of sudden sleep onset.

Tadalafil

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is 10,000 fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 versus PDE6. This lower selectivity of sildenafil for PDE5 vs PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is 9000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and in other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.

The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.

Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.5

Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the most common adverse reactions associated with PDE5 inhibitor therapy.

Apomorphine

Apomorphine has structural similarities to the neurotransmitter dopamine that are thought to contribute to its central dopamine receptor agonist properties. Apomorphine exhibits a high affinity for dopamine D4 receptors, a moderate affinity for dopamine D2, D3, and D5 receptors, and a low affinity for D1 receptors. Apomorphine may be a partial agonist at D1 receptors; however, further studies are needed to confirm this effect. Although the exact mechanism by which apomorphine exerts its therapeutic effects in Parkinson’s disease is unknown, it is thought to occur via activation at postsynaptic D2 receptors in the caudate nucleus and putamen. Apomorphine has a moderate affinity for alpha-1D, alpha-2B, and alpha-2C adrenergic receptors, and a low affinity for the serotonin receptors 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C. Stimulation of the chemoreceptor trigger zone (CTZ) by the drug produces potent emetic actions. Apomorphine is a morphine derivative, but generally does not possess any narcotic effects, with the exception of emesis induction, CNS depression, and respiratory depression.

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.

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.

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).

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.

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).

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.

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.

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; Tadalafil is not indicated for use in women.

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. 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.

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breastfeeding women. Tadalafil is not indicated for use in women. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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. 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.

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.

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.

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

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.

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.

Tadalafil

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; Tadalafil is not indicated for use in women.

Apomorphine

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.

Tadalafil

It is not known if tadalafil is excreted in breastmilk. Adcirca should be used with caution in breastfeeding women. Tadalafil is not indicated for use in women. 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.

Tadalafil

Back pain; dizziness; flushing; headache; indigestion; muscle aches; nausea; stuffy or runny nose. This list may not describe all possible side effects. Call your healthcare provider immediate if you experience signs of an allergic reaction like skin rash, itching or hives, swelling of the face, lips, or tongue; breathing problems; changes in hearing; changes in vision; chest pain; erection lasting more than 4 hours; fast, irregular heartbeat; seizures.

Adverse reactions to tadalafil for the treatment of erectile dysfunction (ED) were evaluated based on worldwide clinical trials of tadalafil involving over 5700 men (mean age 59, range 22 to 88 years). Over 100 patients were treated for 1 year or longer and over 1300 were treated for 6 months or more. During placebo-controlled trials, the discontinuation rate for patients treated with tadalafil (10 or 20 mg) was 3.1% compared to 1.4% in placebo-treated patients. In the treatment of patients with elevated pulmonary arterial pressures (PAH), adverse reactions to tadalafil were evaluated based on worldwide clinical trials involving 398 patients; 311 patients were treated for at least 182 days and 251 patients were treated for at least 360 days. During placebo-controlled trials, the overall rate of discontinuation due to an adverse event was higher in placebo-treated patients than in patients treated with tadalafil 40 mg/day (15% vs. 9%, respectively). In addition, the rate of discontinuation due to an adverse event not related to worsening of PAH was 5% in placebo-treated patients compared to 4% in patients treated with tadalafil 40 mg/day. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the rate of discontinuation due to an adverse effect was 3.6% of tadalafil-treated patients versus 1.6% of placebo-treated patients, and the mean age of study participants was 63 years.

During clinical trials, hypotension was reported in < 2% and hypertension was reported in 1—3% of all tadalafil recipients. The risk for serious hypotension is augmented by the use of nitrates; therefore, the use of tadalafil in patients receiving nitrate therapy is contraindicated. Other cardiac effects reported in less than 2% of patients during clinical trials include angina, chest pain (unspecified), myocardial infarction, orthostatic hypotension, palpitations, syncope, and sinus tachycardia. Sudden cardiac death, stroke, chest pain, palpitations, and sinus tachycardia have all been noted in post-marketing experience with tadalafil. Most of the affected patients had pre-existing cardiovascular risk factors. Many of these events occurred during or shortly after sexual activity. In some cases, the symptoms occurred hours to days after the use of tadalafil and sexual activity. The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure (hypotension) were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates. In addition, tadalafil (20 mg) had no significant effect on supine or standing systolic and diastolic blood pressure in healthy male subjects compared to placebo; there was also no significant effect on heart rate.

The effect of a single 100-mg dose of tadalafil on QT prolongation was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc for tadalafil, relative to placebo, was 2.8 milliseconds using Individual QT correction and 3.5 milliseconds using Fridericia QT correction. A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.

During clinical trials, adverse reactions occurring = 2% of patients with erectile dysfunction, = 9% of patients with pulmonary arterial hypertension, and more frequently in the tadalafil-treated groups than placebo included back pain (2—12%), myalgia (1—14%), and pain in limb (1—3%). Adverse musculoskeletal reactions reported in < 2% of tadalafil recipients included arthralgia and neck pain. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following musculoskeletal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: back pain (2.4% vs 1.4%), extremity musculoskeletal pain (1.4% vs 0%), and myalgia (1.2% vs 0.3%). Adverse musculoskeletal effects reported in less than 1% of patients included arthralgia and muscle spasms. Myalgia lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia was described as diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. Generally, pain was reported as mild or moderate in severity and resolved without medical treatment; severe back pain was reported infrequently. When medical treatment was needed, acetaminophen or NSAIDs were generally effective; however, in a small number of patients who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all tadalafil-treated patients discontinued treatment due to back pain/myalgia. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no medically significant underlying pathology.

Headache occurred in 3—15% of patients during erectile dysfunction clinical trials and in 32—42% of patients during pulmonary arterial hypertension clinical trials; headache was reported more frequently in the tadalafil-treated groups than placebo. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following centrally-mediated effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: headache (4.1% vs 2.3%) and dizziness (1% vs 0.5%). Headache lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Adverse reactions reported in < 2% of tadalafil recipients during clinical trials and affecting the nervous system included hypoesthesia, insomnia, dizziness, paresthesias, vertigo, and somnolence or drowsiness. Migraine, transient global amnesia, seizures, and seizure recurrence have been reported during post-marketing use of tadalafil; due to the voluntary nature of the reports, the frequency of post-marketing adverse reactions is unknown and causality to the drug has not been established.

Dyspepsia occurred in 1—10% of patients during erectile dysfunction (ED) clinical trials and in 10—13% of patients in pulmonary arterial hypertension clinical trials; dyspepsia was reported more frequently in the tadalafil-treated groups than placebo. Other gastrointestinal/digestive adverse reactions reported by tadalafil recipients and more frequently than placebo included nausea (1—11%), viral gastroenteritis (3—5%), gastroesophageal reflux (1—3%), abdominal pain (1—2%), and diarrhea (1—2%). During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following gastrointestinal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: dyspepsia (2.4% vs 0.2%) and diarrhea (1.4% vs 1%). Adverse GI reactions reported in less than 1% of patients included gastroesophageal reflux disease, upper abdominal pain, nausea, and vomiting. Upper abdominal pain lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Dysphagia, elevated hepatic enzymes, esophagitis, gastritis, vomiting, increased GGTP, loose stools, upper abdominal pain, hemorrhoidal hemorrhage, rectal hemorrhage, and xerostomia were reported in < 2% of patients treated with tadalafil during clinical trials.

Nasal congestion occurred in 2—4% of patients during erectile dysfunction clinical trials and in 9% of patients during pulmonary arterial hypertension clinical trials; nasal congestion was reported more frequently in the tadalafil-treated groups than placebo. In addition, pharyngitis (reported as nasopharyngitis, 1—13%), upper and lower respiratory tract infection (3—13%), influenza (2—5%), cough (2—4%), bronchitis (2%), and urinary tract infection (2%) were reported in tadalafil-treated patients during clinical trials. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, nasopharyngitis occurred more frequently in tadalafil-treated patients (2.1%) than placebo-treated patients (1.6%). Dyspnea, epistaxis, and pharyngitis were reported in less than 2% of patients in clinical trials.

Flushing occurred in 1—3% of patients during erectile dysfunction clinical trials and in 6—13% of patients during pulmonary arterial hypertension clinical trials; flushing was reported more frequently in the tadalafil-treated groups than those groups receiving placebo.

During clinical trials, blepharedema or swelling of the eyelids, conjunctivitis, increased lacrimation, and ocular pain were reported in < 2% of tadalafil recipients.

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (n=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (< 0.1% of patients). Post-marketing reports have included cases of visual impairment such as retinal vein occlusion and visual field defects. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision (< 2%) and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy. It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of tadalafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors, such as tadalafil. 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. During clinical trial evaluation of tadalafil, genitourinary effects including increased erection, spontaneous penile erection, and renal impairment (unspecified) were reported in less than 2% of study patients receiving the drug.

During clinical trial evaluation of tadalafil, the following general adverse events were reported in less than 2% of patients receiving tadalafil: asthenia, facial edema, fatigue, and pain (unspecified).

During clinical trial evaluation of tadalafil, the following dermatologic effects were reported in less than 2% of study patients: pruritus, rash (unspecified), and hyperhidrosis. Stevens-Johnson syndrome, exfoliative dermatitis, and urticaria have all been noted in post-marketing experience with tadalafil. Due to the uncontrolled and voluntary nature of post-marketing reports, neither the frequency nor a definitive causal relationship to tadalafil can be established.

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Apomorphine

Apomorphine may cause drowsiness; drowsiness or somnolence was reported in 35% of patients receiving subcutaneous apomorphine in one small controlled clinical trial. Other CNS effects reported in at least 5% of patients during premarketing evaluation of subcutaneous apomorphine included insomnia and headache. During a premarketing maintenance study of sublingual apomorphine, the following centrally-mediated effects occurred in at least 5% of apomorphine-treated patients and more frequently than in the placebo group: somnolence (13%) and headache (6%). There have been reports of patients receiving apomorphine who have fallen asleep while performing activities of daily living. It is possible for episodes of excessive drowsiness to occur well after the start of treatment. Sudden sleep onset with other dopamine agonists has, in some cases, resulted in auto accidents or other harmful events in the course of daily living. Symptoms of excessive drowsiness may not be preceded by warning signs. Patients should be cautioned against driving or operating machinery, working at heights, or performing other tasks that require alertness while receiving apomorphine. Those who have experienced a sudden episode of sleep while taking the drug should generally discontinue apomorphine. Reassessment for oversedation is suggested throughout apomorphine therapy. The use of concomitant CNS depressant medications or sleep disorders may increase the risk of falling asleep while taking this medication; patients should be assessed for these risk factors prior to initiation of the drug and be advised of the additive risks for somnolence. It is not known if a reduction in dosage will subsequently reduce or eliminate excessive somnolence or sudden sleep onset.

During a small clinical trial (n = 29) in Parkinson’s disease patients receiving subcutaneous apomorphine 2 to 10 mg or placebo, the following respiratory effects were reported more frequently with apomorphine than placebo: yawning (40%) and rhinorrhea (20%). During a premarketing maintenance study of sublingual apomorphine, rhinorrhea occurred in 7% of apomorphine-treated patients and more frequently than in the placebo group. Apomorphine is a derivative of the narcotic morphine. Although apomorphine does not share the analgesic properties of addictive potential of narcotics, it does possess certain pharmacologic properties that are similar to the opiate class such as the ability to cause respiratory depression. Respiratory effects or infections reported in at least 5% of patients receiving subcutaneous apomorphine during premarketing evaluation included urinary tract infection, pneumonia, and dyspnea.

Apomorphine causes severe nausea and vomiting at recommended doses due to stimulation in the chemoreceptor trigger zone. Nausea and vomiting are extremely likely when apomorphine is not given with an antiemetic and usually occurs within 5 to 10 minutes of a parenteral dose. Almost all patients (98%) were pre-medicated with trimethobenzamide, an antiemetic, during clinical trial evaluation of subcutaneous apomorphine, beginning 3 days prior to study enrollment. Patients were encouraged to continue for at least 6 weeks. Trimethobenzamide was discontinued by 50% of study patients while continuing apomorphine, with an average time to discontinuation of about 2 months (range: 1 day to 33 months). During clinical trials of subcutaneous apomorphine, the incidence of nausea and/or vomiting with the concurrent use of antiemetic therapy (i.e., trimethobenzamide) in Parkinson’s disease (PD) patients was 31% and 11%, respectively. During a premarketing maintenance study of sublingual apomorphine, nausea or vomiting occurred in 28% and 7%, respectively, of apomorphine-treated patients. In some cases, nausea may be associated with the orthostasis caused by the drug. The effect of trimethobenzamide on reducing nausea and vomiting during treatment with subcutaneous apomorphine was evaluated in a 12-week controlled trial in 194 patients; fewer patients experienced nausea and vomiting during the first 4 weeks of subcutaneous apomorphine treatment while receiving trimethobenzamide versus placebo (43% vs. 59%). However, patients treated with trimethobenzamide had a greater incidence of side effects than those receiving placebo including somnolence (19% vs. 12%), dizziness (14% vs. 8%), and falls (8% vs. 1%). Therefore, the benefit of trimethobenzamide must be balanced against the risk of adverse events, and generally should not be used for more than 2 months.

Apomorphine can cause dose-related hypotension and has the potential to exacerbate coronary and cerebral ischemia. During the clinical trial evaluation of subcutaneous apomorphine, the following adverse cardiac effects were reported in apomorphine-naive patients with Parkinson’s disease: dizziness or orthostatic hypotension (20%), syncope (2%), angina/chest pain (unspecified) (15%), and heart failure (at least 5%). During a premarketing maintenance study of sublingual apomorphine, dizziness occurred in 9% of apomorphine-treated patients and more frequently than in the placebo group. Most syncopal episodes are preceded by dizziness, flushing, nausea/vomiting, pallor, and/or sweating. Orthostatic hypotension and syncope may lead to fainting or increase the risk of falls. During clinical trials of subcutaneous apomorphine, falls and serious falls were reported in 30% and 5% of patients, respectively. During a premarketing maintenance study of sublingual apomorphine, fall (6%) and laceration (6%) occurred more frequently with apomorphine than placebo. The following cardiac-related events were more common in patients receiving concomitant antihypertensive medications or vasodilators than in patients not receiving these medications: hypotension (10%) and serious falls (9%). In patients undergoing subcutaneous apomorphine titration, there was an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (at least a 20 mmHg decrease), and a small number of patients developed severe systolic orthostatic hypotension (at least 30 mmHg decrease and systolic BP 90 mmHg or less). During the titration phase of sublingual apomorphine, 4% of patients experienced syncope, pre-syncope, hypotension, and orthostatic hypotension; patients in the maintenance phase had a lower incidence of these effects (2%). In a QT study with subcutaneous apomorphine exposure similar to that achieved with therapeutic doses of the drug, there was a QTcF prolongation of 10 msec (90% upper confidence interval of 16 msec). Although the extent of exposure of sublingual apomorphine is lower than subcutaneous apomorphine, QT prolongation with sublingual apomorphine cannot be excluded. QT prolongation carries a risk of torsade de pointes. Serious events may be preceded by palpitations and syncope. During clinical development of subcutaneous apomorphine, 4% of patients treated with apomorphine experienced myocardial infarction, cardiac arrest and/or sudden death; some cases of unstable angina and myocardial infarction 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. If patients develop signs and symptoms of coronary or cerebral ischemia, the continued use of apomorphine should be carefully re-evaluated.

Skin contact with the solution or powder of subcutaneous apomorphine may cause an allergic contact dermatitis. Patients and their caregivers should be instructed on the proper handling of the medication. A case of eosinophilic panniculitis with scarring was reported in a patient following the initial subcutaneous injection of apomorphine. During premarketing evaluation of subcutaneous apomorphine, ecchymosis occurred in at least 5% of patients. An injection site reaction occurred in 26% of patients; associated symptoms have included bruising or ecchymosis (16%), granuloma (4%), and pruritus (2%).

During premarketing evaluation of subcutaneous apomorphine, hallucinations were reported in 14% of patients. In one small controlled trial, hallucinations or confusion were reported in 10% of patients receiving subcutaneous apomorphine and 0% of patients receiving placebo. Discontinuation of apomorphine due to hallucinations occurred in 1% of patients. Psychiatric effects reported in at least 5% of patients receiving subcutaneous apomorphine during premarketing evaluation included depression and anxiety. During premarketing evaluation of sublingual apomorphine, hallucinations, delusions, disorientation, or confusion were reported in 6% of patients. Postmarketing reports indicate that new or worsening psychiatric or behavioral effects may occur, some of which may be severe, after starting or increasing the dose of apomorphine. These changes can include paranoia, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Other drugs used to treat Parkinson’s disease can have similar effects on thinking and behavior.

During premarketing evaluation of subcutaneous apomorphine, dyskinesias or worsening of dyskinesia occurred in 24% of patients. Discontinuation of apomorphine due to dyskinesias occurred in 2% of patients. In one small controlled trial, dyskinesias were reported in 35% of patients (n = 7) receiving subcutaneous apomorphine versus 11% of those receiving placebo (n = 1). Although dyskinesia was not reported during premarketing evaluation of sublingual apomorphine, the potential for dyskinesias cannot be excluded.

Apomorphine may cause prolonged painful erections in some patients, and priapism represents a medical emergency. Painful erections were reported in less than 1% of patients receiving subcutaneous apomorphine in clinical trials. A rarely reported motivation for apomorphine abuse is a psychosexual reaction related to the stimulation of penile erection and libido increase. Adverse events that have been reported in males with overuse of subcutaneous apomorphine include frequent penile erections, atypical sexual behavior, heightened libido, dyskinesias, agitation, confusion, and depression. Some patients receiving dopaminergic medications have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. Impulse control disorder was reported during premarketing evaluation of sublingual apomorphine. Impulse control symptoms, such as pathological gambling, libido increase, and hypersexuality, have been reported during postmarketing use of apomorphine. In some cases, the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving apomorphine. Likewise, patients should be instructed to report such changes while receiving apomorphine. Dose reduction or discontinuation should be considered in those who experience these effects.

Gastrointestinal (GI) effects reported in at least 5% of patients during premarketing evaluation of subcutaneous apomorphine included constipation and diarrhea. During a premarketing study of sublingual apomorphine, oral mucosal ulceration and stomatitis were reported in 2% of patients treated with apomorphine during the titration phase. In the maintenance phase, the following effects occurred in at least 5% of apomorphine-treated patients and more frequently than in the placebo group: oral/pharyngeal soft tissue swelling (15%), oral/pharyngeal soft tissue pain and oral paresthesias (13%), oral ulceration and stomatitis (7%), oral mucosal erythema (7%), and xerostomia (6%). In general, oral mucosal irritation was mild to moderate in severity, and usually resolved with treatment discontinuation. However, rechallenge with sublingual apomorphine is not generally recommended after discontinuation due to oral adverse reactions since the reactions may recur and may be more severe than the initial event.

During a placebo-controlled clinical trial (n = 29) of subcutaneous apomorphine in Parkinson’s disease patients receiving apomorphine 2 to 10 mg subcutaneously or placebo, edema or peripheral edema occurred in 10% of apomorphine-treated patients. Other general conditions reported in at least 5% of patients during premarketing evaluation of subcutaneous apomorphine included aggravated Parkinson’s disease, fatigue, weakness, and dehydration. During a premarketing maintenance study of sublingual apomorphine, fatigue occurred in 7% of apomorphine-treated patients and more frequently than in the placebo group.

Musculoskeletal adverse events or other pain-related effects reported in at least 5% of patients during premarketing evaluation of subcutaneous apomorphine included arthralgia, limb pain (musculoskeletal pain), and back pain.

Retinal degeneration (macular degeneration) has been observed in albino rats treated with dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies). This lesion has also been observed when albino rats were exposed to these agents for shorter periods under higher intensity light exposures. Similar changes have not been observed in 2-year carcinogenicity studies in albino mice or in rats or monkeys treated for 1 year. Apomorphine has not been tested in carcinogenicity studies, but based on its mechanism of action it would be expected to cause similar toxicity. The significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.

Hypersensitivity reactions, including urticaria, rash, pruritus, anaphylactoid reactions, and angioedema, may occur following apomorphine administration. Hypersensitivity reactions may be associated with apomorphine or sodium metabisulfite, the sulfite excipient in the products. Mild to life-threatening asthmatic episodes in susceptible patients have also been reported. Hypersensitivity to sodium metabisulfite is seen more frequently in asthmatic than nonasthmatic patients. During a premarketing maintenance study of sublingual apomorphine, hypersensitivity reactions (i.e., facial edema, oral allergy syndrome, and urticaria) occurred in 6% of apomorphine-treated patients and more frequently than in the placebo group.  Rechallenge with sublingual apomorphine is not generally recommended after discontinuation due to oral reactions since the reactions may recur and may be more severe than the initial event. Dermatologic effects reported with sublingual apomorphine which were not related to hypersensitivity included hyperhidrosis (sweating), occurring in at least 5% of patients receiving subcutaneous apomorphine and 6% of patients receiving sublingual apomorphine.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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