Sildenafil / Apomorphine HCl Troches

Sildenafil

Initially developed for the treatment of pulmonary hypertension, angina, and other cardiovascular conditions, sildenafil citrate was accidentally found to be beneficial in males who suffered from erectile dysfunction (ED). Prior to the discovery of its benefits in treating ED, this condition was considered to be an inevitable part of aging in men or due to underlying psychological causes. After its approval in 1998 by the U.S. Food and Drug Administration for the treatment of ED, the popularity of sildenafil citrate has skyrocketed over the past couple of decades as health care providers generally recommend this medication as the first-line therapy in the management of erectile dysfunction in men. Other contributing factors to its appeal and popularity is that sildenafil citrate can be taken orally on demand, is generally well tolerated, with minimal adverse effects.^[1]

Sildenafil citrate is a vasoactive medication belonging to the drug class of phosphodiesterase – 5 enzyme (PDE-5) inhibitors; it is a competitive antagonist of this enzyme. PDE-5 can be found all over the human body especially in the corpus cavernosum within the penis, striated and smooth musculature, as well as in platelets. However, PDE-5 has the largest distribution in the penile corpus cavernosum which is why sildenafil citrate is able to work selectively in this part of the body.^[2]

Sildenafil citrate is generally administered orally. However, it can also be administered intravenously or sublingually. Even though its most popular clinical indication for use is in the management of erectile dysfunction, it is also used in the management of pulmonary hypertension, persistent pulmonary hypertension of the newborn, Raynaud’s phenomenon resistant to other vasodilators, as well as in the prevention of pulmonary edema at high altitudes. After oral ingestion, absorption of sildenafil citrate rapidly occurs mainly in the small intestine from where it is then transported in the bloodstream to its area of action. Sildenafil citrate is metabolized in the liver through the action of the hepatic isoenzymes cytochrome P450 3A4 and cytochrome P450 2C9. Following hepatic metabolism, the metabolites are excreted mainly in the stool and, to a lesser degree, in the urine.^[2][3][4]

Sildenafil citrate is classified as a pregnancy category B drug by the Food and Drug Administration. Studies have not demonstrated definite risks to fetuses when sildenafil is administered to pregnant mothers. At present, there are no definite clinical indications that warrant the administration of sildenafil citrate in women. Studies done till date have not indicated that sildenafil citrate has comparable benefits in women as they do in men. There are other studies that are still ongoing, however, and their outcomes may provide further insight regarding the utility and benefits of sildenafil in women.^[5]

Apomorphine HCl

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.^[6][7]

Sildenafil

Sildenafil plays an indirect role in causing penile erection in men suffering from erectile dysfunction. In normal penile erection, sexual stimulation leads to the activation of the non-adrenergic as well as non-cholinergic nerves in the pelvic parasympathetic plexus. Following the activation of these nerves, the neurotransmitter nitric oxide is then released which then transverses the neuromuscular junction of the smooth muscle of the corpus cavernosum and the penile arteries. Nitric oxide then causes an increase in the production of the intracellular second messenger cyclic guanosine monophosphate (cGMP), which is a cyclic nucleotide derived from guanosine triphosphate (GTP). The release of cGMP leads to an increase in blood flow within the penile arteries as well as the relaxation of the smooth muscles of the corpus cavernosum, thereby resulting in penile erection. Penile detumescence is caused by the release of the phosphodiesterase-5 enzyme, which breaks down cGMP and, therefore leads to the contraction of the penile arteries and the corpus cavernosal smooth muscles.

Sildenafil has a chemical structure that is very similar to cGMP and binds competitively to phosphodiesterase-5 enzyme. By binding to the receptors on PDE-5, sildenafil prevents PDE-5 from binding to and degrading cGMP. This competitive antagonist action of sildenafil allows the actions of cGMP in the penile arteries and corpus cavernosum to be prolonged, resulting in the prolongation of penile erection.^[2][4][7]

In addition to its location in the penile corpus cavernosum, the phosphodiesterase-5 is also located in large amounts within the pulmonary vasculature. In the lungs, PDE-5 breaks down cGMP, similar to its actions in the corpus cavernosum. Sildenafil also acts as a competitive antagonist to PDE-5 in the pulmonary vasculature preventing the breakdown of cGMP. This has the effect of causing a reduction in pulmonary vascular resistance as well as the mean pulmonary artery pressure. Due to this effect on the pulmonary vasculature, sildenafil has been proposed as an adjunct medication in the treatment of primary pulmonary hypertension, a disease of childhood with a typically poor prognosis. However, studies as to its efficacy in the management of this disorder are still ongoing.^[2]

Apomorphine HCI

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.^[8][6][7]

Sildenafil

There are certain conditions under which sildenafil citrate should be administered with caution or outright avoided. Some of these conditions are:

Hypersensitivity: Sildenafil is absolutely contraindicated in individuals who have a demonstrated hypersensitivity to the drug or any of its components.^[9]

Nitrate therapy: Individuals who are not nitrate therapy should not be administered sildenafil citrate. Nitrates are potent vasodilators typically used in the management of cardiac conditions such as angina pectoris. Since sildenafil also a vasodilatory effect through its actions on cGMP, it can potentiate the effects of nitrates when used concurrently which may result in severe hypotension, syncope, and myocardial infarction.^[9]

Hepatic disease: Since sildenafil is metabolized by hepatic isozymes, hepatic diseases may lead to increased plasma levels of sildenafil and a prolongation of its effects. Care should be exercised when administering sildenafil to individuals with hepatic disease.^[9]

Renal disease: Similar to hepatic diseases, renal diseases may prolong the effects of sildenafil citrate due to increased plasma levels as a result of diminished renal excretion. Caution should also be exercised when administering sildenafil to individuals with renal diseases.^[9]

Visual abnormalities: There have been some instances of vision loss in individuals taking sildenafil citrate. The loss of vision is due to a reduction in blood flow to the optic nerve, a condition known as non-arteritic anterior ischemic optic neuropathy (NAION). Individuals with pre-existing visual disturbances may be administered sildenafil only when the benefits clearly outweigh the risks.^[9][10]

Cardiovascular disorders: Caution should be exercised when administering sildenafil to individuals with known cardiac disorders such as arrhythmias, aortic stenosis, heart failure, and myocardial infarction, among others.^[9]

Apomorphine HCI

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^{[6][7][11][12][13][14]}

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7] 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.^[15]

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.^[6][16][7]

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.^[6][7]

Safety and efficacy of apomorphine administration in infants, children, and adolescents less than 18 years of age have not been established.^[7]

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.^[6]

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.^[6][7]

Sildenafil

Toxicity is one of the adverse effects that may be experienced in individuals on sildenafil therapy. The risk of developing toxic effects is especially higher in the presence of hepatic or renal disease, or in individuals on concurrent nitrate therapy. The toxic effects typically present as visual or cardiovascular disturbances. Other adverse reactions that may occur while on sildenafil therapy are tendon rupture, exfoliative dermatitis, hearing loss, seizures, and gastritis, among others.

Apomorphine HCI

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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%).^[6]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6][7]

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.^[6]

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.^[6][7]

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.^[6][7]

Sildenafil

Sildenafil citrate is classified as a Food and Drug Administration pregnancy category B drug. Studies have not demonstrated any evidence of birth defects, miscarriages, or adverse fetal or maternal outcomes when used in pregnancy. Insufficient data is available to make a clear determination about whether sildenafil citrate is expressed in breast milk and if there are any untoward effects.

Apomorphine HCI

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.^{[6][16][7] [5]}

Sildenafil

Sildenafil citrate is classified as a Food and Drug Administration pregnancy category B drug. Studies have not demonstrated any evidence of birth defects, miscarriages, or adverse fetal or maternal outcomes when used in pregnancy. Insufficient data is available to make a clear determination about whether sildenafil citrate is expressed in breast milk and if there are any untoward effects.^[5]

Apomorphine HCI

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.^[6][7]

Store this medication in its original container 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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15. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
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