Vardenafil/Apomorphine HCl Troche

Overview of Vardenafil / Apomorphine HCl Troches

Dosage Strength of Vardenafil / Apomorphine HCl Troches

Vardenafil / Apomorphine HCl Troches: 40/8 mg (10 Troches/Pack)

General Information

Vardenafil

Vardenafil belongs to the phosphodiesterase type 5 (PDE5) inhibitors drug class, a class of drugs commonly indicated for treatment of erectile dysfunction (ED). It is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and tadalafil. This class of drugs does not inhibit prostaglandins as do some agents for treating ED (e.g., alprostadil). Vardenafil and tadalafil are more selective for PDE5 than PDE6, which is present in the retina. This leads to less visual adverse effects such as those reported in sildenafil-treated patients. The advantage of vardenafil may be that it achieves maximum plasma concentration sooner than sildenafil and tadalafil which may result in a faster onset of action. In an analysis of 580 patients, erections improved in 80% of men, and the ability to complete sexual intercourse with ejaculation was increased. Efficacy in treating diabetics and radical prostectomy patients has also been demonstrated. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.1 Vardenafil was approved by the FDA in August 2003 for erectile dysfunction. An orally disintegrating tablet was approved by the FDA in June 2010.

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.2 3

Mechanism of Action

Vardenafil

Vardenafil 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. Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum. Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.

Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. 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 more common adverse reactions associated with PDE inhibitor therapy.

Apomorphine HCl

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.4 2 3

Contraindications/Precautions

Vardenafil

Your health care provider needs to know if you have any of these conditions: bleeding disorders, eye or vision problems, including a rare inherited eye disease called retinitis pigmentosa, anatomical deformation of the penis, Peyronie’s disease, or history of priapism (painful and prolonged erection), heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems, high or low blood pressure, history of blood diseases, like sickle cell anemia or leukemia, history of stomach bleeding, kidney disease, liver disease, stroke, an unusual or allergic reaction to vardenafil, other medicines, foods, dyes, or preservatives, pregnant or trying to get pregnant, breast-feeding.

Vardenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

The safe and effective use of vardenafil in combination with other agents for treating erectile dysfunction has not been studied. Therefore, the use of such combinations is not recommended.

Vardenafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive vardenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once vardenafil has been administered. A suitable time interval following vardenafil dosing for safe administration of nitrates or nitric oxide donors has not been determined.

Vardenafil tablets are not recommended in patients with severe hepatic disease (Child-Pugh class C) or end stage renal disease requiring dialysis (severe renal impairment or renal failure). There are no controlled clinical studies on the safety and efficacy of vardenafil in these patients; therefore, vardenafil use is not recommended until further information is available. Patients with moderate hepatic impairment require a reduction in the starting dose of the regular tablets and a lower maximum dosage (see Indications/Dosage). Patients with mild hepatic impairment or mild to moderate renal impairment do not require adjustments in the vardenafil regular tablet dosage. The concomitant use of certain potent hepatic cytochrome P450 3A4 inhibitors may result in a requirement to adjust the vardenafil dosage (see Dosage and Drug Interactions).5 Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, the orally disintegrating tablets should not be used in patients with moderate or severe hepatic disease (Child-Pugh class B or C) or in patients on hemodialysis. Patients who require lower doses of vardenafil should use the regular tablets.6

Lower starting doses of vardenafil regular tablets should be considered for geriatric patients (>= 65 years) because elderly patients have higher plasma concentrations than younger males (18—45 years) (see Indications/Dosage).5 In phase III clinical trials of the regular tablets, 834 elderly patients participated and there was no difference in safety or effectiveness compared to younger patients.5 In trials with the orally disintegrating tablets, the vardenafil AUC in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients <= 45 years; however, no differences in safety and efficacy were observed between elderly patients and those < 65 years old in placebo-controlled trials.6 Elderly patients may potentially have renal and hepatic impairment which can increase vardenafil plasma concentrations. Because higher plasma concentrations may increase the incidence of adverse reactions, the regular tablet starting dose should be reduced in these patients.5 Patients who require lower doses of vardenafil should use the regular tablets and not the orally disintegrating tablets.6

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. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if vardenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/110); patients with cardiac disease, severe heart failure or coronary artery disease (CAD) which causes unstable angina including those with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis). Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that vardenafil be used with caution in the following: patients with active coronary ischemia 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; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of vardenafil. Vardenafil is contraindicated in patients currently onnitrate/nitrite therapy. In a double-blind, crossover, single-dose study of patients with stable CAD, vardenafil did not cause any impairment in exercise capabilities at levels equivalent to or greater than that achieved during sexual intercourse.7 The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin. When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed.5 The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil not be used in patients with congenital long QT syndrome and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Further, use vardenafil with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.8 9 10 11 12 13

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. Vardenafil and other agents for the treatment of erectile dysfunction should be used 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).5 14

Patients should be reminded that vardenafil offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.

Use vardenafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors, including vardenafil. 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. This can cause permanent loss of vision. Vardenafil use should be discontinued in the event of sudden loss of vision in one or both eyes. Vardenafil use is not recommended in 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. Vardenafil use is not recommended in these patients until further information is available.5 6

Vardenafil is not indicated for use in females. Vardenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.5 6

Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. It is not known if vardenafil is excreted in human breast milk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.5 6

There is no known indication for the use of vardenafil in neonates, infants, or children. Vardenafil should not be prescribed to these populations.

Vardenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, vardenafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.15

Vardenafil should be administered to patients with coagulopathy only after careful benefit vs. risk assessment. Vardenafil alone does not prolong the bleeding time nor does its use in combination with aspirin cause any additive prolongation of the bleeding time. However, vardenafil has not been studied or administered to patients with bleeding disorders or significant active peptic ulcer disease. Therefore administer to these patients after careful benefit-risk assessment.5

Patients with a sudden decrease or loss of hearing (hearing impairment) should stop taking vardenafil and seek prompt medical attention. Hearing loss, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with the intake of PDE5 inhibitors, including vardenafil; however, it is unknown if the hearing loss is directly related to PDE5 inhibitors or to other factors.5 6

The vardenafil orally disintegrating tablets contain aspartame, which is a source of phenylalanine. This may be harmful for people with phenylketonuria. Each tablet contains 1.01 mg of phenylalanine.6

The vardenafil orally disintegrating tablets contain sorbitol. Patients with hereditary fructose intolerance should not take the orally disintegrating tablets.6

This list may not include all possible contraindications.

Apomorphine HCl

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.2 3

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.2 3

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.2 3

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.2 3

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.2 3

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.2 3

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.2 3 8 9 10 16

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.2 3

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.2 3

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.2 3

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.2 3

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.2 3

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.2 3

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.2 3 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.17

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.2 18 3

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.2 3

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

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

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these dopamine agonists, it is not known whether non-ergot derived dopamine agonists, such as apomorphine, can cause these reactions.2 3

Pregnancy

Vardenafil

Apomorphine HCl

Breastfeeding

Vardenafil

Vardenafil is not indicated for use in females and is therefore not recommended during breastfeeding. It is not known if vardenafil is excreted in human breastmilk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.5 6

Apomorphine HCl

Adverse Reactions/Side Effects

Vardenafil

Side effects that you should report to your doctor or health care professional as soon as possible: allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue, breathing problems, changes in hearing, changes in vision, chest pain, fast, irregular heartbeat, prolonged or painful erection, seizures.

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome): back pain, dizziness, flushing, headache, indigestion, muscle aches, nausea, stuffy or runny nose.

Flushing occurred in 11% of those receiving vardenafil film-coated tablets and in 7.6% of patients receiving orally disintegrating tablets. The incidence of flushing appears to increase as the dose increases. Anaphylactoid reactions (including laryngeal edema) occurred in less than 2% of patients. Other events occurring in < 2% of patients include allergic edema, facial edema (angioedema), pruritus, photosensitivity reaction, sweating (hyperhidrosis), erythema, and rash (unspecified). The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.5 6

Headache occurred in 15% of those receiving vardenafil film-coated tablets and in 14.4% of those receiving the orally-disintegrating tablets. The incidence of headache appears to increase as the dose increases. Neurologic effects that occurred in less than 2% of patients included asthenia, hypertonia, hypesthesia, dysesthesia, sleep disorders, amnesia, seizures, and paresthesias. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo. Postmarketing reports indicate that seizures and seizure recurrence have occurred in temporal association with vardenafil use. The incidence of these adverse events is unknown. Transient global amnesia has been reported during post-marketing use of the drug.5 6

Gastrointestinal (GI) adverse reactions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included dyspepsia (4% vs 1%) and nausea/vomiting (2% vs 1%). Dyspepsia also occurred in 2.8% of patients receiving the orally disintegrating tablets. GI effects that occurred in less than 2% of patients included abdominal pain, diarrhea, dysphagia, esophagitis, gastritis, gastroesophageal reflux, vomiting, and xerostomia. Dyspepsia and nausea appear to increase as the dose increases. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.5 6

Arthralgia, myalgia, increased creatine phosphokinase (CPK), and increased muscle tone and cramping (muscle cramps) have been reported in less than 2% of patients receiving vardenafil during clinical trials. Neck pain has been reported with similar frequency. During controlled and uncontrolled clinical trials, back pain was reported in 2% of patients receiving vardenafil. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.5 6

Dizziness occurred in 2% of those receiving vardenafil film-coated tablets and 2.3% of patients receiving orally disintegrating tablets. Dizziness has been associated with a sudden decrease in hearing. Centrally-mediated effects occurring in less than 2% of patients included insomnia, somnolence (drowsiness), and vertigo. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.5 6

During clinical trials, cardiovascular adverse reactions that occurred in less than 2% of patients treated with vardenafil included angina pectoris, chest pain (unspecified), hypertension, hypotension, myocardial ischemia, myocardial infarction, orthostatic hypotension, palpitations, syncope, ventricular tachyarrhythmias (ventricular tachycardia), and sinus tachycardia. The effects of vardenafil on blood pressure were evaluated using single 20 mg doses of vardenafil in patients with erectile dysfunction. Vardenafil caused a mean maximum decrease in supine blood pressure of 7 mm Hg systolic and 8 mm Hg diastolic (compared to placebo), accompanied by a mean maximum increase in heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. After multiple dosing, the effects of vardenafil on blood pressure were similar on Day 31 as on Day 1. Vardenafil may add to the hypotensive effects of antihypertensive agents.5 6

Respiratory conditions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included rhinitis (9% vs 3%), sinusitis (3% vs 1%), and flu-like syndrome (3% vs 2%). The incidence of rhinitis appears to increase as the dose increases. Nasal congestion occurred in 3.1% of patients receiving the orally disintegrating tablets. Respiratory-related effects which occurred in less than 2% of patients included dyspnea, sinus congestion, and pharyngitis. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.5 6

During clinical trials, ejaculation dysfunction occurred in less than 2% of patients treated with vardenafil. Prolonged erections greater than 4 hours and priapism have been reported rarely with PDE5 inhibitors, including vardenafil.

Epistaxis occurred in less than 2% of patients receiving vardenafil in clinical trials.5 6

Phosphodiesterase inhibitors, such as vardenafil, inhibit PDE6 in retinal rods and cones, which are involved in phototransduction in the retina. Changes in color vision were reported in < 2% of patients and occurred as a result of PDE6 inhibition. In single dose studies, dose-related impairment of color discrimination (blue/green) as well as reductions in electroretinogram (ERG) b-wave amplitudes were noted; peak effects were noted near the time of peak plasma levels (approximately 1 hour after dosing). These effects diminished but were still present 6 hours after administration. In a single dose study of 25 healthy males, vardenafil 40 mg did not alter visual acuity, intraocular pressure, or funduscopic and slit lamp findings.5 In an 8-week, multiple-dose, placebo-controlled clinical trial, clinically significant changes in retinal function did not occur as assessed by ERG amplitudes or the Farnsworth-Munsell 100-hue test. The trial was designed to detect retinal function changes that might occur in more than 10% of patients. Of 52 enrollees, 32 subjects completed the study. Two patients in the vardenafil group reported transient cyanopsia (objects appear blue). Other ophthalmic adverse reactions occurring in < 2% of patients receiving vardenafil include blurred vision, chromatopsia, conjunctivitis (increased redness of the eye), dim vision, glaucoma, ocular pain, photophobia, visual impairment, ocular hyperemia, increased intraocular pressure, and watery eyes (lacrimation). Post-marketing reports have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent).5 6 Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors.19 20 21 22 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 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, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy.19 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 vardenafil 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.5 6

The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin (7 msec). The potential effect of vardenafil on the QT interval should be considered when prescribing the drug; the manufacturer recommends against drug use in certain patient groups with risk factors for QT prolongation (see Precautions).5 6

Changes in laboratory values have occurred infrequently. During controlled and uncontrolled clinical trials of vardenafil in over 4430 men (mean age 56, range 18—89 years), increased creatine kinase was reported in 2% of those receiving vardenafil versus 1% of those in the placebo group. Increased GGTP and elevated hepatic enzymes (e.g., abnormal liver function tests) were reported in less than 2% of patients.5 6

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 HCl

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.2 3

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.2 3

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.2 3

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.2 3

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%).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.2 3

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.2 3

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.2 3

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.2 3

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.2 3

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.2

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.2 3

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.2 3

Storage

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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